| First Author | Arble DM | Year | 2023 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 324 |
| Issue | 3 | Pages | E217-E225 |
| PubMed ID | 36652401 | Mgi Jnum | J:335182 |
| Mgi Id | MGI:7467554 | Doi | 10.1152/ajpendo.00152.2022 |
| Citation | Arble DM, et al. (2023) The role of preproglucagon peptides in regulating beta-cell morphology and responses to streptozotocin-induced diabetes. Am J Physiol Endocrinol Metab 324(3):E217-E225 |
| abstractText | Insulin secretion from beta-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring alpha-cells. Physiological paracrine signaling within the microenvironment of the beta-cell is altered after metabolic stress, such as high-fat diet or the beta-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in beta-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (Gcg(Null)) mice and mice with Gcg expression either specifically within the pancreas (Gcg(DeltaPanc)) or the intestine (Gcg(DeltaIntest)). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in Gcg(Null) 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, Gcg(Null) mice had increased pancreas mass via both alpha- and beta-cell hyperplasia and reactivation of Gcg in the intestine normalized beta- but not alpha-cell mass, whereas pancreatic reactivation normalized both beta- and alpha-cell mass. Gcg(Null) and Gcg(DeltaIntest) mice maintained higher beta-cell mass after treatment with STZ compared with control and Gcg(DeltaPanc) 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 beta-cell mass in the Gcg(Null) mice compensated for decreased individual beta-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 beta-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased beta-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized beta-cell mass and glucose-stimulated insulin secretion. Increased beta-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes. |
