Paracrinology of islets and the paracrinopathy of diabetes

Roger H Unger, Lelio Orci

Research output: Contribution to journalReview articlepeer-review

201 Scopus citations


New results have brought to light the importance of the regulation of glucagon by β-cells in the development of diabetes. In this perspective, we examine the normal paracrinology of α- and β-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 α-cells by β-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, α-cells lack constant action of high insulin levels from juxtaposed β-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 α-cells, tonic inhibition of α-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.

Original languageEnglish (US)
Pages (from-to)16009-16012
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 14 2010


  • Glucagon
  • Glycemic control
  • Insulin
  • Leptin
  • Type 1 diabetes

ASJC Scopus subject areas

  • General


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