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

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon () products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body null (Gcg) mice and mice with expression either specifically within the pancreas (Gcg) or the intestine (Gcg). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in Gcg mice compared with wild-type mice. When 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 reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, Gcg mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. Gcg and Gcg mice maintained higher β-cell mass after treatment with STZ compared with control and Gcg mice. Although in vivo insulin response to glucose was normal, global lack of impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the Gcg mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes. We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes.