Emerging Role of Epitranscriptomics in Diabetes Mellitus and Its Complications.

Diabetes mellitus (DM) and its related complications are among the leading causes of disability and mortality worldwide. Substantial studies have explored epigenetic regulation that is involved in the modifications of DNA and proteins, but RNA modifications in diabetes are still poorly investigated. In recent years, posttranscriptional epigenetic modification of RNA (the so-called 'epitranscriptome') has emerged as an interesting field of research. Numerous modifications, mainly N6 -methyladenosine (m6A), have been identified in nearly all types of RNAs and have been demonstrated to have an indispensable effect in a variety of human diseases, such as cancer, obesity, and diabetes. Therefore, it is particularly important to understand the molecular basis of RNA modifications, which might provide a new perspective for the pathogenesis of diabetes mellitus and the discovery of new therapeutic targets. In this review, we aim to summarize the recent progress in the epitranscriptomics involved in diabetes and diabetes-related complications. We hope to provide some insights for enriching the understanding of the epitranscriptomic regulatory mechanisms of this disease as well as the development of novel therapeutic targets for future clinical benefit.

Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents.

Non-alcoholic fatty liver disease (NAFLD) has become the most common hepatic disease, while no drug was approved until now. The previous study reported that the quadruple FFA1/PPAR-α/γ/δ agonist RLA8 provided better efficacy than obeticholic acid on NASH. In the present study, two design strategies were introduced to explore better quadruple FFA1/PPAR-α/γ/δ agonists with improved metabolic stability. These efforts ultimately resulted in the identification of ZLY18, a quadruple FFA1/PPAR-α/γ/δ agonist with twice higher metabolic half-life than RLA8 in the liver microsome. In the triton-1339W-induced hyperlipidemic model, ZLY18 reversed hyperlipidemia to an almost normal level, which exhibited far stronger lipid-lowering effects than that of RLA8. Moreover, ZLY18 significantly decreased steatosis, hepatocellular ballooning, inflammation and liver fibrosis in NASH model even better than RLA8. Further mechanism studies suggested that ZLY18 exerts stronger effects than RLA8 on the regulation of the gene related to lipid synthesis, oxidative stress, inflammation and fibrosis. In addition, ZLY18 is more effective than pirfenidone in the prevention of CCl4-induced liver fibrosis. Besides, ZLY18 has an acceptable safety profile in the acute toxicity study at a high dose of 500 mg/kg. Therefore, ZLY18 represents a novel and highly promising quadruple FFA1/PPAR-α/γ/δ agonist worth of further investigation and development.

Association between neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and diabetic retinopathy among diabetic patients without a related family history.

BACKGROUND: Diabetic retinopathy (DR) is a specific neurovascular complication of diabetes mellitus (DM). Clinically, family history is a widely recognized risk factor for DR, assisting diagnosis and risk strata. However, among a great amount of DR patients without hereditary history like hypertension and diabetes, direct and simple risk factors to assist clinical decisions are still required. Herein, we intend to investigate the associated risk factors for these DR patients based on systemic inflammatory response indexes, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). METHODS: We consecutively enrolled 1030 patients with a definite diagnosis of type 2 diabetes mellitus (T2DM) from the endocrinology department of the Second hospital of People in Yun Nan. Based on funduscopy and family history checking, we excluded patients with a family history of hypertension and diabetes and finally enrolled 264 patients with DR and 206 patients with non-diabetic retinopathy (NDR). Through correlation analysis, univariate and multivariate regression, we further explore the association between NLR, PLR, and DR. On top of that, we investigate the effect of NLR and PLR on risk reclassification of DR. RESULTS: Compared with NDR patients, NLR and PLR levels are significantly higher among DR patients (NLR: 2.36 ± 1.16 in DR group versus 1.97 ± 1.06 in NDR group, p < 0.001; PLR: 11.62 ± 4.55 in DR group versus10.56 ± 4.45 in NDR group, p = 0.012). According to univariate analysis, NLR and PLR add risks to DR. After fully adjusting co-founders, NLR, as both continuous and categorical variate, remains an independent risk factor for DR (OR (95%CI): 1.37 (1.06, 1.78) P = 0.018). And though PLR was not independently associated with DR as a continuous variable (OR (95%CI) 1.05 (0.99, 1.11) p = 0.135), the highest quantile of PLR add two-fold increased risk (OR (95%CI) 2.20 (1.05, 4.59) p = 0.037) in the fully adjusted model for DR. In addition, addition of PLR and NLR to the established factor hemoglobin (Hb) improved the discriminability of the model and assisted the reclassification of DR. After combining PLR and NLR the Area under curve (AUC) of Hb based model raised from 0.76 to 0.78, with a category-free net reclassification improvement (NRI) of 0.532 (p < 0.001) and integrated discrimination improvement (IDI) of 0.029 (p < 0.001). CONCLUSIONS: Systemic inflammatory response indexes NLR and PLR were associated with the presence of DR among patients without associated family history and contributed to improvements in reclassification of DR in addition to Hb.

De Novo Mutation of m.3243A>G together with m.16093T>C Associated with Atypical Clinical Features in a Pedigree with MIDD Syndrome.

BACKGROUND: The syndrome of maternally inherited diabetes and deafness (MIDD) is typically caused by the m.3243A>G mutation and widely considered maternally inherited. In our study, we aimed to investigate the heredity way of the m.3243A>G among pedigrees with MIDD and discover novel mitochondrial DNA mutations related to atypical clinical phenotypes. METHODS: Heteroplasmy levels of the m.3243A>G mutation in peripheral blood, saliva, and urine sediment of 31 individuals from 10 unrelated pedigrees were measured by pyrosequencing. Clinical evaluations including endocrinological, audiological, and magnetic resonance imaging (MRI) examinations, mitochondrial function evaluation in peripheral blood mononuclear cells (PBMCs), and whole mitochondrial DNA (mtDNA) sequencing were performed among the spontaneous mutant pedigrees. RESULTS: Among the 10 unrelated MIDD pedigrees, we found that the de novo m.3243A>G mutation occurred in the family 1957 (F1957). The proband (F1957-II-1) and her son (F1957-III-1) both manifested diabetes with mild bilateral sensorineural hearing loss (SNHL) and abnormal brain MRI, and F1957-III-1 also complained of severe nausea and vomiting. Mitochondrial function evaluation in PBMCs revealed an increased level of ROS generation and decreased levels of ATP and mitochondrial membrane potential (ΔΨm) in the two m.3243A>G carriers. Whole mtDNA sequencing also revealed a de novo heteroplasmic substitution at m.16093T>C in both the proband and her son. CONCLUSIONS: Our study showed that de novo m.3243A>G mutation accompanied by other point mutations may occur in the very early embryonic or germ cell stage without maternal inheritance, bringing about both typical and atypical clinical features.

Fetal sex influences maternal fasting plasma glucose levels and basal ß-cell function in pregnant women with normal glucose tolerance.

AIMS: Fetal sex has recently emerged as a new factor that is related to maternal glucose homeostasis during pregnancy. The present study aimed to investigate the effect of fetal sex on maternal glucose metabolism in women with normal glucose tolerance (NGT) during pregnancy in the Chinese population. METHODS: A total of 877 pregnant women with NGT were recruited at 24-28 weeks of gestation and underwent a 75-g oral glucose tolerance test (OGTT). Pregnant women were divided into two groups according to fetal sex. Physical examinations and laboratory tests were performed. Pancreatic ß-cell function and insulin sensitivity were evaluated using OGTT-derived indices. RESULTS: Compared with women bearing female fetuses, women who delivered male fetuses had higher fasting plasma glucose (FPG) concentrations [4.5 (4.2-4.8) vs. 4.4 (4.2-4.7) mmol/L, P < 0.05], but lower HOMA-ß [161.9 (118.2-238.8) vs. 181.0 (131.7-260.9), P < 0.05] and Stumvoll first phase of insulin secretion [1230.2 (1077.9-1433.7) vs. 1290.9 (1134.0-1493.2), P < 0.05]. Multiple linear regression analysis indicated that the sex of the fetus was independently associated with maternal FPG and HOMA-ß. Further binary logistic regression analyses revealed that the presence of a male fetus was significantly associated with elevated FPG [odds ratio (OR) 1.50; 95% confidence interval (CI) 1.12-2.00; P = 0.006] and lower HOMA-ß (OR 0.70; 95% CI 0.52-0.94; P = 0.018) even after adjustment for potential confounders. CONCLUSIONS: This study provided evidence that maternal glucose metabolism could be affected by fetal sex even in NGT pregnant women. Our results suggest that the presence of male fetuses was independently associated with maternal elevated FPG and lower basal ß-cell function.

Rapid Detection of the mt3243A > G Mutation Using Urine Sediment in Elderly Chinese Type 2 Diabetic Patients.

OBJECTIVE: In this study, we aimed to identify mt3243A > G mutation carriers in a group of Chinese elderly type 2 diabetic patients by a rapid and noninvasive diagnostic system. METHODS: DNA was extracted from blood, saliva, and urine sediment samples. The mutation screening and quantitation of heteroplasmy were performed by high-resolution melting (HRM) curve and pyrosequencing, respectively. Patients with mt3243A > G mutation underwent a detailed audiometric, ophthalmologic, neurological, and cardiac examination. RESULTS: Two patients (2/1041) carrying the mt3243A > G mutation were detected among all type 2 diabetic patients. In patient 1, the heteroplasmy was 0.8%, 2.8%, and 14.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. In patient 2, the heteroplasmy was 5.3%, 8.4%, and 37.7% in peripheral blood leukocytes, saliva, and urine sediment, respectively. Both of the two patients showed hearing impairment. Abnormal ophthalmologic conditions and hyperintensity on T2-weighted magnetic resonance images were showed in patient 1. CONCLUSION: The occurrence of mt3243 A > G mutation was 0.2% in Chinese elderly type 2 diabetic patients. Moreover, detection of mt3243 A > G mutation in urine sediment with high-resolution melting (HRM) curve and pyrosequencing is feasible in molecular genetic diagnosis.

Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development.

INTRODUCTION: The alarming prevalence of type 2 diabetes mellitus (T2DM) stimulated the exploitation of new antidiabetic drugs with extended durability and enhanced safety. In this regard, the free fatty acid receptor 1 (FFA1) and FFA4 have emerged as attractive targets in the last decade. FFA1 has prominent advantages in promoting insulin and incretin secretion while FFA4 shows great potential in incretin secretion, insulin sensitization and anti-inflammatory effects. AREA COVERED: Herein, the authors focus specifically on FFA1 and FFA4 agonists in clinical trials and preclinical development. LY2922470, P11187 and SHR0534 are currently active in clinical trials while the CNX-011-67, SAR1, DS-1558 and BMS-986118 are in preclinical phase. The information for this review is retrieved from Integrity, Scifinder, Espacenet and clinicaltrials.gov databases. EXPERT OPINION: Current proof-of-concept in clinical trials suggests that FFA1 agonists have a significant improvement for T2DM without the risk of hypoglycemia. However, there are still several challenging problems including the mechanism of the receptor and the efficacy and safety of the ligands.