No abstract

The frequency of diabetes mellitus was compared in non-obese diabetic mice before and after inadvertent exposure of the colony to mouse hepatitis virus infection. Prior to exposure, diabetes prevalence and cumulative diabetes incidence in 7-month-old mice was 65% and 25% in females and males, respectively. Diabetes incidence/quarter revealed a seasonal pattern with peaks in winter. After mouse hepatitis exposure, the diabetes incidence in the colony decreased and testing for mouse hepatitis antibody in blood samples revealed a persistent infection. In the offspring of mice delivered by caesarean section, the diabetic incidence increased sharply from a nadir of 36% to 95% and from 9% to 65% in females and males, respectively. In individual mice, diabetes resistance was strongly correlated to high titres of mouse hepatitis virus antibody. The results of this inadvertent viral infection demonstrate that a diabetes-susceptible genotype is strongly modulated by environmental factors. Investigators studying this diabetes model should strive for specific pathogen-free colony status and a high incidence of diabetes before attempting to investigate therapeutic modalities.

Although insulin resistance is known to underlie type 2 diabetes, its role in the development of type 1 diabetes has been gaining increasing interest. In a model of type 1 diabetes, the nonobese diabetic (NOD) mouse, we found that insulin resistance driven by lipid- and glucose-independent mechanisms is already present in the liver of prediabetic mice. Hepatic insulin resistance is associated with a transient rise in mitochondrial respiration followed by increased production of lipid peroxides and c-Jun N-terminal kinase activity. At the onset of diabetes, increased adipose tissue lipolysis promotes myocellular diacylglycerol accumulation. This is paralleled by increased myocellular protein kinase C θ activity and serum fetuin A levels. Muscle mitochondrial oxidative capacity is unchanged at the onset but decreases at later stages of diabetes. In conclusion, hepatic and muscle insulin resistance manifest at different stages and involve distinct cellular mechanisms during the development of diabetes in the NOD mouse.