Combined use of GABA and sitagliptin promotes human ß-cell proliferation and reduces apoptosis.

γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent ß-cell survival and function. In human ß-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic ß-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human ß-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human ß-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ ß-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on ß cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of ß-cell proliferation and a decrease in apoptosis.

A thorough analysis of diabetes research in China from 1995 to 2015: current scenario and future scope.

The prevalence of diabetes has increased dramatically over the past three decades, and currently, China has the largest number of diabetics worldwide; this number continues to grow and puts ongoing strains on the medical resources. In this review, we reviewed the diabetes research conducted in China from 1995 to 2015 with the aim of providing new insights regarding the current status and future perspectives for researchers, diabetes health providers, and respective policy-makers. Remarkable progress has been made in diabetes research in China during the past two decades in terms of both the quantity and publication influence. The progress, however, struggles to adequately manage diabetes in China. Here we addressed opportunities to strengthen researches, including new drug development, high quality studies on health economics, and healthcare quality improvement studies. As the expected wave of diabetic complications is upcoming and overwhelming, we therefore recommend that immediate improvements are required to implement the researches regarding their prevention and treatment.

Dietary Curcumin Intervention Targets Mouse White Adipose Tissue Inflammation and Brown Adipose Tissue UCP1 Expression.

OBJECTIVE: This study aimed to determine whether dietary curcumin intervention targets both white adipose tissue (WAT) inflammation and brown adipose tissue (BAT)-mediated energy expenditure. METHODS: C57BL/6J mice were fed with a low-fat diet, high-fat diet (HFD), or HFD plus curcumin. In addition to assessing the effect of curcumin intervention on metabolic profiles, this study assessed WAT macrophage infiltration and composition and inflammatory cytokine production. Metabolic cages were applied for determining energy expenditure. Raw264.7 (ATCC, Manassas, Virginia) and other cell models were utilized to test the in vitro effect of curcumin treatment. RESULTS: Curcumin intervention reduced WAT macrophage infiltration and altered macrophage functional polarity, as the ratio of M2-like versus M1-like macrophages increased after curcumin intervention. Curcumin treatment reduced M1-like macrophage markers or proinflammation cytokine expression in both macrophages and adipocytes. Curcumin intervention also increased energy expenditure and body temperature in response to a cold challenge. Finally, the in vivo and in vitro investigations suggested that curcumin increased expression of uncoupling protein 1 (UCP1), possibly involving PPAR-dependent and -independent mechanisms. CONCLUSIONS: Curcumin intervention targets both WAT inflammation and BAT UCP1 expression. These observations advanced our knowledge on the metabolic beneficial effects of the curry compound curcumin, bringing us a novel perspective on dietary polyphenol research.

Curcumin and other dietary polyphenols: potential mechanisms of metabolic actions and therapy for diabetes and obesity.

Recent controversy regarding the therapeutic potential of curcumin indicates the challenges to research in this field. Here, we highlight the investigations of curcumin and other plant-derived polyphenols that demonstrate their application to metabolic diseases, in particular, obesity and diabetes. Thus, a number of preclinical and clinical investigations have shown the beneficial effect of curcumin (and other dietary polyphenols) in attenuating body weight gain, improving insulin sensitivity, and preventing diabetes development in rodent models and prediabetic subjects. Other intervention studies with dietary polyphenols have also found improvements in insulin resistance. Recent studies suggest that the metabolic effects of curcumin/polyphenols are linked to changes in the gut microbiota. Thus, research into curcumin continues to provide novel insights into metabolic regulation that may ultimately translate into effective therapy.

Short-Term Curcumin Gavage Sensitizes Insulin Signaling in Dexamethasone-Treated C57BL/6 Mice.

BACKGROUND: Long-term dietary curcumin (>12 wk) improves metabolic homeostasis in obese mice by sensitizing insulin signaling and reducing hepatic gluconeogenesis. Whether these occur only secondary to its chronic anti-inflammatory and antioxidative functions is unknown. OBJECTIVE: In this study, we assessed the insulin sensitization effect of short-term curcumin gavage in a rapid dexamethasone-induced insulin resistance mouse model, in which the chronic anti-inflammatory function is eliminated. METHODS: Six-week-old male C57BL/6 mice received an intraperitoneal injection of dexamethasone (100 mg/kg body weight) or phosphate-buffered saline every day for 5 d, with or without simultaneous curcumin gavage (500 mg/kg body weight). On day 7, insulin tolerance tests were performed. After a booster dexamethasone injection and curcumin gavage on day 8, blood glucose and insulin concentrations were measured. Liver tissues were collected on day 10 for quantitative polymerase chain reaction and Western blotting to assess gluconeogenic gene expression, insulin signaling, and the expression of fibroblast growth factor 21 (FGF21). Primary hepatocytes from separate, untreated C57BL/6 mice were used for testing the in vitro effect of curcumin treatment. RESULTS: Dexamethasone injection impaired insulin tolerance (P < 0.05) and elevated ambient plasma insulin concentrations by ~2.7-fold (P < 0.01). Concomitant curcumin administration improved insulin sensitivity and reduced hepatic gluconeogenic gene expression. The insulin sensitization effect of curcumin was demonstrated by increased stimulation of S473 phosphorylation of protein kinase B (P < 0.01) in the dexamethasone-treated mouse liver, as well as the repression of glucose production in primary hepatocytes (P < 0.001). Finally, curcumin gavage increased FGF21 expression by 2.1-fold in the mouse liver (P < 0.05) and curcumin treatment increased FGF21 expression in primary hepatocytes. CONCLUSION: These observations suggest that the early beneficial effect of curcumin intervention in dexamethasone-treated mice is the sensitization of insulin signaling, involving the stimulation of FGF21 production, a known insulin sensitizer.

Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter.

BACKGROUND: Betaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation. METHODS: Male wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE-/- mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target genes expression levels and the methylation status of the PPAR alpha gene were determined. RESULTS: ApoE-/- mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE-/- mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE-/- mice. In parallel, PPAR alpha promoter methylation level were slightly increased in ApoE-/- mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE-/- mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration. CONCLUSIONS: Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.

The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis.

The type 2 diabetes risk gene TCF7L2 is the effector of the Wnt signaling pathway. We found previously that in gut endocrine L-cell lines, TCF7L2 controls transcription of the proglucagon gene (gcg), which encodes the incretin hormone glucagon-like peptide-1 (GLP-1). Whereas peripheral GLP-1 stimulates insulin secretion, brain GLP-1 controls energy homeostasis through yet-to-be defined mechanisms. We aim to determine the metabolic effect of a functional knockdown of TCF7L2 by generating transgenic mice that express dominant-negative TCF7L2 (TCF7L2DN) specifically in gcg-expressing cells. The gcg-TCF7L2DN transgenic mice showed reduced gcg expression in their gut and brain, but not in pancreas. Defects in glucose homeostasis were observed in these mice, associated with attenuated plasma insulin levels in response to glucose challenge. The defect in glucose disposal was exacerbated with high-fat diet. Brain Wnt activity and feeding-mediated hypothalamic AMP-activated protein kinase (AMPK) repression in these mice were impaired. Peripheral injection of the cAMP-promoting agent forskolin increased brain ß-cat Ser675 phosphorylation and brain gcg expression and restored feeding-mediated hypothalamic AMPK repression. We conclude that TCF7L2 and Wnt signaling control gut and brain gcg expression and glucose homeostasis and speculate that positive cross-talk between Wnt and GLP-1/cAMP signaling is an underlying mechanism for brain GLP-1 in exerting its metabolic functions.

Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes.

BACKGROUND: Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. METHODOLOGY AND PRINCIPAL FINDINGS: We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. CONCLUSIONS AND SIGNIFICANCE: We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.

Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals.

BACKGROUND: Anthocyanins have been shown to improve endothelial function in animal models. However, whether these compounds have similar beneficial effects in humans is largely unknown. METHODS: In a short-term crossover study, 12 hypercholesterolemic individuals were given oral anthocyanins (320 mg) isolated from berries or placebo. Brachial artery flow-mediated dilation (FMD) was assessed before and after the intervention. In a long-term intervention trial (12 weeks), 150 hypercholesterolemic individuals were given anthocyanins (320 mg/day, n = 75) or placebo (n = 75), after which we measured FMD, plasma cGMP, and other serum biomarkers. Another short-term intervention was conducted in the presence of NO-cGMP inhibitors in 6 people and in a rat aortic ring model (n = 8). RESULTS: Significant increases of FMD from 8.3% (0.6%) at baseline to 11.0% (0.8%) at 1 h and 10.1% (0.9%) at 2 h were observed after short-term anthocyanin consumption, concomitantly with increases of plasma anthocyanin concentrations (P < 0.05). In the study participants who received long-term anthocyanin intervention, compared with the control group, we observed significant increases in the FMD (28.4% vs 2.2%), cGMP (12.6% vs -1.2%), and HDL-cholesterol concentrations, but decreases in the serum soluble vascular adhesion molecule-1 and LDL cholesterol concentrations (P < 0.05). The changes in the cGMP and HDL cholesterol concentrations positively correlated with FMD in the anthocyanin group (P < 0.05). In the presence of NO-cGMP inhibitors, the effects of anthocyanin on endothelial function were abolished in human participants and in a rat aortic ring model. CONCLUSIONS: Anthocyanin supplementation improves endothelium-dependent vasodilation in hypercholesterolemic individuals. This effect involves activation of the NO-cGMP signaling pathway, improvements in the serum lipid profile, and decreased inflammation.

Extracellular high dosages of adenosine triphosphate induce inflammatory response and insulin resistance in rat adipocytes.

Adenosine triphosphate (ATP), an important signaling molecule, participates in various pathophysiological processes via the activation of purinergic-receptors. Recent studies have shown that the expression and function of purinergic-receptors (P2-receptors) could be altered in diabetic or hyperinsulinemia conditions. To characterize the effect of ATP on insulin signaling, we treated primary rat adipocytes with varied concentrations of ATP. The pre-treatment led to impaired insulin signaling, i.e., blunted phosphorylation in Insulin Receptor Substrate-1 (IRS-1) tyrosine and Protein Kinase B (PKB) Ser473 in response to insulin treatment, when ATP concentration reached 1mM. We then observed that ATP dose-dependently reduced the level of IκB, a negative regulator of inflammatory response. Consistently, IRS-1 Ser307 phosphorylation in response to insulin treatment, a site for inflammatory pathway to interfere insulin signaling, was enhanced by ATP. Furthermore, effects of ATP on insulin signaling and IκB content were blocked by P2-receptor inhibition. Finally, insulin-stimulated glucose uptake was impaired by ATP in adipocytes but not in the L6 muscle cells. This study therefore shows for the first time the involvement of ATP-evoked P2-receptor activation in mediating the inflammatory response and the generation of insulin resistance in adipocytes.