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Insulin and IGF-I in type 1 diabetes
Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
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. , 81 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 915
Keyword [en]
Type I diabetes, IGF-I, IGF system, insulin, insulin analogues
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-31912Local ID: 17745ISBN: 91-85299-26-X (print)OAI: oai:DiVA.org:liu-31912DiVA: diva2:252735
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
List of papers
1. Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes
Open this publication in new window or tab >>Treatment with insulin lispro changes the insulin profile but does not affect the plasma concentrations of IGF-I and IGFBP-1 in type 1 diabetes
2001 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 55, no 1, 107-112 p.Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24910 (URN)10.1046/j.1365-2265.2001.01327.x (DOI)9313 (Local ID)9313 (Archive number)9313 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Direct comparison of insulin lispro and aspart shows small differences in plasma insulin profiles after subcutaneous injection in type 1 diabetes
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, 1120-1121 p.Article 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
3. Use of a novel double-antibody technique to describe the pharmacokinetics of rapid-acting insulin analogs
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, 1049-1054 p.Article 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
4. Residual β-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes
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
Show others...
2004 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 12, 6305-6309 p.Article 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
5. The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes
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
Show others...
2005 (English)In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 15, no 4, 304-310 p.Article 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

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