Rgs16 is a Pancreatic Reporter of Chronic Hyperglycemia in Diabetes




Ocal, Ozhan

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Diabetes mellitus is a collection of metabolic diseases with chronic hyperglycemia as their common syndrome. Type 1 diabetes results from pancreatic insulin producing beta cell loss due to autoimmune attack and consequent insulin insufficiency, whereas type 2 diabetes occurs as a result of somatic cell insulin resistance under metabolic stress. Therapies include insulin supplementation for type 1 diabetics and diet control and augmented insulin release for type 2 diabetics. G-protein coupled receptors (GPCR) represent the largest non-antibiotic drug targets and several family members are expressed in beta cells. Regulators of G-protein Signaling (RGS) proteins are feedback regulators of GPCRs. Their expression can be induced by GPCR or cross-talk signals to inhibit GPCR pathway, thereby indicating when and where GPCR signaling occurs. Our studies utilizing Rgs16::GFP transgenic mouse previously showed that Rgs16 was expressed in embryonic pancreatic progenitor cells, endocrine cells, and postnatal vessel and ductal associated cells (VDAC). Euglycemic adults lacked pancreatic Rgs16::GFP expression. We investigated diabetic mice to determine if Rgs16::GFP would reactivate during beta cell expansion in adulthood. The type 1 diabetic models of beta cell death were streptozotocin (STZ) treatment and PANIC-ATTAC mice. Type 2 diabetic models consisted of ob/ob mice and diet induced obesity. In each case, Rgs16::GFP expression initiated in islets and VDAC after at least 6 days of chronic hyperglycemia. STZ induced Rgs16::GFP expression was reduced after lowering blood glucose levels with systematic insulin administrations. Furthermore, hyperglycemia dependent Rgs16::GFP expression required metabolic transcription factor Carbohydrate Response Element Binding Protein (ChREBP), as pancreatic Rgs16::GFP was absent in STZ-treated ChREBP KO mice. We found that Rgs16::GFP is also expressed in Pancreatic Ductal Adenocarcinoma (PDAC) tumors and primary tissue culture cells. RNA-Seq analysis revealed that cultured PDAC cells express many genes in common with embryonic progenitors of ductal and endocrine cells and identified expression of 63 GPCRs. In summary, our results suggest that Rgs16::GFP is stimulated by GPCR signals relayed from a "hyperglycemia sensor". We propose that Rgs16 is a faithful pancreatic biomarker of diabetes and Rgs16::GFP PDAC culture and diabetic reporter mice are beneficial resources to identify ligands that stimulate beta cell expansion without promoting cancer.

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