Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes
Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. S M Abdel-Halim , A Guenifi , B He , B Yang , M Mustafa , B Höjeberg , J Hillert , M Bakhiet and S Efend...
Saved in:
Published in | Diabetes (New York, N.Y.) Vol. 47; no. 3; pp. 498 - 504 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.03.1998
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in
islets from the spontaneously diabetic GK rat model of type 2 diabetes.
S M Abdel-Halim ,
A Guenifi ,
B He ,
B Yang ,
M Mustafa ,
B Höjeberg ,
J Hillert ,
M Bakhiet and
S Efendić
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. samy.abdel-halim@molmed.ki.se
Abstract
Glucose-induced insulin release is decreased in the spontaneously diabetic GK rat, a nonobese rodent model of type 2 diabetes.
Forskolin restores the impaired insulin release in both the isolated perfused pancreas and isolated islets from these rats
(Abdel-Halim et al., Diabetes 45:934-940, 1996). We demonstrate here that the insulinotropic effect of forskolin in the GK
rat is due to increased generation of cAMP and that it is associated with overexpression of adenylyl cyclase (AC)-III mRNA
and gene mutations. The AC-III mRNA overexpression was demonstrated by in situ hybridization using oligonucleotide probes
binding to different regions of the rat AC-III mRNA. It was associated with the presence of two point mutations identified
at positions -28 bp (A --> G) and -358 bp (A --> C) of the promoter region of the AC-III gene and was demonstrable in both
GK rat islets and peripheral blood cells. Transfection of COS cells with a luciferase reporter gene system revealed up to
25-fold increased promoter activity of GK AC-III promoter when compared with normal rat promoter (P < 0.0001). In conclusion,
forskolin restores the impaired insulin release in islets of the GK rat through enhanced cAMP generation. This is linked to
overexpression of AC-III mRNA in GK islets due to two functional point mutations in the promoter region of the AC-III gene. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/diabetes.47.3.498 |