Inheritance of a mitochondrial DNA defect and impaired glucose tolerance in BHE/Cdb rats

Abstract

The BHE/Cdb rat strain is an inbred strain that develops impaired glucose tolerance at maturity. The diabetic state is preceded by defects in metabolism that progress with age. Environmental factors, such as diet, affect the time frame for the phenotypic expression of the genotype [1]. Feeding sugar rich and fat rich diets hastens the appearance of impaired glucose tolerance and its complications. The diabetic phenotype has been attributed to point mutations (bp 8204, 8289) in the mtDNA gene for F o ATPase subunit 6 [2] and Herrnstad, (personal communication) because these rats show impaired mitochondrial function, particularly in the control of oxidative phosphorylation [3±5]. No evidence of a point mutation in the tRNA LEU(UUR) has been found nor have we found evidence of muscle or nerve pathology. This rat strain shows a reduction in ATP synthesis efficiency, mitochondrial coupling and b-cell ATP content. A decline in glucose stimulated insulin release also occurs with age [6]. Glucose stimulated insulin release falls from 89.5 ± 10.2 pmol/l to 46.3 ± 22.7 pmol/l at 30 s post glucose injection and from 97.6 ± 21.4 pmol/l to 74.6 ± 11.0 pmol/l at 60 s as the animals age from 50 to 300 days of age. Corresponding values in Sprague Dawley rats (SD) at 300 days of age were 74.6 ± 38.2 pmol/l and 110.7 ± 12.2 pmol/l. The values from BHE/Cdb rats were roughly 30 % less than those of the SD rats. Islets isolated from these rats release 65 % less insulin than islets from control rats of the same age when stimulated by the addition of glucose to the incubation medium. There was, however, only a small difference in islet insulin content (0.021 ± 0.002 pmol/g, 0.020 ± 0.009 pmol/g dry tissue, SD vs BHE/Cdb) at 50 days of age.The F o ATPase subunit 6 (also called subunit a) mutation [2] could account for the age related decline in ATP synthesis efficiency and subsequent alterations in glucose metabolism. A maternal mode of in- Diabetologia (1999) Summary As they age, BHE/Cdb rats develop impaired glucose tolerance. We hypothesized that this intolerance is associated with a previously reported base substitution in the mitochondrial genome. A new screening test was devised to identify animals with the mutation. These animals were bred to animals without the mutation. The progeny were then tested for the presence of the mutation and their glucose tolerance at 100 and 300 days of age. Phenotype and genotype were found to be closely linked and we conclude that the mutation in the mitochondrial ATPase 6 gene explains the age related impaired glucose tolerance in BHE/Cdb rats. [Diabetologia (1999) heritance of the Type II (non-insulin-dependent) diabetes mellitus trait was suspected based on breeding records. If the impaired glucose tolerance was due to the mitochondrial defect, both the impaired glucose tolerance and the DNA mutation should follow a maternal inheritance pattern. To test this hypothesis a cross breeding study of glucose tolerance and mt ATPase sequence was conducted using, as parents, animals with or witho...

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Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains

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mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes

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