An Intestinal FXR Agonist Mitigates Dysbiosis, Intestinal Tight Junctions, and Inflammation in High-Fat Diet-Fed Mice.

SCOPE: To analyze the effects of fexaramine (FEX), as an intestinal FXR agonist, on the modulation of the intestinal microbiota and ileum of mice fed a high-fat (HF) diet. METHODS AND RESULTS: Three-month-old C57Bl/6 male mice are divided into two groups and received a control (C, 10% of energy from lipids) or HF (50% of energy from lipids) diet for 12 weeks. They are subdivided into the C, C + FEX, HF, and HF + FEX groups. FEX is administered (FEX-5 mg kg-1 ) via orogastric gavage for three weeks. Body mass (BM), glucose metabolism, qPCR 16S rRNA gene expression, and ileum gene expression, bile acids (BAs), tight junctions (TJs), and incretin are analyzed. FEX reduces BM and glucose intolerance, reduces plasma lipid concentrations and the Firmicutes/Bacteroidetes ratio, increases the Lactobacillus sp. and Prevotella sp. abundance, and reduces the Escherichia coli abundance. Consequently, the ileal gene expression of Fxr-Fgf15, Tgr5-Glp1, and Cldn-Ocldn-Zo1 is increased, and Tlr4-Il6-Il1beta is decreased. CONCLUSION: FEX stimulates intestinal FXR and improves dysbiosis, intestinal TJs, and the release of incretins, mitigating glucose intolerance and BM increases induced by an HF diet. However, FEX results in glucose intolerance, insulin resistance, and reduces intestinal TJs in a control group, thus demonstrating limitations to this dietary model.

Antioxidant and anti-inflammatory effects of allicin in the kidney of an experimental model of metabolic syndrome.

Background: Recent studies have suggested that metabolic syndrome (MS) encompasses a group of risk factors for developing chronic kidney disease (CKD). This work aimed to evaluate the antioxidant and anti-inflammatory effects of allicin in the kidney from an experimental model of MS. Methods: Male Wistar rats (220-250 g) were used, and three experimental groups (n = 6) were formed: control (C), metabolic syndrome (MS), and MS treated with allicin (16 mg/Kg/day, gastric gavage) (MS+A). MS was considered when an increase of 20% in at least three parameters (body weight, systolic blood pressure (SBP), fasting blood glucose (FBG), or dyslipidemia) was observed compared to the C group. After the MS diagnosis, allicin was administered for 30 days. Results: Before the treatment with allicin, the MS group showed more significant body weight gain, increased SBP, and FBG, glucose intolerance, and dyslipidemia. In addition, increased markers of kidney damage in urine and blood. Moreover, the MS increased oxidative stress and inflammation in the kidney compared to group C. The allicin treatment prevented further weight gain, reduced SBP, FBG, glucose intolerance, and dyslipidemia. Also, markers of kidney damage in urine and blood were decreased. Further, the oxidative stress and inflammation were decreased in the renal cortex of the MS+A compared to the MS group. Conclusion: Allicin exerts its beneficial effects on the metabolic syndrome by considerably reducing systemic and renal inflammation as well as the oxidative stress. These effects were mediated through the Nrf2 pathway. The results suggest allicin may be a therapeutic alternative for treating kidney injury induced by the metabolic syndrome risk factors.

Siolmatra brasiliensis stem extract ameliorates antioxidant defenses and mitigates glycoxidative stress in mice with high-fat diet-induced obesity.

BACKGROUND: Obesity is accompanied by insulin resistance and glucose intolerance, which favor the onset of complications related to oxidative stress. The aim of this study was to investigate the effects and underlying mechanisms of hydroethanolic extract from Siolmatra brasiliensis stems on insulin resistance, glucose intolerance, advanced glycation end product (AGE) formation, and oxidative stress in mice with induced obesity. METHODS: C57BL-6 J mice were fed a high-fat diet for 14 weeks and treated with 125 or 250 mg/kg S. brasiliensis extract during the last 7 weeks. The study assessed glucose tolerance and insulin sensitivity, lipid profile, plasma levels of thiobarbituric acid reactive substances (TBARS, biomarkers of oxidative damage), fluorescent AGEs (biomarkers of advanced glycation), and paraoxonase 1 (PON1) activity (antioxidant enzyme). The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys were also investigated. RESULTS: Siolmatra brasiliensis extract had antiobesogenic effects; improved insulin sensitivity and glucose tolerance; decreased the total plasma cholesterol levels; decreased the levels of glycoxidative stress biomarkers, including AGEs (plasma, liver, kidneys) and TBARS (liver, kidneys); and also improved endogenous antioxidant defenses by increasing the activities of PON1 (plasma), SOD (kidneys), CAT (liver, kidneys), and GSH-Px (kidneys). CONCLUSION: This study expands on our knowledge about the pharmacological properties of S. brasiliensis and substantiates the potential of this plant species to be used as a complementary therapeutic agent to alleviate the metabolic dysfunctions resulting from dyslipidemia and glycoxidative stress.

Effect of Gymnema sylvestre Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance.

Gymnema sylvestre, a plant typical of India, has long been known for its hypoglycemic effects. The objective of this study was to evaluate the effect of G. sylvestre administration on glycemic control, insulin secretion, and insulin sensitivity in patients with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled clinical trial was conducted in 30 patients with IGT. Fifteen patients randomly received G. sylvestre in doses of 300 mg b.i.d. and the other 15 received placebo in the same way. Before and after the intervention, anthropometric and metabolic measurements were taken, including 2-h oral glucose tolerance test (2-h OGTT), fasting plasma glucose, glycated hemoglobin A1c (A1C), and the lipid profile panel. Areas under the curve of glucose and insulin were calculated, as well as the insulinogenic, Stumvoll, and Matsuda indices. Wilcoxon, Mann-Whitney U, and chi-square or Fisher's exact tests were performed, and a P-value ≤.05 was considered statistically significant. There was a significant reduction in 2-h OGTT (9.1 ± 1.2 vs. 7.8 ± 1.7 mmol/L, P = .003), A1C (5.8 ± 0.3% vs. 5.4 ± 0.4%, P = .025), body weight, body mass index, and low-density lipoprotein cholesterol levels in the G. sylvestre group, with an increment in the Matsuda index (1.8 ± 0.8 vs. 2.4 ± 1.2, P = .008). At the end of the intervention, 46.7% of the patients obtained normal values in A1C. In conclusion, G. sylvestre administration in patients with IGT decreased 2-h OGTT and A1C, increasing insulin sensitivity. There were also improvements in anthropometric measures and the lipid profile.

A novel nitroalkene vitamin E analogue inhibits the NLRP3 inflammasome and protects against inflammation and glucose intolerance triggered by obesity.

Chronic metabolic diseases, like obesity, type II diabetes and atherosclerosis often involve a low-grade and sterile systemic inflammatory state, in which activation of the pro-inflammatory transcription factor NF-kB and the NLRP3 inflammasome play a major role. It is well established that genetic inhibition of the NLRP3 inflammasome ameliorates acute and chronic inflammation. Indeed, accumulating experimental evidences in murine models and also in humans suggest that inhibition of the NLRP3 inflammasome might be a suitable approach to tackle the deleterious effects of chronic metabolic diseases. In this work, we explored our previously synthesized nitroalkene-Trolox™ derivative named NATx0, as a non-conventional anti-inflammatory strategy to treat chronic inflammatory diseases, such as obesity-induced glucose intolerance. We found that NATx0 inhibited NF-kB nuclear translocation and pro-inflammatory gene expression in macrophages in vitro. In addition, treatment with NATx0 prevented NLRP3 inflammasome activation after LPS/ATP stimulation in macrophages in vitro. When tested acutely in vivo, NATx0 inhibited neutrophil recruitment in zebrafish larvae, and also diminished IL-1ß production after LPS challenge in mice. Finally, when NATx0 was administered chronically to diet-induced obese mice, it decreased muscle tissue inflammation and glucose intolerance, leading to improved glucose homeostasis. In conclusion, we propose that this novel nitroalkene-Trolox derivative is a suitable tool to tackle acute and chronic inflammation in vitro and in vivo mainly due to inhibition of NF-kB/NLRP3 activation.

Palmatine ameliorates high fat diet induced impaired glucose tolerance.

BACKGROUND: The impaired glucose tolerance (IGT) is a representative prediabetes characterized by defective glucose homeostasis, and palmatine (PAL) is a natural isoquinoline alkaloid with multiple pharmacological effects. Our study aims to investigate the therapeutic effect of PAL on the impaired glucose tolerance. METHODS: Male Sprague-Dawley rats were used to establish an IGT model with high fat diet (HFD). Oral glucose tolerance test (OGTT) and further biochemical analysis were conducted to determine the effect of PAL on glucose intolerance in vivo. Molecular details were clarified in a cellular model of IGT induced by Palmitate (PA) on INS-1 cells. RESULTS: Our study demonstrated a relief of IGT with improved insulin resistance in HFD induced rats after PAL treatment. Besides, promoted pancreas islets function was validated with significantly increased ß cell mass after the treatment of PAL. We further found out that PAL could alleviate the ß cell apoptosis that accounts for ß cell mass loss in IGT model. Moreover, MAPK signaling was investigated in vivo and vitro with the discovery that PAL regulated the MAPK signaling by restricting the ERK and JNK cascades. The insulin secretion assay indicated that PAL significantly promoted the defective insulin secretion in PA-induced INS-1 cells via JNK rather than ERK signaling. Furthermore, PAL treatment was determined to significantly suppress ß cell apoptosis in PA-induced cells. We thus thought that PAL promoted the PA-induced impaired insulin release by inhibiting the ß cell apoptosis and JNK signaling in vitro. CONCLUSION: In summary, PAL ameliorates HFD-induced IGT with novel mechanisms.

Eplerenone Implantation Improved Adipose Dysfunction Averting RAAS Activation and Cell Division.

Introduction: Mineralocorticoid receptor (MR) activation within adipose tissue, triggers inflammation and metabolic syndrome development. The pharmacological blockade of MR provides beneficial effects for adipose tissue. Our study evaluates the impact of eplerenone implantation upon obesity. Experimental approach: A group of mice with implanted placebo pellets were fed using two types of diet, a normal (ND) or a high fat (HFD) diet. Additionally, a group of mice fed HFD were implanted with an eplerenone pellet. Metabolic and biochemical parameters were assessed in each animal group. Adipocyte size and lipid accumulation were investigated in the liver and adipose tissue. We evaluated the components of renin-angiotensin-aldosterone system (RAAS) locally in adipose tissue. Key results: Eplerenone reduced HFD-induced body weight gain, fasting glucose levels, fat accumulation, HFD-induced adipocyte size and liver lipid accumulation and improved glucose tolerance. In the adipose tissue, HFD significantly increased the mRNA levels of the RAAS molecules relative to the ND group. Eplerenone lowered RAAS mRNA levels, components of lipid metabolism and markers of inflammation in HFD-fed animals. Conclusion: MR antagonism with eplerenone diminishes insulin resistance that is related to obesity partly via a reduction of RAAS activation, inflammatory progression and cytokines induction. This suggests that eplerenone should be further studied as a therapeutic option for obesity and overweight.

Palmatine ameliorates high fat diet induced impaired glucose tolerance

BACKGROUND: The impaired glucose tolerance (IGT) is a representative prediabetes characterized by defective glucose homeostasis, and palmatine (PAL) is a natural isoquinoline alkaloid with multiple pharmacological effects. Our study aims to investigate the therapeutic effect of PAL on the impaired glucose tolerance. METHODS: Male Sprague-Dawley rats were used to establish an IGT model with high fat diet (HFD). Oral glucose tolerance test (OGTT) and further biochemical analysis were conducted to determine the effect of PAL on glucose intolerance in vivo. Molecular details were clarified in a cellular model of IGT induced by Palmitate (PA) on INS-1 cells. RESULTS: Our study demonstrated a relief of IGT with improved insulin resistance in HFD induced rats after PAL treatment. Besides, promoted pancreas islets function was validated with significantly increased ß cell mass after the treatment of PAL. We further found out that PAL could alleviate the ß cell apoptosis that accounts for ß cell mass loss in IGT model. Moreover, MAPK signaling was investigated in vivo and vitro with the discovery that PAL regulated the MAPK signaling by restricting the ERK and JNK cascades. The insulin secretion assay indicated that PAL significantly promoted the defective insulin secretion in PA-induced INS-1 cells via JNK rather than ERK signaling. Furthermore, PAL treatment was determined to significantly suppress ß cell apoptosis in PA-induced cells. We thus thought that PAL promoted the PA-induced impaired insulin release by inhibiting the ß; cell apoptosis and JNK signaling in vitro. CONCLUSION: In summary, PAL ameliorates HFD-induced IGT with novel mechanisms.

Impact of glucocorticoid treatment before pregnancy on glucose homeostasis of offspring exposed to glucocorticoid in adult life.

AIMS: To explore the impact of GC administration periconceptionally on the glucose metabolism of adult offspring (male and female) and whether this periconception exposure might influence the metabolic outcomes when the offspring are also treated with dexamethasone in adult life. MATERIALS AND METHODS: Rats received a daily injection of dexamethasone (1 mg/kg, body mass) or saline solution (1 mL/kg body mass) for 7 consecutive days prior became pregnant. Male and female offspring had glucose homeostasis assessed at 3- and 6-month-old and after dexamethasone treatment (1 mg/kg, body mass) or vehicle for 5 consecutive days. Then, murinometric, functional, biochemical, and histomorphometric analyses were performed. KEY FINDINGS: Male and female offspring born from rats treated with GC prior to becoming pregnant had none of the murinometric and metabolic outcomes (i.e., body mass, food intake, blood glucose, plasma triacylglycerol, and glucose tolerance) changed up to 6-month-old. None of the expected diabetogenic effects caused by dexamethasone treatment at 6-month of age (i.e., elevation in fasting blood glucose, plasma insulin, triacylglycerol, and albumin, glucose intolerance, insulin insensitivity, augmentation in hepatic glycogen content, and increase in pancreatic islet mass) was observed in offspring born from rats treated with dexamethasone in the prepregnancy period. However, periconceptional exposure to GC predisposed the offspring of both sexes to a higher prevalence of augmented fed blood glucose values. SIGNIFICANCE: These results give validity for the use of GC as anti-inflammatory purposes in this critical periconceptional period, but highlight the importance to consider all parental habits when interpreting adult outcomes.

Effect of Linagliptin versus Metformin on Insulin Secretion, Insulin Sensitivity and Glucose Control in Subjects with Impaired Glucose Tolerance / Efecto de la Linagliptina Frente a la Metformina en la Secreción de Insulina, Sensibilidad a la Insulina y Control de la Glucosa en Sujetos con Intolerancia a la Glucosa

ABSTRACT Aim: The aim of the study is to evaluate the effect of linagliptin versus metformin on insulin secretion, insulin sensitivity and glucose control in patients with impaired glucose tolerance (IGT). Patients and methods: A randomized, double-blind, clinical trial with parallel groups was per-formed on 16 adults with IGT. Lipid profile and haemoglobin (HbA1c) were evaluated prior to and after the intervention. Glucose and insulin were measured at 0, 30, 60, 90 and 120 minutes after a 75-g oral dextrose load. Eight patients received metformin (500 mg) twice a day before meals for three months. The remaining eight patients received placebo (500 mg) in the morning and linagliptin (5 mg) in the evening before meals. The area under the curve (AUC) of glucose and insulin, total insulin secretion, first-phase of insulin secretion, and insulin sensitivity were assessed. Results: After linagliptin administration, a significant decrease in glucose at 90 minutes (10.8 ± 2.6 vs 7.9 ± 2.2 mmol/L, p < 0.05), 120 minutes (8.8 ± 0.9 vs 6.5 ± 2.1 mmol/L, p < 0.05) and AUC of glucose (1168 ± 210 vs 953 ± 207 mmol/L, p < 0.05) were observed. Metformin administration decreased insulin significantly at 0 minutes (94.8 ± 25.8 vs 73.8 ± 24.6 pmol/L, p < 0.05). Conclusion: Three-month administration of linagliptin in patients with IGT decreased glucose at 90 and 120 minutes after a 75-g oral dextrose load and AUC of glucose. Metformin decreased insulin at 0 minutes.

RESUMEN Objetivo: El objetivo del estudio es evaluar el efecto de la linagliptina frente a la metformina en la secreción de insulina, la sensibilidad a la insulina, y el control de la glucosa en pacientes con intolerancia a la glucosa (IG). Pacientes y métodos: Se realizó un ensayo clínico aleatorio de doble ciego con grupos paralelos a 16 adultos con IG. El perfil lipídico y la hemoglobina (Hba1C) se evaluaron antes y después de la intervención. La glucosa y la insulina se midieron a los 0, 30, 60, 90 y 120 minutos después de un carga oral de 75-g dextrosa. Ocho pacientes recibieron metformina (500 mg) dos veces al día antes de las comidas por tres meses. Los ocho pacientes restantes recibieron placebo (500 mg) por la mañana y linagliptina (5 mg) por la noche antes de las comidas. El área bajo la curva (ABC) de la glucosa y la insulina, la secreción total de insulina, la primera fase de la secreción de insulina, y la sensibilidad a la insulina, fueron evaluadas. Resultados: Luego de la administración de la linagliptina, se observó una disminución significativa de la glucosa a los 90 minutos (10.8 ± 2.6 vs 7.9 ± 2.2 mmol/L, p < 0.05), 120 minutos (8.8 ± 0.9 mmol/L p < 0.05) y el ABC de la glucosa (1168 ± 210 vs 953 ± 207 mmol/L, p < 0.05). La administración de metformina redujo significativamente la insulina a los 0 minutos (94.8 ± 25.8 vs 73.8 ± 24.6 pmol/L, p < 0.05). Conclusión: Tres meses de administración de linagliptina en pacientes con IG disminuyó la glucosa a los 90 y 120 minutos después de una carga oral de dextrosa de 75-g y el ABC de la glucosa. La metformina disminuyó la insulina en 0 minutos.

Taurine supplementation in high-fat diet fed male mice attenuates endocrine pancreatic dysfunction in their male offspring.

Obesity in fathers leads to DNA damage and epigenetic changes in sperm that may carry potential risk factors for metabolic diseases to the next generation. Taurine (TAU) supplementation has demonstrated benefits against testicular dysfunction and pancreatic islet impairments induced by obesity, but it is not known if these protective actions prevent the propagation of metabolic disruptions to the next generation; as such, we hypothesized that paternal obesity may increase the probability of endocrine pancreatic dysfunction in offspring, and that this could be prevented by TAU supplementation in male progenitors. To test this, male C57Bl/6 mice were fed on a control diet (CTL) or a high-fat diet (HFD) without or with 5% TAU in their drinking water (CTAU and HTAU) for 4 months. Subsequently, all groups of mice were mated with CTL females, and the F1 offspring were identified as: CTL-F1, CTAU-F1, HFD-F1, and HTAU-F1. HFD-fed mice were normoglycemic, but glucose intolerant and their islets hypersecreted insulin. However, at 90 days of age, HFD-F1 offspring displayed normal glucose homeostasis and adiposity, but reduced glucose-induced insulin release. HFD-F1 islets also exhibited ß- and α-cell hypotrophy, and lower δ-cell number per islet. Paternal TAU supplementation prevented the decrease in glucose-induced insulin secretion and normalized ß-cell size and δ-cell number, and increased α-cell size/islet in HTAU-F1 mice. In conclusion, HFD consumption by male founders decreases ß-cell secretion and islet-cell distribution in their offspring. TAU attenuates the deleterious effects of paternal obesity on insulin secretion and islet-cell morphology in F1 offspring.

Sclareol-loaded lipid nanoparticles improved metabolic profile in obese mice.

Sclareol is a bioactive hydrophobic diterpene in the essential oil isolated from Salvia sclarea (Fam. Lamiaceae). Sclareol has been widely studied due to its anti-inflammatory and antioxidant effects. AIMS: The present study aimed to evaluate the effects of Sclareol in different formulations (solid lipid nanoparticle and free) on the metabolic profile of obese mice. MAIN METHODS: Swiss male mice were randomly divided into two groups: standard diet (STD) and high-fat diet (HFD). After obesity induction, each group was divided into three treatment groups: free Sclareol (Sc), Sclareol-loaded lipid nanoparticle (L-Sc) and blank lipid nanoparticle (L). Treatments were performed every day during 30 days. KEY FINDINGS: L-Sc improves obese mice metabolic profile by decreasing adiposity, ameliorating insulin sensitivity, glucose tolerance and increasing the HDL plasma levels. In addition, L-Sc decreased the expression of NF-KB, MCP-1 and SERBP-1. SIGNIFICANCE: The use of sclareol together with lipid nanocarriers may be promising for the treatment of metabolic disorders by reducing adipose tissue.

Southern Brazilian native fruit shows neurochemical, metabolic and behavioral benefits in an animal model of metabolic syndrome.

In this work, we evaluated the effects of Psidium cattleianum (Red Type) (PcRT) fruit extract on metabolic, behavioral, and neurochemical parameters in rats fed with a highly palatable diet (HPD) consisted of sucrose (65% carbohydrates being 34% from condensed milk, 8% from sucrose and 23% from starch, 25% protein and 10% fat). Animals were divided into 4 groups: standard chow, standard chow + PcRT extract (200 mg/Kg/day by gavage), HPD, HPD + extract. The animals were treated for 150 days. Concerning chemical profiling, LC/PDA/MS/MS analysis revealed cyanidin-3-O-glucoside as the only anthocyanin in the PcRT extract. Our results showed that the animals exposed to HPD presented glucose intolerance, increased weight gain and visceral fat, as well as higher serum levels of glucose, triacylglycerol, total cholesterol, LDL-cholesterol and interleukin-6. These alterations were prevented by PcRT. In addition, HPD caused an increase in immobility time in a forced swimming test and the fruit extract prevented this alteration, indicating an antidepressant-like effect. PcRT treatment also prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD consumption. Moreover, PcRT extract was able to restore Ca2+-ATPase activity in the prefrontal cortex, hippocampus, and striatum, as well as Na+,K+-ATPase activity in the prefrontal cortex and hippocampus. PcRT treatment decreased thiobarbituric acid-reactive substances, nitrite, and reactive oxygen species levels and prevented the reduction of superoxide dismutase activity in all cerebral structures of the HPD group. Additionally, HPD decreased catalase in the hippocampus and striatum. However, the extract prevented this change in the hippocampus. Our results showed that this berry extract has antihyperglycemic and antihyperlipidemic effects, and neuroprotective properties, proving to be a potential therapeutic agent for individuals with metabolic syndrome.

Differential actions of PPAR-α and PPAR-ß/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice.

BACKGROUND AND AIMS: Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-ß/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice. MATERIAL AND METHODS: Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-ß (C plus PPAR-ß/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-ß (HF plus PPAR-ß/δ agonist). RESULTS: HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-ß/δ agonist. CONCLUSIONS: This work provides evidence that the PPAR-ß/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.

Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance.

Chlorogenic acid has been described as a novel polyphenol with metabolic effects on glucose homeostasis. The aim of this study was to evaluate the effect of chlorogenic acid administration on glycemic control, insulin secretion, and insulin sensitivity in patients with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled clinical trial was performed in 30 patients with IGT; 15 patients randomly assigned to oral chlorogenic acid received 400 mg three times per day for 12 weeks, and the other 15 patients received placebo in the same way. Before and after the intervention, anthropometric and metabolic measurements, including fasting plasma glucose (FPG), glycated hemoglobin A1c, and a lipid profile, were performed. Area under the curve of glucose and insulin as well as the insulinogenic, Stumvoll, and Matsuda indices were calculated. Wilcoxon, Mann-Whitney U, and chi-square tests were performed, and P ≤ .05 was considered statistically significant. There were significant decreases in FPG (5.7 ± 0.4 vs. 5.5 ± 0.4 mmol/L, P = .002), insulinogenic index (0.71 ± 0.25 vs. 0.63 ± 0.25, P = .028), body weight, body mass index, waist circumference, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein levels in the chlorogenic acid group, with an increment in the Matsuda index (1.98 ± 0.88 vs. 2.30 ± 1.23, P = .002). There were no significant differences in the placebo group. In conclusion, chlorogenic acid administration in patients with IGT decreased FPG and insulin secretion, while increasing insulin sensitivity and improving both anthropometric evaluations and the lipid profile.

Effect of Linagliptin Versus Metformin on Glycemic Variability in Patients with Impaired Glucose Tolerance.

BACKGROUND: Impaired glucose tolerance (IGT) and glycemic variability may be associated with increased risk of micro- and macrovascular complications. The aim of this study was to assess the effect of linagliptin versus metformin on glycemic variability in patients with IGT. MATERIAL AND METHODS: A randomized, double-blind clinical trial with parallel groups was carried out in 16 adult patients with IGT, overweight or obesity. All patients signed an informed consent. The therapies were randomly assigned: (a) metformin 500 mg bid (n = 8) or (b) linagliptin 5 mg a.m. and placebo p.m. (n = 8), both for 90 days. At the beginning of the trial and 3 months later, fasting glucose, glycated hemoglobin A1c, oral glucose tolerance test (OGTT), and glycemic variability [area under the curve (AUC) of glucose, mean amplitude of glycemic excursion (MAGE), standard deviation (SD) of glucose, coefficient of variation (CV) of glucose, and mean blood glucose (MBG)] were measured. Mann-Whitney U, Wilcoxon, and Fisher exact tests were used for statistical analyses. RESULTS: Both groups were similar in basal characteristics. After linagliptin administration, a significant decrease in glucose levels at 120 min of OGTT (9.0 ± 0.9 vs. 6.9 ± 2.2 mmol/L, P = 0.012) was observed. Glycemic variability showed a similar behavior and there were no significant differences in the AUC, MAGE, SD of glucose, CV of glucose, and MBG between groups. CONCLUSION: Linagliptin administration resulted in better glycemic control according to the decrease of glucose levels by the OGTT at 120 min in patients with IGT. Meanwhile, glycemic variability was not modified in any of the study groups.

International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial.

BACKGROUND: Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. METHODS AND RESULTS: NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified. CONCLUSIONS: Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.

Benefits of L-alanine or L-arginine supplementation against adiposity and glucose intolerance in monosodium glutamate-induced obesity.

PURPOSE: L-alanine (Ala) and L-arginine (Arg) have been reported to regulate pancreatic ß-cell physiology and to prevent body fat accumulation in diet-induced obesity. Here, we assessed growth and adiposity parameters, glucose tolerance, insulin secretion and the expression of insulin and nutrient-regulated proteins in monosodium glutamate (MSG)-obese mice supplemented with either Ala or Arg. METHODS: Male newborn C57Bl/6 mice received a daily subcutaneous injection of MSG or saline solution (CTL group), during the first 6 days of life. From 30 to 90 days of age, MSG and CTL mice received or not 2.55 % Ala (CAla or MArg groups) or 1.51 % Arg-HCl (CArg or MArg groups) in their drinking water. RESULTS: Adult MSG mice displayed higher adiposity associated with lower phosphorylation of the adipogenic enzyme, ACC, in adipose tissue. Glucose intolerance in MSG mice was linked to lower insulin secretion and to lower expression of IRß in adipose tissue, as well as AS160 phosphorylation in skeletal muscle. Perigonadal fat depots were smaller in Ala and Arg mice, while retroperitoneal fat pads were decreased by Ala supplementation only. Both Ala and Arg improved fed-state glycemia as well as IRß and pAS160 content, but only Ala led to improved glucose tolerance and insulin secretion. Adipostatic signals were increased in MAla mice, as indicated by enhanced AMPK phosphorylation and pACC content in fat depots. CONCLUSIONS: Ala supplementation led to more pronounced metabolic improvements compared to Arg, possibly due to suppression of lipogenesis through activation of the AMPK/ACC pathway.

Hyperprolactinemia induced by hCG leads to metabolic disturbances in female mice.

The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin ß-subunit (hCGß+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGß+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGß+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGß+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies.

Effect of Artemisia dracunculus Administration on Glycemic Control, Insulin Sensitivity, and Insulin Secretion in Patients with Impaired Glucose Tolerance.

To evaluate the effect of Artemisia dracunculus on glycemic control, insulin sensitivity, and insulin secretion in patients with impaired glucose tolerance (IGT). A randomized, double blind, placebo-controlled clinical trial was performed in 24 patients with diagnosis of IGT. Before and after the intervention, glucose and insulin levels were measured every 30 min for 2 h after a 75-g dextrose load, along with glycated hemoglobin A1c (A1C) and lipid profile. Twelve patients received A. dracunculus (1000 mg) before breakfast and dinner for 90 days; the remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first phase of insulin secretion, and insulin sensitivity were calculated. Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests were used for statistical analyses. The institutional ethics committee approved the protocol. After A. dracunculus administration, there were significant decreases in systolic blood pressure (SBP; 120.0 ± 11.3 vs. 113.0 ± 11.2 mmHg, P < .05), A1C (5.8 ± 0.3 vs. 5.6% ± 0.4%, P < .05), AUC of insulin (56,136.0 ± 27,426.0 vs. 44,472.0 ± 23,370.0 pmol/L, P < .05), and total insulin secretion (0.45 ± 0.23 vs. 0.35 ± 0.18, P < .05), with a significant increase in high-density lipoprotein cholesterol (HDL-C) (1.3 ± 0.3 vs. 1.4 ± 0.3 mmol/L, P < .05). There were no significant differences after placebo administration. A. dracunculus administration for 90 days in patients with IGT significantly decreased SBP, A1C, AUC of insulin, and total insulin secretion with a significant increase in HDL-C levels.