Downregulation of mTORC1 and Mcl-1 by lipid-oversupply contributes to islet β-cell apoptosis and dysfunction

Pancreatic fi-cell apoptosis is a key feature of diabetes and can be induced by chronic exposure to saturated fatty acids (FAs). However, the underlying mechanisms remain poorly understood. We presently evaluated the role of Mcl-1 and mTOR in mice fed with high-fat-diet (HFD) and fi-cells exposed to the overloaded palmitic acid (PA). Compared with normal-chow-diet (NCD)-fed mice, HFD group showed impaired glucose tolerance after two months. Along with the diabetes progression, pancreatic islets first became hypertrophic and then atrophic, the ratio of fi-cell:a-cell increased in the islets of four months HFD-fed mice while decreased after six months. This process was accompanied by significantly increased fi-cell apoptosis and AMPK activity, and decreased Mcl-1 expression and mTOR activity. Consistently, glucose-induced insulin secretion dropped. In terms of mecha-nism, PA with lipotoxic dose could activate AMPK, which in turn inhibited ERK-stimulated Mcl-1Thr163 phos-phorylation. Meanwhile, AMPK blocked Akt activity to release Akt inhibition on GSK3fi, followed by GSK3fi-initiated Mcl-1Ser159 phosphorylation. The context of Mcl-1 phosphorylation finally led to its degradation by ubiquitination. Also, AMPK inhibited the activity of mTORC1, resulting in a lower level of Mcl-1. Suppression of mTORC1 activity and Mcl-1 expression positively related to fi-cell failure. Alteration of Mcl-1 or mTOR expression rendered different tolerance of fi-cell to different dose of PA. In conclusion, lipid oversupply-induced dual modulation of mTORC1 and Mcl-1 finally led to fi-cell apoptosis and impaired insulin secretion. The study may help further understand the pathogenesis of fi-cell dysfunction in case of dyslipidemia, and provide promising therapeutic targets for diabetes.

Automated summary

Pancreatic fi-cell apoptosis is a key feature of diabetes and can be induced by chronic exposure to saturated fatty acids. This study evaluated the role of Mcl-1 and mTOR in high-fat-diet-induced diabetes in mice and palmitic acid-exposed fi-cells. The results showed that the dysregulation of Mcl-1 and mTOR led to fi-cell apoptosis and impaired insulin secretion, providing potential therapeutic targets for diabetes.