| Autor: |
Arble DM; Department of Biological Sciences, Marquette University, Milwaukee, Wisconsin, United States., Hutch CR; Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States., Hafner H; Department of Pediatrics, Division of Diabetes, Endocrinology and Metabolism, University of Michigan Medicine, Ann Arbor, Michigan, United States., Stelmak D; Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States., Leix K; Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States., Sorrell J; Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, United States., Pressler JW; Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, United States., Gregg B; Department of Pediatrics, Division of Diabetes, Endocrinology and Metabolism, University of Michigan Medicine, Ann Arbor, Michigan, United States., Sandoval DA; Department of Pediatrics, Section of Nutrition and Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States. |
| Abstrakt: |
Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon ( Gcg ) 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 Gcg peptides in β-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 ΔPanc ) or the intestine (Gcg ΔIntest ). 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 α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. Gcg Null and Gcg ΔIntest mice maintained higher β-cell mass after treatment with STZ compared with control and Gcg ΔPanc 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 β-cell mass in the Gcg Null 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. NEW & NOTEWORTHY 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. |
