Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.
Author
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
Publishing year
2006
Language
English
Pages
3494-3500
Publication/Series
Diabetes
Volume
55
Issue
12
Links
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