Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice

• Published in: Diabetologia 2005-01, Vol.48 (1), p.58-67
• Main Authors: SONE, H, KAGAWA, Y
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Area Under Curve; Biological and medical sciences; Blood Glucose - metabolism; Carbohydrates; Cell Division; Cell growth; Cellular Senescence - physiology; Cholesterol - blood; Diabetes; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Dietary Fats; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Acids, Nonesterified - blood; Glucose; Glucose Tolerance Test; Hyperglycemia; Hypotheses; Insulin - blood; Insulin resistance; Islets of Langerhans - pathology; Islets of Langerhans - physiopathology; Kinases; Laboratory animals; Male; Medical sciences; Mice; Mice, Inbred C57BL; Nutrition; Oxidative stress; Pathogenesis; Plasma; Proteins; Senescence
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-004-1605-2

During the pathogenesis of type 2 diabetes insulin resistance causes compensatory proliferation of beta cells. As beta cells have a limited replication potential, this compensatory proliferation might accelerate cellular senescence and lead to diabetes. We examined the cellular senescence of beta cells after proliferation during lipoglucotoxicity. Senescence-associated markers in beta cells were examined in nutrient-induced diabetic C57BL/6J mice that were fed a high-fat diet. After 4 and 12 months of the high-fat diet, intraperitoneal glucose tolerance tests (IPGTTs) and histochemical analyses of Ki-67, p38, senescence-associated beta-galactosidase, and beta cell mass were performed. At 4 months, the AUC for plasma insulin levels during the IPGTT (AUC(insulin)) was higher, beta cell mass was 3.1-fold greater, and the proliferation of beta cells was 2.2-fold higher than in the control group. However, at 12 months, AUC(insulin) declined, the frequency of Ki-67-positive beta cells decreased to one-third that of the control group, and the senescence-associated, beta-galactosidase-positive area increased to 4.7-fold that of the control group. Moreover, small amounts of p38, which is induced by oxidative stress and mediates cellular senescence, were found in beta cells from the high-fat diet group, but not in beta cells from the control group. Furthermore, the senescence-associated, beta-galactosidase-positive area in the high-fat diet group had a highly significant negative correlation with AUC(insulin) (r=-0.852, p