application) Type 2 diabetes is characterized by insulin resistance and beta-cell failure resulting in uncontrolled hyperglycemia. The basis of the beta-cell defect is presently unclear. A growing body of evidence indicates insulin-signaling proteins are present in the islets and contribute to the maintenance of glucose homeostasis. Thus, normal beta-cells show glucose-stimulated phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1). Secondly, mice with a targeted disruption of the IR show loss of insulin secretory response to glucose and progressive glucose intolerance. Third, primary islets and beta-cell lines derived from IRS-1 knockout mice show reduced insulin content and blunted secretory responses to multiple stimuli, and IRS-2 knockout mice manifest a defect in beta-cell development. These data indicate the presence of an insulin-signaling pathway in the islets/beta-cells potentially linked to glucose signaling that plays an important role in islet function. The goals of this proposal are to understand the mechanisms by which the insulin-signaling proteins modulate beta-cell function and to delineate the cross-talk between the insulin- and glucose-signaling pathways. Our studies will be directed at the following specific aims: 1) to identify the cellular mechanisms by which proteins in the insulin-signaling pathway modulate insulin secretion and synthesis in response to different stimuli, 2) to determine the alterations in glucose metabolism in islets/beta-cells isolated from mice lacking the IR and the IRS proteins and to study the effects of re-expression of the proteins in the knockout cell lines, and 3) to evaluate the expression of insulin signaling proteins and glucose metabolism in islets isolated from rodent models of diabetes. My earlier training in islet physiology and metabolism and the experience I am currently gaining as a research fellow at the Joslin Diabetes Center have provided me with a unique perspective to explore the significance of the insulin signaling pathway in islet/beta-cell function. The mentoring support of Prof. Kahn and the academic environment of the Joslin Diabetes Center and Harvard Medical School provides me with an excellent opportunity to continue my investigation in type 2 diabetes and further develop my skills to attain my goals as an independent investigator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002885-03
Application #
6524088
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$109,565
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Negahdar, Maria; Aukrust, Ingvild; Johansson, Bente B et al. (2012) GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation. Biochim Biophys Acta 1822:1705-15
Cheng, Kim; Ho, Kenneth; Stokes, Rebecca et al. (2010) Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets. J Clin Invest 120:2171-83
Pissios, Pavlos; Ozcan, Umut; Kokkotou, Efi et al. (2007) Melanin concentrating hormone is a novel regulator of islet function and growth. Diabetes 56:311-9
He, Zhiheng; Opland, Darren M; Way, Kerrie J et al. (2006) Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia. Arterioscler Thromb Vasc Biol 26:787-93
Gunton, Jenny E; Kulkarni, Rohit N; Yim, SunHee et al. (2005) Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122:337-49
Hennige, Anita M; Ozcan, Umut; Okada, Terumasa et al. (2005) Alterations in growth and apoptosis of insulin receptor substrate-1-deficient beta-cells. Am J Physiol Endocrinol Metab 289:E337-46
Kulkarni, Rohit N (2005) New insights into the roles of insulin/IGF-I in the development and maintenance of beta-cell mass. Rev Endocr Metab Disord 6:199-210
Goren, H Joseph; Kulkarni, Rohit N; Kahn, C Ronald (2004) Glucose homeostasis and tissue transcript content of insulin signaling intermediates in four inbred strains of mice: C57BL/6, C57BLKS/6, DBA/2, and 129X1. Endocrinology 145:3307-23
Otani, Kenichi; Kulkarni, Rohit N; Baldwin, Aaron C et al. (2004) Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice. Am J Physiol Endocrinol Metab 286:E41-9
Kulkarni, Rohit N; Jhala, Ulupi S; Winnay, Jonathon N et al. (2004) PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J Clin Invest 114:828-36

Showing the most recent 10 out of 17 publications