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


METHODS
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.


RESULTS
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<0.01).


CONCLUSIONS
Beta cell senescence occurred in diet-induced type 2 diabetes and led to insufficient insulin release. These findings suggest that cellular senescence contributes to the pathogenesis of diet-induced diabetes.
Sone
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High Technology Research Centre, Kagawa Nutrition University, 3-9-21 Chiyoda, Sakado, 350-0288, Japan.
Kagawa
Y
Y
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division; D016922:Cellular Senescence / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000503:physiopathology*; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D001786:Blood Glucose; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D002784:Cholesterol