Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that anti-diabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic alpha-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor-E2-related factor 2 (NRF2)-mediated antioxidant response via inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally-occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial-mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes.

Mitochondrial glycerol 3‐phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high‐fat diet [HFD] and db/db). Liver‐specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet‐induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA‐sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)‐related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)‐induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion–induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2‐bis (2‐aminophenoxy) ethane N,N,N´,N´‐tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin‐D (Cyp‐D) knockdown. mGPDH promoting Cyp‐D ubiquitination was also observed. Finally, liver‐specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp‐D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.