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A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of
F Mauvais-Jarvis1, A Virkamaki, M D Michael
1Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.
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.