Abstract
BackgroundPalmitate is a potent inducer of endoplasmic reticulum (ER) stress in β-cells. In type 2 diabetes, glucose amplifies fatty-acid toxicity for pancreatic β-cells, leading to β-cell dysfunction and death. Why glucose exacerbates β-cell lipotoxicity is largely unknown. Glucose stimulates mTORC1, an important nutrient sensor involved in the regulation of cellular stress. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased β-cell ER stress.Principal FindingsWe found that glucose amplifies palmitate-induced ER stress by increasing IRE1α protein levels and activating the JNK pathway, leading to increased β-cell apoptosis. Moreover, glucose increased mTORC1 activity and its inhibition by rapamycin decreased β-cell apoptosis under conditions of glucolipotoxicity. Inhibition of mTORC1 by rapamycin did not affect proinsulin and total protein synthesis in β-cells incubated at high glucose with palmitate. However, it decreased IRE1α expression and signaling and inhibited JNK pathway activation. In TSC2-deficient mouse embryonic fibroblasts, in which mTORC1 is constitutively active, mTORC1 regulated the stimulation of JNK by ER stressors, but not in response to anisomycin, which activates JNK independent of ER stress. Finally, we found that JNK inhibition decreased β-cell apoptosis under conditions of glucolipotoxicity.Conclusions/SignificanceCollectively, our findings suggest that mTORC1 mediates glucose amplification of lipotoxicity, acting through activation of ER stress and JNK. Thus, mTORC1 is an important transducer of ER stress in β-cell glucolipotoxicity. Moreover, in stressed β-cells mTORC1 inhibition decreases IRE1α protein expression and JNK activity without affecting ER protein load, suggesting that mTORC1 regulates the β-cell stress response to glucose and fatty acids by modulating the synthesis and activity of specific proteins involved in the execution of the ER stress response. This novel paradigm may have important implications for understanding β-cell failure in type 2 diabetes.
Highlights
In type 2 diabetes mellitus (T2DM), elevated blood glucose and free-fatty acids (FFAs) induce b-cell dysfunction and apoptosis leading to exacerbation and progression of diabetes, a process called glucolipotoxicity [1]
Consistent with the antiapoptotic effect of rapamycin in b-cells exposed to glucolipotoxicity conditions, we found that rapamycin attenuated caspase 3 cleavage in INS-1E cells incubated at 22.2 mmol/l glucose with palmitate (Figure 1B)
The main findings of this study are that: 1. glucose amplifies fatty acid-induced endoplasmic reticulum (ER) stress and apoptosis in b-cells; and 2. mammalian target of rapamycin complex 1 (mTORC1) regulates the ER stress response under conditions of glucolipotoxicity through modulation of the IRE1a-Jun N-terminal kinase (JNK) pathway without affecting global protein or proinsulin biosynthesis
Summary
In type 2 diabetes mellitus (T2DM), elevated blood glucose and free-fatty acids (FFAs) induce b-cell dysfunction and apoptosis leading to exacerbation and progression of diabetes, a process called glucolipotoxicity [1]. There is ample evidence that palmitate induces b-cell dysfunction and apoptosis via activation of ER stress [8,9,10,11], probably due to alteration of b-cell calcium fluxes and downregulation of carboxypeptidase E [12], which perturbs the folding and maturation of secreted and membrane-bound proteins in the ER This activates a complex signaling network called the unfolded protein response (UPR) aimed at adaptation and restoration of normal ER function, pursued by translation attenuation, degradation of misfolded proteins and increased protein folding capacity through augmented transcription of ER chaperones, such as BIP. Our study tested the hypothesis that glucose augments lipotoxicity by stimulating mTORC1 leading to increased b-cell ER stress
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