Aims Metformin treatment for type 2 diabetes mellitus (T2DM) can be limited by gastrointestinal (GI) adverse events (AEs), resulting in treatment discontinuation. We investigated whether once‐daily metformin extended release (XR) is superior in terms of GI tolerability, with non‐inferior efficacy, compared with thrice‐daily metformin immediate release (IR) in treatment‐naïve Chinese patients with T2DM. Materials and Methods This prospective, open‐label, randomized, multicentre, phase IV interventional study enrolled Chinese T2DM patients to receive either metformin XR or metformin IR with a 2‐week screening period, a 16‐week treatment period and a 2‐week follow‐up period without treatment. Co‐primary endpoints were a non‐inferiority assessment of metformin XR vs metformin IR in glycated haemoglobin (HbA1c) least squares mean (LSM) change from baseline to week 16 and the superiority of GI tolerability for metformin XR vs metformin IR. Results Overall, 532 patients were randomized to metformin IR (n = 267) or metformin XR (n = 265). The HbA1c LSM change was −1.61% and −1.58% in each group, respectively (LSM difference, 0.03; 95% confidence interval [CI], −0.10, 0.17). Incidences of drug‐related AEs were 26.5% (n = 66) in the metformin IR‐only group and 32.2% (n = 85) in the metformin XR‐only group, and GI AEs were 23.8% and 22.3% in each group, respectively (difference, −1.52; 95% CI, −8.60, 5.56). The treatment difference met the predefined non‐inferiority upper CI margin of 0.4% in HbA1c. Conclusions Metformin XR was non‐inferior to metformin IR for the LSM change in HbA1c from baseline to week 16 and not superior to metformin IR for overall GI AE incidence during treatment of Chinese T2DM patients.

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was −1.07% (−1.19%, −0.95%) in the dorzagliatin group and −0.50% (−0.68%, −0.32%) in the placebo group (estimated treatment difference, −0.57%; 95% confidence interval: −0.79%, −0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

Abstract. Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, Wu G, Shi L, Feng Z, Qiu L, Li Q, Guo X, Luo Z, Lu J, Shan Z, Yang W, Ji Q, Yan L, Li H, Yu X, Li S, Zhou Z, Lv X, Liang Z, Lin S, Zeng L, Yan J, Ji L, Weng J (The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou; Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing; Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing; Objective. Progressive b-cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes, but comparative data on b-cell-protective therapies are lacking in the early stage of type 2 diabetes. Here we evaluated the comparative glycaemic efficacy and impact on b-cell function of three antihyperglycaemic agents that have a b-cell-protective effect, exenatide, insulin and pioglitazone, in newly diagnosed patients with type 2 diabetes.Design and methods. In this 48-week, multicentre, parallel-group study, 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1 : 1 : 1 to receive exenatide, insulin or pioglitazone. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from baseline. Secondary end-points included effects on weight, blood pressure, lipid profiles and b-cell function assessed by homeostasis model assessment, fasting proinsulin:insulin (PI/I), disposition index (DI) and acute insulin response (AIR).Results. At week 48, mean [95% confidence interval (CI)] HbA 1c changes from baseline were À1.8% (À1.55% to À2.05%) with exenatide, À1.7% (À1.52% to À1.96%) with insulin and À1.5% (À1.23% to À1.71%) with pioglitazone. Treatment differences were À0.20% (95% CI À0.46% to 0.06%) for exenatide versus insulin (P = 0.185), and À0.37% (95% CI À0.63% to À0.12%) for exenatide versus pioglitazone (P = 0.002). Significant improvements from baseline in AIR, PI/I and DI were observed with all treatments, with the greatest improvements in DI, as well as weight, blood pressure and lipid profile, observed with exenatide.Conclusions. All three agents showed efficacy regarding glycaemic control and metabolic benefits; however, exenatide showed the greatest efficacy. b-cell function improved in all treatment groups; hence, early initiation of b-cell-protective therapy may halt the decline in b-cell function in type 2 diabetes.

Bone morphogenetic protein (BMP)‐9 has been reported to regulate energy balance in vivo. However, the mechanisms underlying BMP9‐mediated regulation of energy balance remain incompletely understood. Here, we investigated the role of BMP9 in energy metabolism. In the current study, we found that hepatic BMP9 expression was down‐regulated in insulin resistance (IR) mice and in patients who are diabetic. In mice fed a high‐fat diet (HFD), the overexpression of hepatic BMP9 improved glucose tolerance and IR. The expression of gluconeogenic genes was down‐regulated, whereas the level of insulin signaling molecule phosphorylation was increased in the livers of Adenovirus‐BMP9‐treated mice and glucosamine‐treated hepatocytes. Furthermore, BMP9 overexpression ameliorated triglyceride accumulation and inhibited the expression of lipogenic genes in both human hepatocellular carcinoma HepG2 cells treated with a fatty acid mixture as well as the livers of HFD‐fed mice. In hepatocytes isolated from sterol regulatory element‐binding protein (SREBP)‐1c knockout mice, the effects of BMP9 were ablated. Mechanistically, BMP9 inhibited SREBP‐1c expression through the inhibition of liver X receptor response element 1 activity in the SREBP‐1c promoter. Taken together, our results show that BMP9 is an important regulator of hepatic glucose and lipid metabolism.—Yang, M., Liang, Z., Yang, M., Jia, Y., Yang, G., He, Y., Li, X., Gu, H. F., Zheng, H., Zhu, Z., Li, L. Role of bone morphogenetic protein‐9 in the regulation of glucose and lipid metabolism. FASEB J. 33, 10077–10088 (2019). http://www.fasebj.org

Background: Recurrence of high-risk diabetic feet, after wound, healing is a common challenge among diabetic patients. Continuous use of an offloading device significantly prevents recurrence of high-risk diabetic feet, although patient adherence is imperative to ensuring this therapy's clinical efficacy. In this study, we explored clinical outcomes of patients with a high-risk diabetic foot who had been prescribed with custom-molded offloading footwear under different adherence conditions. Methods: A total of 48 patients (17 females and 31 males) with high-risk diabetic feet, who had been with prescribed offloading footwear in 13 medical centers across 4 cities, were enrolled in the current study. The patients were assigned into either continuous offloading therapy (COT, n = 31) or interrupted offloading therapy (IOT, n = 17) groups, according to their adherence to the therapy. All patients were followed up monthly, and differences in recurrence, amputation, and deaths between the groups were analyzed at 4 months after therapy. Results: Forty-eight patients met our inclusion criteria and were therefore included in the final analysis. Among them, 31 were stratified into the COT group and adhered to offloading therapy throughout the study period, whereas 17 were grouped as IOT and exhibited interrupted adherence to offloading therapy. We found statistically significant differences in recurrence rates (0 vs 38.46%, p < 0.01), amputation (0 vs 11.76%, p < 0.01), and deaths (0% vs 5.88%, p < 0.01) between the groups during follow-up. Conclusion: Patients' adherence is imperative to efficacy of custom-molded offloading footwear during treatment of high-risk diabetic foot. Further studies are needed to elucidate the role of improved design of the offloading device and the need for enhanced patient education for improved adherence.

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Objective: Zinc-a 2 -glycoprotein (ZAG) has recently been characterized as a potent metabolic regulator. However, the effects of anti-diabetic agents on circulating ZAG levels in humans remain largely unknown. To explore the possible mechanisms by which the dipeptidyl peptidase-IV (DPP-IV) inhibitor improves insulin resistance, we investigated the effect of sitagliptin, a DPP-IV inhibitor, on circulating cytokine levels in newly diagnosed type 2 diabetes (nT2DM) patients. Design and methods: A subset of 141 subjects with nT2DM were assigned to receive placebo (nZ47) or sitagliptin (nZ94) for 3 months. Before and after treatment, subjects received a 75 g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp (EHC), and measurement of ZAG and adiponectin (ADI) concentrations. Results: Circulating ZAG levels were lower in nT2DM than in control individuals (P!0.01). After 3 months of sitagliptin treatment, HbA1c, fasting plasma glucose, postprandial glucose, 2-h insulin after glucose overload, triglycerides, and homeostasis model assessment of insulin resistance (HOMA-IR) were decreased significantly compared with pre-treatment (P!0.05 or P!0.01), whereas the glucose infusion rate during the stable period of the clamp (M values) during EHC were significantly increased (P!0.01). In addition, circulating ZAG and ADI concentrations were significantly increased along with improved glucose metabolism and insulin sensitivity compared with pre-treatment (both P!0.01) and the change of ZAG (DZAG) was positively associated with DADI, DHOMA-IR, DBMI, Dfasting insulin and negatively associated with D tumor necrosis factor-a (TNF-a). Furthermore, sitagliptin treatment resulted in significantly lowered plasma TNF-a level (P!0.05). Conclusion: A low level of circulating ZAG is associated with insulin resistance and sitagliptin treatment significantly increases circulating ZAG levels. These observations have implications in relation to the mode of action of the DPP-IV inhibitor as an insulin sensitizing agent.

BackgroundGhrelin modulates many physiological processes. However, the effects of intestinal ghrelin on hepatic glucose production (HGP) are still unclear. The current study was to explore the roles of intestinal ghrelin on glucose homeostasis and insulin signaling in the liver.MethodsThe system of intraduodenal infusion and intracerebral microinfusion into the nucleus of the solitary tract (NTS) in the normal chow-diet rats and pancreatic-euglycemic clamp procedure (PEC) combined with [3-3H] glucose as a tracer were used to analyze the effect of intestinal ghrelin. Intraduodenal co-infusion of ghrelin, tetracaine and Activated Protein Kinase (AMPK) activator (AICAR), or pharmacologic and molecular inhibitor of N-methyl-D-aspartate receptors within the dorsal vagal complex, or hepatic vagotomy in rats were used to explore the possible mechanism of the effect of intestinal ghrelin on HGP.ResultsOur results demonstrated that gut infusion of ghrelin inhibited duodenal AMP-dependent protein kinase (AMPK) signal pathways, increased HGP and expression of gluconeogenic enzymes, and decreased insulin signaling in the liver of the rat. Intraduodenal co-infusion of ghrelin receptor antagonist [D-Lys3]-GHRP-6 and AMPK agonist with ghrelin diminished gut ghrelin-induced increase in HGP and decrease in glucose infusion rate (GIR) and hepatic insulin signaling. The effects of gut ghrelin were also negated by co-infusion with tetracaine, or MK801, an N-methyl-D-aspartate (NMDA) receptor inhibitor, and adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shNR1) within the dorsal vagal complex, and hepatic vagotomy in rats. When ghrelin and lipids were co-infused into the duodenum, the roles of gut lipids in increasing the rate of glucose infusion (GIR) and lowering HGP were reversed.ConclusionsThe current study provided evidence that intestinal ghrelin has an effect on HGP and identified a neural glucoregulatory function of gut ghrelin signaling.Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0321-y) contains supplementary material, which is available to authorized users.