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Phenotyping of Individual Pancreatic Islets Locates Genetic Defects in Stimulus Secretion Coupling to Niddm1i Within the Major Diabetes Locus in GK Rats

¹ Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
² Karolinska Institute, Center for Molecular Medicine, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden

The major diabetes quantitative trait locus (Niddm1), which segregates in crosses between GK rats affected with spontaneous type 2–like diabetes and normoglycemic F344 rats, encodes at least two different diabetes susceptibility genes. Congenic strains for the two subloci (Niddm1f and Niddm1i) have been generated by transfer of GK alleles onto the genome of F344 rats. Whereas the Niddm1f phenotype implicated insulin resistance, the Niddm1i phenotype displayed diabetes related to insulin deficiency. Individual islets from 16-week-old congenic rats were characterized for insulin release and oxygen tension (pO₂). In the presence of 3 mmol/l glucose, insulin release from Niddm1f and Niddm1i islets was 5 pmol · g^-1 · s^-1 and pO₂ was 120 mmHg. Similar recordings were obtained from GK and F344 islets. When glucose was raised to 11 mmol/l, insulin release increased significantly in Niddm1f and F344 islets but was essentially unchanged in islets from GK and Niddm1i. The high glucose concentration lowered pO₂ to the same extent in islets from all strains. Addition of 1 mmol/l tolbutamide to the perifusion medium further increased pulsatile insulin release threefold in all islets. The pulse frequency was 0.4 min^-1. -Ketoisocaproate (11 mmol/l) alone increased pulsatile insulin release eightfold in islets from Niddm1f, Niddm1i, and control F344 rats but had no effect on insulin release from GK islets. These secretory patterns in response to -ketoisocaproate were paralleled by reduction of pO₂ in Niddm1f, Niddm1i, and control F344 islets and no change of pO₂ in GK islets. The results demonstrate that Niddm1i carries alleles of gene(s) that reduce glucose-induced insulin release and that are amenable to molecular identification by genetic fine mapping.

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