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Rgs16 is a pancreatic reporter of chronic hyperglycemia in diabetes
Author(s) -
Ocal Ozhan,
Asterholm Ingrid W.,
Brekken Rolf A.,
Cleaver Ondine,
Scherer Philipp E.,
Wilkie Thomas M.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.759.6
Subject(s) - medicine , endocrinology , biology , enteroendocrine cell , progenitor cell , streptozotocin , diabetes mellitus , microbiology and biotechnology , stem cell , hormone , endocrine system
Diabetes mellitus is a collection of metabolic diseases characterized by chronic hyperglycemia. Type 1 diabetes results from insulin insufficiency due to autoimmune dependent depletion of insulin producing beta cells, whereas type 2 diabetes occurs as a consequence of somatic cell insulin resistance. G‐protein coupled receptors (GPCR) represent the largest non‐antibiotic drug targets and dozens of them are expressed in beta cells. Regulator of G‐protein Signaling (RGS) proteins are feedback modulators of GPCRs. Their expression can be induced by GPCR or cross‐talk pathways, indicating when and where GPCR signaling occurs. Our studies with Rgs16::GFP transgenic mice showed Rgs16 expression in embryonic pancreas progenitors, differentiating endocrine cells, and postnatal vessel and ductal associated cells (VDAC). Pancreatic Rgs16::GFP was absent in normal glycemic adults, but was reactivated by diabetic conditions and pancreatic ductal adenocarcinoma (PDAC). In all tests with type 1 diabetic models of streptozotocin (STZ) treatment and PANIC‐ATTAC mice and type 2 diabetic models of ob/ob mice and diet induced obesity, Rgs16::GFP expression initiated in islets and VDAC after at least 6 days of persistent hyperglycemia. STZ induced Rgs16::GFP expression was reduced by lowering blood glucose levels with insulin administration. Diabetic Rgs16::GFP induction required the metabolic transcription factor ChREBP, as STZ treated ChREBP KO mice lacked Rgs16::GFP expression. Our results suggest that Rgs16::GFP responds to GPCR signals relayed from a “chronic hyperglycemia” sensor which stimulates islets and ductal progenitor cells. We determined the GPCR profile of PDAC culture cells that we plan to use, together with diabetic Rgs16::GFP reporter mice, to identify ligands that stimulate beta cell expansion without promoting cancer.