The role of preproglucagon peptides in regulating b-cell morphology and responses to streptozotocin-induced diabetes

Insulin secretion from b-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring a-cells. Physiological paracrine signaling within the microenvironment of the b-cell is altered after metabolic stress, such as high-fat diet or the b-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in b-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either spe-cifically within the pancreas (GcgDPanc) or the intestine (GcgDIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both a- and b-cell hyperplasia and reactivation of Gcg in the intestine nor-malized b- but not a-cell mass, whereas pancreatic reactivation normalized both b- and a-cell mass. GcgNull and GcgDIntest mice maintained higher b-cell mass after treatment with STZ compared with control and GcgDPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of b-cell mass in the GcgNull mice compensated for decreased individual b-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes. NEW & NOTEWORTHY We examined the role of Gcg on b-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased b-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normal-ized b-cell mass and glucose-stimulated insulin secretion. Increased b-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes