Cutting the brakes to prevent Type 2 Diabetes onset: augmenting insulin secretion and conserving pancreatic beta‐cell mass by deleting Gαz

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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. The second messenger molecule, cyclic AMP (cAMP), amplifies glucose‐stimulated insulin secretion and has been suggested to preserve beta‐cell mass. Pathways that inhibit beta‐cell cAMP production are pathologically upregulated in T2D. One such pathway is mediated by Prostaglandin E2 (PGE2) receptor 3 (EP3), a G protein‐coupled receptor whose expression, as well as that of its natural ligand, PGE2, are both up‐regulated in islets collected from T2D mice and humans. While EP3 is ubiquitously expressed, in the beta‐cell it couples to a unique and non‐ubiquitously expressed G protein, Gz. We hypothesized the genetic elimination of the catalytic a‐subunit of Gz (Gαz) would augment beta‐cell function and mass, preventing or delaying the onset of hyperglycemia in the BTBR ob/ob mouse model of T2D. As expected, Gαz‐null ob/ob mice were as obese and as insulin resistant as wild‐type ob/ob mice, consistent with little to no liver, adipose, or muscle Gaz expression, but displayed near‐normal fasting blood glucose levels. Fasting euglycemia in Gaz‐null ob/ob mice correlated directly with elevated plasma insulin levels, suggesting that Gαz‐null ob/ob beta‐cells were able to better compensate for the increased insulin demand of obesity and insulin resistance. To test this directly, we isolated islets from Gaz‐null and wild‐type ob/ob mice, and found higher insulin content and insulin secretion from Gaz‐null ob/ob islets. To further elucidate the molecular mechanisms augmenting beta cell function in Gaz‐null ob/ob islets, we considered the influence of Gaz on glucagon‐like peptide‐1 (GLP‐1), which is a cAMP‐stimulatory gut/islet hormone. We postulated that, in the beta‐cell, Gaz signaling competes with GLP‐1 receptor signling to block the full effects of GLP‐1 on beta‐cell function and/or mass. To test this hypothesis, we subjected wild‐type and Gaz‐null ob/ob mice to intraperitoneal and oral glucose challenge, and found the Gaz‐null mutation partially restored glucose tolerance after an oral glucose challenge but not an intraperitoneal glucose challenge. Plasma levels of the GLP‐1 were not different between the genotypes, but intra‐islet GLP‐1 produced and secreted by alpha cells was altered in Gaz‐null ob/ob islets. Increased GLP‐1 responsiveness of Gaz‐null ob/ob islets was tested directly ex‐vivo by treatment with the stable GLP‐1 analog, exendin‐4. In sum, we identified a key role for Gαz in the islet pathophysiology of T2D and confirmed that deleting Gaz allowed for a more efficient response of the beta‐cell to a physiologic potentiator of insulin secretion and beta‐cell mass, GLP‐1.Support or Funding InformationMolecular and Applied Nutrition Training Program T32