Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

Z. Asghar, D. Yau, F. Chan, D. LeRoith, C. B. Chan, M. B. Wheeler

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Aims/hypothesis: Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes. Materials and methods: Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function. Results: Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice. Conclusions/ interpretation: Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction.

Original languageEnglish
Pages (from-to)90-99
Number of pages10
JournalDiabetologia
Volume49
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

Keywords

  • Beta cell compensation
  • Beta cell dysfunction
  • Insulin resistance
  • Insulin secretion

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