A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of

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F Mauvais-Jarvis1, A Virkamaki, M D Michael

  • 1Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.

Diabetes
|December 16, 2000
PubMed

Insights

Muscle insulin resistance surprisingly improves glucose tolerance in mice by enhancing insulin secretion and substrate redistribution. This suggests muscle communicates with other tissues to regulate insulin sensitivity.

Area of Science:

  • Metabolic diseases
  • Endocrinology
  • Molecular biology

Background:

  • Type 2 diabetes involves defects in insulin secretion and action.
  • Isolated muscle insulin resistance (MIRKO mice) doesn't disrupt glucose homeostasis.
  • Beta-cell insulin resistance (betaIRKO mice) causes severe glucose intolerance due to impaired insulin release.

Purpose of the Study:

  • To investigate the interaction between muscle insulin resistance and altered insulin secretion.
  • To explore how combined insulin resistance in muscle and beta-cells affects glucose homeostasis.

Main Methods:

  • Created double tissue-specific insulin receptor knockout mice (betaIRKO-MIRKO).
  • Compared glucose tolerance and insulin secretion in betaIRKO-MIRKO mice versus betaIRKO mice.
  • Analyzed substrate redistribution and glucose uptake in various tissues.

Main Results:

  • BetaIRKO-MIRKO mice showed improved glucose tolerance compared to betaIRKO mice.
  • Enhanced glucose-stimulated acute insulin release was observed in betaIRKO-MIRKO mice.
  • Substrate redistribution led to increased glucose uptake in adipose tissue and liver, with maintained muscle glucose uptake.

Conclusions:

  • Muscle insulin resistance positively influences glucose-stimulated insulin secretion from beta-cells.
  • Substrate shunting to non-muscle tissues contributes to improved glucose tolerance.
  • Muscle communicates with other tissues, potentially via substrate availability or endocrine signaling, to regulate systemic insulin sensitivity.

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