Ferroptosis is a novel form of nonapoptotic regulated cell death (RCD). It features iron-dependent lipid peroxide accumulation accompanied by inadequate redox enzymes, especially glutathione peroxidase 4 (GPX4). RAS-selective lethal 3 (RSL3), erastin, and ferroptosis inducing 56 (FIN56) induce ferroptosis via different manners targeting GPX4 function. Acyl-CoA synthetase long-chain family 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenases (LOXs) participate in the production of lipid peroxides. Heat shock protein family B member 1 (HSPB1) and nuclear receptor coactivator 4 (NCOA4) regulate iron homeostasis preventing ferroptosis caused by the high concentration of intracellular iron. Ferroptosis is ubiquitous in our body as it exists in both physiologic and pathogenic processes. It is involved in glucose-stimulated insulin secretion (GSIS) impairment and arsenic-induced pancreatic damage in the pathogenesis of diabetes. Moreover, iron and the iron-sulfur (Fe-S) cluster influence each other, causing mitochondrial iron accumulation, more reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, failure in biosynthesis of insulin, and ferroptosis in β-cells. In addition, ferroptosis also engages in the pathogenesis of diabetic complications such as myocardial ischemia and diabetic cardiomyopathy (DCM). In this review, we summarize the mechanism of ferroptosis and especially its association with type 2 diabetes mellitus (T2DM).

Circular RNA (circRNA) is involved in the pathological processes of various diseases. CircRNA is more stable than linear RNAs and is expressed in high levels in tissues, making it a better biomarker candidate than linear RNAs. In this study, we aimed to identify potential circRNA biomarkers of gestational diabetes mellitus (GDM). A retrospective case–control study was conducted using data and samples from women treated at a hospital in China between July 10, 2017, and February 15, 2018. We collected serum samples from 40 healthy pregnant women (controls) and 40 women with GDM (cases) during the second trimester as well as 65 controls and 65 cases during the third trimester of pregnancy. Placenta tissues and neonatal cord blood were each from another 20 cases and 20 controls. We selected six circRNAs (hsa_circRNA_0054633, hsa_circRNA_103410, hsa_circRNA_063981, hsa_circRNA_102682, hsa_circRNA_0018508, and hsa_circRNA_406918) as candidate biomarkers and used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to measure their concentrations in the serum and placental tissues. The Pearson correlation test was used to assess the correlation between various circRNAs and between circRNA and clinical variables. The area under the receiver operating characteristic (ROC) curve was used to assess the diagnostic value of circRNAs for GDM at each stage. Hsa_circRNA_0054633 was highly expressed in the blood during the second and third trimesters; its expression was also high in the placenta but low in the cord blood (P < 0.05). Hsa_cirRNA_0054633 was highly correlated with GHBA1 and GHBA1c levels in maternal blood samples at various stages of the GDM group (including placental tissue and umbilical cord blood) (P < 0.05). Hsa_circRNA_063981, hsa_circRNA_102682, and hsa_circRNA_103410 were also differentially expressed between the case and control groups at different stages (P < 0.05). There was a strong correlation between hsa_circRNA_0054633 and hsa_circRNA_103410 levels in third-trimester maternal blood (P = 0.000, r = 0.554) and in neonatal umbilical cord blood (P = 0.000, r = 0.866). Hsa_circRNA_0054633 showed a significant diagnostic value in the second and third trimesters of pregnancy, placenta, and cord blood (AUC = 0.793, 0.664, 0.747, and 0.783, respectively, P < 0.001). This study suggests that hsa_cirRNA_0054633 is abnormally expressed in GDM patients and may play a potential role in the development of GDM. The possibility of using circRNAs for the diagnosis of GDM requires additional investigation in future studies.

Some recent studies have suggested that the use of dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with cancer development. However, some other studies suggest no such association. The aim of the present study was to evaluate the effect of DPP4i on the risk of developing cancers. The electronic databases PubMed, Medline, EMBASE, Web of Science and Cochrane Library and the clinical trial registry were searched for published and unpublished randomized clinical trials on humans. Eligible studies were RCTs conducted in patients with type 2 diabetes mellitus, comparing DPP4i with a placebo or other active drugs. A total of 72 trials with 35,768 and 33,319 patients enrolled for DPP4i and the comparison drugs, respectively. Overall, no significant associations were detected between the use of DPP4i and cancer development, in comparison with the use of other active drugs or placebo. The results were consistent across pre-defined subgroups stratified by type of DPP4i, type of cancer, drug for comparison, trial duration, or baseline characteristics. The results of this meta-analysis suggest that patients with type 2 diabetes treated with DPP4i do not have a higher risk of developing cancers than patients treated with a placebo or other drugs.

Pancreatic β‑cells are the only source of insulin in humans. Mitochondria uses pyruvate to produce ATP as an intermediate link between glucose intake and insulin secretion in β‑cells, in a process known as glucose‑stimulated insulin secretion (GSIS). Previous studies have demonstrated that GSIS is negatively regulated by various factors in the mitochondria, including tRNA^Leu mutations, high p58 expression, reduced nicotinamide nucleotide transhydrogenase activity, abnormal levels of uncoupling proteins and reduced expression levels of transcription factors A, B1 and B2. Additionally, oxidative stress damages mitochondria and impairs antioxidant defense mechanisms, leading to the increased production of reactive oxygen species, which induces β‑cell dysfunction. Inflammation in islets can also damage β‑cell physiology. Inflammatory cytokines trigger the release of cytochrome c from the mitochondria via the NF‑κB pathway. The present review examined the potential factors underlying mitochondrial dysfunction and their association with islet β‑cell failure, which may offer novel insights regarding future strategies for the preservation of mitochondrial function and enhancement of antioxidant activity for individuals with diabetes mellitus.

Adipogenesis is orchestrated by a highly ordered network of transcription factors including peroxisome-proliferator activated receptor-gamma (PPARγ) and CCAAT-enhancer binding protein (C/EBP) family proteins. High mobility group protein AT-hook 2 (HMGA2), an architectural transcription factor, has been reported to play an essential role in preadipocyte proliferation, and its overexpression has been implicated in obesity in mice and humans. However, the direct role of HMGA2 in regulating the gene expression program during adipogenesis is not known. Here, we demonstrate that HMGA2 is required for C/EBPβ-mediated expression of PPARγ, and thus promotes adipogenic differentiation. We observed a transient but marked increase of Hmga2 transcript at an early phase of differentiation of mouse 3T3-L1 preadipocytes. Importantly, Hmga2 knockdown greatly impaired adipocyte formation, while its overexpression promoted the formation of mature adipocytes. We found that HMGA2 colocalized with C/EBPβ in the nucleus and was required for the recruitment of C/EBPβ to its binding element at the Pparγ2 promoter. Accordingly, HMGA2 and C/EBPβ cooperatively enhanced the Pparγ2 promoter activity. Our results indicate that HMGA2 is an essential constituent of the adipogenic transcription factor network, and thus its function may be affected during the course of obesity.