Novel Mechanisms Regulating Platelet and Pancreatic Beta Cell Function in Type 2 Diabetes Mellitus
Authors: Wisinski Jaclyn , Reuter Austin , Kimple Michelle 
Published: November 2023

Mortality from cardiovascular disease has declined over the past couple of decades, while the diabetic population, with nearly two‐fold greater risk, has seen minimal benefit. A significant contributing factor to the diabetic pro‐thrombotic state is the downregulation of anti‐platelet activating mechanisms that normally maintain high levels of inhibitory cAMP to prevent aggregation. Yet these same signaling pathways that are important to maintain proper platelet function may also be important in the insulin‐secreting beta‐cell, as signaling by cAMP in pancreatic beta cells enhances insulin secretion and promotes beta‐cell replication and survival. Although many mechanisms of cAMP regulation have been well studied, little attention has been paid to the Gαi family member, Gαz, which inhibits cAMP production. The expression of Gαz is the most limited out of all of the non‐sensory‐cell Gαi subfamily members, but interestingly, it is expressed in both platelets and beta cells. Thus, we hypothesize the Gαz signaling pathway, including its receptor, EP3, and the endogenous ligand, PGE2, is a critical link between the pathophysiology of diabetes and cardiovascular disease. Specifically, we postulate the flux through the Gαz signaling pathway is dysfunctionally up‐regulated in diabetic beta cells and platelets, inhibiting cAMP production in beta cells to limit insulin secretion and in platelets to reduce inhibitory tone making them hypersensitive. Using the BTBR leptin ob type 2 diabetes mouse model, with and without expression of Gαz, we evaluated general hemostatic function and glucose metabolism. At 10–11 weeks of age, tail bleeding times and overall blood loss were assessed following tail tip amputation. In vivo glucose metabolism was monitored using fasting blood glucose measurements. As early as 8 weeks of age, when Gαz expressing BTBR ob were hyperglycemic (>500mg/dl), the Gαz‐null BTBR ob mice maintained euglycemia and were not statistically different from BTBR lean controls. Of note, the protection from hyperglycemia occurred in spite of obesity and insulin resistance. Upon ex vivo investigation, the Gαz‐null BTBR ob islets had significantly greater insulin content than wild‐type BTBR ob islets, thus a sufficient amount of insulin was secreted to allow for euglycemia. Only wild‐type BTBR ob islets had elevated expression of EP3, the receptor to which Gαz couples, and was therefore responsive to the EP3 selective agonist, sulprostone. To understand the signaling mechanism downstream of EP3/Gαz, we used cAMP analogs and sulprostone to reveal cAMP‐dependent and –independent pathways that lead to inhibition of insulin secretion. This study shows that Gαz signaling in islets and possibly in platelets can contribute not only to type 2 diabetes onset but also to the co‐morbidity of cardiovascular disease.Support or Funding InformationThis work is supported by the American Diabetes Association (1‐14‐BS‐115) and the NIH National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK R01 DK102598) both awarded to M.E.K.