Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Anders Rosengren

Postdoctoral research fellow

Default user image.

Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.

Author

  • Charlotte Granhall
  • Anders Rosengren
  • Erik Renström
  • Holger Luthman

Summary, in English

The effects of genetic variation on molecular functions predisposing to type 2 diabetes are still largely unknown. Here, in a specifically designed diabetes model, we couple separate gene loci to mechanisms of P-cell pathology. Niddm1i is a major glucose-controlling 16-Mb region in the diabetic GK rat that causes defective insulin secretion and corresponds to loci in humans and mice associated with type 2 diabetes. Generation of a series of congenic rat strains harboring different parts of GK-derived Niddm1i enabled fine mapping of this locus. Congenic strains carrying the GK genotype distally in Niddm1i displayed reduced insulin secretion in response to both glucose and high potassium, as well as decreased single-cell exocytosis. By contrast, a strain carrying the GK genotype proximally in Niddm1i exhibited both intact insulin release in response to high potassium and intact single-cell exocytosis, but insulin secretion was suppressed when stimulated by glucose. Islets from this strain also failed to respond to glucose by increasing the cellular ATP-to-ADP ratio. Changes in P-cell mass did not contribute to the secretory defects. We conclude that the failure of insulin secretion in type 2 diabetes includes distinct functional defects in glucose metabolism and insulin exocytosis of the P-cell and that their genetic fundaments are encoded by different loci within Niddm1i.

Department/s

  • Genetics
  • Diabetes - Islet Patophysiology

Publishing year

2006

Language

English

Pages

3494-3500

Publication/Series

Diabetes

Volume

55

Issue

12

Document type

Journal article

Publisher

American Diabetes Association Inc.

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Genetics
  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1939-327X