Differential effects of PGAM5 knockout on high fat high fructose diet and methionine choline-deficient diet induced non-alcoholic steatohepatitis (NASH) in mice.

BACKGROUND: Phosphoglycerate mutase 5 (PGAM5), a phosphatase involved in mitochondrial homeostasis, is reported to be closely related to the metabolic stress induced by high-fat diet (HFD) or cold. In this study, we aimed to investigate the effects of PGAM5 on hepatic steatosis, inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). METHODS AND RESULTS: We generated PGAM5 global knockout (GKO) mice and their wildtype (WT) littermates using CRISPR/CAS9. The mice were fed with a high fat high fructose (HFHF) diet for 12 weeks or a methionine choline-deficient (MCD) diet (methionine choline supplemented (MCS) as control) for 6 weeks. Hepatic PGAM5 expression was up-regulated in humans with NASH and WT mice fed with HFHF and MCS, and reduced in WT mice fed with MCD diet. In HFHF-fed mice, GKO had reduced body weight, hepatic triglyceride (TG) content and serum transaminase along with decreased hepatic pro-inflammatory and pro-fibrotic responses compared with their WT control. GKO had increased expression of antioxidative gene glutathione peroxidase-6 (GPX6) and activation of mammalian target of rapamycin (mTOR). In mice fed with MCS diet, GKO significantly increased serum TNF-α and IL-6 and decreased hepatic GPX6 mRNA expression. There was no difference in hepatic steatosis, inflammation or fibrosis between GKO and WT mice fed with MCD diet. We investigated the role of PGAM5 deficiency in a variety of cell types. In differentiated THP-1 cells, PGAM5 silencing significantly increased pro-inflammatory cytokine secretion and decreased antioxidative proteins, including nuclear factor erythroid 2- related factors (NRF2), heme oxygenase-1 (HO-1) and GPX6 without affecting mTOR activity. In HepG2 cells with steatosis, PGAM5 knockdown reduced insulin sensitivity, increased mTOR phosphorylation and reduced the expression of NRF2, catalase (CAT), HO-1 and GPX6. Conversely, PGAM5 knockdown reduced TG accumulation, increased insulin sensitivity, and increased antioxidative genes in 3T3-L1 cells, despite the up-regulation in mTOR phosphorylation. CONCLUSIONS: PGAM5-KO relieved hepatic steatosis and inflammation in HFHF model, promoted inflammation in MCS-fed mice and had no effects on the MCD-fed model. The distinct effects may be owing to the different effects of PGAM5-KO on anti-oxidative pathways in energy-dependent, possible involves mTOR, and/or cell type-dependent manner. Our findings suggest that PGAM5 can be a potential therapeutic target for NASH.

Consensus of Chinese experts on strengthening personalized prevention and treatment of type 2 diabetes.

Up to now, there has not yet been guidance or consensus from Chinese experts in the field of personalized prevention and treatment of type 2 diabetes. In view of the above, the endocrinology diabetes Professional Committee of Chinese Non-government Medical Institutions Association, the integrated endocrinology diabetes Professional Committee of the integrated medicine branch of Chinese Medical Doctor Association, and the diabetes education and microvascular complications group of the diabetes branch of the Chinese Medical Association organized relevant experts to discuss and reach the "Chinese expert consensus on strengthening personalized prevention and treatment of type 2 diabetes" for reference in clinical practice.

Association between biologic therapy and fracture incidence in patients with selected rheumatic and autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To investigate the effect of biologic therapy on risk of fracture in selected rheumatic and autoimmune diseases. METHODS: The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2021. Randomized clinical trials (RCTs) comparing biological disease-modifying antirheumatic drugs (bDMARDs) with non-bDMARDs or placebo in patients with five selected rheumatic and autoimmune diseases were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95 % confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. RESULTS: A total of 100 RCTs involving 51,413 participants fulfilled the inclusion criteria. In patients with psoriasis (Ps), and psoriatic arthritis (PsA), compared with placebo or non-bDMARDs therapy, the risk of major osteoporotic fracture (OR, 0.34 [95 %Cl, 0.15-0.76], p = 0.009), hip fracture (OR, 0.22 [95 %Cl, 0.05-0.89], p = 0.03), and osteoporotic non-vertebral fracture (OR, 0.26 [95 %Cl, 0.10-0.62], p = 0.003) were significantly decreased with the use of bDMARDs. In patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), systemic lupus erythematosus (SLE), and inflammatory bowel diseases (IBD), the risk of fracture were not changed with biologic treatment. CONCLUSIONS: The existing evidence from RCTs indicated the use of bDMARDs was associated with a low risk of major osteoporotic fracture, hip fracture, and osteoporotic non-vertebral fracture in patients with Ps and PsA. There are still urgent needs for studies regarding the actions of biologic therapies on the risk of bone fractures in systemic inflammatory diseases.

Quality of life in people with type 2 diabetes in the 3 years following initiation of second-line therapy: The DISCOVER study.

AIMS: To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. METHODS: HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories. RESULTS: Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia. CONCLUSIONS: Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Standards of medical care for type 2 diabetes in China 2019.

The prevalence of diabetes in China has increased rapidly from 0.67% in 1980 to 10.4% in 2013, with the aging of the population and westernization of lifestyle. Since its foundation in 1991, the Chinese Diabetes Society (CDS) has been dedicated to improving academic exchange and the academic level of diabetes research in China. From 2003 to 2014, four versions of Chinese diabetes care guidelines have been published. The guidelines have played an important role in standardizing clinical practice and improving the status quo of diabetes prevention and control in China. Since September 2016, the CDS has invited experts in cardiovascular diseases, psychiatric diseases, nutrition, and traditional Chinese medicine to work with endocrinologists from the CDS to review the new clinical research evidence related to diabetes over the previous 4 years. Over a year of careful revision, this has resulted in the present, new version of guidelines for prevention and care of type 2 diabetes in China. The main contents include epidemiology of type 2 diabetes in China; diagnosis and classification of diabetes; primary, secondary, and tertiary diabetes prevention; diabetes education and management support; blood glucose monitoring; integrated control targets for type 2 diabetes and treatments for hyperglycaemia; medical nutrition therapy; exercise therapy for type 2 diabetes; smoking cessation; pharmacologic therapy for hyperglycaemia; metabolic surgery for type 2 diabetes; prevention and treatment of cardiovascular and cerebrovascular diseases in patients with type 2 diabetes; hypoglycaemia; chronic diabetic complications; special types of diabetes; metabolic syndrome; and diabetes and traditional Chinese medicine.

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial.

Despite the current guideline's recommendation of a timely stepwise intensification therapy, the "clinical inertia", termed as the delayed treatment intensification, commonly exists in the real world, which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy. In this clinical trial performed in 237 centers in China, 5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks. The patients who did not reach the glycated hemoglobin A1c (HbA1c) goal were then further randomized into glimepiride, gliclazide, repaglinide, or acarbose group for an additional 24-week triple therapy. A mean HbA1c reduction of 0.85% was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks. Further HbA1c reductions in the 24-week triple therapy stage were 0.65% in glimepiride group, 0.70% in gliclazide group, 0.61% in repaglinide group, and 0.45% in acarbose group. The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide, but not for acarbose, compared with glimepiride, when added to metformin/sitagliptin dual therapy. The incidences of adverse events (AEs) were 29.2% in the dual therapy stage and 30.3% in the triple therapy stage. Metformin/sitagliptin as baseline therapy, with the addition of a third oral antihyperglycemic agent, including glimepiride, gliclazide, repaglinide, or acarbose, was effective, safe and well-tolerated for achieving an HbA1c <7.0% goal in type 2 diabetic patients inadequately controlled with previous therapies. The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.

Longitudinal association between fasting blood glucose concentrations and first stroke in hypertensive adults in China: effect of folic acid intervention.

Background: Diabetes is a known risk factor for stroke, but data on its prospective association with first stroke are limited. Folic acid supplementation has been shown to protect against first stroke, but its role in preventing first stroke in diabetes is unknown.Objectives: This post hoc analysis of the China Stroke Primary Prevention Trial tested the hypotheses that the fasting blood glucose (FBG) concentration is positively associated with first stroke risk and that folic acid treatment can reduce stroke risk associated with elevated fasting glucose concentrations.Design: This analysis included 20,327 hypertensive adults without a history of stroke or myocardial infarction, who were randomly assigned to a double-blind daily treatment with 10 mg enalapril and 0.8 mg folic acid (n = 10,160) or 10 mg enalapril alone (n = 10,167). Kaplan-Meier survival analysis and Cox proportionate hazard models were used to test the hypotheses with adjustment for pertinent covariables.Results: During a median treatment duration of 4.5 y, 616 participants developed a first stroke (497 ischemic strokes). A high FBG concentration (≥7.0 mmol/L) or diabetes, compared with a low FBG concentration (<5.0 mmol/L), was associated with an increased risk of first stroke (6.0% compared with 2.6%, respectively; HR: 1.9; 95% CI: 1.3, 2.8; P < 0.001). Folic acid treatment reduced the risk of stroke across a wide range of FBG concentrations ≥5.0 mmol/L, but risk reduction was greatest in subjects with FBG concentrations ≥7.0 mmol/L or with diabetes (HR: 0.66; 95% CI: 0.46, 0.97; P < 0.05). There was a significant interactive effect of FBG and folic acid treatment on first stroke (P = 0.01).Conclusions: In Chinese hypertensive adults, an FBG concentration ≥7.0 mmol/L or diabetes is associated with an increased risk of first stroke; this increased risk is reduced by 34% with folic acid treatment. These findings warrant additional investigation. This trial was registered at clinicaltrials.gov as NCT00794885.

Type 1 diabetes stigma in China: a call to end the devaluation of individuals living with a manageable chronic disease.

Stigma is a significant barrier to improving care for individuals with type 1 diabetes mellitus (T1DM). This commentary describes this phenomenon in China, where stigma has led to labeling and devaluing of individuals with T1DM. Difficulties finding a spouse and regulations restricting admission to universities and government employment have forced many individuals to hide their diabetes. The shame, fear, and guilt stemming from stigma may preclude the use of insulin pumps; multiple daily injections, which require pre-meal insulin dosing at school or the workplace; participation in research studies; and general health-seeking behaviors. A multifaceted, multilevel approach is urgently needed and should involve improving public awareness and understanding of T1DM; adoption by health care providers of holistic rather than biomedical approaches to disease management; patient counseling on positive coping skills; and expansion of the scope of research to consider the psychosocial realities of diabetes care in China. Recent media attention in the form of a nationally broadcasted documentary on T1DM is an important step in the right direction. We believe that coordinated action by multiple stakeholders can lead to meaningful improvements in treatment, ultimately leading to better physical and emotional health outcomes for individuals living with this manageable chronic disease.

Analysis of the associations between vitamin D and albuminuria or ß-cell function in Chinese type 2 diabetes.

OBJECTIVE: To investigate the associations of 25-(OH)D and ß -cell function or insulin resistance or albuminuria in Chinese type 2 diabetic patients. METHODS: In total, 1408 type 2 diabetic patients without vitamin D supplement were included in this retrospective study. RESULTS: Comparison between patients with and without 25-(OH)D deficiency indicated that, compared with patients with 25-(OH)D≥50 nmol/L, patients with 25-(OH)D<50 nmol/L showed a higher level of urine albumin-creatinine ratio (ACR) (90.15±10.30 mg/g versus 52.79±14.97 mg/g). Multiple regression analysis indicated that 25-(OH)D was independently and negatively correlated with urine ACR (OR=0.985, 95%CI 0.972-0.999, P=0.03), adjusted by age, diabetic duration, HBP duration, SBP, HbA1c, creatinine, LDL-C, triglyceride, total cholesterol, and HDL-C. Compared with patients with normal level of urine ACR, patients with higher level of urine ACR showed a significant lower level of 25-(OH)D (34.49±13.52 nmol/L versus 37.46±13.6 nmol/L, P=0.00). Analysis of the associations of 25-(OH)D and ß-cell function or insulin resistance showed that 25-(OH)D may not correlate with ß-cell function or insulin resistance. CONCLUSION: 25-(OH)D was independently associated with albuminuria in Chinese type 2 diabetic patients but was not associated with ß-cell function or insulin resistance.

Efficacy and safety of traditional chinese medicine for diabetes: a double-blind, randomised, controlled trial.

BACKGROUND: Treatment of diabetes mellitus with Traditional Chinese Medicine has a long history. The aim of this study is to establish the safety and efficacy of traditional Chinese medicine combined with glibenclamide to treat type 2 diabetes mellitus. METHODS: In a controlled, double blind, multicentre non-inferiority trial, 800 patients with unsatisfactory glycemic control (fasting glucose 7-13 mmol/L and HbA1c 7-11%) were randomly assigned to receive Xiaoke Pill, a compound of Chinese herbs combined with glibenclamide, or Glibenclamide in two study groups - drug naive group, and patients previously treated with metformin monotherapy (metformin group). Outcome measures at 48 weeks were the incidence and rate of hypoglycemia, mean difference in HbA1c, and proportion of patients with HbA1c<6.5%. FINDINGS: In drug naïve group, the total hypoglycemia rate and the mild hypoglycemic episode in the Xiaoke Pill arm were 38% (p = 0.024) and 41% (p = 0.002) less compared to Glibenclamide arm; in Metformin group, the average annual rate of hypoglycemia was 62% lower in Xiaoke Pill arm (p = 0.003). Respective mean changes in HbA1c from baseline were -0.70% and -0.66% for Xiaoke Pill and Glibenclamide, with a between-group difference (95% CI) of -0.04% (-0.20, 0.12) in the drug naïve group, and those in metformin group were -0.45% and -0.59%, 0.14% (-0.12, 0.39) respectively. The respective proportions of patients with a HbA1c level <6.5% were 26.6% and 23.4% in the drug naïve group and 20.1% and 18.9% in the metformin group. INTERPRETATION: In patients with type 2 diabetes and inadequate glycaemic control, treatment with Xiaoke Pill led to significant reduction in risk of hypoglycemia and similar improvements in glycemic control after 48 weeks compared to Glibenclamide. TRIAL REGISTRATION: Chinese Clinical Trial Register number, ChiCTR-TRC-08000074.

Effects of Chinese medicine Tongxinluo on hyperglycemia and beta-cell damage in streptozotocin-induced diabetic rats.

BACKGROUND: Oxidative stress has been implicated in the onset and progression of diabetes. Tongxinluo is a traditional Chinese medicine with potent antioxidant properties. The aim of this study was to test the hypothesis that pretreatment with Tongxinluo has similar effects as melatonin on preventing hyperglycemia and beta-cell damage in a rat model of streptozotocin (STZ)-induced diabetes. METHODS: Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 each): normal control (NC) group; STZ group (70 mg/kg, i.p.); Tongxinluo (1.0 g×kg(-1)×d(-1)) pretreated (TXL + STZ) group and melatonin (200 µg×kg(-1)×d(-1)) pretreated (MLT + STZ) group. Tongxinluo and melatonin were administered by gavage beginning 8 days before STZ injection and continuing until the end of the study (15 days after STZ administration). Blood glucose levels and body weights, malondialdehyde (MDA), and reduced glutathione (GSH) levels were measured, and immunofluorescence studies were performed in all of the groups. RESULTS: Pretreatment with Tongxinluo, as with melatonin, attenuated severe hyperglycemia and weight loss induced by STZ. In pancreatic homogenates, MDA levels were significantly lower and GSH levels were significantly higher in Tongxinluo pretreated group and in melatonin pretreated group than those in STZ group. Values of insulin staining were significantly improved in Tongxinluo pretreated group and in melatonin pretreated group as compared with those in STZ group. CONCLUSIONS: Tongxinluo, as melatonin, prevented hyperglycemia and beta-cell destruction induced by STZ in rats through reducing oxidative stress in pancreatic tissues. Tongxinluo may provide an alternative therapy for the prevention and treatment of diabetes.