Expression of the autosomal recessive (db) gene in homozygous (db/db) C57BL/KsJ mice results in a severe and eventually fatal diabetic syndrome. Many studies of the diabetic mouse have used lean litter-mates (+ /?) as controls despite evidence suggesting a gene dosage effect in heterozygous animals. In order to study the gene dosage effect of the diabetes (db) gene on insulin release in the heterozygote, perifusion experiments were performed on isolated islets of Langerhans of diabetic (db/db), heterozygous (+/db), and normal (+ / +) control mice. Islets of normal controls exhibited a fivefold greater increase in insulin release than did those of diabetics in response to 16.7 mM D-glucose. The insulin secretory response of islets of heterozygotes to glucose was intermediate, being twofold greater than that of diabetics but only about half of that of normal controls. Biphasic insulin release in response to glucose was observed only in islets of normal controls. Islets of all three genotypes exhibited biphasic insulin release in response to 10 mM D-glyceraldehyde; however, overall insulin release in both heterozygotes and diabetics remained diminished as compared with the response of normal controls. This is in contrast to the situation we have previously reported in islets of fasted or aging rats in which, though manifesting defects in glucose-stimulated insulin release, the islets are able to respond normally to 10 mM D-glyceraldehyde in respect to both the dynamic secretory pattern and quantity of insulin released. Our data suggest a gene dosage effect of the (db) gene on glucose-stimulated insulin release in heterozygous (+/db) C57BL/KSJ mice.

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