It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic ss-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal ss-cell population for the insulin secretory demand, especially by promoting ss-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in ss-cell growth and survival. Increased IRS-2 expression promotes ss-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous ss-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet ss-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, ss-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in ss-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in ss-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of ss-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve ss-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increae IRS-2 expression in ss-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic ss-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in ss-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary ss-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic ss-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous ss-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to ss-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate ss-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes.
Type-2 diabetes is caused by a decrease in functional pancreatic ss-cell mass that is no longer able to compensate for the peripheral insulin resistance, and thus maintaining an effective ss-cell population by promoting ss-cell survival and protection is key for delaying the onset of type-2 diabetes. IRS-2 plays a pivotal role in ss-cell growth and survival, and its expression is tightly controlled (predominately at the transcriptional level), but little is known about this regulation. The overall goal of this application is to get better insight into the molecular mechanism behind transcriptional control of IRS-2 in ss-cells, that may eventually lead to a novel therapeutic means of promoting ss-cell survival via maintaining optimal IRS-2 expression to subsequently delay, perhaps indefinitely, the onset of diabetes.
|Coats, Brittney R; Schoenfelt, Kelly Q; Barbosa-Lorenzi, Valéria C et al. (2017) Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity. Cell Rep 20:3149-3161|
|Flak, Jonathan N; Patterson, Christa M; Garfield, Alastair S et al. (2014) Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci 17:1744-1750|
|Rhodes, Christopher J; White, Morris F; Leahy, John L et al. (2013) Direct autocrine action of insulin on ?-cells: does it make physiological sense? Diabetes 62:2157-63|
|Diaferia, Giuseppe R; Jimenez-Caliani, Antonio J; Ranjitkar, Prerana et al. (2013) ?1 integrin is a crucial regulator of pancreatic ?-cell expansion. Development 140:3360-72|
|Gregg, Brigid E; Moore, Patrick C; Demozay, Damien et al. (2012) Formation of a human ?-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97:3197-206|
|Leen, Jason L S; Izzo, Angelo; Upadhyay, Chandani et al. (2011) Mechanism of action of glucagon-like peptide-2 to increase IGF-I mRNA in intestinal subepithelial fibroblasts. Endocrinology 152:436-46|
|Leinninger, Gina M; Opland, Darren M; Jo, Young-Hwan et al. (2011) Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab 14:313-23|
|Syed, Ismail; Kyathanahalli, Chandrashekara N; Jayaram, Bhavaani et al. (2011) Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet. Diabetes 60:2843-52|
|Jayaram, Bhavaani; Syed, Ismail; Kyathanahalli, Chandrashekara N et al. (2011) Arf nucleotide binding site opener [ARNO] promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion in INS 832/13 ?-cells and rat islets. Biochem Pharmacol 81:1016-27|
|Tsunekawa, Shin; Demozay, Damien; Briaud, Isabelle et al. (2011) FoxO feedback control of basal IRS-2 expression in pancreatic ?-cells is distinct from that in hepatocytes. Diabetes 60:2883-91|
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