Characterization of Impaired Glucose Tolerance - Insulin Sensitivity, Islet Function and Metabolic Risk Factors

Hillevi Larsson

Research output: ThesisDoctoral Thesis (compilation)

Abstract

This thesis presents a three-year prospective study on metabolic characteristics of impaired glucose tolerance (IGT) and the regulation of insulin sensitivity versus islet function in relation to changes in glucose tolerance. 108 non-diabetic women aged 57-58 years were randomly selected from a population of women born in 1935 with a high prevalence of IGT. At baseline and follow-up, glucose tolerance was determined with an oral glucose tolerance test, insulin sensitivity was measured using a euglycemic, hyperinsulinemic clamp, and islet function was measured after arginine injection at fasting, 14 and >25 mmol/L glucose levels. Androgen activity was measured as the ratio of testosterone to sex hormone-binding globulin, and muscle fiber size and distribution as well as capillary density were determined from a muscle biopsy.

At the baseline examination in 1993-94, 71 women had normal glucose tolerance (NGT) and 37 had IGT. The women with IGT were characterized by hyperinsulinemia, insulin resistance, hypertension and dyslipidemia. Androgen activity was increased in IGT compared to NGT. The percentage of type I, IIa and IIx muscle fibers was not altered, while the size of the type IIa and IIx muscle fibers was increased in IGT. In women with NGT, insulin sensitivity and insulin secretion were inversely related in a hyperbolic manner, indicating that insulin secretion is upregulated to match the degree of insulin resistance in order to maintain normal glucose tolerance. The islet compensation index (CI) was calculated as the insulin sensitivity times insulin secretion to enable quantification of the relation between these parameters. In IGT the CI was reduced compared to NGT. Thus, in the IGT group the insulin secretion was decreased in relation to insulin sensitivity, suggesting deficient adaptation of islet function to insulin resistance. A multifaceted islet dysfunction was evident in women with IGT, who manifested a reduced glucose potentiation of insulin secretion and a decreased glucose inhibition of glucagon secretion. Furthermore, the relative proinsulin secretion was increased in the IGT compared to the NGT group.

86 women participated in the three-year follow-up study in 1996-97. We found that the yearly progression from IGT to diabetes was 1.1%, from NGT to diabetes 0.6% and from NGT to IGT 7%. Subjects who developed IGT (n=13) or diabetes (n=2) during the study had increased baseline levels of 2h glucose and triglycerides. Moreover, changes in insulin sensitivity during the study were inversely related to alterations in insulin secretion in the individual subjects. The follow-up glucose tolerance was independently predicted by a low islet compensation index, increased glucagon secretion and a high 2h glucose at baseline.

We conclude that islet adaptation to the individual degree of insulin sensitivity is of paramount importance for glucose tolerance, and that increased glucagon secretion is a novel risk factor for developing glucose intolerance.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Clinical Sciences, Malmö
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date1999 May 12
Publisher
ISBN (Print)91-628-3519-X
Publication statusPublished - 1999

Bibliographical note

Defence details

Date: 1999-05-12
Time: 13:00
Place: Medical Research Center, Malmö University Hospital , Malmö

External reviewer(s)

Name: Kahn, Steven
Title: Dr
Affiliation: Washington University, Seattle, USA

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Subject classification (UKÄ)

  • Clinical Medicine

Free keywords

  • Endocrinology
  • muscle fiber type
  • androgen activity
  • proinsulin
  • glucagon
  • insulin secretion
  • insulin sensitivity
  • Impaired glucose tolerance
  • type 2 diabetes
  • sekretion
  • diabetologi
  • Endokrinologi
  • diabetology
  • secreting systems

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