Mitochondria-associated ER membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca²⁺ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca²⁺ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4) interacts with and stabilizes IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca²⁺ accumulation, mitochondrial dysfunction and ER stress. Furthermore, Pdk4^-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

Objective: This study sought to investigate whether the metabolically healthy obese (MHO) phenotype is associated with an increased risk of incident type 2 diabetes in a Korean population and, if so, whether systemic inflammation affects this risk in MHO individuals. Design and Methods: The study population comprised 36 135 Koreans without type 2 diabetes. Participants were stratified by body mass index (cutoff value, 25.0 kg/m²) and metabolic health state (assessed using Adult Treatment Panel-III criteria). High-sensitive C-reactive protein (hsCRP) was used as a surrogate marker of systemic inflammation. Subjects were classified into low (ie, hsCRP < 0.5 mg/L) and high (ie, hsCRP ≥ 0.5 mg/L) systemic inflammation groups. Results: During a median followup of 36.5 months (range, 4.8–81.7 mo), 635 of the 36 135 individuals (1.8%) developed type 2 diabetes. The MHO group had a significantly higher risk of incident type 2 diabetes (multivariate-adjusted hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16–2.11) than the metabolically healthy nonobese (MHNO) group. However, the risk of the MHO group varied according to the degree of systemic inflammation. Compared with the MHNO/low systemic inflammation group, the risk of type 2 diabetes in the MHO/low systemic inflammation group was not significantly elevated (multivariate-adjusted HR, 1.61; 95% CI, 0.77–3.34). However, the MHO/high systemic inflammation group had an elevated risk of incident type 2 diabetes (multivariate-adjusted HR, 3.73; 95% CI 2.36–5.88). Conclusions: MHO subjects show a substantially higher risk of incident type 2 diabetes than MHNO subjects. The level of systemic inflammation partially explains this increased risk.

Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.