leptin and Alcoholic-Intoxication

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Topics: Adiponectin; Adipose Tissue; Alcoholic Intoxication; Animals; Carbohydrate Metabolism; Cell Death; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Fatty Liver; Genetic Predisposition to Disease; Genome, Mitochondrial; Hepatitis C; Humans; Insulin Resistance; Leptin; Lipid Metabolism; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Biological; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Reactive Oxygen Species

Both animal and human work suggests that the ghrelin system may be involved in the mechanisms that regulate the development and maintenance of alcohol use disorder. Previously, in a Phase 1b study, we tested pharmacological blockade of the growth hormone secretagogue receptor 1a (GHS-R1a, also known as the ghrelin receptor), in heavy drinking individuals with PF-5190457, an orally bioavailable, potent and selective GHS-R1a inverse agonist. We report here the effects of PF-5190457 on endocrine blood concentrations of amylin, gastric inhibitory polypeptide, glucagon-like peptide 1, insulin, leptin, pancreatic polypeptide, peptide YY, thyroid stimulating hormone, free triiodothyronine (T3), thyroxine (T4), cortisol, prolactin, and glucose during PF-5190457 dosing, as compared to placebo, in absence of alcohol as well as during an alcohol challenge when PF-5190457 was on steady-state. Blood hormone levels were largely unaffected by PF-5190457, both during dosing and in the context of alcohol challenge. The safety-related relevance of these findings to further develop PF-5190547 in alcohol use disorder is discussed. CLINICALTRIALS.GOV: NCT02039349. This article is part of the special issue on 'Neuropeptides'.

Topics: Adult; Alcoholic Intoxication; Azetidines; Dose-Response Relationship, Drug; Drug Inverse Agonism; Ethanol; Female; Ghrelin; Hormones; Humans; Islet Amyloid Polypeptide; Leptin; Male; Prolactin; Receptors, Ghrelin; Single-Blind Method; Spiro Compounds

Gastrointestinal hormones are essential in postburn metabolism. Since near 50% of burn victims test positive for blood alcohol levels at hospital admission and have inferior outcomes compared to nonintoxicated burn patients; we hypothesized that the gastrointestinal hormone secretion is compromised in intoxicated burn victims. To test our theory, we quantified gastrointestinal hormones serum levels in a combine ethanol intoxication and burn injury mouse model. Thus, mice received a daily dose of ethanol for 3 days, rested 4 days, and were given ethanol 3 additional days. Mice underwent 15% TBSA scald burn 30 minutes after their last ethanol dose. Serum samples were collected 24 hours after burn injury. Nonintoxicated burned mice exhibited an increase in glucose, insulin, ghrelin, plasminogen activator inhibitor-1, leptin, and resistin by 1.4-, 3-, 13.5-, 6.2-, 9.4-, and 2.4-fold, respectively, compared to sham vehicle mice (P < .05). Burn injury also reduced serum gastric inhibitory polypeptide (GIP) by 32% compared to sham-injured, vehicle-treated mice. Leptin, resistin, glucagon-like peptide-1, as well as insulin, were not different from sham groups when intoxication preceded burn injury. Nevertheless, in burned mice treated with ethanol, gastric inhibitory polypeptide and glucagon serum levels exhibited a significant fold increase of 3.5 and 4.7, respectively. With these results, we conclude that 24 hours after burn injury, mice developed significant changes in gastrointestinal hormones, along with hyperglycemia. Moreover, the combined insult of burn and ethanol intoxication led to additional hormonal changes that may be attributed to a potential pancreatic dysfunction. Further multiday studies are required to investigate the etiology, behavior, and clinical significance of these hormonal changes.

Topics: Alcoholic Intoxication; Animals; Blood Glucose; Burns; Ethanol; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Mice, Inbred C57BL; Models, Animal; Plasminogen Activator Inhibitor 1; Resistin

To estimate the association between patterns of alcohol consumption and biomarkers of coronary heart disease (CHD) risk.. Cross-sectional study among 10,793 individuals representative of the Spanish population aged ≥ 18 years. The threshold between moderate and heavy drinking was 40 g of alcohol/day in men and 24 g/day in women. Binge drinking was defined as intake of ≥ 80 g of alcohol in men and ≥ 60 g in women at any drinking occasion in the preceding 30 days. Analyses were performed with generalized linear models with adjustment for the main confounders, and results were expressed as the percentage change in the geometric mean (PCGM). Compared to non-drinkers, moderate and heavy drinkers had progressively higher serum HDL-cholesterol, with a PCGM ranging from 4.8% (95% CI: 3.7-6.0%) in moderate drinkers without binge drinking (MNB) to 9.6% (5.1-14.2%) in heavy drinkers with binge drinking (HB). Fibrinogen decreased progressively with alcohol intake, from -2.2% (-3.1 to -1.3%) in MNB to -5.8% (-9.4 to -2.0%) in HB. Leptin, glycated hemoglobin and the HOMA-index also decreased with increasing alcohol intake, and particularly with binge drinking.. Moderate alcohol intake is associated with improved HDL-cholesterol, fibrinogen and markers of glucose metabolism, which is consistent with the reduced CHD risk of moderate drinkers in many studies. Heavy and binge drinking were also associated with favorable levels of CHD biomarkers; since these drinking patterns produce substantial health harms, our results should not be used to promote alcohol consumption.

Topics: Adult; Aged; Alcohol Drinking; Alcoholic Intoxication; Biomarkers; Blood Glucose; Cholesterol, HDL; Coronary Disease; Cross-Sectional Studies; Female; Fibrinogen; Glycated Hemoglobin; Homeostasis; Humans; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Risk Factors; Spain; Young Adult

As, for ethical reasons, it is difficult to investigate by an experiment the effect of acute intoxication on leptin levels in alcoholics, we tested the hypothesis of lowered levels as an effect of acute ethanol intake in healthy volunteers. The subjects comprised (1) 17 healthy male participants, recruited via newspaper advertisements [age 29+/-3.75 years, body mass index (BMI) 24.3+/-3.5, leptin at baseline 3.3+/-3.1 ng/ml]; (2) for comparison, leptin levels of 16 male alcoholic patients at day 1 of withdrawal were used. They were characterized as follows: (mean, median, standard deviation and range) age in years (41.1, 40.5, 10.2, 24, 57), BMI (23.3, 21.7, 5.4, 16.6, 37.5), 1,032 g of ethanol (median) consumed within the last 7 days, leptin levels 2.3 mg/ml. A placebo-controlled double-blind trial was performed. Leptin levels of blood samples were taken at baseline (t(1)), before ethanol intake (t(2)), when blood alcohol had reached its maximum (t(3)) and the morning after (t(4)). The oral dose of ethanol administered was 0.6 g/kg ethanol. (1) VOLUNTEERS: (a) the ethanol and placebo group exhibited leptin levels corresponding closely with levels measured at baseline (t(1)) (rs=0.85, p<0.0001) and follow-up (t(4)) (rs=0.768, p<0.0001). (b) Leptin levels for the placebo and the alcohol-consuming (verum) group did not differ significantly at baseline, after ethanol intake or on the morning after [Mann-Whitney U-test (p=0.669, p=1.0 and p=0.887, respectively)]. (2) Leptin levels in relation to BMI did not significantly differ at any measurement time in either group. (3) Leptin levels/BMI of the healthy volunteers at t(1) and t(4) were not significantly different from those of 16 alcoholics. The data do not support the hypothesis of a significant effect of acute moderate alcohol intake on leptin levels in healthy volunteers.

Topics: Adult; Alcohol Drinking; Alcoholic Intoxication; Body Mass Index; Double-Blind Method; Humans; Leptin; Male; Middle Aged; Randomized Controlled Trials as Topic; Reference Values