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    • br Introduction Type diabetes T D affects million

    2018-11-13


    Introduction Type 2 diabetes (T2D) affects 380 million individuals worldwide, and its prevalence will further increase in the coming decades with the obesity epidemic (IDF Diabetes Atlas, 2013). T2D is characterized by progressive loss of pancreatic β cell function and insulinopenia, and by non-suppressed post-prandial glucagon secretion by pancreatic α abiraterone acetate (D\'Alessio, 2011). β cell failure is associated with β cell apoptosis and a progressive decrease in β cell mass (Butler et al., 2003; Rahier et al., 2008). β cell death is probably secondary to metabolic stress mediated by high levels of saturated free fatty acids (FFAs) and glucose (Poitout and Robertson, 2008). Possible mechanisms of metabolic stress-induced β cell apoptosis in T2D include endoplasmic reticulum (ER) stress (Kharroubi et al., 2004), oxidative stress (Carlsson et al., 1999) and ceramide production (Shimabukuro et al., 1998), and this culminates in activation of the intrinsic or mitochondrial pathway of apoptosis (Cunha et al., 2012; Gurzov and Eizirik, 2011). A high-fat and high-sugar diet decreases β cell mass but increases α cell mass in nonhuman primates (Fiori et al., 2013). Recent evidence obtained in mice, monkeys and humans suggests that β cells may dedifferentiate and adopt α cell characteristics (Fiori et al., 2013; Gao et al., 2014; Talchai et al., 2012; White et al., 2013), putatively contributing to the decreased insulin production and increased glucagon secretion in T2D. α Cell dysfunction and hyperglucagonemia is induced by postprandial lipemia in healthy subjects and by treating mouse islets with triglyceride-rich lipoproteins (Niederwanger et al., 2014). Pancreatic α and β cells have similar embryonic origins (Teitelman et al., 1993), and are equally exposed to metabolic stress during the evolution of T2D, but it remains unclear whether metabolic stress affects α cell survival. Here we examined the presence of apoptosis and ER stress in α and β cells of T2D individuals and in human islets exposed to palmitate. Both cell types show signs of ER stress, but only β cells progress to apoptosis. To clarify the mechanisms involved, we developed a method to fluorescence-activated cell sorting (FACS)-isolate pure (>90%) and viable (>90%) rat α cells. In keeping with the human islet data, palmitate induced ER stress in α and β cells, but apoptosis was only present in β cells. This α cell resistance to lipotoxicity is due to higher anti-apoptotic protein expression.
    Materials and Methods
    Results
    Discussion The molecular mechanisms that lead to increased glucagon and decreased insulin levels in T2D remain to be clarified. β Cell failure is, at least in part, related to progressive β cell loss (Butler et al., 2003; Mizukami et al., 2014; Rahier et al., 2008). It is unclear whether α cell viability is affected by the long-term metabolic stress inherent to the disease. We presently observed increased β but not α cell apoptosis in islets from T2D patients. Both α and β cells from T2D patients presented an increased ER area, a phenomenon previously shown by us (Marchetti et al., 2007) to be part of the UPR (Marciniak and Ron, 2006). These findings indicate that both α and β cells face chronic ER stress, but while α cells adapt and even increase hormone production, β cells fail and eventually undergo apoptosis. This is supported by observations in genetically modified mice. α Cell-specific Xbp1 deletion increases ER stress without affecting α cell survival, but Xbp1-deficient α cells cannot suppress glucagon secretion after glucose stimulation (Akiyama et al., 2013). In contrast, β cell-specific Xbp1 deletion impairs glucose-stimulated insulin secretion and leads to β cell loss (Lee et al., 2011). The α cell resistance to apoptosis was reproduced when human islets or FACS-purified rat α and β cells were exposed in vitro to palmitate, the most common circulating saturated FFA that is thought to contribute to β cell failure and T2D (Forouhi et al., 2014; Paolisso et al., 1995): in both cases, palmitate activated the UPR, but only β cells underwent apoptosis, indicating that α cells are well equipped to survive metabolic ER stress. These differences in palmitate-induced apoptosis between α and β cells were confirmed at three different glucose concentrations, i.e. 6.1mM, 10mM and 20mM. Marked eIF2α phosphorylation was shown in α cells of high fat diet-induced or genetically obese mice (Engin et al., 2014); in β cells, hyperactivation of this branch of the UPR is particularly cytotoxic (Cnop et al., 2007). This phenomenon is not part of a broad and non-specific resistance of α cells to apoptosis, since these cells showed similar susceptibility as β cells to apoptosis triggered by chemical ER stressors.