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


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.
Georgia
Senta
S
Larry Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.
Hinault
Charlotte
C
Kawamori
Dan
D
Hu
Jiang
J
Meyer
John
J
Kanji
Murtaza
M
Bhushan
Anil
A
Kulkarni
Rohit N
RN
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006943:Hyperglycemia / Q000235:genetics*; D006965:Hyperplasia / Q000503:physiopathology; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008099:Liver / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D056742:Cyclin D2; D019938:Cyclin D1; D011972:Receptor, Insulin