期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 37, 页码 16009-16012出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006639107
关键词
glucagon; glycemic control; insulin; leptin; type 1 diabetes
资金
- Veterans Affairs North Texas Health Care System
- Amylin Pharmaceuticals
- Swiss National Science Foundation
New results have brought to light the importance of the regulation of glucagon by beta-cells in the development of diabetes. In this perspective, we examine the normal paracrinology of alpha-and beta-cells in nondiabetic pancreatic islets. We propose a Sherringtonian model of coordinated reciprocal secretory responses of these juxtaposed cells that secrete glucagon and insulin, hormones with opposing actions on the liver. As insulin is a powerful inhibitor of glucagon, we propose that within-islet inhibition of alpha-cells by beta-cells creates an insulin-to-glucagon ratio that maintains glycemic stability even in extremes of glucose influx or efflux. By contrast, in type 1 diabetes mellitus, alpha-cells lack constant action of high insulin levels from juxtaposed beta-cells. Replacement with exogenous insulin does not approach paracrine levels of secreted insulin except with high doses that overinsulinize the peripheral insulin targets, thereby promoting glycemic volatility. Based on the stable normoglycemia of mice with type 1 diabetes during suppression of glucagon with leptin, we conclude that, in the absence of paracrine regulation of alpha-cells, tonic inhibition of alpha-cells improves the dysregulated glucose homeostasis. These results have considerable medical implications, as they suggest new approaches to normalize the extreme volatility of glycemia in diabetic patients.
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