Taste Receptors Function as Nutrient Sensors in Pancreatic Islets: A Potential Therapeutic Target for Diabetes.

Glucose, amino acids, and free fatty acids are critical nutrients participating in stimulating or regulating the hormone secretion of islets. These nutrients are believed to be metabolized by pancreatic endocrine cells to function. However, recent evidence suggests that taste receptors, which play key roles in the oral cavity to sense glucose (sweet taste), amino acids (umami taste), and free fatty acids (fatty taste), are expressed in pancreatic islet cells and may act to sense these nutrients to regulate pancreatic hormone secretion, including insulin and glucagon. Disorders in these taste receptor pathways in islets may contribute to the pathogenesis of diabetes, or it may influence hyperglycemia, disturbance in amino acid metabolism, or hyperlipidemia. In this review, we su mMarize the expression and hormone-regulating functions of sweet, umami, and fatty taste receptors acting as nutrient sensors in pancreatic islets in vitro and in vivo. We discuss the potential roles of these taste receptor-nutrient sensor pathways in islets targeted to develop therapeutic strategies for diabetes and related disease.

Vitamin D inhibits bone loss in mice with thyrotoxicosis by activating the OPG/RANKL and Wnt/ß-catenin signaling pathways.

Objective: Vitamin D and thyroid hormones have crucial roles in bone metabolism. This study aims to explore the effects of vitamin D on bone metabolism in mice with thyrotoxicosis and its mechanisms. Methods: 12-week-old mice were randomly divided into 6 groups (6 mice/group), the control (CON) group, vitamin D (VD) group, low-dose LT4 (Low LT4) group, low-dose LT4+VD (Low LT4+VD) group, high-dose LT4 (High LT4) group, high-dose LT4+VD (High LT4+VD) group, LT4 was provided every day and vitamin D3 every other day for 12 weeks. Thyroid function, 25-hydroxy vitamin D, type I collagen carboxy-terminal peptide (CTX), and type I procollagen amino-terminal peptide were determined. In addition, microcomputed tomography, bone histology and histomorphometry, a three-point bending test, and the mRNA expression of osteoprotegerin (OPG), receptor activator of nuclear factor-κB ligand (RANKL) and ß-catenin in bone were conducted. Results: The BMD of lumbar vertebrae and femur decreased and the bone microstructure was destroyed significantly in thyrotoxicosis mice. Addition of vitamin D improved the BMD and bone microstructure only in the low LT4+VD group. Mice with thyrotoxicosis had a significantly higher level of CTX (P<0.05), which was decreased by treatment with vitamin D (P<0.05). The eroded surface per bone surface (Er. S/BS) of the cancellous bone and elongated surface/endocortical perimeter (Er. S/E Pm) of the cortical bone significantly increased in the Low LT4 and High LT4 groups (P<0.05). Treatment with vitamin D significantly decreased the Er. S/BS and Er. S/E Pm. But, treatment with vitamin D did not significantly improve the toughness and rigidity of bones. The ratio of OPG to RANKL and mRNA expression of ß-catenin in the Low LT4+VD group were higher than that in the Low LT4 group (P<0.05). Conclusion: In mice with thyrotoxicosis, treatment with vitamin D can inhibit bone resorption and improve the BMD and trabecular bone architecture by increasing the ratio of OPG to RANKL and upregulating the expression of Wnt/ß-catenin.

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.

Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis.

BACKGROUND: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER). METHODS: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. RESULTS: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER. CONCLUSION: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose low-density lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone.

Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study.

OBJECTIVE: This study aimed to investigate the changes in inflammatory biomarkers between newly diagnosed type 2 diabetes (T2DM) patients under one-year acarbose treatments and those under metformin managements. METHODS: Seventy patients with newly diagnosed T2DM and 32 volunteers with normal glucose tolerance (normal controls, NCs) were enrolled. Seventy patients with T2DM were randomly assigned to two subgroups and treated with acarbose (n=34) or metformin (n=36) for 1 year. Blood glucose, insulin, glycosylated hemoglobin (A1C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and inflammatory biomarker levels (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), and ferritin) were detected at 0, 6 and 12 months. RESULTS: After adjusting for sex, the waist-to-hip ratio (WHR) and body mass index (BMI), higher fasting plasma glucose (FPG), standard meal test 1/2 hr and 2 hr glucose, TG, TC, LDL-C, IL-6, TNF-α, IL-2 and ferritin levels were observed in T2DM group than in NCs (P<0.05). After 6 months of treatment, TNF-α levels were significantly decreased in both subgroups, and IL-6 and ferritin levels were significantly decreased after 12 months (P<0.05). However, no significant differences in the IL-6, TNF-α and ferritin levels were observed between the two subgroups. Moreover, significantly higher IL-6 and TNF-α levels were detected in the T2DM group than in NCs after 12 months of treatment (P<0.05). CONCLUSION: Patients with newly diagnosed T2DM exhibited a marked chronic inflammatory state characterized by increased IL-6, TNF-α, IL-1ß, IL-2 and ferritin levels. After 1 year of treatment with acarbose or metformin, IL-6, TNF-α, IL-1ß and ferritin levels were significantly decreased compared with the baseline. The anti-inflammatory effects of acarbose and metformin were comparable and required a long-term treatment (1 year), but the characteristics were different. Further investigations are needed to determine whether this effect was independent of the hypoglycemic effects.

Berberine Modulates Gut Microbiota and Reduces Insulin Resistance via the TLR4 Signaling Pathway.

Berberine, a natural compound extracted from several Chinese herbs including Coptis chinensis, has been shown to have anti-obesity effects and prevents insulin resistance in high-fat diet (HFD)-fed obese rats by modulating the gut microbiota; however, the molecular mechanisms underlying these activities remain unknown. We investigated the effects of berberine on obesity and insulin resistance by examining the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4)/tumor necrosis factor (TNF)-α signaling pathway in livers of HFD-fed obese rats. Our results showed that 8-week berberine (200 mg/kg) treatment significantly reduced fasting blood glucose, triglyceride, low-density lipoprotein-cholesterol and insulin resistance in HFD-fed obese rats. However, berberine had no significant effects on body weight, visceral fat mass or the visceral fat to body weight ratio. Berberine also attenuated HFD-induced hepatic steatosis. A prolonged HFD altered the gut microbiota composition by reducing protective bacteria like Bifidobacterium and increasing gram negative bacteria like Escherichia coli, which resulted in increased LPS release into plasma. Berberine reversed these effects and inhibited LPS-induced TLR4/TNF-α activation, resulting in increased insulin receptor and insulin receptor substrate-1 expression in the liver. These findings suggested that berberine may reduce insulin resistance, at least in part by modulating the gut microbiota along with inhibiting LPS/TLR4/TNF-α signaling in the liver.

Efficacy of Aloe Vera Supplementation on Prediabetes and Early Non-Treated Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The aim of this study was to evaluate evidence for the efficacy of aloe vera on managing prediabetes and early non-treated diabetes mellitus. We performed a systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials until 28 January 2016. A total of five randomized controlled trials (RCTs) involving 415 participants were included. Compared with the controls, aloe vera supplementation significantly reduced the concentrations of fasting blood glucose (FBG) (p = 0.02; weighed mean difference [WMD]: -30.05 mg/dL; 95% confidence interval [CI]: -54.87 to -5.23 mg/dL), glycosylated hemoglobin A1c (HbA1c) (p < 0.00001; WMD: -0.41%; 95% CI: -0.55% to -0.27%), triglyceride (p = 0.0001), total cholesterol (TC) (p < 0.00001), and low density lipoprotein-cholesterol (LDL-C) (p < 0.00001). Aloe vera was superior to placebo in increasing serum high density lipoprotein-cholesterol (HDL-C) levels (p = 0.04). Only one adverse event was reported. The evidence from RCTs showed that aloe vera might effectively reduce the levels of FBG, HbA1c, triglyceride, TC and LDL-C, and increase the levels of HDL-C on prediabetes and early non-treated diabetic patients. Limited evidence exists about the safety of aloe vera. Given the small number and poor quality of RCTs included in the meta-analysis, these results are inconclusive. A large-scale, well-designed RCT is needed to further address this issue.

Silybin reduces obliterated retinal capillaries in experimental diabetic retinopathy in rats.

Silybin has been previously reported to possess anti-inflammatory properties, raising the possibility that it may reduce vascular damage in diabetic retinopathy. Present study was designed to investigate this potential effect of silybin and its underlying mechanisms in experimental diabetic retinopathy. Diabetes was induced with streptozotocin (STZ) plus high-fat diet in Sprague-Dawley rats, and silybin was administrated for 22 weeks after the induction of diabetes. Histochemical and immunofluorescence techniques were used to assess the obliterated retinal capillaries, leukostasis, and level of retinal intercellular adhesion molecule-1 (ICAM-1). Western blot was performed to quantitate the expression of retinal ICAM-1. Results showed that silybin treatment significantly prevented the development of obliterated retinal capillaries in diabetes, compared with vehicle treatment. In addition, leukostasis and level of the retinal ICAM-1 were found to decrease considerably in silybin-treated diabetic groups. In conclusion, these results indicate that silybin reduces obliterated retinal capillaries in experimental diabetes, and the recovered retinal vascular leukostasis and level of ICAM-1 at least partly contributes to the preventive effect of silybin.

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.

Cellular production of n-3 PUFAs and reduction of n-6-to-n-3 ratios in the pancreatic beta-cells and islets enhance insulin secretion and confer protection against cytokine-induced cell death.

OBJECTIVE: To evaluate the direct impact of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the functions and viability of pancreatic beta-cells. RESEARCH DESIGN AND METHODS: We developed an mfat-1 transgenic mouse model in which endogenous production of n-3 PUFAs was achieved through overexpressing a C. elegans n-3 fatty acid desaturase gene, mfat-1. The islets and INS-1 cells expressing mfat-1 were analyzed for insulin secretion and viability in response to cytokine treatment. RESULTS: The transgenic islets contained much higher levels of n-3 PUFAs and lower levels of n-6 PUFAs than the wild type. Insulin secretion stimulated by glucose, amino acids, and glucagon-like peptide-1 (GLP-1) was significantly elevated in the transgenic islets. When challenged with tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and gamma-interferon (IFN-gamma), the transgenic islets completely resisted cytokine-induced cell death. Adenoviral transduction of mfat-1 gene in wild-type islets and in INS-1 cells led to acute changes in the cellular levels of n-3- and n-6 PUFAs and recapitulated the results in the transgenic islets. The expression of mfat-1 led to decreased production of prostaglandin E(2) (PGE(2)), which in turn contributed to the elevation of insulin secretion. We further found that cytokine-induced activation of NF-kappaB and extracellular signal-related kinase 1/2 (ERK(1/2)) was significantly attenuated and that the expression of pancreatic duodenal hemeobox-1 (PDX-1), glucokinase, and insulin-1 was increased as a result of n-3 PUFA production. CONCLUSIONS: Stable cellular production of n-3 PUFAs via mfat-1 can enhance insulin secretion and confers strong resistance to cytokine-induced beta-cell destruction. The utility of mfat-1 gene in deterring type 1 diabetes should be further explored in vivo.

[A multicenter randomized controlled clinical trial on blood glucose lowering effects of domestic Acarbose (capsule) in type 2 diabetic patients].

OBJECTIVE: To assess the efficacy, tolerability, and safety of the domestic Acarbose capsule (DAC, produced by Luzhou Baoguang Pharmaceutical Co. LTD) in treating patients with type 2 diabetes mellitus. METHODS: One hundred and seventy nine type 2 diabetic patients were randomly divided into DAC (group A, 89 patients) and Glucoby (group B, 90 patients) treatment groups. The trial consisted of a 2-4 weeks equilibrated period followed by an 8 week course of treatments. All of the patients were followed up at the 4th week and 8th week after the commencement of the treatments. One hundred and sixty five patients completed the trial, with 81 in group A and 84 in group B. RESULTS: At the 4th week of the treatments, an average reduction of 1.81 and 2.08 mmol/L of fasting blood glucose (FBG) was found in group A and group B, respectively (P > 0.05); and an average reduction of 5.43 and 5.09 mmol/ L of postprandial blood glucose (PBG) was found in group A and group B, respectively (P > 0.05). At the 8th week, an average reduction of 2.35 and 2.62 mmol/L FBG was found in group A and group B, respectively (P > 0.05); and an average of reduction of 5.93 and 5.98 mmol/L of PBG was found in group A and group B, respectively (P > 0.05); The mean HbA(1c) was lowered by 1.07% and 1.20% by DAC and Glucoby respectively (P > 0.05). The incidence rate of side effects in group A was 32.53%, less than that in group B (48.81%). Flatulence was the most common side effect. The clinical effects of both Glucoby and DAC were more significant at the 8th week than at the 4th week. CONCLUSION: DAC is as effective and safe as Glucobay for treating type 2 diabetic patients.

[The change of atherogenic index of plasma (AIP) level in type 2 diabetic pedigrees and the response of AIP to Acarbose or Glimepiride in therapy of type 2 diabetes mellitus].

The alterations in atherogenic index of plasma (AlP) in type 2 diabetic patients and their normoglycemic first-degree relatives (NFDR) were investigated, and the effects of Acarbose or Glimepiride on AIP in 99 type 2 diabetic patients were evaluated. Triglycerride (TG), total cholesterol, high density lipoprotein-cholesterol (HDL-C) levels were analyzed, and Log (TG/HDL-C) was calculated as AIP in 62 type 2 diabetic patients and their 67 NFDR from 29 type 2 diabetic pedigrees and in 45 healthy controls without family histories of diabetes. Also analyzed were the same parameters in 99 type 2 diabetic patients before and after therapy with Acarbose or Glimepiride. The results revealed that diabetic patients and their NFDR had significantly higher AIP than did the controls, whereas no significant differences were seen between diabetic patients and their NFDR. Positive correlation of AIP between type 2 diabetic patients and their offspring were observed (r = 0.241, P < 0.05). After 8 weeks therapy with Acarbose, the AIP of type 2 diabetic patients was decreased significantly, and no differences were observed for AIP levels in Glimepiride group although the AIP was lower when compared with the untreated level. As a significant inverse correlation of small dense low density lipoprotein (sdLDL) with AIP was confirmed, our data suggest that diabetic patients and their NFDR from type 2 diabetic pedigrees had significantly higher AIP than did controls; AIP could be decreased by therapy with Acarbose in type 2 diabetic patients; Glimepiride may bring potential benefit to type 2 diabetic patients by influencing sdLDL.