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Hedman, Christina
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Publications (10 of 11) Show all publications
van Dijk, P. R., Logtenberg, S. J. J., Chisalita, I. S., Hedman, C., Groenier, K. H., Gans, R. O. B., . . . Bilo, H. J. G. (2016). Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes. Journal of Clinical Endocrinology and Metabolism, 101(6), 2493-2501
Open this publication in new window or tab >>Different Effects of Intraperitoneal and Subcutaneous Insulin Administration on the GH-IGF-1 Axis in Type 1 Diabetes
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2016 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 6, p. 2493-2501Article in journal (Refereed) Published
Abstract [en]

Context: In type 1 diabetes mellitus, low levels of insulin-like growth factor -1 (IGF-1) and IGF binding protein-3 (IGFBP-3) and high levels of GH and IGFBP-1 are present, probably due to portal vein insulinopenia. Objective: To test the hypothesis that continuous ip insulin infusion (CIPII) has a more pronounced effect than sc insulin therapy on regulation of the GH-IGF-1 axis. Design: This was a prospective, observational case-control study. Measurements were performed twice at a 26-week interval. Setting: Two secondary care hospitals in the Netherlands participated in the study. Patients: There were a total of 184 patients, age-and gender-matched, of which 39 used CIPII and 145 sc insulin therapy for the past 4 years. Outcomes: Primary endpoint included differences in IGF-1. Secondary outcomes were differences in GH, IGFBP-1, and IGFBP-3. Results: IGF-1 was higher with CIPII as compared to SC insulin therapy: 124 mu g/liter (95% confidence interval [CI], 111-138) vs 108 mu g/liter (95% CI 102-115) (P = .035). Additionally, IGFBP-3 concentrations were higher and IGFBP-1 and GH concentrations were lower with CIPII as compared to SC insulin therapy: 3.78 mg/liter (95% CI, 3.49 - 4.10) vs 3.31 mg/liter (95% CI, 3.173.47) for IGFBP-3, 50.9 mu g/liter (95% CI, 37.9 - 68.2) vs 102.6 mu g/liter (95% CI, 87.8 - 119.8) for IGFBP-1 and 0.68 mu g/liter (95% CI, 0.44 - 1.06) vs 1.21 mu g/liter (95% CI, 0.95-1.54) for GH, respectively. In multivariate analysis, IGF-1 had no significant association with HbA1c. Conclusions: The GH-IGF-1 axis may be affected by the route of insulin administration with CIPII counteracting dysregulation of the GH-IGF1 axis present during sc insulin therapy.

Place, publisher, year, edition, pages
ENDOCRINE SOC, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-130291 (URN)10.1210/jc.2016-1473 (DOI)000378821100026 ()27115061 (PubMedID)
Note

Funding Agencies|Zwols Wetenschapsfonds Isala Klinieken; Sanofi-Aventis The Netherlands B.V.

Available from: 2016-07-31 Created: 2016-07-28 Last updated: 2017-04-24
Van dijk, P. R., Logtenberg, S. J., Chisalita, I. S., Hedman, C. A., Groenier, K. H., Gans, R. O., . . . Bilo, H. J. (2015). After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.. Growth Hormone & IGF Research, 25(6), 316-319
Open this publication in new window or tab >>After 6years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level.
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2015 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 6, p. 316-319Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Low concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII).

DESIGN: Nineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population.

RESULTS: In 2012, IGF-I Z-scores (-0.7; 95% confidence interval -1.3, -0.2) were significantly higher than at the start of the 2006 study (-2.5; -3.3, -1.8), the end of the SC (-2.0; -2.6, -1.5) and CIPII (-1.6; -2.1, -1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively.

CONCLUSION: After 6years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM.

Keywords
IGF-I; Intraperitoneal insulin; Type 1 diabetes mellitus
National Category
Endocrinology and Diabetes Physiology
Identifiers
urn:nbn:se:liu:diva-124061 (URN)10.1016/j.ghir.2015.08.007 (DOI)000366962800009 ()26336814 (PubMedID)
Note

Funding agencies: Medical Research Council of Southeast Sweden (FORSS); Stichting Zwols Wetenschapsfonds Isala Klinieken (ZWIK)

Available from: 2016-01-19 Created: 2016-01-19 Last updated: 2018-01-10
Hedman, C. A., Frystyk, J., Lindström, T., Oskarsson, P. & Arnqvist, H. J. (2014). Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clinical Endocrinology, 81(1), 58-62
Open this publication in new window or tab >>Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion
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2014 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 81, no 1, p. 58-62Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104324 (URN)10.1111/cen.12296 (DOI)000337735900009 ()23865977 (PubMedID)
Available from: 2014-02-16 Created: 2014-02-16 Last updated: 2017-12-06
Hedman, C., Frystyk, J., Lindström, T., Oskarsson, P. & Arnqvist, H. (2009). Intraperitoneal insulin delivery gives higher circulating IGF-I activity than CSII in type 1 diabetes. In: in DIABETOLOGIA, vol 52 (pp. S376-S377). , 52
Open this publication in new window or tab >>Intraperitoneal insulin delivery gives higher circulating IGF-I activity than CSII in type 1 diabetes
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2009 (English)In: in DIABETOLOGIA, vol 52, 2009, Vol. 52, p. S376-S377Conference paper, Published paper (Refereed)
Abstract [en]

n/a

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20611 (URN)
Available from: 2009-09-16 Created: 2009-09-15 Last updated: 2009-09-16
Lindström, T., Frystyk, J., Hedman, C., Flyvbjerg, A. & Arnqvist, H. (2006). Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration. Clinical Endocrinology, 65(6), 776-782
Open this publication in new window or tab >>Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration
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2006 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 6, p. 776-782Article in journal (Refereed) Published
Abstract [en]

Objective  To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes.

Patients  Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3·6–5·4%) were selected for the study. Twenty-two men and 24 women [age 41·3 ± 13·8 years (mean ± SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41·3 ± 13·0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins.

Results  Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9·7 ± 5·3 [median 8·1, interquartile range (IQR) 3·6] mg/l in patients with diabetes duration less than 10 years and 17·8 ± 10·7 (median 14·7, IQR 7·5) mg/l in patients with longer duration (P = 0·0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 ± 91 pmol/l). C-peptide levels in controls averaged 492 ± 177 pmol/l. HbA1c was 5·7 ± 0·6% in patients without detectable C-peptide and 5·6 ± 0·4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17·3 ± 11·1 vs. 10·6 ± 5·8 mg/l (P < 0·005)] and in the controls [10·1 ± 2·9 mg/l (P < 0·001 vs. patients without detectable C-peptide)].

Conclusions  The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual β-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37793 (URN)10.1111/j.1365-2265.2006.02666.x (DOI)38647 (Local ID)38647 (Archive number)38647 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
Hedman, C. (2005). Insulin and IGF-I in type 1 diabetes. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Insulin and IGF-I in type 1 diabetes
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with type I diabetes have alterations in the GH/IGF system with reduced levels of circulating IGF-I, as well as other disturbances in the components of the IGF system.

Alterations of both local and circulating IGF-I and its binding proteins (IGFBPs) have been associated with metabolic and vascular manifestations of diabetes and also with atherosclerosis. Short-acting insulin analogues have been developed in order to obtain more physiologic insulin profiles than with human regular insulin when injected subcutaneously.

We examined the effects on the IGF system of good glycaemic control, of two diets with different amount of protein and of the short-acting insulin analogue lispro in continuous subcutaneous insulin infusion (CSII) (pump therapy). We also compared the free insulin profiles of the insulin analogues lispro and aspart. As a new tool we used the combination of two different insulin assays that detect human insulin only, or both human insulin and analogues.

This thesis shows that the circulating IGF system exhibits several pronounced aberrations in patients with type I diabetes, even if glycaemic control is normal or near normal. These abnormalities are not, or are only weakly, related to glycaemic control estimated by HbA1c. In contrast, they are related to the presence of residual p-cell function, indicating that portal insulin delivery is required for a normal IGF system. Treatment with insulin analogue lispro, despite giving higher peripheral insulin peaks than human regular insulin, does not alter the levels of IGF-I and IGFBP-I in patients with good glycaemic control and longstanding, Cpeptide negative type 1 diabetes treated with CSII. Furthermore, IGFBP-I levels do not differ after a single s c injection of each of the insulin analogues aspart and lispro. A two-fold increase in protein intake, from 10E% to 20E%, in patients with longstanding type 1 diabetes does not affect the altered IGF system.

The free insulin profiles of insulin analogues aspart and lispro resemble each other, but insulin lispro showed a slightly faster uptake, reached the maximum peak concentration earlier, and showed a more rapid decline than did insulin aspart. These differences are, however, small in comparison with the large differences in the insulin profiles between lispro and human regular insulin. The accumulated evidence suggests that possible differences between these insulin analogues are of little or no clinical importance.

The combination of insulin assays that detect human insulin alone, or both human insulin and analogues provides a new tool for studying insulin pharmacokinetics. Using this technique, it is possible to separately assess the contribution of insulin analogues (lispro and aspart) and human insulin to the free insulin profiles.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2005. p. 81
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 915
Keywords
Type I diabetes, IGF-I, IGF system, insulin, insulin analogues
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31912 (URN)17745 (Local ID)91-85299-26-X (ISBN)17745 (Archive number)17745 (OAI)
Public defence
2005-10-28, Aulan, Hälsans Hus, Campus US, Linköpings Universitet, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-27Bibliographically approved
Hedman, C., Frystyk, J., Fridell, K., Jönsson, A., Flyvbjerg, A., Lindström, T. & Arnqvist, H. (2005). The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes. Growth Hormone & IGF Research, 15(4), 304-310
Open this publication in new window or tab >>The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes
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2005 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 15, no 4, p. 304-310Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31658 (URN)10.1016/j.ghir.2005.06.013 (DOI)17470 (Local ID)17470 (Archive number)17470 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2017-12-13Bibliographically approved
Hedman, C., Frystyk, J., Lindström, T., Chen, J.-W., Flyvbjerg, A., Ørskov, H. & Arnqvist, H. (2004). Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes. Journal of Clinical Endocrinology and Metabolism, 89(12), 6305-6309
Open this publication in new window or tab >>Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes
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2004 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 12, p. 6305-6309Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24672 (URN)10.1210/jc.2004-0572 (DOI)6905 (Local ID)6905 (Archive number)6905 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
Lindström, T., Hedman, C. & Arnqvist, H. (2002). Use of a novel double-antibody technique to describe the pharmacokinetics of rapid-acting insulin analogs. Diabetes Care, 25(6), 1049-1054
Open this publication in new window or tab >>Use of a novel double-antibody technique to describe the pharmacokinetics of rapid-acting insulin analogs
2002 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 25, no 6, p. 1049-1054Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE—To measure the contribution of bedtime intermediate-acting human insulin on the morning plasma insulin profiles after injection of the rapid-acting insulin analogs lispro and aspart in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—A total of 14 patients with type 1 diabetes, aged 35 ± 13 years (mean ± SD), participated in this single-blind, randomized crossover study. After taking their usual injection of human intermediate-acting insulin the night before, they were given insulin aspart or insulin lispro (10 units) before a standardized breakfast. The contribution of continuing absorption of the human insulin was measured using a monoclonal antibody not cross-reacting with insulin aspart or lispro, whereas the contribution of the analogs was estimated by subtraction after measurement of all plasma free insulin using an antibody cross-reacting equally with human insulin and both analogs.

RESULTS—The correlation coefficient of the fasting free insulin concentrations measured with both insulin methods was 0.95. Fasting free insulin was 95 ± 25 pmol/l before administration of insulin aspart, when determined with enzyme-linked immunosorbent assay detecting only human insulin, and 71 ± 20 pmol/l before administration of insulin lispro (NS). Both insulin analogs gave marked peaks of free insulin concentrations, lispro at 40 ± 3 min and aspart at 55 ± 6 min after injection (P = 0.01). The later part of the profiles, from 4.5 to 5.5 h after injection, were similar and showed almost no contribution of the insulin analogs.

CONCLUSIONS—The combination of insulin assays that detect human insulin only or both human insulin and analogs provides a new tool for studying insulin pharmacokinetics. Using this technique, we showed that 4.5 h after administration of the rapid-acting insulin analogs lispro and aspart, the free insulin levels are almost only attributable to the intermediate-acting insulin given at bedtime.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24906 (URN)10.2337/diacare.25.6.1049 (DOI)9309 (Local ID)9309 (Archive number)9309 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
Hedman, C., Lindström, T. & Arnqvist, H. (2001). Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes [Letter to the editor]. Diabetes Care, 24, 1120-1121
Open this publication in new window or tab >>Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes
2001 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 24, p. 1120-1121Article in journal, Letter (Refereed) Published
Abstract [en]

No abstract available.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24916 (URN)10.2337/diacare.24.6.1120 (DOI)9320 (Local ID)9320 (Archive number)9320 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
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