Alcohol Consumption, Mediating Biomarkers, and Risk of Type 2 Diabetes Among Middle-Aged Women

OBJECTIVE—The purpose of this study was to investigate whether adiponectin concentrations and biomarkers of inflammation, endothelial dysfunction, and insulin resistance mediate the association between alcohol consumption and diabetes. RESEARCH DESIGN AND METHODS—In a nested case-control study of 705 women with incident diabetes and 787 matched control subjects, we examined the adjusted relationship between baseline alcohol consumption and risk of diabetes before and after adjustment for markers of inflammation/endothelial dysfunction (C-reactive protein, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, tumor necrosis factor-α receptor 2, and interleukin-6), fasting insulin, and adiponectin concentrations. RESULTS—Alcohol consumption was associated with a decreased risk of diabetes (odds ratio per 12.5 g/day increment in alcohol use 0.58; 95% CI 0.49–0.69; P 2% of the observed relationship. Without adjustment for BMI, these biomarkers individually explained slightly more of the association, but <10% in all cases. Adiponectin accounted for 25% in a fully adjusted model and for 29% without adjustment for BMI. CONCLUSIONS—In this population of women, alcohol consumption was inversely associated with risk of type 2 diabetes. Adiponectin appeared to be a mediator of this association, but circulating biomarkers of inflammation, endothelial dysfunction, and fasting insulin did not explain this association. These results suggest that further research is needed into the potentially mediating roles of other biomarkers affected by alcohol consumption

Changes in Alcohol Consumption and Subsequent Risk of Type 2 Diabetes in Men

Objective -The objective of this study was to investigate the association of four-year changes in alcohol consumption with subsequent risk of type 2 diabetes. Research Design and Methods - We prospectively examined 38,031 men from the Health Professionals Follow-up Study free of diagnosed diabetes or cancer in 1990. Alcohol consumption was reported on food frequency questionnaires and updated every four years. Results - A total of 1905 cases of type 2 diabetes occurred during 428,497 person-years of follow-up. A 7.5 g/day (~half a glass) increase in alcohol consumption over four years was associated with lower diabetes risk among initial nondrinkers (multivariable hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.60-1.00) and drinkers initially consumin

Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists.Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50 mM) and rebaudioside A (12.5 mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release.Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155 μM) further enhanced casein and safflower oil induced-serotonin release.Exposure of ileal tissue segments to serotonin (30 μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100 μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10 μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.</p

Docosahexaenoyl serotonin emerges as most potent inhibitor of IL-17 and CCL-20 released by blood mononuclear cells from a series of N-acyl serotonins identified in human intestinal tissue

Fatty acid amides (FAAs), conjugates of fatty acids with ethanolamine, mono-amine neurotransmitters or amino acids are a class of molecules that display diverse functional roles in different cells and tissues. Recently we reported that one of the serotonin-fatty acid conjugates, docosahexaenoyl serotonin (DHA-5-HT), previously found in gut tissue of mouse and pig, attenuates the IL-23-IL-17 signaling axis in LPS-stimulated mice macrophages. However, its presence and effects in humans remained to be elucidated. Here, we report for the first time its identification in human intestinal (colon) tissue, along with a series of related N-acyl serotonins. Furthermore, we tested these fatty acid conjugates for their ability to inhibit the release of IL-17 and CCL-20 by stimulated human peripheral blood mononuclear cells (PBMCs). Serotonin conjugates with palmitic acid (PA-5-HT), stearic acid (SA-5-HT) and oleic acid (OA-5-HT) were detected in higher levels than arachidonoyl serotonin (AA-5-HT) and DHA-5-HT, while eicosapentaenoyl serotonin (EPA-5-HT) could not be quantified. Among these, DHA-5-HT was the most potent in inhibiting IL-17 and CCL-20, typical Th17 pro-inflammatory mediators, by Concanavalin A (ConA)-stimulated human PBMCs. These results underline the idea that DHA-5-HT is a gut-specific endogenously produced mediator with the capacity to modulate the IL-17/Th17 signaling response. Our findings may be of relevance in relation to intestinal inflammatory diseases like Crohn's disease and Ulcerative colitis

Effect of red wine consumption on biomarkers of oxidative stress

Aims: To evaluate the effect of acute and chronic consumption of red wine or de-alcoholized red wine with a similar antioxidant capacity on plasma total antioxidant capacity (TEAC), nuclear factor-κB (NF-κB) activity and F2-isoprostanes (8-iso-PGF2α) in healthy men. Methods: Nineteen healthy men with an increased waist circumference (≥94 cm) and a body mass index above 25 kg/m2 participated in a randomized, controlled crossover design trial. They daily consumed 450 ml of red wine (four drinks; 41.4 g alcohol) or 450 ml of de-alcoholized red wine during dinner for 4 weeks each. On the last day of each treatment period, blood was collected before and 1 h after a standardized dinner with red wine or de-alcoholized red wine and also 24-h urine was collected. Results: Absolute TEAC levels were higher 1 h after dinner with red wine compared with dinner with de-alcoholized red wine (1.3 versus 1.1 mmol Trolox equivalents/l; P = 0.03). Consumption of dinner together with de-alcoholized red wine acutely stimulated NF-κB activity in peripheral blood mononuclear cells (0.4-0.7 HeLa equivalents/2.5 μg protein; P = 0.006), whereas this increase was completely suppressed when the dinner was combined with red wine. A chronic increase in urinary 8-iso-PGF2α after 4 weeks of red wine consumption compared with de-alcoholized red wine consumption (157 pg/mg creatinine and 141 pg/mg creatinine, respectively, P = 0.006) was also observed. Conclusions: Consumption of a moderate dose of red wine can acutely increase plasma TEAC and suppress NF-κB activation induced by a meal. Controversially, 4 weeks of red wine consumption compared with de-alcoholized red wine consumption increases the oxidative lipid damage marker 8-iso-PGF2α

The noncaloric sweetener rebaudioside a stimulates glucagon-like peptide 1 release and increases enteroendocrine cell numbers in 2-dimensional mouse organoids derived from different locations of the intestine

Background: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine is modulated by nutrients. Preparations from the Stevia rebaudiana plant, including rebaudioside A, are increasingly being used as noncaloric sweeteners. Objective: We investigated the effects of rebaudioside A on enteroendocrine cells by assessing both cell numbers as well as their secretory capacity in an organoid model. Methods: A 2-dimensional organoid model derived from duodenal, jejunal, and ileal crypts of a C57BL/6J mouse was developed and characterized with the use of gene expression and immunofluorescence. We stimulated these organoids with 10 mmol/L rebaudioside A for 1 h and measured their GLP-1, PYY, and cholecystokinin release. We also analyzed the effects of rebaudioside A on gene expression in enteroendocrine cells after an 18-h incubation. Results: The 2-dimensional organoids contained crypt cells and differentiated villus cells, including enterocytes and goblet and enteroendocrine cells. These enteroendocrine cells stained positive for GLP-1, PYY, and serotonin. The cultured 2-dimensional organoids maintained their location-specific gene expression patterns. Compared with the control, rebaudioside A induced GLP-1 secretion 1.7-fold in the duodenum (P <0.01), 2.2-fold in the jejunum (P <0.01), and 4.3-fold in the ileum (P <0.001). PYY release was increased by rebaudioside A 3-fold in the ileumcompared with the control (P <0.05). Long-term (18-h) stimulation with the sweetener induced the expression of the enteroendocrine-specific markers chromogranin A, glucagon, Pyy, and cholecystokinin 3.5- (P <0.001), 3.5- (P <0.001), 3.8- (P <0.05), and 6.5-fold (P <0.001), respectively. Conclusions: These results show novel ex vivo effects of rebaudioside A on enteroendocrine cells of the mouse small intestine and highlight potentially new applications for rebaudioside A in metabolic diseases.</p

Alcohol consumption and type 2 diabetes: Influence of genetic variation in alcohol dehydrogenase

OBJECTIVE - We sought to investigate whether a polymorphism in the alcohol dehydrogenase 1c (ADH1C) gene modifies the association between alcohol consumption and type 2 diabetes. RESEARCH DESIGN AND METHODS - In nested case-control studies of 640 women with incident diabetes and 1,000 control subjects from the Nurses' Health Study and 383 men with incident diabetes and 382 control subjects from the Health Professionals Follow-Up Study, we determined associations between the ADH1C polymorphism, alcohol consumption, and diabetes risk. RESULTS - Moderate to heavy alcohol consumption (>5 g/day for women and >10 g/day for men) was associated with a decreased risk of diabetes among women (odds ratio [OR] 0.45 [95% CI 0.33- 0.63]) but not men (1.08 [0.67-1.75]). ADH1C genotype modified the relation between alcohol consumption and diabetes for women (Pinteraction = 0.02). The number of ADH1C*2 alleles, related to a slower rate of ethanol oxidation, attenuated the lower risk of diabetes among women consuming ≥5 g alcohol/day (Ptrend = 0.002). These results were not significant among men. Results were similar in pooled analyses (Pinteraction = 0.02) with ORs for diabetes among moderate drinkers of 0.44 (95% CI 0.21- 0.94) in ADH1C*1 homozygotes, 0.65 (0.39 -1.06) for heterozygotes, and 0.78 (0.50-1.22) for ADH1C*2 homozygotes compared with those for ADH1C*1 homozygote abstainers (Ptrend = 0.02). CONCLUSIONS - ADH1C genotype modifies the association between alcohol consumption and diabetes. The ADH1C*2 allele, related to a slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. This suggests that the association between alcohol consumption and diabetes may be causal but mediated by downstream metabolites such as acetate rather than ethanol itself

The effect of moderate alcohol consumption on fat distribution and adipocytokines

Objective: To investigate the effect of moderate alcohol consumption on fat distribution, adipose tissue secreted proteins (adiponectin and resistin), and insulin sensitivity in healthy middle-aged men with abdominal obesity. Research Methods and Procedures: Thirty-four healthy men between 35 and 70 years old, with increased waist circumference (>= 94 cm), participated in a randomized, controlled cross-over design trial. They drank 450 mL of red wine (40 grams of alcohol) or 450 mL of de-alcoholized red wine daily during 4 weeks. At the end of each treatment period, fat distribution, adipose tissue proteins, and insulin sensitivity index (ISI) were measured. Results: Subcutaneous and abdominal fat contents and body weight did not change after 4 weeks of moderate alcohol consumption. Liver fat (quip index) was slightly higher after consumption of red wine (6.8 +/- 0.1) as compared with de-alcoholized red wine (6.5 0.1) but not significantly different (p = 0.09). Plasma adiponectin concentration increased (p < 0.01) to 6.0 +/- 0.1 mu g/mL after 28 days of moderate alcohol consumption compared with de-alcoholized red wine (5.5 +/- 0.1 mu g/mL). Serum resistin concentrations and ISI were not affected by alcohol consumption. Percentage changes in serum resistin correlated significantly with changes in ISI (r = -0.69, p < 0.01), whereas this correlation was not present between changes in plasma adiponectin and IST (r = 0.31, p = 0.22). Discussion: Moderate alcohol consumption for 4 weeks is not associated with differences in subcutaneous and abdominal fat contents or body weight. Thus, the 10% increase in adiponectin was not associated with a change in fat distribution or body weight change