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

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-galactosidasepositive 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.

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…This latter study, together with other more recent reports (Hancock et al , 2011; Lanza et al , 2012; Price et al , 2012), has questioned early associations between CR and enhanced mitochondrial content (Nisoli et al , 2005). Furthermore, despite evidence suggesting that increased mitochondrial abundance can be an advantageous adaptive response to energy deficit, genetically induced mitochondrial biogenesis has been associated with age‐related diseases such as cardiomyopathy (Lehman et al , 2000), renal fibrosis (Hickey et al , 2011) and diabetes (Sawada et al , 2014), all of which have been associated with cellular senescence (Chimenti et al , 2003; Sone & Kagawa, 2005; Ning et al , 2013). …”

Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion

“…The C57Bl/6 mouse strain is notoriously susceptible to these effects, exhibiting a 2 . 2-fold increase in b-cell mass and proliferation after 4 months on a high-fat diet versus a control diet (Sone & Kagawa 2005). However, these mice eventually become diabetic and lose their b-cell mass due to increased b-cell apoptosis and reduced b-cell proliferation.…”

BAD: undertaker by night, candyman by day

“…During weight gain associated with obesity, apoptosis influences b-cell mass dynamics. Along with increased proliferation and b-cell hypertrophy, attenuated apoptosis contributes to obesity-induced b-cell mass expansion (Pick et al, 1998;Lupi et al, 2002;Sone and Kagawa, 2005). Genetic models are just beginning to uncover the functional relevance of the intrinsic and extrinsic pathways of apoptosis in b-cell mass adaptation under these settings (Jetton et al, 2005;Liadis et al, 2007;Danial et al, 2008).…”