Vitamin A influences the incretin hormone profiles by activating the retinoic acid receptor ß.

BACKGROUND: This study aimed to investigate the impact of Vitamin A (VA) on intestinal glucose metabolic phenotypes. METHODS: Male C57BL/6 mice were randomized assigned to a VA-normal diet (VAN) or a VA-deficient diet (VAD) for 12 weeks. After12 weeks, the VAD mice were given 30 IU/g/d retinol for 10 days and VAN diet (VADN) for 10 weeks. By using glucose tolerance tests, immunofluorescence staining, quantitative polymerase chain reaction, siRNA transduction, and enzyme-linked immunosorbent assay, the glucose metabolic phenotypes as well as secretory function and intracellular hormone changes of STC-1 were assessed. RESULTS: VAD mice showed a decrease of glucose-stimulated insulin secretion and a loss of intestinal glucagon-like peptide-1 (GLP-1) expression. Through reintroducing dietary VA to VAD mice, the intestinal VA levels, GLP-1 expression and normal glucose can be restored. The incubation with retinol increased VA signaling factors expression within STC-1 cells, especially retinoic acid receptor ß (RARß). The activation of RARß restored intracellular incretin hormone synthesis and secretory function. CONCLUSIONS: VA deficiency leads to an imbalance of intestinal glucose metabolic phenotypes through a mechanism involving RARß signaling pathway, suggesting a new method to achieve the treatment for VAD induced glucose metabolism impairment.

Association Between Serum Zinc and Non-Alcoholic Fatty Liver Disease and Advanced Liver Fibrosis: NHANES 2011-2016.

Limited and inconclusive evidence exists regarding the correlation between serum zinc levels and non-alcoholic fatty liver disease (NAFLD) and advanced fibrosis. The objective of this cross-sectional study was to investigate the association between serum zinc concentration and both NAFLD and advanced liver fibrosis among the United States (US) adults. 3398 subjects from National Health and Nutrition Examination Survey (NHANES) 2011-2016 were included. Serum zinc concentration was measured by inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). NAFLD was diagnosed with Hepatic Steatosis Index (HSI), and advanced fibrosis risk was assessed by NAFLD Fibrosis Score (NFS). Weighted logistic regression and restricted cubic splines (RCS) were used to examine the association between serum zinc concentration and NAFLD and advanced fibrosis. Linear trend tests were conducted by incorporating the median of serum zinc quartiles as a continuous variable in the models. We employed sensitivity analysis and subgroup analysis to enhance the robustness of our results. The results from the RCS regression revealed no evident nonlinear relationship between serum zinc concentration and the presence of NAFLD and advanced fibrosis (p-nonlinear > 0.05). Compared with those in the lowest quartile (Q1) of serum zinc concentrations, the odds ratios (95% confidence intervals) of NAFLD were 1.49 (0.89,2.49) in Q2, 0.99 (0.68,1.45) in Q3, and 2.00 (1.40,2.86) in Q4 (p-trend = 0.002). Similarly, the odds ratios (95% confidence intervals) for advanced fibrosis in Q2-4 compared to Q1 were 0.86 (0.50,1.47), 0.60 (0.26,1.39), and 0.41 (0.21,0.77), respectively (p-trend = 0.006). Subgroup analyses and sensitivity analyses reinforce the same conclusion. The investigation revealed a positive linear relationship between serum zinc concentrations and the probability of developing NAFLD. Conversely, an inverse correlation was observed between serum zinc concentrations and the incidence of advanced liver fibrosis among individuals diagnosed with NAFLD.

Associations between Vitamin D Levels and Insulin Resistance in Non-Diabetic Obesity: Results from NHANES 2001-2018.

OBJECTIVE: Obesity is often accompanied by insulin resistance (IR) and diabetes. We explored the association between vitamin D levels and IR in non-diabetic obesity. METHODS: We conducted a cross-sectional study based on the data of National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018. Non-diabetic individuals (aged ≥20 years) with obesity (BMI ≥ 30kg/m2) were included in the study. And HOMA-IR ≥ 2.5 was defined as IR. The multivariable linear regression models were constructed to evaluate the associations between levels of 25(OH)D and HOMA-IR. We calculated the odds ratio (OR) and 95% confidential intervals (CIs) for associations between 25(OH)D deficiency and IR in obesity using multivariable logistic regression models. RESULTS: Overall, a total of 3887 individuals were included in this study. Serum vitamin D level was significant lower in obesity participants with IR than that of non-IRs. The linear regression models showed that vitamin D level was inversely associated with HOMA-IR in obesity after adjusting for covariables (ß=-0.15, 95%CI (-0.28, -0.02), p = 0.028). And the multivariable logistic regression models indicated an association between vitamin D deficiency and IR in obesity ((OR= 1.38, 95%CI (1.09-1.73), p = 0.007)). The further stratified regression analyses among different BMI demonstrated that vitamin D deficiency (OR = 1.4, 95%CI (1.05,1.86), p = 0.022) only contributed to developing IR in class I obesity. CONCLUSION: This study suggested an association of vitamin D levels with IR in obesity. And vitamin D deficiency contributed to IR in class I obesity.

Diabetes Pharmacotherapy and its effects on the Skeletal Muscle Energy Metabolism.

The disorders of skeletal muscle metabolism in patients with Type 2 diabetes mellitus (T2DM), such as mitochondrial defection and glucose transporters (GLUTs) translocation dysfunctions, are not uncommon. Therefore, when anti-diabetic drugs were used in various chronic diseases associated with hyperglycemia, the impact on skeletal muscle should not be ignored. However, current studies mainly focus on muscle mass rather than metabolism or functions. Anti-diabetic drugs might have a harmful or beneficial impact on skeletal muscle. In this review, we summarize the upto- date studies on the effects of anti-diabetic drugs and some natural compounds on skeletal muscle metabolism, focusing primarily on emerging data from pre-clinical to clinical studies. Given the extensive use of anti-diabetic drugs and the common sarcopenia, a better understanding of energy metabolism in skeletal muscle deserves attention in future studies.

Inhibition of PI3K/AKT signaling pathway prevents blood-induced heterotopic ossification of the injured tendon.

Objective: It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. Methods: A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for in vivo and in vitro HO treatment. Results: Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model. Conclusion: Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.

Mouse islet-derived stellate cells are similar to, but distinct from, mesenchymal stromal cells and influence the beta cell function.

AIMS: Evidence is accumulating of the therapeutic benefits of mesenchymal stromal cells (MSCs) in diabetes-related conditions. We have identified a novel population of stromal cells within islets of Langerhans - islet stellate cells (ISCs) - which have a similar morphology to MSCs. In this study we characterize mouse ISCs and compare their morphology and function to MSCs to determine whether ISCs may also have therapeutic potential in diabetes. METHODS: ISCs isolated from mouse islets were compared to mouse bone marrow MSCs by analysis of cell morphology; expression of cell-surface markers and extracellular matrix (ECM) components; proliferation; apoptosis; paracrine activity; and differentiation into adipocytes, chondrocytes and osteocytes. We also assessed the effects of co-culture with ISCs or MSCs on the insulin secretory capacity of islet beta cells. RESULTS: Although morphological similar, ISCs were functionally distinct from MSCs. Thus, ISCs were less proliferative and more apoptotic; they had different expression levels of important paracrine factors; and they were less efficient at differentiation down multiple lineages. Co-culture of mouse islets with ISCs enhanced glucose induced insulin secretion more effectively than co-culture with MSCs. CONCLUSIONS: ISCs are a specific sub-type of islet-derived stromal cells that possess biological behaviors distinct from MSCs. The enhanced beneficial effects of ISCs on islet beta cell function suggests that they may offer a therapeutic target for enhancing beta cell functional survival in diabetes.

Genetic lineage tracing reveals stellate cells as contributors to myofibroblasts in pancreas and islet fibrosis.

Pancreatic stellate cells (PSCs) are suggested to play an important role in the development of pancreas and islet fibrosis. However, the precise contributions and solid in vivo evidence of PSCs to the fibrogenesis remain to be elucidated. Here, we developed a novel fate-tracing strategy for PSCs by vitamin A administration in Lrat-cre; Rosa26-tdTomato transgenic mouse. The results showed that stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibrosis. In addition, stellate cells in islets increase and contribute partly to myofibroblasts pool in streptozocin-induced acute or chronic islet injury and fibrosis. Furthermore, we substantiated the functional contribution of PSCs to fibrogenesis of pancreatic exocrine and islet in PSCs ablated mice. We also found stellate cells' genetic ablation can improve pancreatic exocrine but not islet fibrosis. Together, our data indicates that stellate cells are vital/partial contributors to myofibroblasts in pancreatic exocrine/islet fibrosis.

Effect of Chiglitazar and Sitagliptin on Bone Mineral Density and Body Composition in Untreated Patients with Type 2 Diabetes.

Aim: To evaluate the changes in bone mineral density (BMD) and body composition in untreated patients with type 2 diabetes mellitus (T2DM) before and after chiglitazar or sitagliptin treatment. Methods: A total of 81 patients with T2DM were randomly divided to receive chiglitazar or sitagliptin treatment for 24 weeks (54 in the chiglitazar group and 27 in the sitagliptin group). We measured the spine lumbar BMD, hip BMD, fat mass (FM), fat-free mass (FFM), percent body fat (%BF), android FM, gynoid FM and skeleton muscle mass (SMM) using dual-energy X-ray absorptiometry (DEXA) and examined serum adiponectin (ADP) levels at baseline and the end of the study. Results: There were no significant changes in the BMD of the L2-4, femoral neck, trochanter or total hip as well as in the BMC after 24 weeks of treatment with chiglitazar or sitagliptin. After chiglitazar administration, the FM, gynoid FM and gynoid to total FM ratio were higher, while the android to total FM ratio and the android to gynoid FM ratio (AOI) were significantly lower. Sitagliptin intervention did not result in statistically significant differences in total fat loss, but it did cause significant decreases in %BF and AOI as well as increases in the FFM, gynoid to total FM ratio and SMM. The ADP levels had significantly negative associations with AOI in all eligible patients. Conclusion: The chiglitazar had no deleterious effects on BMD and resulted in body fat redistribution in untreated patients with T2DM. Trial Registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02173457).

Effects of a Novel Glucokinase Activator, Dorzagliatin, on Glycemic Control and Glucose Fluctuation in Drug-Naïve Patients with Type 2 Diabetes Mellitus.

Aim: The prevalence rate of type 2 diabetes mellitus (T2DM) has been increasing and a large proportion of patients still do not achieve adequate or sustainable glycemic control on the basis of previous hypoglycemic treatment. In this present study, we explored whether dorzagliatin, a novel glucokinase activator (GKA), could improve glycemic control and lessen glucose fluctuation in drug-naïve patients with T2DM. Methods: A self-comparative observational study of 25 drug-naïve patients with T2DM (aged 18-75 years and HbA1c of 7.5%-11.0%) treated with dorzagliatin 75 mg twice daily for 52 weeks. Before and after dorzagliatin intervention, the serum levels of hemoglobin A1c (HbA1c), insulin, and C-peptide were measured repeatedly during fasting and after a mixed meal. The continuous glucose monitoring (CGM) device was also used to obtain 24-hour glucose profiles and assess the changes in glycemic variability parameters. Results: After 52 weeks of treatment with dorzagliatin, a numerally greater reduction in HbA1c of 1.03% from the baseline was observed in patients with T2DM, accompanied by significant improvement in insulin resistance and insulin secretion. Moreover, the standard deviation of blood glucose (SDBG) and the mean amplitude of glycemic excursion (MAGE) derived from CGM data were significantly decreased after dorzagliatin therapy. The 24-h glucose variation profile showed that study patients had obviously lower mean glucose levels during the postprandial period from the baseline to week 52, an effect also demonstrated by the significant decrease in the incremental area under glucose concentration versus time curve for 2 h (iAUC0-2 h) after meals. Conclusions: This study suggests that dorzagliatin therapy could effectively improve glycemic control and glucose fluctuation in drug-naïve patients with T2DM.

Perilipin 2 Protects against Lipotoxicity-Induced Islet Fibrosis by Inducing Islet Stellate Cell Activation Phenotype Changes.

Aims: We explored whether and how perilipin 2 (Plin2) protected islets against lipotoxicity-induced islet dysfunction by regulating islet stellate cells (ISCs) activation. Methods: Six-week-old male rats were given a high-fat diet or a control diet for 28 weeks. Glucose metabolic phenotypes were assessed using glucose/insulin tolerance tests, masson, and immunohistochemical staining. ISCs activation levels were assessed from rats and palmitic acid- (PA-) treated cultured ISCs by immunofluorescence, Oil red O staining, electron microscopy, quantitative PCR, and western blotting. Changes in ISCs phenotype of activation degree and its underlying mechanisms were assessed by target gene lentiviral infection, high-performance liquid chromatography (HPLC), and western blotting. Results: Obese rats showed glucose intolerance, decreased endocrine hormone profiles, and elevated expression of α-smooth muscle actin (α-SMA), a polygonal appearance without cytoplasmic lipid droplets of ISCs in rats and isolated islets. PA-treated cultured ISCs exhibited faster proliferation and migration abilities with the induction of mRNA levels of lipid metabolism proteins, especially Plin2. The overexpression of Plin2 resulted in ISCs "re-quiescent" phenotypes associated with inhibition of the Smad3-TGF-ß signaling pathways. Conclusions: Our observations suggest a protective role of Plin2 in weakening ISCs activation. It may serve as a novel therapeutic target for preventing islet fibrosis for T2DM.

Increased Glycemic Variability Evaluated by Continuous Glucose Monitoring is Associated with Osteoporosis in Type 2 Diabetic Patients.

Background: Subjects with type 2 diabetes mellitus (T2DM) are susceptible to osteoporosis. This study was conducted to evaluate the association between glycemic variability evaluated by continuous glucose monitoring (CGM) and osteoporosis in type 2 diabetic patient. Methods: A total of 362 type 2 diabetic subjects who underwent bone mineral density (BMD) measurement and were monitored by a CGM system from Jan 2019 to May 2020 were enrolled in this cross-sectional study. Glycemic variability was calculated with the Easy GV software, including 24-hour mean blood glucose (24-h MBG), the standard deviation of 24-h MBG (SDBG), coefficient of variation (CV), mean amplitude of glycemic excursions (MAGE), and time in range between 3.9 and 10.0 mmol/L (TIR). Other potential influence factors for osteoporosis were also examined. Results: Based on the T-scores of BMD measurement, there were 190 patients with normal bone mass, 132 patients with osteopenia and 40 patients with osteoporosis. T2DM patients with osteoporosis showed a higher 24-h MBG, SDBG, CV, and MAGE, but a lower TIR (all p < 0.05). Multivariate logistic regression analysis revealed that age, female gender, body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), serum uric acid (SUA) and MAGE independently contribute to osteoporosis, and corresponding odds ratio [95% confidence interval (CI)] was 1.129 (1.072-1.190), 4.215 (1.613-11.012), 0.801 (0.712-0.901), 2.743 (1.385-5.431), 0.993 (0.988-0.999), and 1.380 (1.026-1.857), respectively. Further receiver operating characteristic analysis with Youden index indicated that the area under the curve and its 95% CI were 0.673 and 0.604-0.742, with the optimal cut-off value of MAGE predicting osteoporosis being 4.31 mmol/L. Conclusion: In addition to conventional influence factors including age, female gender, BMI, LDL-C and SUA, increased glycemic variability assessed by MAGE is associated with osteoporosis in type 2 diabetic patients.

Comparative Evaluation of Chiglitazar and Sitagliptin on the Levels of Retinol-Binding Protein 4 and Its Correlation With Insulin Resistance in Patients With Type 2 Diabetes.

Aims: We evaluated the efficacy and significant changes in the levels of retinol-binding protein 4 (RBP-4) and insulin resistance in patients with type 2 diabetes mellitus (T2DM) treated with chiglitazar versus sitagliptin. Methods: Eighty-one T2DM patients with haemoglobin A1c (HbA1c) level of 7.5%-10.0% were selected. Based on the study criteria, patients were randomly assigned to receive chiglitazar (32 mg), chiglitazar (48 mg), or sitagliptin (100 mg) orally for 24 weeks. Sociodemographic and anthropometric characteristics, lipid profiles, glucose profiles, and serum RBP-4 levels were determined at baseline and at the end of the therapy. Results: After treatment for 24 weeks, significant changes in fasting blood glucose (FBG), fasting insulin (Fins), 2 h-blood glucose (2h-BG), the score values of insulin resistance/insulin secretion/ß cell function (HOMA-IR, HOMA-IS, and HOMA-ß), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein cholesterol (HDL-C), and RBP-4 levels were detected in patients with chiglitazar administration and sitagliptin administration. Changes in RBP-4 levels were positively correlated with changes in HOMA-IR and 2 h-BG in linear regression. Conclusions: Chiglitazar showed a greater improvement in parameters of diabetes than sitagliptin, and changes in serum RBP-4 levels were associated with changes in insulin-sensitizing parameters. Clinical Trial Registration: ClinicalTrials.gov, CT.gov identifier: NCT02173457.

Basal Insulin Reduces Glucose Variability and Hypoglycaemia Compared to Premixed Insulin in Type 2 Diabetes Patients: A Study Based on Continuous Glucose Monitoring Systems.

Aims: To examine the glycaemic variability and safety of basal and premixed insulin by using continuous glucose monitoring (CGM) systems. Methods: 393 patients with type 2 diabetes mellitus (T2DM) treated with basal or premixed insulin for more than 3 months were enrolled. Patients were classified into a basal insulin group or premixed insulin group according to their insulin regimens. CGMs were used for 72 h with their previous hypoglycaemic regimen unchanged. The following glycaemic parameters were calculated for each 24 h using CGM data. Results: Despite similar HbA1c and fasting C-peptide concentrations, glycaemic variability (GV), including the mean amplitude of glycaemic excursion (MAGE), standard deviation (SD) and coefficient of variation (CV), and the time below range (TBR) were significantly lower in the basal insulin group than these in the premixed insulin group. Night-time hypoglycaemia was lower in the basal insulin group than that in the premixed insulin group (p<0.01). Among participants with haemoglobin A1c (HbA1c) < 7%, the GV and TBR were higher in the premixed insulin group than that in the basal insulin group. Conclusion: Compared with basal insulin, the patients who use premixed insulin had higher GV, smaller TIR and an increased incidence of hypoglycaemia. For patients who use premixed insulin and with HbA1c < 7%, more attention needs to be given to hypoglycaemic events and asymptomatic hypoglycaemia. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03566472.

Effect of chiglitazar and sitagliptin on glucose variations, insulin resistance and inflammatory-related biomarkers in untreated patients with type 2 diabetes.

AIMS: To evaluate glycemic variations, changes in insulin resistance and oxidative stress after chiglitazar or sitagliptin treatment in untreated patients with type 2 diabetes mellitus (T2DM). METHODS: Based on the study inclusion and exclusion criteria, 81 patients with T2DM were randomly divided to receive chiglitazar or sitagliptin treatment for 24 weeks. Continuous glucose monitoring (CGM) systems were conducted for 72 h in eligible patients. We analyzed the following glycemic variation parameters derived from the CGM data and measured the serum levels of hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 2-h postprandial blood glucose (2-h PBG), fasting insulin (Fins) and inflammatory-related indicators at baseline and the end of the study. RESULTS: After treatment for 24 weeks, our data showed a similar reduction in HbA1c between chiglitazar and sitagliptin. The 24-h mean blood glucose (MBG), standard deviation (SD) and mean amplitude of glycemic excursion (MAGE) were significantly decreased, and the time in range (TIR) was increased after chiglitazar and sitagliptin therapy. Chiglitazar administration led to significant improvement in insulin resistance/insulin secretion (HOMA-IR, HOMA-IS), interleukin-6 (IL-6), prostaglandin F2α (PGF-2α), 17-hydroxyprogesterone (17-OHP) and adiponectin (ADP) score values compared with sitagliptin administration. CONCLUSIONS: Chiglitazar therapy effectively reduced glucose variation and showed a larger improvement in insulin resistance and inflammatory parameters than sitagliptin.

Evaluating Glycemic Control During Basalin or Lantus Administration in Adults With Controlled Type 2 Diabetes Mellitus Using Continuous Glucose Monitoring.

Aim: This study aims at evaluating glycemic control during Basalin or Lantus administration in adults with controlled type 2 diabetes mellitus using continuous glucose monitoring system (CGM). Methods: 47 patients with well-controlled T2DM using both Basalin and oral hypoglycemic drugs were recruited. CGM were applied from day 1 to day 3 with the unchanged dose of Basalin and then removed from day 4. A washout was performed with Lantus at the same dose as Basalin from day 4 to day 10. Then patients were continued to install the CGM under Lantus administration from day 11 to day 13. Variables of CGM, such as the area under the curve (AUC) for both hyperglycemia and hypoglycemia, 24h mean blood glucose (24h MBG), 24h standard deviation of blood glucose (24h SDBG), 24h mean amplitude of glycemic excursion (24h MAGE), PT (percentage of time), and time in range (TIR), were calculated and compared between Basalin group and Lantus group. Results: The group of Lantus showed lower 24h MBG (p<0.01), 24h MAGE (p<0.05), and lower 24h SDBG (p<0.01) than the Basalin group. Lantus-treated patients had a lower PT and AUC when the cut-off point for blood glucose was 10 mmol/L (p<0.05) and 13.9 mmol/L (p<0.05), respectively. In this study, no patient developed symptomatic hypoglycemia, few hypoglycemia was observed and there was no difference of hypoglycemia between the two groups. Conclusion: In patients with well-controlled T2DM who were treated with insulin glargine, Lantus group showed lower MBG, GV, and lower PT (BG > 10.0 mmol/L, BG > 13.9 mmol/L) than Basalin group. In summary, for T2DM population with HbA1c ≤ 7%, Lantus may be a better choice compared with Basalin.

Association of glycemic variability and hypoglycemia with distal symmetrical polyneuropathy in adults with type 1 diabetes.

Previous studies exploring the influence of glycemic variability (GV) on the pathogenesis of distal symmetrical polyneuropathy (DSPN) in type 1 diabetes (T1DM) produced conflicting results. The aim of this study was to assess the relationship between GV and DSPN in T1DM. Adults with T1DM were included in this cross-sectional study and asked to undergo 3-day CGM. GV quantified by coefficient of variation (CV) and mean amplitude of glucose excursions (MAGE) were obtained from CGM. Clinical characteristics and biochemical assessments were collected for analysis. The study comprised 152 T1DM patients (53.9% males) with mean age of 44.2 year. Higher levels of age and duration of diabetes and lower levels of total cholesterol, LDL, fasting C-peptide and postprandial C-peptide were observed in DSPN subjects. DSPN groups displayed a higher blood glucose between 00:00 and 12:59 according to the CGM profile. Higher MAGE and CV were associated with increased risk of DSPN in the fully adjusted model. Meanwhile, a significant association between measurements of hypoglycemia, especially nocturnal hypoglycemia, and DSPN was found after multiple tests. CGM parameters describing the glycemic variability and hypoglycemia were potential risk factors for DSPN in adults with T1DM.

Ethnicity Differences in the Association of UCP1-3826A/G, UCP2-866G/A and Ala55Val, and UCP3-55C/T Polymorphisms with Type 2 Diabetes Mellitus Susceptibility: An Updated Meta-Analysis.

BACKGROUND: The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) has been extensively studied, while conclusions remain contradictory. Thus, we performed this meta-analysis to elucidate whether the UCP1-3826A/G, UCP2-866G/A, Ala55Val, and UCP3-55C/T polymorphisms are associated with T2DM. METHODS: Eligible studies were searched from PubMed, Cochrane Library, and Web of Science database before 12 July 2020. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of the association. Heterogeneity analysis, subgroup analysis, sensitivity analysis, and publication bias were also performed. RESULTS: A total of 38 case-control studies were included in this meta-analysis. The overall results revealed significant association between T2DM and the UCP2 Ala55Val polymorphism (recessive model: OR = 1.25, 95% CI 1.12-1.40, P < 0.01; homozygous model: OR = 1.33, 95% CI 1.03-1.72, P = 0.029, respectively). In subgroup analysis stratified by ethnicity, T2DM risk was increased with the UCP2 Ala55Val polymorphism (allele model: OR = 1.17, 95% CI 1.02-1.34, P = 0.023; recessive model: OR = 1.28, 95% CI 1.13-1.45, P < 0.01; homozygous model: OR = 1.39, 95% CI 1.05-1.86, P = 0.023, respectively), while decreased with the UCP2-866G/A polymorphism in Asians (dominant model: OR = 0.86, 95% CI 0.74-1.00, P = 0.045). CONCLUSIONS: Our results demonstrate that the UCP2-866G/A polymorphism is protective against T2DM, while the UCP2 Ala55Val polymorphism is susceptible to T2DM in Asians.

Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects.

Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, ß-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.

Microvesicles mediate sorafenib resistance in liver cancer cells through attenuating p53 and enhancing FOXM1 expression.

Drug resistance in cancer, still poses therapeutic challenges and tumor microenvironment plays a critical role in it. Microvesicles (MVs) are effective transporters of the molecular information between cells and regulate the tumor microenvironment. They contribute to the drug resistance by transferring functional molecules between cells. Herein we report the effects of liver cancer cell-secreted MVs on sorafenib resistance in liver cancer cells HepG2 and Huh7 both in vitro and in vivo. In our study, these cancer cell-secreted MVs affected the anti-proliferative effect of sorafenib in a dose- and time-dependent manner and also inhibited the sorafenib induced apoptosis in vitro. Further, in in-vivo xenograft mice models, liver cancer cell-secreted MVs increased the tumor volume even after sorafenib treatment. Further, HGF, also got elevated in liver cancer cell-secreted MVs treatment group and activated Ras protein expression. miR-25 in the cancer cell-secreted MVs was transferred to their host cells HepG2 and Huh7 cells and reversed the sorafenib induced expression of tumor suppressor p53. This in turn induced the expression of FOXM1, a key regulator of cell cycle progression and thus affected the anti-proliferative effect of sorafenib. Therefore, this study reveals that liver cancer cell-derived MVs can mediate sorafenib resistance in the liver cancer cells, suggesting that these MVs may not be utilized as vehicles for anti-cancer drug delivery in liver cancer treatments.