Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes.
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 beta-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 beta-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 beta-cell and that their genetic fundaments are encoded by different loci within Niddm1i.
Granhall
Charlotte
C
Lund University, Department of Clinical Sciences, Malmö, CRC, Bldg. 91, Fl. 11, Entrance 72, UMAS, SE-205 02 Malmö, Sweden.
Rosengren
Anders H
AH
Renström
Erik
E
Luthman
Holger
H
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004594:Electrophysiology; D005089:Exocytosis; D014644:Genetic Variation; D016678:Genome; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007700:Kinetics; D051336:Mitochondrial Membranes / Q000502:physiology; D012313:RNA / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344
D017931:DNA Primers; D007328:Insulin; D012313:RNA