miR-146a promotes M2 macrophage polarization and accelerates diabetic wound healing by inhibiting the TLR4/NF-κB axis.

We tried to unveil the clinical significance of miR-146a as a biomarker in M2 macrophage polarization in diabetic wound healing. Initially, we found reduced miR-146a in macrophages of diabetic patients. Next, dual-luciferase assay verified that toll-like receptor 4 (TLR4) was a target gene of miR-146 and was negatively regulated by miR-146. Moreover, after ectopic expression and depletion experiments of miR-146 and/or TLR4, lipopolysaccharide-induced inflammatory response of macrophages was detected. The results revealed that overexpression of miR-146a promoted the M2 macrophage polarization by suppressing the TLR4/nuclear factor-kappaB (NF-κB) axis, so as to enhance wound healing in diabetic ulcers. Further, mouse models with diabetic ulcers were established to investigate the effects of miR-146a on diabetic wound healing in vivo, which revealed that miR-146a promoted wound healing in diabetic ulcers by inhibiting the TLR4/NF-κB axis. In conclusion, we demonstrate that miR-146a can induce M2 macrophage polarization to enhance wound healing in diabetic ulcers by inhibiting the TLR4/NF-κB axis.

Vitamin D and iodine status was associated with the risk and complication of type 2 diabetes mellitus in China.

The purpose of this study was to assess the relationship between 25-hydroxyvitamin D (25(OH)D), urinary iodine concentration (UIC), and type 2 diabetes mellitus (T2DM) risk and complications and to establish a model to predict T2DM in the general population. A total of 567 adults (389 T2DM patients and 178 controls) were enrolled, and the levels of 25(OH)D, iodine, and blood biochemical parameters were measured. Pearson's correlation analysis showed an inverse correlation between 25(OH)D level, UIC, and T2DM risk. Low 25(OH)D level was a risk factor for developing T2DM (OR, 0.81; 95% CI, 1.90-2.63; P = 0.043) after adjustment for multiple risk factors. 25(OH)D level and UIC were inversely correlated with short-term and long-term glucose levels. 25(OH)D deficiency was also associated with a high incidence of T2DM complicated with thyroid dysfunction. A prediction model based on 25(OH)D, iodine status, and other risk factors was established and recommended to screen high-risk T2DM in the general population and provide early screening and timely treatment for them.

MiR-27a promotes insulin resistance and mediates glucose metabolism by targeting PPAR-γ-mediated PI3K/AKT signaling.

This study aimed to establish a high-fat diet (HFD)-fed obese mouse model and a cell culture model of insulin resistance (IR) in mature 3T3-L1 adipocytes. A dual-luciferase reporter assay (DLRA) was confirmed interaction between miR-27a and the 3'-untranslated region (UTR) of Peroxisome proliferator-activated receptor (PPAR)-γ. The inhibition of PPAR-γ expression by microRNA (miR)-27a in IR cells at both the protein and mRNA levels was confirmed by a mechanistic investigation. Moreover, the 3'-UTR of PPAR-γ was found to be a direct target of miR-27a, based on the DLRA. Furthermore, antagomiR-27a upregulated the activation of PI3K/Akt signaling and glucose transporter type 4 (GLUT4) expression at the protein and mRNA levels. Additionally, the PPAR inhibitor T0070907 repressed the insulin sensitivity upregulated by antagomiR-27a, which was accompanied by the inhibition of PPAR-γ expression and increased levels of AKT phosphorylation and GLUT4. The PI3K inhibitor wortmannin reduced miR-27a-induced increases in AKT phosphorylation, glucose uptake, and GLUT4. miR-27a is considered to be involved in the PPAR-γ-PI3K/AKT-GLUT4 signaling axis, thus leading to increased glucose uptake and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. Therefore, miR-27a is a novel target for the treatment of IR in obesity and diabetes.

Anti-PD-1 pembrolizumab induced autoimmune diabetes in Chinese patient: A case report.

RATIONALE: Programmed cell death-1 protein (PD-1) antibody is an immune-checkpoint inhibitor that triggers anti-tumor response by enhancing immune response. Although PD-1 antibody has been reported effective in some malignant tumor, it can also induce significant immune-related adverse events (irAEs) such as autoimmune diabetes. PATIENT CONCERNS: A 67-year-old male patient with non-small cell lung cancer (NSCLS) presented with polydipsia, polyuria, weakness, and weight loss after use of anti-programmed cell death-1 antibody therapy. Hyperglycemia, high serum ketone, low bicarbonate and high anion gap were compatible with the criteria of diabetic ketoacidosis (DKA). DIAGNOSES: Autoimmune diabetes and diabetic ketoacidosis (DKA). The presence of low serum titers of c-peptide, high blood glucose together with diabetic ketoacidosis (DKA) that occurs shortly after the use of pembrolizumab strongly supported the diagnosis of anti-PD-1 induced autoimmune diabetes. INTERVENTIONS: The patient stopped using pembrolizumab while continuous subcutaneous insulin infusion (CSII) was started at the same time. The insulin infusion was switched to multiple daily injection (MDI) after he was discharged from hospital. OUTCOMES: The patient is now a well-controlled insulin-dependent patient with palliative care of NSCLS. LESSONS: Autoimmune diabetes induced by anti-programmed cell death-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) therapy is a rare, but life threatening immune-related side effect. Physicians should closely monitor diabetes-related indexes of patients who have been undergoing the treatment of anti-PD-1/PD-L1 therapy.

Reduced Serum Levels of Brain-Derived Neurotrophic Factor Are Related to Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is involved in obesity, type 2 diabetes mellitus (T2DM), and cognitive dysfunction. The present study sought to assess the role of serum levels of BDNF in the pathophysiological process of mild cognitive impairment (MCI), a preclinical phase of dementia in 715 Chinese patients with T2DM. METHODS: Cross-sectional data were obtained from 715 patients with T2DM recruited from a Chinese diabetes center. Serum levels of BDNF were measured with sandwich enzyme-linked immunosorbent assay. The influence of BDNF on MCI was examined using univariate and multivariate binary logistic regression analyses. RESULTS: In univariate and multivariate logistic regression analyses, for each one-unit increase of BDNF, the unadjusted and adjusted risk of MCI decreased by 9% (OR 0.91; 95% CI 0.88-0.93, p < 0.001) and 6% (0.94; 0.87-0.98, p < 0.001) respectively. In multivariate models comparing the first (Q1), second and third quartiles against the fourth quartile of BDNF, BDNF in Q1 and Q2 were associated with MCI, and increased risk of MCI by 275% (OR 3.75; 95% CI 2.38-6.03) and 155% (2.55; 1.32-4.02). These results suggested that for each 1 ng/mL increase of serum level of BDNF, the association became stronger among obese diabetic patients (OR 0.91, 95% CI 0.85-0.96; p < 0.001) versus nonobese diabetic patients (OR 0.95, 95% CI 0.86-0.98; p = 0.001). CONCLUSION: The present data demonstrated that reduced serum levels of BDNF were associated with increased risk of MCI and might be useful for identifying diabetic patients at risk of dementia for early prevention strategies.