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  • 1.
    Andersson, Peter
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Gustafsson, T
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Insulin-like growth factor binding proteins-2 to -6 are expressed by human vascular smooth muscle cells.1999In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 163, no 2, p. 281-288Article in journal (Refereed)
    Abstract [en]

    We have investigated the expression and secretion of insulin-like growth factor binding proteins (IGFBPs-1 to -6) in human vascular smooth muscle cells (hVSMCs) cultured from human renal arteries. Solution hybridization was used to determine IGFBP nRNA levels and Western immunoblot to detect the corresponding peptides. The hVSMCs expressed mRNAs for IGFBPs-2 to -6, IGFBP-1 mRNA was not detected. IGFBPs-3, -4 and -6 mRNAs were the most abundant, IGFBP-5 was also highly expressed, whereas the IGFBP-2 mRNA was just above the limit of detection. Serum starvation for 48 h significantly decreased the mRNA levels of IGFBPs-2 to -5 and tended to decrease IGFBP-6 mRNA also. IGFBPs-2, -4, -5 and -6 peptides could be detected in conditioned medium, but IGFBP-3 peptide was not detected. IGFBP-4 was the only peptide detected without any concentration step. Low-molecular-mass immunoreactive degradation products were found for IGFBPs-2 and -4. Exogenous IGFBPs-1, -3 and -4 in concentrations of 50 ng/ml inhibited DNA synthesis induced by 1 nM IGF-I, whereas IGFBPs-2, -5 and -6 had no significant inhibitory effects at this concentration. We conclude from these results that all IGFBPs except IGFBP-1 are expressed in hVSMC. Our results indicate that locally produced, in addition to circulating,, IGFBPs may have an important role in the regulation of hVSMC.

  • 2.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    The role of IGF-system in vascular insulin resistance2008In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 40, no 9, p. 588-592Article, review/survey (Refereed)
    Abstract [en]

    Insulin and IGF-I are closely related peptides, which interact by several mechanisms. In high supraphysiological concentrations (=10-8M), they cross-react with each other's receptors with 100- to 1000-fold lower affinity than with their cognate receptors. This can cause confusion, since in many in vitro studies, insulin has been used in high unphysiological concentrations, which activate IGF-I receptors. Due to the differences in affinity, insulin and IGF-I probably do not activate each other's receptors in vivo. IGF-I receptors are several-fold more abundant than insulin receptors in human micro- and macrovascular endothelial cells and in human vascular smooth muscle cells. Both insulin and IGF-I receptor protein can be demonstrated and they are activated by their cognate ligand at physiological concentrations of 10-9-10-10M. In vascular smooth muscle cells, IGF-I but not insulin stimulates metabolism and growth. IGF-I stimulates DNA-synthesis and growth in microvascular endothelial cells, but neither insulin nor IGF-I have any effect on macrovascular endothelial cells. Both insulin and IGF-I have been shown to stimulate nitric oxide production in endothelial cells, but only the effect of IGF-I was obtained at a physiological concentration. In both endothelial and vascular smooth muscle cells, insulin and IGF-I receptors occur as insulin/ICF-I hybrid receptors with high affinity to IGF-I and low for insulin. Due to the low number of insulin receptors and the presence of hybrid receptors the insulin receptor signal is probably too attenuated to elicit biological effects, explaining the insulin resistance of vascular cells in vitro. In vivo both insulin and IGF-I have been reported to increase muscle blood flow in physiological concentrations. Whether this is due to direct effects on endothelial cells or indirectly induced is not clear. The effect of insulin is attenuated by insulin resistance. In conclusion, the in vitro data suggest that endothelial cells and vascular smooth muscle cells are sensitive to IGF-I, but insensitive to insulin, and this is due to a preponderance of IGF-I receptors and the presence of insulin/IGF-l hybrid receptors. © Georg Thieme Verlag KG Stuttgart · New York.

  • 3.
    Bachrach-Lindström, Margaretha
    et al.
    Linköping University, Department of Medicine and Care, Nursing Science. Linköping University, Faculty of Health Sciences.
    Unosson, Mitra
    Linköping University, Department of Medicine and Care, Nursing Science. Linköping University, Faculty of Health Sciences.
    Ek, Anna-Christina
    Linköping University, Department of Medicine and Care, Nursing Science. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Assessment of nutritional status using biochemical and anthropometric variables in a nutritional intervention study of women with hip fracture2001In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 20, no 3, p. 217-223Article in journal (Refereed)
    Abstract [en]

    Background & Aims: The aim of this study of women with hip fracture was to describe nutritional status with biochemical markers and anthropometric variables, and to evaluate the effect of nutritional intervention with the intention of increasing protein and energy intake.

    Methods: The first consecutive 44 women were included, and used as controls. The next 44 were matched for age, fracture and mental state. Anthropometric variables, IGF-I, hormones and serum albumin were collected 4–6 days (baseline), 1 and 3 months after surgery. Twenty-four women filled out a 7-day food record.

    Results: At baseline, one fourth had BMI <20 kg/m2and subnormal triceps skinfold thickness. Baseline serum albumin, IGF-I and growth hormone levels were low, probably as an acute response to trauma. Women with BMI <20 kg/m2had lower IGF-I levels compared to those with higher BMI. At 3 months, one-third of both groups were protein and energy malnourished. The intervention group obtained higher daily energy percentage from fat but none of the groups reached their calculated energy need.

    Conclusions: Using biochemical markers in the acute postoperative situation to assess nutritional status is not recommended. The intervention had no impact on anthropometric or biochemical variables.

  • 4. Bakhtadze, E
    et al.
    Borg, H
    Stenström, G
    Fernlund, P
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Ekbom-Schnell, A
    Bolinder, J
    Eriksson, JW
    Gudbjörnsdottir, S
    Nyström, L
    Groop, LC
    Sundkvist, G
    HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 8, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients. Subjects and methods: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743. Results: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003). Conclusions/ interpretation: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes. © Springer-Verlag 2006.

  • 5.
    Bakhtadze, E
    et al.
    Lund University.
    Cervin, C
    Lund University.
    Lindholm, E
    Lund University.
    Borg, H
    Lund University.
    Nilsson, P
    Lund University.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Bolinder, J
    Karolinska University.
    Eriksson, J W
    Umeå University Hospital.
    Gudbjornsdottir, S
    Sahlgrens University Hospital.
    Nystrom, L
    Umeå University Hospital.
    Agardh, C D
    Lund University.
    Landin-Olsson, M
    Lund University Hospital.
    Sundkvist, G
    Lund University Hospital.
    C Groop , L C
    Lund University Hospital.
    Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15-34 years) but not in middle-aged (40-59 years) diabetic patients2008In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 51, no 12, p. 2224-2232Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes in children is characterised by autoimmune destruction of pancreatic beta cells and the presence of certain risk genotypes. In adults the same situation is often referred to as latent autoimmune diabetes in adults (LADA). We tested whether genetic markers associated with type 1 or type 2 diabetes could help to discriminate between autoimmune and non-autoimmune diabetes in young (15-34 years) and middle-aged (40-59 years) diabetic patients.

    In 1,642 young and 1,619 middle-aged patients we determined: (1) HLA-DQB1 genotypes; (2) PTPN22 and INS variable-number tandem repeat (VNTR) polymorphisms; (3) two single nucleotide polymorphisms (rs7903146 and rs10885406) in the TCF7L2 gene; (4) glutamic acid decarboxylase (GAD) and IA-2-protein tyrosine phosphatase-like protein (IA-2) antibodies; and (5) fasting plasma C-peptide.

    Frequency of risk genotypes HLA-DQB1 (60% vs 25%, p =9.4x10(-34); 45% vs 18%, p= 1.4x10(-16)), PTPN22 CT/TT (34% vs 26%, p=0.0023; 31% vs 23%, p=0.034), INS VNTR class I/I (69% vs 53%, p=1.3x10(-8); 69% vs 51%, p=8.5x10(-5)) and INS VNTR class IIIA/IIIA (75% vs 63%, p=4.3x10(-6); 73% vs 60%, p=0.008) was increased in young and middle-aged GAD antibodies (GADA)-positive compared with GADA-negative patients. The type 2 diabetes-associated genotypes of TCF7L2 CT/TT of rs7903146 were significantly more common in young GADA-negative than in GADA-positive patients (53% vs 43%; p=0.0004). No such difference was seen in middle-aged patients, in whom the frequency of the CT/TT genotypes of TCF7L2 was similarly increased in GADA-negative and GADA-positive groups (55% vs 56%).

    Common variants in the TCF7L2 gene help to differentiate young but not middle-aged GADA-positive and GADA-negative diabetic patients, suggesting that young GADA-negative patients have type 2 diabetes and that middle-aged GADA-positive patients are different from their young GADA-positive counterparts and share genetic features with type 2 diabetes.

  • 6.
    Bjarnegård, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Jönsson, A.
    Department of Internal Medicin, Jönköping Hospital, Jönköping, Sweden.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Impaired endothelial independent vasodilatation in women with type 1 diabetes2008Manuscript (preprint) (Other academic)
  • 7.
    Bjarnegård, Niclas
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Jonsson, Anders
    Jönköping Hospital.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Long-term hyperglycaemia impairs vascular smooth muscle cell function in women with type 1 diabetes mellitus2009In: DIABETES and VASCULAR DISEASE RESEARCH, ISSN 1479-1641, Vol. 6, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    Observations of increased stiffness in the elastic aorta in women with diabetes, but not men, emphasise the need for further analysis regarding early abnormalities in arterial wall properties of women with type 1 diabetes mellitus (DM).

    Ultrasound was used to study the wall properties of the distal brachial artery (BA) in 37 type 1 diabetic women (aged 22-45 years) without evident complications and in 53 controls (C). Blood samples were drawn for later analysis.

    Flow-mediated dilatation (FMD) was slightly lower in DM than C, 8.1 +/- 4.3% vs. 10.3 +/- 4.9% (p&lt;0.05), and nitrate-mediated dilatation (NMD) was markedly lower, 21.7 +/- 6.6% vs. 31.4 +/- 5.7% (p&lt;0.001). Lumen diameter, intima-media thickness and distensibility were similar in DM and C. Insulin-like growth factor (IGF-1) was lower in DM than C, 231 +/- 65 vs. 349 +/- 68 ng/ml (p&lt;0.001). Glycosylated haemoglobin (HbA(1C)) and matrix metalloproteinase (MMP-9) were independent predictors of the reduced NMD in the DM.

    Brachial artery responsiveness to an exogenous donor of nitric oxide (NO) was markedly reduced in type 1 diabetic women despite only limited reduction in endothelium-dependent dilatation. The negative association between NMD and HbA(1C) suggests that long-term hyperglycaemia impairs vascular smooth muscle cell function in DM.

  • 8. Blomgren, J
    et al.
    Ekman, Bertil
    Andersson, P-O
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Non-physiological levels of circulating cortisol in growth hormone-treated hypopituitary adults after conventional cortisone substitution2004In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 64, no 2, p. 132-139Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the usefulness of measuring plasma cortisol profiles in growth hormone-treated hypopituitary adults and to compare these with cortisol levels in healthy controls. Methods: Eleven ACTH-deficient adult patients received 12.5 mg cortisone-acetate orally at 16.00 h and 25 mg at 07.00 h. The patients arrived in the ward at 12.00 h. After tablet intake at 16.00 h, samples for serum cortisol were taken at hourly intervals for the next 24 h, except between 07.00 and 12.00 h when samples were drawn every half hour, 24-h urinary free cortisol (24-h-UFC) excretion was collected simultaneously. For comparison, 8 healthy controls were investigated. Results: The patients had circulating cortisol levels with very low plasma cortisol at 07.00 h before their morning dose of cortisone acetate. At the same time period, controls had their highest plasma cortisol levels. After tablet intake the patients had a rapid initial absorption of cortisol, but a marked variability in the morning peak levels (Cmax), and the Cmax was in general higher and occurred 90 min later than the Cmax in the controls. The 24-h-UFC excretion and 24-h area under the curve (24-h-AUC) did not differ between patients and controls. The female patients had higher 24-h-AUC for plasma cortisol (p=0.032) and tended to have higher plasma cortisol peaks in the morning, but had levels of 24-h-UFC similar to those of the male patients. Conclusions: Conventional cortisone substitution with a twice-daily replacement regimen in hypopituitary adults results in abnormal circulating cortisol profiles with low or non-measurable morning values and variable individual peaks. This suggests that the present dosing schemes have to be improved and that cortisone substitution should be individualized.

  • 9. Bojestig, M
    et al.
    Nyström, Fredrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Karlberg, Bengt E
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed.
    The renin-angiotensin-aldosterone system is suppressed in adults with Type 1 diabetes2000In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 1, no 4, p. 353-356Article in journal (Refereed)
    Abstract [en]

    Poor glycaemic control and high blood pressure are two important risk factors for the development of retinopathy and nephropathy in Type 1 diabetes. The renin-angiotensin-aldosterone system (RAAS) may be involved in this process, since treatment with angiotensin-converting enzyme (ACE) inhibitors postpones the development of these complications. We investigated whether plasma renin activity (PRA), plasma angiotensin II (Ang II) and atrial natriuretic peptide (ANP) differed in Type 1 diabetic patients compared with healthy controls. We recruited 80 patients with Type 1 diabetes of more than 10 years' duration and 75 age-matched controls. We found that PRA and Ang II concentrations were significantly lower in patients than in the controls. The levels of ANP, on the other hand, were higher in patients than in controls. PRA correlated negatively to the mean value of HbA1c during the previous five years. PRA and Ang II were significantly lower in patients with mean HbA1c. >8.4% compared with those with mean HbA1c 7.2%. In summary, we found patients with Type 1 diabetes to have RAAS suppression and increased ANP levels, suggesting a state of fluid retention.

  • 10. Bolinder, J
    et al.
    Fernlund, P
    Borg, H
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Björk, E
    Blohmé, G
    Eriksson, JW
    Nyström, L
    Östman, J
    Sundkvist, G
    Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non-autoimmune (type 2) diabetes2005In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 65, no 7, p. 585-594Article in journal (Refereed)
    Abstract [en]

    Objective. To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults. Material and methods. Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age. Results. Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001). Conclusions. Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis. © 2005 Taylor & Francis.

  • 11. Borg, H
    et al.
    Björk, E
    Bolinder, J
    Eriksson, JW
    Nyström, L
    Jeppsson, J-O
    Sundkvist, G
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yrs) in the Diabetes Incidence Study in Sweden (DISS)2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, no 2, p. 173-181Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis. We aimed to evaluate how an aetiology-based classification, as recommended in the ADA and WHO guidelines for classification of diabetes mellitus, matches clinical judgement in the Diabetes Incidence Study in Sweden (DISS), a study covering incident cases of diabetic patients aged 15 to 34 years. Methods. During a 1-year period (1998), blood samples were taken at diagnosis and 4 months (median) thereafter. Patients were classified according to clinical judgement by the reporting physicians and assessments of islet antibodies (ICA, GADA, and IA-2A) and plasma C-peptide. Results. In 1998, 422 patients were registered in DISS. Among the 313 patients participating in the follow-up, most with clinical Type 1 diabetes (185/218, 85%, 95% CI 79-89%) were islet antibody positive (ab+) at diagnosis. In addition, 14 out of 58 (24%, 14-37%) with clinical Type 2 diabetes and 21 out of 37 (57%, 40-73%) with unclassifiable diabetes were antibody positive at diagnosis. Further to this, 4 out of 33 (12%, 3-28%) were antibody negative with clinical Type 1 diabetes and 4 out of 44 (9%, 3-22%) with Type 2 had converted to antibody positive at follow-up. Among those who were constantly antibody negative, 10 out of 29 (34%, 18-54%) with clinical Type 1 and 1 out of 16 (6%, 0-30%) with unclassifiable diabetes had fasting plasma C-peptide concentrations below the normal range (<0.25 nmol/l) at follow-up. Conclusion/interpretation. Most young adults with clinical Type 1 diabetes (199/218, 91%) had objective Type 1 (ab+ at diagnosis/follow-up and/or low fasting plasma C-peptide concentrations at follow-up), as did one third (18/58, 31%) with clinical Type 2 diabetes and more than half (22/37, 59%) with unclassifiable diabetes. About 10% of those who were antibody negative converted to antibody positive. Our study underlines that a classification considering aetiology is superior to clinical judgement.

  • 12.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Changes in insulin and IGF-I receptor expression during differentiation of human preadipocytes2009In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 19, no 2, p. 101-111Article in journal (Refereed)
    Abstract [en]

    Mature adipocytes originate from fibroblast-like precursor cells, preadipocytes, which differentiate to obtain the characteristics of adipocytes. Our aim was to investigate how differentiation of human preadipocytes affects the distribution of insulin receptors (IR) and IGF-I receptors (IGF-IR) and other cell characteristics. Preadipocytes were differentiated using indomethacine, dexamethasone, isobutyl-methylxantine (IBMX) and high concentration of insulin. Gene expression was quantified by real-time RT-PCT in preadipocytes (PA), differentiated preadipocytes (dPA) and mature adipocytes (mAD). The amount of expressed receptor protein was analyzed using receptor specific ELISAs and Western blot. We also studied DNA synthesis with radiolabeled thymidine incorporation and glucose accumulation with radiolabeled glucose. Differentiation of PA increased gene expression of IR but not IGF-IR, GLUT4, growth hormone receptor (GHR) and adiponectin appeared or increased. In PA and dPA only IR-A was expressed whereas also IR-B was detected in mAD. By Western blot and ELISA, IR and IGF-IR was phosphorylated by their own ligant at 1 nM and in dPA the acitivation of both receptors was stimulated by IGF-I, but not insulin, at 1 nM. Accumulation of glucose in PA was increased by insulin at 10 nM and by IGF-I at 1 nM and 10 nM. DNA synthesis was increased by insulin and IGF-I at 10 nM.

    In conclusion, both IR and IGF-IR are present in human preadipocytes and adipocytes. Differentiation is characterized by an increased IR/IGF-IR ratio.

  • 13.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Brännmark, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Strålfors, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Differential effects of IGF-I, IGF-II and insulin in human preadipocytes and adipocytes - Role of insulin and IGF-I receptors2011In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 339, no 02-jan, p. 130-135Article in journal (Refereed)
    Abstract [en]

    We compared insulin and IGF effects in adipocytes expressing IR (insulin receptors), and preadipocytes expressing IR and IGF-IR (IGF-I receptors). Treatment of adipocytes with insulin, IGF-II or IGF-I resulted in phosphorylation of IR. Order of potency was insulin greater thanIGF-IIgreater than IGF-I. In preadipocytes IR, IGF-IR and insulin/IGF-I hybrid receptors (HR) were detected. Treatment of preadipocytes with IGF-I and IGF-II 10(-8) M resulted in activation of IGF-IR and IR whereas insulin was more potent in activating IR, with no effect on IGF-IR. In adipocytes glucose transport was 100-fold more sensitive to insulin than to IGFs and the maximal effect was higher with insulin. In preadipocytes glucose accumulation and DNA synthesis was equally sensitive to insulin and IGFs but the maximal effect was higher with IGF-I. In conclusion, insulin and IGF-I activate their cognate receptors and IGF-I also HR. IGF-II activates IR, IGF-IR and HR. Insulin and IGF-I are partial agonists to each others receptors.

  • 14.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Islam, Rakibul
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalita, Ioana Simona
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects2012In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 215, no 1, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Diabetes is associated with microcirculatory dysfunction and heart failure and changes in insulin and IGF1 levels. Whether human cardiac microvascular endothelial cells (HMVEC-Cs) are sensitive to insulin and/or IGF1 is not known. We studied the role of insulin receptors (IRs) and IGF1 receptors (IGF1Rs) in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF1 in HMVEC-Cs and human umbilical vein endothelial cells (HUVECs). IR and IGF1R gene expression was studied using real-time RT-PCR. Receptor protein expression and phosphorylation were determined by western blot and ELISA. Metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate inflammatory responses. According to gene expression and protein in HMVEC-Cs and HUVECs, IGF1R is more abundant than IR. Immunoprecipitation with anti-IGF1R antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF1 hybrid receptors in HMVEC-Cs. IGF1 at a concentration of 10(-8) mol/l significantly stimulated phosphorylation of both IGF1R and IR in HMVEC-Cs. In HUVECs IGF1 10(-8) mol/l phosphorylated IGF1R. IGF1 stimulated DNA synthesis at 10(-8) mol/l and glucose accumulation at 10(-7) mol/l in HMVEC-Cs. TNF-alpha dramatically increased E-selectin expression, but no inflammatory or anti-inflammatory effects of insulin, IGF1 or high glucose were seen. We conclude that HMVEC-Cs express more IGF1Rs than IRs, and mainly react to IGF1 due to the predominance of IGF1Rs and insulin/IGF1 hybrid receptors. TNF-alpha has a pronounced pro-inflammatory effect in HMVEC-Cs, which is not counteracted by insulin or IGF1.

  • 15.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Islam, Rakibul
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalita, Simona
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Role of insulin and IGF-I receptors in human cardiac microvascular endothelial cells; metabolic, mitogenic and anti-inflammatory effectsManuscript (preprint) (Other academic)
    Abstract [en]

    Diabetes is associated with coronary microcirculatory dysfunction and heart failure as well as changes in insulin and IGF-I levels. Our aim was to study the role of insulin receptors and IGF-I receptors in metabolic, mitogenic and anti-inflammatory responses to insulin and IGF-I in human cardiac microvascular endothelial cells (HMVEC-C) and, for comparison, also human umbilical vein endothelial cells (HUVEC). Insulin receptor (IR) and IGF-I receptor (IGF-IR) gene expression was studied with real-time RT-PCR. Receptor protein expression and phosphorylation was determined with Western blot and ELISA. The metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate the anti-inflammatory responses. IGF-IR was more abundant than IR both regarding gene expression and protein in HMVEC-C and HUVEC. Immunoprecipitation with anti-IGF-IR antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF-I hybrid receptors in these cells. IGF-I 10-8 M significantly stimulated phosphorylation of both IGF-IR and IR in HMVEC-C. In HUVEC IGF-I 10-8 M phosphorylated IGF-IR. IGF-I also stimulated DNA synthesis at 10-8 M and glucose accumulation at 10-7 M. TNF-α significantly increased E-selectin expression whereas no effects were found by insulin, IGF-I or high glucose.

    We conclude that HMVEC-C express more IGF-I receptors than insulin receptors and at physiological concentrations of insulin and IGF-I mainly reacts to IGF-I probably due to the predominance of IGF-I receptors and insulin/IGF-I hybrid receptors. TNF-α has a pronounced pro-inflammatory effect in HMVEC-C which is not counteracted by insulin or IGF-I.

  • 16.
    Bäck, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wahlström, Ola
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Kjölhede, Preben
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Gasslander, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Differential expression of insulin and IGF-I receptors in human tissuesManuscript (preprint) (Other academic)
    Abstract [en]

    Insulin and IGF-I are related peptides with similar structure. They both signal via their cognate receptors, the insulin receptor (IR) and the insulin-like growth factor (IGF)-I receptor (IGF-IR).

    Our aim was to simultaneously measure the amount of insulin and IGF-I receptors in different human tissues and also the IR-A and IR-B isoforms to study tissue specific expression

    Renal artery intima-media, myometrium, skeletal muscle or liver tissue samples were obtained from patients undergoing surgery. IR, IGF-IR, IR-A and IR-B gene expression was investigated with real-time RT-PCR and expression of IR and IGF-IR protein was examined by Western blot and ELISA.

    Renal arteries and myometrium expressed the IGF-IR gene to a higher extent than the IR gene, liver expressed more IR than IGF-IR and skeletal muscle expressed almost equal amounts of both receptors. IR-B was the most abundant isoform in all tissues. With Western blot we could detect IR in skeletal muscle, liver and myometrium. With ELISA we found that, normalized to total protein, the highest levels of IGF-IR were found in renal arteries and myometrium and low levels in skeletal muscle and liver. The highest levels of IR were found in liver.

    In conclusion there is a large variation in the quantity and ratio of insulin receptors and IGF-I receptors expressed in different tissues, the extremes being arterial intima media with predominantly IGF-I receptors and liver with predominantly insulin receptors. This suggests that differential expression of insulin and IGF-I receptors is a key mechanism in regulation of growth and metabolism.

  • 17.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 6, p. 891-898Article in journal (Refereed)
    Abstract [en]

    Objective: There are conflicting results regarding the association of circulating IGF1 with cardiovascular (CV) morbidity and mortality. We assessed the relationship between IGF1 levels and heart failure (HF), ischemic heart disease (IHD), and CV mortality in an elderly population taking into account the possible impact of angiotensin converting enzyme (ACE) inhibitors. Design and methods: A total of 851 persons aged 66-81 years, in a rural Swedish municipality, were subjected to medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples. They were then followed for 8 years. Results and conclusion: Patients on ACE inhibitors had higher IGF1 levels compared with those without ACE inhibitors. In patients on ACE inhibitors, higher IGF1 values were found in patients with an ejection fraction (EF) less than40% compared with EF greater than= 40%, in patients with higher proBNP levels in quartile 4 vs 1, and in patients with IHD when compared to those without ACE inhibitors (P less than 0.001). In patients without ACE inhibitors, no relationship was found between IGF1 levels and HF or IHD. In multivariate regression, only ACE inhibitors, ECG changes characteristic for IHD, and gender had a significant impact on IGF1. Patients with higher IGF1 levels in quintiles 4 and 5 compared to quintiles 1 and 2 had a 50% higher risk for CV death (P=0.03). This was significant after adjustment for well-known CV risk factors and ACE inhibitors (P=0.03). Conclusions: Our results show that treatment with ACE inhibitors in an elderly population is associated with increased IGF1 levels, especially in patients with impaired cardiac function or IHD. High IGF1 levels tend to be associated with an increased risk for CV mortality.

  • 18.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care in Linköping.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Proinsulin and IGFBP-1 predicts mortality in an elderly population2014In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 174, no 2, p. 260-267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    High IGFBP-1 in elderly subjects is related to all-cause and cardiovascular (CV) mortality. We studied the relation of IGFBP-1 to cardiometabolic risk factors and cardiovascular and all-cause mortality, and also the impact of proinsulin and insulin on this association in an unselected elderly primary health care population.

    HYPOTHESIS:

    Our hypothesis was that proinsulin and insulin may have an impact on the association of high IGFBP-1 levels with all-cause and CV-mortality in elderly.

    DESIGN, SETTING AND PARTICIPANTS:

    A cross-sectional and prospective study was carried out in a rural Swedish population. 851 persons aged 66-81 years were evaluated by medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples, and were followed prospectively for up to 12 years.

    RESULTS:

    At baseline, in a multivariate analysis, IGFBP-1 was associated with gender, N-terminal proBNP (NT pro-BNP), blood glucose, body mass index (BMI), insulin and proinsulin, estimated glomerular filtration rate (eGFR) and haemoglobin (Hb). During the follow-up period there were 230 deaths (27%), of which 134 (16%) were due to CV mortality. When divided into tertiles there was a significant difference for CV mortality and all-cause mortality between tertiles of IGFBP-1 and proinsulin. For insulin there was a significant difference only for all-cause mortality. After adjustment for well-known risks factors, proinsulin and IGFBP-1 had significant impact on all-cause mortality but only proinsulin on CV mortality.

    CONCLUSION:

    Only proinsulin is an independent predictor for both all-cause mortality and CV mortality when comparing IGFBP-1, insulin, and proinsulin as prognostic biomarkers for CV and all-cause mortality in an elderly population.

  • 19.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Johansson, Git
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Liefvendahl, Ellinor
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bäck, Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF22009In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 43, no 5-6, p. 231-239Article in journal (Refereed)
    Abstract [en]

    Whether insulin, in physiological concentrations, has direct effects on vascular smooth muscle cells (VSMC) remains controversial. Our aim was to characterize the mechanism for insulin resistance in VSMCs. For comparison, effects of insulin-like growth factor (IGF)-I and IGF-II were also studied. Cultured human aortic smooth muscle cells (HASMC) were used. Receptor mRNA was analysed by quantitative RT-PCR and receptor protein by ELISA and Western Blot. The biological effects were studied by thymidine incorporation and glucose accumulation.

    In HASMC both mRNA and protein expression of IGF-I receptors (IGF-IR) were 5 fold higher compared to insulin receptor (IR). IR isoform A mRNA was 13 times more expressed than IR isoform B. Immunoprecipitation and Western blot showed co precipitation of IR and IGF-IR indicating the presence of hybrid IR/IGF-IR.

    Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I 10-9-10-8mol l-1 and IGF-II 10-8mol l-1. IR β-subunit was phosphorylated by IGF-I 10-8mol l-1 but not by insulin. IGF-I stimulated IRS-I at 10-8mol l-1, Akt and Erk 1/2 at 10-9-10-8mol l-1, respectively. IGF-II stimulated Akt at 10-8mol l-1 whereas insulin had no effect. IGF-I and IGF-II at a concentration of 10-8-10-7mol l-1 significantly stimulated 3H-thymidine incorporation, whereas insulin did not. 14C-Glucose accumulation was stimulated by IGF-I or IGF-II 10-8-10-7mol l-1, and also by insulin 10-7mol l-1.

    Our results suggest that IGF-IR and hybrid IR/IGF-IR are activated by physiological concentrations of IGF-I and IGF-II in HASMC and this causes downstream signaling and biological effects, while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF-IR and incorporation of IR into hybrid IR/IGF-IR.

  • 20. Chisalita, SI
    et al.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    IGF-I receptors are more expressed than insulin receptors in human coronary artery endothelial cells.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 1191-Conference paper (Other academic)
  • 21.
    Chisalita, Simona I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Expression and function of receptors for insulin-like growth factor-I and insulin in human coronary artery smooth muscle cells2005In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 48, no 10, p. 2155-2161Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Hyperinsulinaemia and insulin resistance, as well as low IGF-I, have been implicated in the pathogenesis of cardiovascular disease. Little is known about direct effects of IGF-I and insulin on human coronary artery smooth muscle cells (HCASMCs). Our aim was to characterise the expression and function of IGF-I receptor (IGF-IR) and insulin receptor (IR) in HCASMCs. Materials and methods: Cultured HCASMCs were used. mRNA expression was measured by quantitative real-time RT-PCR analysis. Receptor proteins, phosphorylation of β-subunits and the presence of hybrid IR/IGF-IR were analysed by immunoprecipitation and western blotting. DNA synthesis and glucose metabolism were assessed using [3H]thymidine incorporation and D-[U-14C]glucose accumulation respectively. Results: The mRNA expression of IGF-IR was approximately eight-fold higher than that of IR in HCASMCs. The presence of IGF-IR and IR could be demonstrated by immunoprecipitation and western blot analysis. Phosphorylation of the IGF-IR β-subunit was obtained by IGF-I at 10−10–10−8 mol/l and insulin at 10−8 mol/l. Insulin and IGF-I at 10−10–10−9 mol/l phosphorylated the IR β-subunit. When immunoprecipitated with monoclonal anti-IR α-subunit or IGF-IR α-subunit antibodies, we found bands in slightly different positions, suggesting the presence of hybrid IR/IGF-IR. IGF-I at 10−9–10−8 mol/l significantly stimulated [3H]thymidine incorporation and at a concentration of 10−9–10−7 mol/l also D-[U-14C]glucose accumulation in HCASMCs. Insulin at 10−9–10−7 mol/l had no effect on DNA synthesis, but increased glucose accumulation at 10−7 mol/l. Conclusions/interpretation: Our study provides experimental evidence that IGF-IR and possibly hybrid IR/IGF-IR play a role in HCASMCs.

  • 22.
    Chisalita, Simona I.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Dekker Nitert, Marloes
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Characterisation of receptors for IGF-I and insulin: evidence for hybrid insulin/IGF-I receptor in human coronary artery endothelial cells2006In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 16, no 4, p. 258-266Article in journal (Refereed)
    Abstract [en]

    Objective: Coronary artery disease is a prevalent cause of morbidity and mortality in diabetes. Little is known about insulin-like growth factor-I receptors (IGF-IR) and insulin receptors (IR) in human coronary endothelium. Our aim was to characterize IGF-IR and IR in human coronary artery endothelial cells (HCAEC).

    Design: Cultured human coronary artery endothelial cells were used. Gene expression was measured by quantitative real-time RTPCR analysis and receptor affinity by ligand binding. Receptor protein, phosphorylation of IGF-IR and IR b-subunit as well as the presence of hybrid insulin receptor/Insulin-like growth factor-I receptor (Hybrid IR/IGF-IR) was analyzed by immunoprecipitation and Western blot. Postreceptor effects of insulin and IGF-I were assed by 3H-thymidine incorporation.

    Results: The gene expression of IGF-IR was several folds higher than that of IR. and insulin receptor isoform A (IR-A) was 20-fold more expressed than insulin receptor isoform B (IR-B) in HCAEC. The specific binding of 125I-IGF-I was higher than that of 125Iinsulin. Insulin and the new long acting insulin analog, glargine, interacted with the IGF-IR with over thousand and 100-fold less potency than IGF-I itself, whereas IGF-II had 6 times lower potency than IGF-I. Phosphorylation of the IGF-IR b-subunit was obtained by concentrations of 10-10–10-8 M IGF-I, 10-6 M of insulin, inconsistently by 10-8 M insulin and not at all by 10-10–10-9 M insulin. The IR b-subunit was phosphorylated by insulin and IGF-I at concentrations of 10-9–10-8 M. When immunoprecipitating with specific monoclonal anti-IR or anti-IGF-IR a-subunit antibodies we found bands situated in slightly different positions suggesting the presence of Hybrid IR/IGF-IR. IGF-I, IGF-II and insulin (10-9–10-7 M) had no significant effect on 3H-thymidine incorporation into DNA.

    Conclusions: Human coronary endothelial cells express more IGF-IR than IR, mainly IR-A, and also Hybrid IR/IGF-IR. Both IGF-I and insulin phosphorylate their receptors, but only IGF-I seems to phosphorylate Hybrid IR/IGF-IR. Our study provides experimental evidence for a possible role of IGF-IR, IR and Hybrid IR/IGF-IR in human coronary artery endothelial cells.

  • 23.
    Chisalita, Simona Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells2004In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 286, p. E896-E901Article in journal (Refereed)
    Abstract [en]

    Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR ß-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [3H]glucose and [3H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of 125I-IGF-I was higher than that of 125I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR ß-subunit was shown in HAEC for IGF-I (10-8 M) and insulin (10-6 M) and in HMVEC for IGF-I and glargine (10-8 M, 10-6 M). IGF-I 10-7 M stimulated incorporation of [3H]thymidine into DNA, and 10-9–10-7 M also the incorporation of [3H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10-9–10-7 M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin  ctivates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.

  • 24.
    Chisalita, Simona Ioana
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Eson Jennersjö, Pär
    Borensberg Health Centre, Linköping.
    Paulsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Westermark, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control2009In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 46, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0 +/- A 4.1 years (mean +/- A SE), body weight 82.5 +/- A 5.0 kg, BMI (body mass index) 27.7 +/- A 1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

  • 25.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Vascular Endothelial Growth Factor and Transforming Growth Factor-β1 Regulate the Expression of Insulin-Like Growth Factor-Binding Protein-3, -4, and -5 in Large Vessel Endothelial Cells2000In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 141, no 6, p. 2062-2067Article in journal (Refereed)
    Abstract [en]

    We investigated the effect of diabetes-associated growth factors on the expression of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IGFBPs) in cultured endothelial cells from bovine aorta. Gene expression was measured by solution hybridization, and proteins were measured by enzyme-linked immunosorbent assay, RIA, or Western blot. The cells expressed messenger RNA (mRNA) for IGFBP-2 through -6 and IGFBP-2 through -5 proteins were detected in conditioned medium. Vascular endothelial growth factor inhibited IGFBP-3 mRNA (P < 0.01) and protein expression and increased IGFBP-5 mRNA (P < 0.001) and protein. Transforming growth factor-β1 inhibited IGFBP-3 (P < 0.01), IGFBP-4 (P < 0.01), and IGF-I mRNA expression, whereas at the protein level only IGFBP-3 was significantly decreased. IGF-I, insulin, or angiotensin II did not affect IGF-I or IGFBP mRNA expression. At the protein level, IGF-I clearly increased IGFBP-5 levels in conditioned medium. In conclusion, vascular endothelial growth factor and transforming growth factor-β1 regulate IGFBP expression in bovine aortic endothelial cells. These observations provide a new aspect of regulation for the IGF-system in macrovascular endothelium, with possible implications for subendothelial smooth muscle cells and development of diabetic angiopathy.

  • 26.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Bertil
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MKC-2, GE: endomed. Linköping University, Faculty of Health Sciences.
    Inhibitory effect of diabetes on proliferation of vascular smooth muscle after balloon injury in rat aorta2000In: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 1, no 2, p. 101-109Article in journal (Refereed)
    Abstract [en]

    The effect of streptozotocin-induced diabetes on cell proliferation in rat aortic intima-media, as well as on local gene expression of transforming growth factor-β1 (TGF-β1) was studied. TGF-β1 mRNA was measured by solution hybridization and TGF-β1 protein by ELISA. Proliferation was measured by bromodeoxyuridine incorporation into DNA two days after balloon injury. All BrdU-labelled cells observed were smooth muscle cells. After a diabetes duration of 2 and 4 weeks, labelled cells were significantly fewer compared with controls. Circulating levels of total TGF-β1 were lowered in rats with 2 weeks diabetes. Although the balloon injury procedure by itself stimulated the gene expression of TGF-β1, no significant difference in TGF-β1 mRNA content between diabetic and control rats after injury was found. In conclusion: vascular smooth muscle proliferation in vivo is inhibited by the diabetic state in this model of insulin deficient diabetes and this inhibition is not related to an impaired local expression of TGF-β1.

  • 27.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Chen, Yun
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wasteson, Maria
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    PDGF-BB-induced DNA synthesis is delayed by angiotensin II in vascular smooth muscle cells1998In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 274, no 5, p. H1742-H1748Article in journal (Refereed)
    Abstract [en]

    The interaction of ANG II with platelet-derived growth factor (PDGF)-BB-induced DNA synthesis was studied in cultured rat aortic smooth muscle cells. PDGF-BB-induced DNA synthesis was delayed (∼6–8 h) by ANG II as shown by a time-course experiment. Losartan, an AT1-receptor antagonist, blocked the transient inhibitory effect of ANG II, whereas the AT2-receptor antagonist PD-123319 had no effect. Autocrine- or paracrine-acting transforming growth factor-β1 (TGF-β1), believed to be a mediator of ANG II-induced inhibitory effects, was not responsible for the delay of PDGF-BB-induced DNA synthesis, because a potent TGF-β1 neutralizing antibody could not reverse this effect of ANG II, nor was the delay of the PDGF-BB effect caused by inhibition of PDGF-β-receptor phosphorylation as shown by Western blot analysis of immunoprecipitated PDGF-β receptor. In conclusion, our results show that ANG II can exert a transient inhibitory effect on PDGF-BB-induced proliferation via the AT1 receptor.

  • 28.
    Dahlfors, Gunilla
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Effect of nitric oxide on vascular smooth muscle cell proliferation and insulin-like growth factor binding protein expressionManuscript (preprint) (Other academic)
    Abstract [en]

    A possible interaction between nitric oxide (NO) and the insulin-like growth factor (IGF)-system was studied in cultured rat aortic smooth muscle cells. The NO-donor SNAP markedly inhibited basal and sernm-induced DNA synthesis while addition of L-NAME, an inhibitor of endogenous NO production, had no effect. L-NAME did also not significantly affect IGF-I, angiotensin II or TGF-ß1- induced effects on DNA synthesis. IGF-I was shown to stimulate the expression of IGFBP-4 mRNA, as measured by an RNase-protection assay, and angiotensin II inhibited expression of IGFBP-2 mRNA. Addition of L-NAME did not significantly change the effect of IGF-I or angiotensin II on IGFBP mRNA expression, neither did L-NAME or SNAP affect basal expression of IGFBP-2, -4 or -6 mRNA. In conclusion, we found no evidence for interaction of NO with the IGF-system in smooth muscle cells. Nitric oxide did not regulate the expression of IGFBPs and IGF-I-induced smooth muscle cell proliferation was not affected by inhibition of endogenous NO production.

  • 29.
    Dekker Nitert, Marloes
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Chisalitaa, Simona I.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Olsson, Karolina
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bornfeldt, Karin E.
    Department of Pathology, University of Washington School of Medicine, Seattle, USA.
    Arnqvist, Hans J.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    IGF-I/insulin hybrid receptors in human endothelial cells2005In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 229, no 1-2, p. 31-37Article in journal (Refereed)
    Abstract [en]

    Vascular complications are common in diabetes. IGF-I receptors (IGF-IR) and insulin receptors (IR) in endothelial cells might respond to altered levels of IGF-I and insulin, resulting in altered endothelial function in diabetes. We therefore studied IGF-IR and IR gene expression, ligand binding, receptor protein, and phosphorylation in human umbilical vein endothelial cells (HUVEC). IGF-IR mRNA was more abundant than IRmRNAin freshly isolatedHUVEC(IGF-IR/IR ratio 7.1±1.5) and in culturedHUVEC(ratio 3.5±0.51). Accordingly, specific binding of 125I-IGF-I (0.64±0.25%) was higher than that of 125I-insulin (0.25±0.09%). Protein was detected for both  eceptors and IGF-I/insulin hybrid receptors. IGF-IR phosphorylation was stimulated by 10−10 to 10−8M IGF-I. IR were activated by 10−9 to 10−8M insulin and IGF-I. We conclude that HUVEC express more IGF-IR than IR, and also express hybrid receptors. Both IGF-I and insulin phosphorylate their own receptors but only IGF-I seems to phosphorylate hybrid receptors.

  • 30. Ekberg, Karin
    et al.
    Brismar, Tom
    Johansson, Bo-Lennart
    Lindström, Per
    Juntti-Berggren, Lisa
    Norrby, Anders
    Berne, Christian
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Bolinder, Jan
    Wahren, John
    C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy2007In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 30, no 1, p. 71-76Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE - C-peptide replacement in animals results in amelioration of diabetes-induced functional and structural abnormalities in peripheral nerves. The present study was undertaken to examine whether C-peptide administration to patients with type 1 diabetes and peripheral neuropathy improves sensory nerve function. RESEARCH DESIGN AND METHODS - This was an exploratory, double-blinded, randomized, and placebo-controlled study with three study groups that was carried out at five centers in Sweden. C-peptide was given as a replacement dose (1.5 mg/day, divided into four subcutaneous doses) or a dose three times higher (4.5 mg/day) during 6 months. Neurological examination and neurophysiological measurements were performed before and after 6 months of treatment with C-peptide or placebo. RESULTS - The age of the 139 patients who completed the protocol was 44.2 ± 0.6 (mean ± SE) years and their duration of diabetes was 30.6 ± 0.8 years. Clinical neurological impairment (NIA) (score >7 points) of the lower extremities was present in 86% of the patients at baseline. Sensory nerve conduction velocity (SCV) was 2.6 ± 0.08 SD below body height-corrected normal values at baseline and improved similarly within the two C-peptide groups (P < 0.007). The number of patients responding with a SCV peak potential improvement >1.0 m/s was greater in C-peptide-treated patients than in those receiving placebo (P < 0.03). In the least severely affected patients (SCV < 2.5 SD below normal at baseline, n = 70) SCV improved by 1.0 m/s (P < 0.014 vs. placebo). NIA score and vibration perception both improved within the C-peptide-treated groups (P < 0.011 and P < 0.002). A1C levels (7.6 ± 0.1% at baseline) decreased slightly but similarly in C-peptide- and placebo-treated patients during the study. CONCLUSIONS - C-peptide treatment for 6 months improves sensory nerve function in early-stage type 1 diabetic neuropathy. © 2007 by the American Diabetes Association.

  • 31.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Blomgren, Johan
    Internal Medicine County Hospital, Eksjö.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    A randomised double blind crossover study comparing two and four dose hydrocortisone regimen with regard to quality for life, cortisol and ACTH profiles in patients with primary adrenal insufficiency2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Context

    Current guidelines on how to divide the daily cortisol substitution dose in patients with primary adrenal insufficiency (PAI) are controversial and mainly based on empirical data.

    Objective

    To assess how an equal dose of hydrocortisone given either four times daily or twice daily influence diurnal profiles of cortisol and ACTH, patient preferences and health related quality of life (HRQoL).

    Design

    Double blind, crossover.

    Methods

    Fifteen patients with PAI (6 women) were included. Capsules of hydrocortisone or placebo were given at 07:00, 12:00, 16:00 and 22:00 h in 4-week treatment periods: either one period with four doses (10+10+5+5 mg) or one period with two doses (20+0+10+0 mg). Diurnal profiles of cortisol and ACTH were collected and area under the curve (AUC) was calculated. Questionnaires were used to evaluate patient preferences and HRQoL.

    Results

    The four-dose regimen gave a higher serum cortisol before tablet intake in the morning (P = 0.027) and a higher 24-h-cortisolAUC (P < 0.0001) compared with the two-dose period. In contrast a lower median plasma ACTH in the morning before tablet intake (P = 0.003) and a lower 24-h-ln(ACTHAUC) were found during the four-dose period. The patients preferred the four-dose regimen (P = 0.03), and the HRQoL scores tended to be higher (high score indicates better HRQoL) for the four-dose period.

    In summary a four-dose regimen gives increased availability of cortisol and an enhanced effect with a less elevated ACTH in the morning in comparison with a two-dose regimen but the effect on HRQoL remains inconclusive.

  • 32.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Blomgren, J.
    Internal Medicine County Hospital, Eksjö, Sweden.
    Andersson, P.-O.
    Internal Medicine County Hospital, Eksjö, Sweden.
    Carlsson, M.
    Internal Medicine County Hospital, Kalmar, Sweden.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Variable Sensitivity to the Glucocorticoid Activity of Cortisol in Patients with Primary Adrenal Insufficiency: Assessment with ACTH Profiles2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 13, p. 961-966Article in journal (Refereed)
    Abstract [en]

    Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addisons disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 +/- 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2 249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r = -0.56), at 10:00 h (r = -0.51), and at 10.30 h (r = -0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.

  • 33.
    Ekman, Bertil
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Gerdle, Björn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Rehabilitation Medicine. Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Growth hormone substitution titrated to obtain IGF-I levels in the physiological range in hypopituitary adults: Effects upon dynamic strength, endurance and EMG2003In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 90, no 5-6, p. 496-504Article in journal (Refereed)
    Abstract [en]

    We studied the effects of individualised growth hormone (GH) substitution, aiming at normal insulin-like growth factor I (IGF-I) levels, on biomechanical output and surface electromyogram (EMG) of isokinetic muscle strength and endurance performance in 18 hypopituitary adults and compared with 17 matched healthy controls. The muscle function tests consisted of isokinetic contractions of the right knee extensors, from which torque and EMG were recorded. Three patients were excluded from the final analysis of the muscle function tests due to technical errors and one control subject moved from the area during the study. We found that GH-deficient adults without GH substitution were weaker and had less endurance than healthy control subjects. At the group level, plasma levels of IGF-I were normalised but generally no significant effects upon biomechanical output and EMG were found after dose titration and 6 months of a constant GH dose. However, subjects with the largest changes in IGF-I had significantly better biomechanical output and EMG compared to those with small changes in IGF-I. This finding may indicate that the net increase in IGF-I levels is critical for improvements in biomechanical output, EMG and perception of fatigue to occur.

  • 34.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Gerdle, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Improved muscle function in GH substituted adults is related to increase in circulating IGF-IManuscript (preprint) (Other academic)
    Abstract [en]

    We studied the effects of individualized growth hormone substitution, aiming at normal IGF-I levels, on biomechanical output and EMG of isokinetic muscle strength and endurance performance in 18 hypopituitary adults compared with matched controls. The muscle function tests consisted of isokinetic contractions of the dght knee extensors, and torque and EMG were recorded. Plasma levels of IGF-I were normalized, and peak torque at 90° s-1, and peak torque endurance level increased after dose titration and 6 months constant GH-dose. The change in IGF-I correlated positively with the changes in biomechanical output and EMG variables and a negative correlation existed with the perception of fatigue. Despite improvement during GH-substitution the patients still had about 10-20 % less muscle strength and endurance compared with the controls at the study end. In summary we found that individualized GH substitution improves muscle function and that the net increase in IGF-I levels indicates generally increases in biomechanical output and EMG variables and a lower perception of fatigue.

  • 35.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Toss, Göran
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, p. 49-57Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.

    DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.

    RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.

    CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

  • 36.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes2000In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 143, no 4, p. 505-510Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM.

    DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction.

    RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14).

    CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.

  • 37.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Öhman, Peter K
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system2002In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 57, no 4, p. 473-479Article in journal (Refereed)
    Abstract [en]

    objective To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin–angiotensin–aldosterone system (RAAS), natriuretic peptides and urine free cortisol.

    study design Open study with control group. The patients were titrated in dose steps of 0·17 mg GH/day every 6–8 weeks until an IGF-I level around the mean + 1 SD was attained (Tmax). After another month the dose was reduced by 0·17 mg (minimum dose 0·17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (Tend), and this maintenance dose was held constant for 6 months.

    subjects Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects.

    measurements Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels.

    results Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0·03). PRA was elevated on the highest GH dose (Tmax) compared to baseline (P < 0·01), but returned to baseline and levels of controls at Tend. Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0·09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0·01), but increased after GH substitution (P < 0·01) to levels found in with the controls.

    conclusions We found no major changes of the variables in the circulating renin–angiotensin–aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.

  • 38. Graham, J
    et al.
    Kockum, I
    Sanjeevi, CB
    Landin-Olsson, M
    Nyström, L
    Sundkvist, G
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Blohmé, G
    Lithner, F
    Littorin, B
    Scherstén, B
    Wibell, L
    Östman, J
    Lernmark, Å
    Breslow, N
    Dahlquist, G
    Negative asociation between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset.1999In: European journal of immunogenetics, ISSN 0960-7420, E-ISSN 1365-2370, Vol. 26, p. 117-127Article in journal (Refereed)
  • 39.
    Gustafsson, T
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Andersson, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Different inhibitory actions of IGFBP-1, -2 and-4 on IGF-1 effects in vascular smooth muscle cells.1999In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 161, p. 245-253Article in journal (Refereed)
  • 40.
    Gustafsson, T
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Andersson, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Chen, Y
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Magnusson, JO
    Magnusson, JO
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Interaction of angiotensin II and the insulin-like growth factor system in vascular smooth muscle cells.1999In: American journal of physiology, ISSN 0002-9513, Vol. 277, p. 499-507Article in journal (Refereed)
  • 41.
    Gutefeldt, Kerstin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Hedman, Christina A
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Thyberg, Ingrid S M
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Upper extremity impairments in type 1 diabetes with long duration: common problems with great impact on daily life2017In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, p. 1-8Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the prevalence, activity limitations and potential risk factors of upper extremity impairments in type 1 diabetes in comparison to controls.

    METHODS: In a cross-sectional population-based study in the southeast of Sweden, patients with type 1 diabetes <35 years at onset, duration ≥20 years, <67 years old and matched controls were invited to answer a questionnaire on upper extremity impairments and activity limitations and to take blood samples.

    RESULTS: Seven hundred and seventy-three patients (ages 50 ± 10 years, diabetes duration 35 ± 10 years) and 708 controls (ages 54 ± 9 years) were included. Shoulder pain and stiffness, hand paraesthesia and finger impairments were common in patients with a prevalence of 28-48%, which was 2-4-folds higher than in controls. Compared to controls, the patients had more bilateral impairments, often had coexistence of several upper extremity impairments, and in the presence of impairments, reported more pronounced activity limitations. Female gender (1.72 (1.066-2.272), p = 0.014), longer duration (1.046 (1.015-1.077), p = 0.003), higher body mass index (1.08 (1.017-1.147), p = 0.013) and HbA1c (1.029 (1.008-1.05), p = 0.007) were associated with upper extremity impairments.

    CONCLUSIONS: Compared to controls, patients with type 1 diabetes have a high prevalence of upper extremity impairments, often bilateral, which are strongly associated with activity limitations. Recognising these in clinical practise is crucial, and improved preventative, therapeutic and rehabilitative interventions are needed. Implications for rehabilitation Upper extremity impairments affecting the shoulder, hand and fingers are common in patients with type 1 diabetes, the prevalence being 2-4-fold higher compared to non-diabetic persons. Patients with diabetes type 1 with upper extremity impairments have more pronounced limitations in daily activities compared to controls with similar impairments. Recognising upper extremity impairments and activity limitations are important and improved preventive, therapeutic and rehabilitation methods are needed.

    The full text will be freely available from 2018-11-05 13:21
  • 42.
    Haarhaus, Mathias
    et al.
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform2013In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, no 2, p. 167-174Article in journal (Refereed)
    Abstract [en]

    Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

  • 43.
    Hedman, Christina A
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Frystyk, Jan
    Aarhus University and Aarhus University Hospital, Denmark.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Oskarsson, Per
    Karolinska University Hospital, Stockholm, Sweden.
    Arnqvist, Hans J
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion2014In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, no 1, p. 58-62Article in journal (Refereed)
    Abstract [en]

    Objective

    Type 1 diabetes (T1D) is associated with low IGF-I and altered levels of IGF-binding proteins (IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I bioactivity is affected by the route of insulin administration and that continuous intraperitoneal insulin infusion (CIPII) has a more pronounced effect than continuous subcutaneous insulin infusion (CSII).

    Design and methods

    We compared 10 patients with T1D on CIPII with 20 age- and sex-matched patients on CSII. Blood sampling was carried out 7–9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation (KIRA) assay. IGF-I was also measured by immunoassay together with IGF-II, IGFBP-1 and IGFBP-2.

    Results

    When compared with subcutaneous insulin, intraperitoneal insulin resulted in (CIPII vs CSII) higher IGF-I bioactivity (1·83 ± 0·76 vs 1·16 ± 0·24 μg/l; P = 0·02), IGF-I (120 ± 35 vs 81 ± 19 μg/l; P = 0·01) and IGF-II (1050 ± 136 vs 879 ± 110 μg/l; P = 0·02). By contrast, log-transformed IGFBP-1 was reduced (P = 0·013), whereas log-transformed IGFBP-2 was not different (P = 0·12). There was a positive correlation between IGF bioactivity and IGF-I (r = 0·69; P < 0·001) and an inverse correlation between IGF-I bioactivity and log10 IGFBP-1 (r = −0·68, P < 0·001).

    Conclusion

    The in vitro IGF-I bioactivity was higher in patients treated with CIPII compared with CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF system in T1D.

  • 44.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Frystyk, J
    Aarhus University Hospital.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Oskarsson, P
    Karolinska University.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Intraperitoneal insulin delivery gives higher circulating IGF-I activity than CSII in type 1 diabetes2009In: in DIABETOLOGIA, vol 52, 2009, Vol. 52, p. S376-S377Conference paper (Refereed)
    Abstract [en]

    n/a

  • 45.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Frystyk, Jan
    Medical Research Laboratories, Clinical Institute and Medical Department, Aarhus University Hospital, Aarhus, Denmark.
    Fridell, Karin
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Anna
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Flyvbjerg, Allan
    Medical Research Laboratories, Clinical Institute and Medical Department, Aarhus University Hospital, Aarhus, Denmark.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes2005In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 15, no 4, p. 304-310Article in journal (Refereed)
    Abstract [en]

    Objective In type 1 diabetes the circulating IGF-system is altered with low IGF-I and changes in levels of IGF-binding proteins (IGFBPs) which may be of importance for the development of diabetes complications. Our aim was to study if IGF-I, as supported by experimental data in animals, can be affected by dietary protein intake.

    Design and methods Twelve patients with type 1 diabetes, age 37.5 ± 10.0 years (mean ± SD), diabetes duration 20.1 ± 9.3 years and HbA1c 6.3 ± 0.6% were allocated to isocaloric diets with either low normal protein content (LNP), (10 E%; 0.9 g protein/kg body weight) or high normal protein content (HNP) (20 E%; 1.8 g protein/kg body weight) in an open randomised cross-over study. Each diet was taken for 10 days with a wash-out period of 11 days in between. Circulating levels of total and free IGF-I and -II, IGFBP-1, -2 and -3 and GH-binding protein (GHBP) as well as ghrelin were measured with validated in-house immunoassays.

    Results At day 10, urinary urea excretion was 320 ± 75 mmol/24 h during LNP diet compared with 654 ± 159 mmol/24 h during HNP diet (p < 0.001). There were no changes in body weight or glycaemic control between the diets. Fasting levels of total IGF-I were 121 ± 33 μg/L after LNP and 117 ± 28 μg/L after HNP diet (ns) and the corresponding concentrations of IGFBP-1 were 142(141) and 132(157) μg/L [median (IQR)] (ns). There were no differences in plasma concentrations of total IGF-II, free IGF-I and -II, IGFBP-3, GHBP and ghrelin, whereas a small difference was found for IGFBP-2 (302 ± 97 vs. 263 ± 66 μg/L; LNP vs. HNP; p < 0.04).

    Conclusions A twofold change of the dietary protein intake does not influence the altered circulating IGF-system in type 1 diabetes. In order to affect the IGF-system other interventions must be used.

  • 46.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Frystyk, Jan
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Chen, Jian-Wen
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Flyvbjerg, Allan
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Ørskov, Hans
    Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 12, p. 6305-6309Article in journal (Refereed)
    Abstract [en]

    The GH-IGF-I axis is disturbed in patients with type 1 diabetes. Our aim was to investigate whether abnormalities are found in patients in very good glycemic control and, if so, to estimate the role of residual β-cell function. Patients with hemoglobin A 1c (HbA 1c) less than 6% (reference range, 3.6-5.4%) were selected for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± SD), with a diabetes duration of 17.8 ± 14.6 yr participated. Healthy controls (15 women and nine men), aged 41.3 ± 13.0 yr, were also studied. Overnight fasting serum samples were analyzed for HbA 1c, C peptide, free and total IGFs, IGF-binding proteins (IGFBPs), GH-binding protein, and IGFBP-3 proteolysis. HbA 1c was 5.6 ± 0.5% in patients and 4.4 ± 0.3% in controls. Total IGF-I was 148 ± 7 μg/liter in patients and 178 ± 9 μg/liter in controls (P < 0.001). Free IGF-I, total IGF-II, IGFBP-3, and GH-binding protein were lower, whereas IGFBP-1, IGFBP-1-bound IGF-I, and IGFBP-2 were elevated compared with control values. Patients with detectable C peptide (≥100 pmol/liter) had higher levels of total IGF-I, free IGF-I, and total IGF-II and lower levels of IGFBP-1 and IGFBP-2 than those with an undetectable C peptide level despite having identical average HbA 1c. IGFBP-3 proteolysis did not differ between patients and controls. Despite very good glycemic control, patients with type 1 diabetes and no endogenous insulin production have low free and total IGF-I. Residual β-cell function, therefore, seems more important for the disturbances in the IGF system than good metabolic control per se, suggesting that portal insulin delivery is needed to normalize the IGF system.

  • 47.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes2001In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 24, p. 1120-1121Article in journal (Refereed)
    Abstract [en]

    No abstract available.

  • 48.
    Hedman, Christina
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Orre-Pettersson, A-C
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes2001In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 55, no 1, p. 107-112Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE IGF-I levels in patients with type 1 diabetes without endogenous insulin production are low. Our aim was to examine whether the plasma insulin profile obtained by treatment with the insulin analogue lispro has a different effect on plasma concentrations of IGF-I and IGFBP-1 than that seen during treatment with conventional human insulin (regular insulin).

    DESIGN AND PATIENTS Twelve patients with type 1 diabetes, age 47·8 ± 2·4 years (mean ± SEM), body mass index 26·5 ± 1·0 kg/m2, diabetes duration 30·5 ± 3·2 years participated in this open label randomized cross-over study. IGF-I and IGFBP-1 levels were measured at the end of 6 weeks treatment with each insulin being administered by a continuous subcutaneous insulin infusion. IGF-I was measured fasting while IGFBP-1, free insulin and blood glucose were measured fasting and repeatedly after a morning meal preceded by an insulin bolus dose.

    RESULTS Lispro gave a marked insulin peak of 135 ± 20 pmol/l 50 minutes after injection. After an initial rapid rise, human regular insulin reached a plateau of approximately 50 pmol/l. The plasma free insulin area under the curve (AUC) from 0710 h to 0910 h was more than twice as large on lispro as on regular insulin (P = 0·01). Plasma IGF-I concentration was 78·8 ± 10·9 µg/l on lispro and 82·3 ± 10·5 µg/l on human regular insulin (not significant). AUC for IGFBP-1 did not show a significant difference even when divided from 0710 h to 0910 h and from 0930 h to 1430 h. Blood glucose AUC after administration of the bolus was significantly lower during treatment with lispro (P = 0·006) but glycosylated haemoglobin (HbA1c) was 6·4 ± 0·2% on both therapies.

    CONCLUSIONS Our results indicate that the effect of lispro on IGF-I and IGFBP-1 in patients with type 1 diabetes does not differ from that of human regular insulin.

  • 49. Henricsson, Marianne
    et al.
    Nyström, Lennarth
    Blohmé, Göran
    Östman, Jan
    Kullberg, Carin
    Svensson, Maria
    Schölin, Anna
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    Björk, Elisabeth
    Bolinder, Jan
    Eriksson, Jan
    Sundkvist, Göran
    The incidence of retinopathy 10 years after diagnosis in young adult people with diabetes: Results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS)2003In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 26, no 2, p. 349-354Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE - To estimate the prevalence and severity of diabetic retinopathy (DR) 10 years after diagnosis in a nationwide population-based cohort study of young adult diabetic patients in Sweden. RESEARCH DESIGN AND METHODS - The Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases of diabetes aged 15-34 years in Sweden. In 1987-1988, 806 cases were reported, and 627 (78%) of them were followed up with regard to retinopathy 8-10 years later. The assessment was based on retinal photographs in most cases (86%). RESULTS - Ten years after diagnosis, retinopathy was found in 247 patients (39%). The retinopathy was mild in 206 (33%), whereas 30 (4.8%) patients had moderate nonproliferative DR (NPDR) and 11 (1.8%) had proliferative DR (PDR). Patients with retinopathy had worse glycemic control during the years than patients without (HbA1c 8.1 ▒ 1.5% and 6.8 ▒ 1.2%, respectively, P < 0.001). In a Cox regression analysis, time to retinopathy was related to high HbA1c (P < 0.001) and high BMI (P = 0.001). Patients with type 2 diabetes had an increased prevalence of severe retinopathy (NPDR or PDR) compared with those with type 1 diabetes (14 of 93 [15%] versus no or mild 24 of 471 [5%], respectively, P < 0.001). CONCLUSIONS - Despite modern diabetes management, 39% of young adult diabetic patients developed retinopathy within the first 10 years of the disease. Nevertheless, compared with the prevalence of retinopathy (63%), after a similar duration of diabetes before the Diabetes Control and Complications Trial, this prevalence was clearly lower. Current treatment aimed to achieve strict glycemic control has reduced the risk for developing retinopathy.

  • 50.
    Jamali, R
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Bao, M
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology. Östergötlands Läns Landsting, MC - Medicincentrum, EMT-endo.
    IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells2003In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 179, no 2, p. 267-274Article in journal (Refereed)
    Abstract [en]

    Apoptosis of vascular smooth muscle cells (VSMCs) is of importance in the development of diabetic angiopathy. Our aim was to evaluate the effect of insulin and IGF-I on apoptosis in VSMCs. Rat aortic VSMCs were used and apoptosis was induced by serum starvation. As apoptotic markers we measured caspase-3 activity, histone-associated DNA fragments by ELISA and nuclear morphology by DAPI (4',6-diamidino-2-phenylindole) staining. Phosphorylation of IGF-I receptors was evaluated by Western blot. Serum starvation had increased caspase-3 activity even after 3 h. The highest activity was found after 3-12 h. IGF-I 10-9 M inhibited serum starvation-induced caspase-3 activity with a maximal effect after 12 h. When studied after starvation for 12 h, significant inhibitory effects on caspase-3 were found at IGF-I concentrations of 10-8-10-7 M (P<0.01) and at an insulin concentration of 10-6 M (P<0.01). DNA fragmentation was detected by ELISA after 24 h and chromatin condensation and nuclear fragmentation by DAPI staining after 24 and 48 h respectively. IGF-I dose-dependently reduced apoptosis evaluated by ELISA, reaching a maximal effect at 10-9 M. Insulin reduced apoptosis but the effect was weaker and a higher concentration was needed. IGF-I (10-8 M) and insulin at a very high concentration (10-6 M) phosphorylated IGF-I receptors. Taken together, IGF-I and insulin have anti-apoptotic effects on VSMCs but the effect of insulin is only found at high unphysiological concentration.

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