4．糖代謝関連臓器と加齢：モデル動物

Abstract

The incidence of type 2 diabetes and metabolic diseases increases with age. Clarification of the underlying mechanisms in age-dependent worsening of such metabolic disorders is crucial for developing more effective strategies for prevention and treatment. However, due to limitations in studying aging-related changes, especially at the tissue level in humans, investigations with adequate animal models are important. Therefore, we investigated 2 inbred lines of mouse, the Nagoya-Shibata-Yasuda (NSY) mouse and the Fatty Liver Shionogi (FLS) mouse. By analyzing NSY mice, which spontaneously develop type 2 diabetes mellitus through impaired insulin secretion and insulin resistance in an age dependent manner, we demonstrated that environmental factors, including infant nutritional condition, modified aging-related metabolic changes, and the effect of genetic components on glucose metabolism, vary according to age. In FLS mice which developed non-alcoholic steatohepatitis with normal feed, accumulation of hepatic lipids caused by reduced VLDL secretion progressed to hepatic inflammation and fibrosis, which was ameliorated by vector-induced hepatic expression of microsomal triglyceride transfer protein, a key molecule for VLDL secretion. In addition, the glucose intolerance of this mouse exhibited 2 different phases: age-related deterioration due to worsening of insulin sensitivity up to 6 months, followed by time-dependent amelioration owing to increased capacity of insulin secretion and β-cell mass thereafter, suggesting slow adaptive β-cell expansion in this model. These results indicate that age-related metabolic changes are an integral part of multiple organ dysfunctions, each of which has a different period of worsening, and which collectively leads to disease.