Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes.
The insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling system coordinates peripheral insulin action and pancreatic beta cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that beta cell-specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted beta cell growth, survival, and insulin secretion that prevented diabetes in Irs2-/- mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in beta cells, especially specific cAMP agonists, could be rational treatments for beta cell failure and diabetes.
Hennige
Anita M
AM
Howard Hughes Medical Institute, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Burks
Deborah J
DJ
Ozcan
Umut
U
Kulkarni
Rohit N
RN
Ye
Jing
J
Park
Sunmin
S
Schubert
Markus
M
Fisher
Tracey L
TL
Dow
Matt A
MA
Leshan
Rebecca
R
Zakaria
Mark
M
Mossa-Basha
Mahmud
M
White
Morris F
MF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048429:Cell Size; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000517:prevention & control*; D004041:Dietary Fats / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate; D015854:Up-Regulation
D004041:Dietary Fats; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin