Metabolic manifestations of insulin deficiency do not occur without glucagon action
- 13 August 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (37), 14972-14976
- https://doi.org/10.1073/pnas.1205983109
Abstract
To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR(-/-)) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR(-/-) mice with similar β-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.Keywords
This publication has 43 references indexed in Scilit:
- Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in miceJCI Insight, 2012
- Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeoverJCI Insight, 2012
- Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused ratsAmerican Journal of Physiology-Endocrinology and Metabolism, 2011
- Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in MiceDiabetes, 2011
- Paracrinology of islets and the paracrinopathy of diabetesProceedings of the National Academy of Sciences, 2010
- Leptin therapy in insulin-deficient type I diabetesProceedings of the National Academy of Sciences, 2010
- Insulin Signaling in α Cells Modulates Glucagon Secretion In VivoCell Metabolism, 2009
- The CREB coactivator TORC2 is a key regulator of fasting glucose metabolismNature, 2005
- Hyperglucagonemia and Its SuppressionNew England Journal of Medicine, 1978
- Congenital lipodystrophy: An endocrine study in three siblingsThe Journal of Pediatrics, 1978