A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes

Citation
F. Mauvais-jarvis et al., A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes, DIABETES, 49(12), 2000, pp. 2126-2134
Citations number
46
Categorie Soggetti
Endocrynology, Metabolism & Nutrition","Endocrinology, Nutrition & Metabolism
Journal title
DIABETES
ISSN journal
00121797 → ACNP
Volume
49
Issue
12
Year of publication
2000
Pages
2126 - 2134
Database
ISI
SICI code
0012-1797(200012)49:12<2126:AMTETI>2.0.ZU;2-M
Abstract
Type 2 diabetes is a polygenic disease characterized by defects in both ins ulin secretion and insulin action. We have previously reported that isolate d insulin resistance in muscle by a tissue-specific insulin receptor knocko ut ((MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas b eta -cell-specific insulin receptor knockout (beta IRKO) mice manifest seve re progressive glucose intolerance due to loss of glucose-stimulated acute- phase insulin release. To explore the interaction between insulin resistanc e in muscle and altered insulin secretion, me created a double tissue-speci fic insulin receptor knockout in these tissues. Surprisingly, beta IRKO-MIR KO mice show an improvement rather than a deterioration of glucose toleranc e when compared to beta IRKO mice. This is due to improved glucose-stimulat ed acute insulin release and redistribution of substrates with increased gl ucose uptake in adipose tissue and liver in vivo, without a significant dec rease 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 i mproved glucose tolerance. These data suggest that muscle, either via chang es in substrate availability or by acting as an endocrine tissue, communica tes with and regulates insulin sensitivity in other tissues.