Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Traditional Chinese medicine for the treatment of diabetic kidney disease: A study-level pooled analysis of 44 randomized controlled trials.

Background: Accumulating evidence suggests that traditional Chinese medicine (TCM) has significant effects on reducing 24-h urinary protein (24-h UPRO) and improves renal function indices. The current level of evidence-based medicine is still not enough due to the limitation of clinical center size and sample size. Objective: We aimed to update the current evidence on the efficacy of TCM in the treatment of diabetic kidney disease (DKD). Methods: PubMed, Embase, the Cochrane Library, and SinoMed were searched to identify randomized controlled trials (RCTs) comparing the clinical efficacy of TCM combined with Western medicine with that of Western medicine alone for the treatment of DKD. The main outcome measure was 24-h UPRO. The secondary outcomes were serum creatinine (Scr), blood urea nitrogen (BUN), glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG). Meta-analyses were performed using random-effects models. The revised Cochrane risk-of-bias tool was used to assess the risk of bias. Results: A total of 44 RCTs with 3,730 participants were included. The summary estimates showed that compared with Western medicine alone, TCM combined with Western medicine significantly improved 24-h UPRO [standardized mean difference (SMD) -1.10, 95% confidence interval (CI) -1.45 to -0.74]. Moreover, TCM combined with Western medicine significantly reduced the levels of other renal function indices, including Scr (SMD -1.25, 95% CI: -1.69 to -0.81) and BUN (SMD -0.75, 95% CI: -1.10 to -0.40). TCM combined with Western medicine also showed greater benefits in reducing the levels of FBG (SMD -0.31, 95% CI: -0.47 to -0.15) and HbA1c (SMD -0.62, 95% CI: -0.89 to -0.36) in patients with DKD. In addition, superior effects on the lipid profile were noted in the TCM combined with Western medicine group in terms of TG (SMD -1.17, 95% CI: -1.76 to -0.59) and TC (SMD -0.95, 95% CI: -1.43 to -0.47). The risk of bias could have resulted from selective reports, unclear randomization methods, unblinded assignments, and some missing data. Conclusion: The results of this meta-analysis suggest that TCM combined with Western medicine has significant effects on reducing 24-h UPRO and improves renal function indices and lipid profiles compared with Western medicine alone for DKD. However, the results should be interpreted with caution due to the risk of bias of the included trials. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=213199], identifier [CRD: 42020213199].

Effects of Berberine Plus Inulin on Diabetes Care in Patients With Latent Autoimmune Diabetes in Adults: Protocol for a Randomized Controlled Trial.

Background: Latent autoimmune diabetes in adults (LADA) is a heterogeneous form of diabetes, characterized by autoimmune destruction of pancreatic ß-cells as well as insulin resistance and is triggered by environmental factors in the context of genetic susceptibility. Berberine (BBR), a small alkaloid isolated from medicinal plants, has antidiabetic, anti-inflammatory, and antibacterial effects. Inulin is a common prebiotic that has been shown to improve glycemic control, alter the gut microbiota and suppress inflammation. The primary purpose of this study was to evaluate the effects of oral BBR and inulin combined with insulin therapy on diabetes care in patients with LADA. Methods and Analysis: We will conduct a single-center, prospective, randomized, double-blind, placebo-controlled trial. A total of 240 patients with LADA who have started insulin therapy will be randomly allocated either to the intervention or control group. After a 1-week run-in period, they will complete a 3-month treatment of BBR alone, inulin plus BBR, inulin alone, or placebo. Anthropometric and clinical data will be collected at five time points: baseline, 3 months, 6 months, 9 months, and 12 months from baseline. The primary outcome was the change in glycated hemoglobin levels. Dynamic blood glucose parameters, ß-cell function, and gut microbiota, as well as adverse events and quality of life will be monitored. Discussion: Glycemic control is critical for preventing the progression of diabetes. Although insulin is a recommended treatment for patients with LADA, there are currently no drugs that can effectively prevent the progressive destruction of pancreatic ß-cells or maintain their function. Several studies have found that when berberine and prebiotics are used alone, they have beneficial metabolic effects. This clinical research protocol will assess the efficacy of the combined treatment of berberine plus inulin and provide new ideas for future pharmacological research and clinical practices in diabetes care and glycemic control for LADA patients. Ethics and Dissemination: This study has been approved by the Ethics Committee of National Clinical Research Center of the Second Xiangya Hospital of Central South University (approval number: 2021-046). Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04698330.

Aqueous Extract of Guava (Psidium guajava L.) Leaf Ameliorates Hyperglycemia by Promoting Hepatic Glycogen Synthesis and Modulating Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is a major global health concern. Psidium guajava L. (guava) is widely used for food as well as a folk medicine. Previous studies have shown its anti-diabetic and anti-inflammatory properties. However, the underlying mechanisms remains to be elusive. In this study, we assessed the potential therapeutic effects of aqueous extract of guava leaves (GvAEx) on T2DM and explored their potential mechanisms in vivo and in vitro. GvAEx was gavage administered for 12 weeks in diabetic db/db mice. Our results have demonstrated that GvAEx significantly lowered fasting plasma glucose levels (p < 0.01) and improved glucose tolerance and insulin sensitivity (p < 0.01, p < 0.05, respectively). Additionally, GvAEx increased hepatic glycogen accumulation, glucose uptake and decreased the mRNA expression levels of gluconeogenic genes. Furthermore, GvAEx-treatment caused higher glucose transporter 2 (GLUT2) expression in the membrane in hepatocytes. Notably, for the first time, we have elaborated the possible mechanism of the hypoglycemic effect of GvAEx from the perspective of intestinal microbiota. GvAEx has significantly changed the composition of microbiota and increased short chain fatty acid (SCFA) -producing Lachnospiraceae family and Akkermansia genus in the gut. Taken together, GvAEx could alleviate hyperglycemia and insulin resistance of T2DM by regulating glucose metabolism in the liver and restoring the gut microbiota. Thus, GvAEx has the potential for drug development against T2DM.

Nutritional Status in Chinese Patients with Obesity Following Sleeve Gastrectomy/Roux-en-Y Gastric Bypass: A Retrospective Multicenter Cohort Study.

Metabolic surgery (MS) is one of the most effective therapies for treating obesity. Due to the lack of multicenter cohort research on nutritional evaluations after surgery in Chinese patients, we explored the changes in nutritional status following MS in Chinese patients. This was a retrospective study of patients (n = 903) who underwent sleeve gastrectomy (SG) (n = 640) or Roux-en-Y gastric bypass (RYGB) (n = 263) for obesity at five different hospitals in China between 17 February 2011, and 20 December 2019. Major nutrients were evaluated at baseline and 1, 3, 6, and 12 months postoperatively. Hb levels decreased, and anemia prevalence increased at 12 months after MS in the premenopausal female group. Moreover, patients with preoperative anemia had an increased risk of postoperative anemia. The ferritin levels (p < 0.001) decreased and iron deficiency increased (p < 0.001) at 12 months after MS among premenopausal females. No significant changes in folate deficiency and vitamin B12 deficiency were found throughout the study. The bone mineral density (BMD) of the femoral neck, lumbar spine, and total hip significantly decreased from baseline to 12 months after MS; however, no new patients developed osteopenia or osteoporosis after MS. Based on 12 months of follow-up, premenopausal females presented a high incidence of anemia after MS. Although we found no differences in osteopenia and osteoporosis prevalence after MS, the BMD did decrease significantly, which suggests that nutrient supplements and long-term follow-up are especially necessary postoperation.

Identification of Sorafenib as a Treatment for Type 1 Diabetes.

Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.

Gender-differential effects on blood glucose levels between acarbose and metformin in Chinese patients with newly diagnosed type 2 diabetes: a sub-analysis of the MARCH trial.

Using the data from the trial of Metformin and AcaRbose in Chinese as the initial Hypoglycemic treatment (MARCH), this study was performed to compare the differential effects of acarbose and metformin on glucose metabolism after stratification by gender. Six hundred and forty patients who had finished the whole 48-week follow-up were included. The reduction of haemoglobin A1c (HbA1c) was comparable between acarbose- and metformin-treated patients among either females or males, and it was also similar between males and females treated with either acarbose or metformin for 24 and 48 weeks. The dropping of fasting plasma glucose (FPG) in acarbose-treated females was significantly less than that in metformin-treated females at both 24 and 48 weeks. Furthermore, the decrease of 2-hour postprandial glucose (2hPPG) in acarbose-treated males was significantly greater than that in metformin-treated males at both 24 and 48 weeks. Multiple linear regression analysis showed that drug selection was an independent factor affecting the decrease of FPG in female patients while it independently influenced 2hPPG in males at week 24 and 48. The reductions of FPG and 2hPPG at week 24 and 48 were also significantly different between metformin-treated females and metformin-treated males although gender was not an independent regulating factor. Our study indicates that there might be gender-differential effects on FPG and 2hPPG reduction when the comparisons are made between acarbose and metformin treatments.

The potential application of Cordyceps in metabolic-related disorders.

Changes in the global economy resulted in sedentary lifestyle and excessive calorie intake, increasing the incidence of metabolic diseases, which subsequently became a universal public concern. The difficulties of managing chronic diseases did not dampen researchers' enthusiasm for studying new therapeutics or adjuvant treatments. Cordyceps spp. is a kind of traditional Chinese herbal medicine; however, our understanding of this medicine remains at an initial stage. Recently, an increasing number of studies have demonstrated the potential of Cordyceps as a therapeutic agent for the effective treatment of metabolic-related disorders by exerting a variety of activities, including but not limited to anti-inflammatory, immunoregulatory, hypoglycemic, renoprotective and cardiovascular-protective effects. This article reviews the potential efficacy and underlying mechanisms of Cordyceps and its major bioactive ingredients in metabolic syndrome and its associated comorbidities.

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune-mediated destruction of insulin-producing ß cells. Recent studies showed that in addition to malaria, artemisinin and its derivative, artesunate (AS), could alleviate several autoimmune diseases. However, whether AS has a role in the prevention or treatment of T1D is still unknown. Therefore, in this study we administrated AS or DMSO in the drinking water of nonobese diabetic (NOD) mice, a mouse model of T1D. We found that AS administration significantly prevented the incidence of T1D. The frequency of IL-4-producing CD4+ single-positive T cells and CD8+ T cells was significantly elevated, and IFN-γ-producing T cells were reduced in the spleen and pancreatic lymph nodes. In the pancreas, the skewing to IL-4-producing T cells was also observed. In addition, more regulatory T cells were found in the pancreas. mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, were decreased. In addition, AS administration promoted the functional maturity of ß cells in vitro. Our findings demonstrate that AS administration can prevent T1D in NOD mice mainly by reducing autoimmune T cells and increasing protective T cells. Our data constitute the first functional study of AS in T1D, which may provide a new rationale for future translational studies.-Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., Zhou, Z., Zheng, P. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

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.

The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARγ activity.

BACKGROUND AND PURPOSE: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis. EXPERIMENTAL APPROACH: The effects of Chinese herbal medicines or components isolated from extracts of A. membranaceus, on adipocyte thermogenesis were analysed by assessing expression of uncoupling protein 1 (UCP1) by qPCR. Eight-week-old C57BL6/J male mice were fed a high-fat diet for 8 weeks and then randomized to two groups treated with vehicle or formononetin for another 8 weeks. Glucose tolerance tests and staining of adipose tissue with haematoxylin and eosin were carried out. Whole-body oxygen consumption was measured with an open-circuit indirect calorimetry system. KEY RESULTS: Extracts of A. membranaceus increased expression of Ucp1 in primary cultures of mouse adipocytes. Formononetin was the only known component of A. membranaceus extracts to increase adipocyte Ucp1 expression. Diet-induced obese mice treated with formononetin gained less weight and showed higher energy expenditure than untreated mice. In addition, formononetin binds directly with PPARγ. CONCLUSIONS AND IMPLICATION: Taken together, our study demonstrates that the Chinese herbal medicine from A. membranaceus and its constituent formononetin have the potential to reduce obesity and associated metabolic disorders. Our results suggest that formononetin regulates adipocyte thermogenesis as a non-classical PPARγ agonist.

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.

Simultaneous determination of eight catechins and four theaflavins in green, black and oolong tea using new HPLC-MS-MS method.

A simple, rapid and accurate analytical method was developed for the analysis of eight tea catechins and four theaflavins simultaneously in three types of tea (green, black and oolong tea), using ultra high performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HPLC-MS-MS) in multiple-reaction monitoring (MRM) mode. This method using HPLC-MS-MS in positive mode was performed on a CAPCELL PAK C18 MGIII (2.0mm×100mm, 3µm) column (Shiseido) with the mobile phase consisting of 0.1% aqueous formic acid (A) and methanol (B) in gradient elution at a flow rate of 0.3mLmin-1, and the column temperature set at 30°C. The optimized HPLC-MS-MS methodology is selective and specific, and was validated for eight catechins and four theaflavins widely reported in different teas. Satisfactory linearity was achieved in linear range (0.02-5µgmL-1 for catechins and 0.02-20µgmL-1 for theaflavins) and fine determination coefficient (r2>0.9935). The recoveries ranged from 65% to 115% with the RSD ranging from 2.4% to 6.7%. The methodology was used to evaluate the target polyphenols concentration in three types of tea samples.

Current and Future Clinical Applications of Zinc Transporter-8 in Type 1 Diabetes Mellitus.

OBJECTIVE: To evaluate the utility of zinc transporter-8 (ZnT8) in the improvement of type 1 diabetes mellitus (T1DM) diagnosis and prediction, and to explore whether ZnT8 is a potential therapeutic target in T1DM. DATA SOURCES: A search was conducted within the medical database PubMed for relevant articles published from 2001 to 2015. The search terms are as follows: "ZnT8," "type 1 diabetes," "latent autoimmune diabetes in adults," "type 2 diabetes," "islet autoantibodies," "zinc supplement," "T cells," "ß cell," "immune therapy." We also searched the reference lists of selected articles. STUDY SELECTION: English-language original articles and critical reviews concerning ZnT8 and the clinical applications of islet autoantibodies in diabetes were reviewed. RESULTS: The basic function of ZnT8 is maintaining intracellular zinc homeostasis, which modulates the process of insulin biosynthesis, storage, and secretion. Autoantibodies against ZnT8 (ZnT8A) and ZnT8-specific T cells are the reliable biomarkers for the identification, stratification, and characterization of T1DM. Additionally, the results from the animal models and clinical trials have shown that ZnT8 is a diabetogenic antigen, suggesting the possibility of ZnT8-specific immunotherapy as an alternative for T1DM therapy. CONCLUSIONS: ZnT8 is a novel islet autoantigen with a widely potential for clinical applications in T1DM. However, before the large-scale clinical applications, there are still many problems to be solved.

Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial.

BACKGROUND: Metformin is the only first-line oral hypoglycaemic drug for type 2 diabetes recommended by international guidelines with proven efficacy, safety, and cost-effectiveness. However, little information exists about its use in Asian populations. We aimed to ascertain the effectiveness of the α-glucosidase inhibitor acarbose, extensively adopted in China, compared with metformin as the alternative initial therapy for newly diagnosed type 2 diabetes. METHODS: In this 48-week, randomised, open-label, non-inferiority trial, patients who were newly diagnosed with type 2 diabetes, with a mean HbA1c of 7·5%, were enrolled from 11 sites in China. After a 4-week lifestyle modification run-in, patients were assigned to 24 weeks of monotherapy with metformin or acarbose as the initial treatment, followed by a 24-week therapy phase during which add-on therapy was used if prespecified glucose targets were not achieved. Primary endpoints were to establish whether acarbose was non-inferior to metformin in HbA1c reduction at week 24 and week 48 timepoints. The non-inferiority margin was 0·3%, with an expected null difference in the change from baseline to week 48 in HbA1c. Analysis was done on a modified intention-to-treat population. This study was registered with Chinese Clinical Trial Registry, number ChiCTR-TRC-08000231. FINDINGS: Of the 788 patients randomly assigned to treatment groups, 784 patients started the intended study drug. HbA1c reduction at week 24 was -1·17% in the acarbose group and -1·19% in the metformin group. At week 48, the HbA1c reduction was -1·11% (acarbose) and -1·12% (metformin) with difference 0·01% (95% CI -0·12 to 0·14, p=0·8999). Six (2%) patients in the acarbose group and seven (2%) patients in the metformin group had serious adverse events, and two (1%) and four (1%) had hypoglycaemic episodes. INTERPRETATION: This study provides evidence that acarbose is similar to metformin in efficacy, and is therefore a viable choice for initial therapy in Chinese patients newly diagnosed with type 2 diabetes. FUNDING: Bayer Healthcare (China) and Double Crane Phama.

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.

Anti-apoptotic function and mechanism of ginseng saponins in Rattus pancreatic ß-cells.

Apoptosis is the main form of ß-cell death in diabetes. Ginseng has been used as an anti-diabetic herb for several thousand years in Asia with ginsenoside Rg1 and ginsenoside Rb1 as important active ingredients. In this study, we demonstrated ginsenoside Rg1 and Rb1 protect ß-cells from high glucose/cytokine-induced pancreatic ß-cell apoptosis via inhibiting nitric oxide (NO) production and regulating apoptosis-related genes. Among these genes, Bax, Fas and Caspase-3 gene expressions were up-regulated by high glucose, whereas only Bax and Caspase-3 gene expression were elevated by cytokines. In these two stimuli-induced apoptotic cells, Rg1 down-regulated Fas gene expression, while Rb1 decreased Caspase-3 gene expression. As a conclusion, Fas signal pathway and mitochondria stress is mostly related to anti-diabetes function of ginsenoside Rg1, while Caspase-3 pathway is essential when Rb1 is present.

Modulation of monocyte hyperresponsiveness to TLR ligands by 1,25-dihydroxy-vitamin D3 from LADA and T2DM.

To investigate the differences of Toll-like receptors (TLRs) expression and response of monocyte and modulation of 1,25-dihydroxy-vitamin D3 on monocyte activity. Peripheral blood monocytes were collected from 23 healthy controls, 18 latent autoimmune diabetes in adults (LADA), and 22 type 2 diabetes mellitus (T2DM), respectively. CD14, TLR2 and TLR4 expression were analyzed. Moreover, the effect of 1,25-dihydroxy-vitamin D3 (1,25(OH)(2)D3) on monocyte response to lipoteichoic acid (LTA) and lipopolysaccharide (LPS) was evaluated in vitro by measuring phosphorylation level of NF-kappaB-p65 and associated cytokine production. Monocytes showed significantly higher surface CD14 expression from LADA compared with that from T2DM and controls, and high expression of TLR4 from LADA and T2DM than controls. After incubation with LPS or LTA, decreased surface expressions of CD14 were observed on monocytes from T2DM and controls, in contrast to the increased on monocytes from LADA. Activation of NF-kappaB and amounts of IL-1beta and TNF-alpha production by stimulation with ligands significantly increased in LADA and T2DM, which was modulated by 1,25(OH)(2)D3 to similar level, as compared to controls. The modulation of 1,25(OH)(2)D3 on monocytes makes us to consider more potency of vitamin D3 as therapy in LADA and T2DM.