Role of the heterotrimeric inhibitory G‐protein, Gαz, and its unique G‐protein coupled receptor, EP3, in the progression and pathophysiology of Type 2 Diabetes

The hyperglycemia of Type 2 Diabetes (T2D) results from a combination of factors, including insulin resistance, impaired and inefficient insulin secretion, and destruction of pancreatic beta‐cells. Pathways that inhibit beta‐cell cyclic AMP (cAMP) production are pathologically upregulated in T2D. Prostaglandin E2 (PGE2) receptor 3 (EP3), a G protein‐coupled receptor whose expression is up‐regulated in islets of T2D mice and humans, acts through a unique inhibitory G protein, Gz to reduce islet cAMP production. In contrast to expectations, genetic deletion of EP3 greatly accelerates hyperglycemia in the BTBR LeptinOb/Ob (BTBR‐Ob) model of T2D, likely through unregulated adipose tissue lipolysis and severe glucolipotoxicity. In contrast to the ubiquitously‐expressed EP3, the catalytic α‐subunit of Gz (Gαz) is quite tissue‐limited. We back‐crossed the Gαz‐null mutation into the BTBR‐Ob strain for more than 10 generations. Gαz‐null BTBR‐Ob mice maintained normal fasting blood glucose levels, even though they were as obese and insulin resistant as T2D wild‐type controls. Euglycemia correlated directly with elevated plasma insulin levels, islet insulin content and insulin secretion, the latter stimulated by glucose or the glucagon‐like peptide 1 (GLP‐1) agonist, exendin‐4. With the known paracrine effect(s) of GLP‐1 and other islet hormones on beta‐cell function and mass, we quantified the percentage of GLP‐1‐postive alpha‐cells by immunofluorescence of pancreas sections, revealing a strong effect of the Gαz‐null mutation independent of the Ob mutation. To confirm effects on GLP‐1 secretion, isolated islets were cultured overnight and the medium assayed for active GLP‐1. Somatostatin, expressed in delta‐cells and a negative regulator of beta‐cell cAMP production, was also analyzed. Islets from Ob mice secreted significantly more active GLP‐1 into culture medium than lean controls, with no further impact of the Gαz‐null mutation: a result at odds with active GLP‐1 immunofluorescence data. Islets from lean Gαz‐null mice and wild‐type BTBR‐Ob mice secreted significantly more somatostatin into culture medium than wild‐type lean controls, with the Gαz‐null mutation reversing this effect in the BTBR‐Ob background. These somewhat paradoxical results may be due to multiple factors, including islet isolation selecting for healthier, intact islets and/or maintenance of glucolipotoxic conditions being necessary in culturing islets isolated from BTBR‐Ob mice. We are currently exploring the effects of glucolipotoxicity on our hormone secretion assays. To summarize, we have identified a central role for Gαz in the islet pathophysiology of T2D, potentially through both beta‐cell autonomous and intra‐islet cell‐cell communication mechanisms, confirming loss of Gαz permits a more efficient beta‐cell response to glucose and GLP‐1, a physiologic regulator of beta‐cell function and mass. Support or Funding Information VA Merit Review Award: I01 BX003700‐01A1, VA BLR&D R01 DK102598, NIH/NIDDK American Diabetes Association Innovative Basic Science Award: 1‐14‐BS‐115 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .