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Diabetes. 2010 Apr;59(4):987-96. doi: 10.2337/db09-0838. Epub 2010 Jan 26.

Cyclin D2 is essential for the compensatory beta-cell hyperplastic response to insulin resistance in rodents.

Author information

1
Larry Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Abstract

OBJECTIVE:

A major determinant of the progression from insulin resistance to the development of overt type 2 diabetes is a failure to mount an appropriate compensatory beta-cell hyperplastic response to maintain normoglycemia. We undertook the present study to directly explore the significance of the cell cycle protein cyclin D2 in the expansion of beta-cell mass in two different models of insulin resistance.

RESEARCH DESIGN AND METHODS:

We created compound knockouts by crossing mice deficient in cyclin D2 (D2KO) with either the insulin receptor substrate 1 knockout (IRS1KO) mice or the insulin receptor liver-specific knockout mice (LIRKO), neither of which develops overt diabetes on its own because of robust compensatory beta-cell hyperplasia. We phenotyped the double knockouts and used RT-qPCR and immunohistochemistry to examine beta-cell mass.

RESULTS:

Both compound knockouts, D2KO/LIRKO and D2KO/IRS1KO, exhibited insulin resistance and hyperinsulinemia and an absence of compensatory beta-cell hyperplasia. However, the diabetic D2KO/LIRKO group rapidly succumbed early compared with a relatively normal lifespan in the glucose-intolerant D2KO/IRS1KO mice.

CONCLUSIONS:

This study provides direct genetic evidence that cyclin D2 is essential for the expansion of beta-cell mass in response to a spectrum of insulin resistance and points to the cell-cycle protein as a potential therapeutic target that can be harnessed for preventing and curing type 2 diabetes.

PMID:
20103709
PMCID:
PMC2844846
DOI:
10.2337/db09-0838
[Indexed for MEDLINE]
Free PMC Article

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