Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.
(2006) In Diabetes 55(12). p.3494-3500- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/164354
- author
- Granhall, Charlotte LU ; Rosengren, Anders LU ; Renström, Erik LU and Luthman, Holger LU
- organization
- publishing date
- 2006
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Diabetes
- volume
- 55
- issue
- 12
- pages
- 3494 - 3500
- publisher
- American Diabetes Association Inc.
- external identifiers
-
- wos:000242446800036
- scopus:33845542356
- ISSN
- 1939-327X
- DOI
- 10.2337/db06-0796
- language
- English
- LU publication?
- yes
- id
- 0656aac0-ea78-4790-953c-e79633d62de6 (old id 164354)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17130497&dopt=Abstract
- date added to LUP
- 2016-04-01 16:55:30
- date last changed
- 2022-01-28 23:06:37
@article{0656aac0-ea78-4790-953c-e79633d62de6,
abstract = {{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.}},
author = {{Granhall, Charlotte and Rosengren, Anders and Renström, Erik and Luthman, Holger}},
issn = {{1939-327X}},
language = {{eng}},
number = {{12}},
pages = {{3494--3500}},
publisher = {{American Diabetes Association Inc.}},
series = {{Diabetes}},
title = {{Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.}},
url = {{http://dx.doi.org/10.2337/db06-0796}},
doi = {{10.2337/db06-0796}},
volume = {{55}},
year = {{2006}},
}