H Sone1, Y Kagawa. 1. High Technology Research Centre, Kagawa Nutrition University, 3-9-21 Chiyoda, Sakado, 350-0288, Japan.
Abstract
AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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.
Authors: H Kaneto; J Fujii; T Myint; N Miyazawa; K N Islam; Y Kawasaki; K Suzuki; M Nakamura; H Tatsumi; Y Yamasaki; N Taniguchi Journal: Biochem J Date: 1996-12-15 Impact factor: 3.857
Authors: Kathrin Maedler; Adriano Fontana; Frédéric Ris; Pavel Sergeev; Christian Toso; José Oberholzer; Roger Lehmann; Felix Bachmann; Andrea Tasinato; Giatgen A Spinas; Philippe A Halban; Marc Y Donath Journal: Proc Natl Acad Sci U S A Date: 2002-06-11 Impact factor: 11.205
Authors: Stephan C Collins; Michael B Hoppa; Jonathan N Walker; Stefan Amisten; Fernando Abdulkader; Martin Bengtsson; Jane Fearnside; Reshma Ramracheya; Ayo A Toye; Quan Zhang; Anne Clark; Dominique Gauguier; Patrik Rorsman Journal: Diabetes Date: 2010-02-11 Impact factor: 9.461
Authors: João F Passos; Glyn Nelson; Chunfang Wang; Torsten Richter; Cedric Simillion; Carole J Proctor; Satomi Miwa; Sharon Olijslagers; Jennifer Hallinan; Anil Wipat; Gabriele Saretzki; Karl Lenhard Rudolph; Tom B L Kirkwood; Thomas von Zglinicki Journal: Mol Syst Biol Date: 2010-02-16 Impact factor: 11.429