Downregulation of the voltage-dependent calcium channel (VDCC) beta-subunit mRNAs in pancreatic islets of type 2 diabetic rats.
The present study was undertaken to determine whether altered expression of the VDCC beta-subunits in pancreatic beta-cells could play a role in the changes in beta-cell sensitivity to glucose that occur with diabetes. Application of competitive RT-PCR procedure revealed that in normal Wistar rats, LETO and prediabetic OLETF rats, the beta(2)-subunit mRNA levels were 60-200-fold greater than the levels for the beta(3)-subunit. These findings suggest that the beta(2)-subunit as well as the beta-cell type VDCC1 alpha(1)-subunit may be the predominant form of the VDCC expressed in pancreatic beta-cells. The levels of mRNA encoding the beta-subunits and the beta-cell type alpha(1)-subunit as well as insulin were significantly reduced in diabetic rats. Perfusion experiments revealed that diabetic rats showed the higher basal insulin secretion and profoundly impaired insulin secretory responses to glucose compared with non-diabetic rats. Alternatively, impaired insulin secretory responses to glucose in high dose glucose-infused rats were recovered partly with the elevation of mRNA levels of the VDCC beta(2)- and beta(3)-subunits as well as the alpha(1)-subunit by the treatment with diazoxide. Thus, considering the possibility that the most striking effect of the VDCC alpha(1) beta-subunit coexpression in pancreatic beta-cells might occur on activation kinetics like the skeletal muscle, the impairment of further activation of the VDCCs to acute glucose challenge caused by the reduced expressions of the alpha(1) beta-subunits mRNAs in type 2 diabetic animals might be at least partly associated with the alterations in beta-cell sensitivity to glucose.
Iwashima
Y
Y
Department of Internal Medicine, Sano Hospital, Suehiro 3-3-1-15, Asahikawa 078-8133, Japan. iwashima@msb.biglobe.ne.jp
Abiko
A
A
Ushikubi
F
F
Hata
A
A
Kaku
K
K
Sano
H
H
Eto
M
M
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D020334:Rats, Inbred OLETF; D017208:Rats, Wistar
D000199:Actins; D002120:Calcium Channel Agonists; D015220:Calcium Channels; D017931:DNA Primers; D007328:Insulin; D021122:Protein Subunits; D012333:RNA, Messenger; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D005947:Glucose