Gabriele E. Sonnenberg

Gallstones: Genetics Versus Environment

ObjectiveThe aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. Summary Background DataGallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. MethodsA gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. ResultsIn the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P < .003), obesity (BMI > 30, relative risk 3.7, P < .001), age > 50 (relative risk 2.5, P < .001), and a positive family history of previous cholecystectomy in a first-degree family member (relative risk 2.2, P < .01). In the family study the additive genetic heritability of symptomatic gallstones was 29% (P < .02), age and gender were significant covariates and explained 9.3% of the phenotypic variation in gallbladder disease. ConclusionsThese data suggest that genetic factors are responsible for at least 30% of symptomatic gallstone disease. However, the true role of heredity in gallstone pathogenesis is probably higher because data based on symptomatic gallbladder disease underestimates the true prevalence in the population.

Leptin: a significant indicator of total body fat but not of visceral fat and insulin insensitivity in African-American women.

The recently cloned adipose tissue hormone leptin has been proposed to be involved in the neuroendocrine regulation of adiposity and its metabolic sequelae. Visceral fat is known to predict reduced insulin sensitivity and associated adverse metabolic profiles. In this study, we report the first evaluation of the relationships between leptin levels and total body fat, visceral fat, and insulin sensitivity in a cohort of premenopausal African-American women. Thirty-four subjects were analyzed for total fat mass and visceral fat by dual-energy X-ray absorptiometry and computerized axial tomography, respectively. Insulin sensitivity (SI) was assessed using Bergmans minimal model. Results showed that fasting leptin levels strongly correlated with total body fat mass (r = 0.797, P < 0.001). Correlations of leptin with visceral fat (r = 0.54, P < 0.001) and SI (r = −0.419, P = 0.02) were dependent on total body fat. In conclusion, leptin levels reflect total body fat mass, and although visceral fat is known to predict reduced insulin sensitivity independently, leptin did not. Our data thus suggest that diverse mechanisms are responsible for the regulation of total body versus visceral fat distribution, with its metabolic and health risks.

Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4

Abstract—Multiple studies have identified resting heart rate as a risk factor for cardiovascular disease independent of other cardiovascular disease risk factors (such as dyslipidemia and hypertension). Previous studies have examined heart rate in hypertensive individuals, but little is known about the genetic determination of resting heart rate in a normal population. Therefore, our objective was to perform a genome screen on a population containing normotensive and hypertensive individuals. We performed variance decomposition linkage analysis using maximum likelihood methods at ≈10 cM intervals in 2209 individuals of predominantly North European ancestry. We estimated the heritability of resting heart rate to be 26% and obtained significant evidence of linkage (logarithm of the odds [LOD]=3.9) for resting heart rate on chromosome 4q. This signal is in the same region as a quantitative trait locus (QTL) for long QT syndrome 4 and a QTL for heart rate in rats. Within the 1-LOD unit support interval, there are 2 strong candidates: ankyrin-B and myozenin 2.

Short-Term Comparison of Once- versus Twice-Daily Administration of Glimepiride in Patients with Non-Insulin-Dependent Diabetes Mellitus

OBJECTIVE: To investigate the metabolic effects and frequency of adverse events with 6 mg of glimepiride, a new oral sulfonylurea, given both in once- and twice-daily dosages to patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: This 15-week study involved 161 subjects with NIDDM. Subjects were randomized into two groups. For 4 weeks, group 1 received glimepiride 3 mg twice daily, and group 2 received glimepiride 6 mg once daily. After a 3-week placebo-washout period, twice- and once-daily regimens were crossed over for a second 4-week treatment period. Subjects were hospitalized at the end of each placebo or active-treatment phase. Their glucose concentrations were recorded at 20 time points over a 24-hour period, and their insulin and C-peptide concentrations were recorded at 16 time points over the same period. Parameters that were calculated included fasting, 24-hour, and postprandial concentrations of glucose, insulin, and C-peptide. RESULTS: One hundred six patients were randomized to receive treatment; 94 completed the entire study. Existing physiologic mechanisms of glucose control were apparently unimpaired by glimepiride treatment. Insulin concentrations increased more during the postprandial glucose peaks than when subjects were fasting. Both twice- and once-daily regimens proved equally effective in reducing concentrations of fasting, postbreakfast, postlunch, and postdinner plasma glucose. Twenty-four-hour mean glucose concentrations showed a slightly greater decrease from baseline for the twice-daily regimen; the difference between the regimens was statistically significant but not clinically meaningful. The incidence of adverse events with glimepiride approximated that obtained with placebo, with both groups reporting only one adverse event, headache, in more than 5% of the subjects. CONCLUSIONS: Glimepiride is equally effective whether administered once or twice daily. Glimepiride seems to stimulate insulin production primarily after meals, when plasma glucose concentrations are highest, but controls blood glucose throughout the day.

Low- and high-frequency insulin secretion pulses in normal subjects and pancreas transplant recipients: role of extrinsic innervation.

Low-frequency ultradian and high-frequency insulin secretion pulses were studied in normal subjects and in metabolically stable pancreas transplant recipients. Insulin secretion pulsatility was evaluated after deconvoluting the pulsatile plasma C peptide concentrations with its kinetic coefficients. In normal subjects, ultradian insulin secretion pulses with periodicities of 75-115 min were consistently observed during the 24-h secretory cycle. Pulse period and relative amplitude during the overnight rest (95 +/- 4 min and 27.6 +/- 2.4%) were similar to those during the steady state of continuous enteral feeding (93 +/- 5 min and 32.6 +/- 3.3%). Sampling at 2-min intervals revealed the presence of high-frequency insulin secretion pulses with periodicities of 14-20 min and an average amplitude of 46.6 +/- 5.4%. Pancreas transplant recipients had normal fasting and fed insulin secretion rates. Both low- and high-frequency insulin secretion pulses were present. The high-frequency pulse characteristics were identical to normal. Low-frequency ultradian pulse periodicity was normal but pulse amplitude was increased. Thus, ultradian insulin secretory pulsatility is a consistent feature in normal subjects. The low- and high-frequency secretion pulsatilities are generated independent of extrinsic innervation. Autonomic innervation might modulate low-frequency ultradian pulse amplitude exerting a dampening effect.

Splanchnic Insulin Dynamics and Secretion Pulsatilities in Abdominal Obesity

Insulin secretion, clearance dynamics, and their relationship to peripheral plasma insulin and glucose levels were monitored during three 12-h periods of overnight rest, intake of three meals, and continuous enteral feeding of mixed nutrients. The low-frequency ultradian and the high-frequency insulin secretion pulsatility characteristics during the steady-states of overnight rest and continuous enteral feeding were also examined. In abdominally obese subjects, the insulin secretion rate was consistently higher than normal by 2.3-fold. Peripheral plasma insulin levels were increased by 3.4-fold during the overnight period and by 4- to 5-fold during the two fed states. Endogenous insulin clearance was significantly reduced during feeding. Both low- and high-frequency insulin secretory pulsatilities were detected in the abdominally obese subjects. Pulse periods were within the normal range. Pulse maxima, nadirs, and absolute amplitudes were increased concomitant with the increase in insulin secretion. Ultradian relative pulse amplitudes, however, were blunted. A significantly higher pulse-to-pulse variability was observed in the abdominally obese subjects compared with normal subjects. Furthermore, a significantly higher level of interindividual variability in the nutrient-stimulated insulin secretion and in the ultradian pulse characteristics was observed. Thus in abdominal obesity, the increase in pancreatic insulin output is limited and the secretory pulsatilities are aberrant, suggesting a defect in the insulin secretory process. Diminished insulin clearance contributes to the degree of peripheral hyperinsulinemia compensating for the insulin resistance characteristic of this form of obesity.

Obesity-related dyslipidemia associated with FAAH, independent of insulin response, in multigenerational families of Northern European descent

UNLABELLED A more thorough understanding of the genetic architecture underlying obesity-related lipid disorders could someday facilitate cardiometabolic risk reduction through early clinical intervention based upon improved characterization of individual risk. In recent years, there has been tremendous interest in understanding the endocannabinoid system as a novel therapeutic target for the treatment of obesity-related dyslipidemia. AIMS N-arachidonylethanolamine activates G-protein-coupled receptors within the endocannabinoid system. Fatty acid amide hydrolase (FAAH) is a primary catabolic regulator of N-acylethanolamines, including arachidonylethanolamine. Genetic variants in FAAH have inconsistently been associated with obesity. It is conceivable that genetic variability in FAAH directly influences lipid homeostasis. The current study characterizes the relationship between FAAH and obesity-related dyslipidemia, in one of the most rigorously-phenotyped obesity study cohorts in the USA. MATERIALS & METHODS Members of 261 extended families (pedigrees ranging from 4 to 14 individuals) were genotyped using haplotype tagging SNPs obtained for the FAAH locus, including 5 kb upstream and 5 kb downstream. Each SNP was tested for basic obesity-related phenotypes (BMI, waist and hip circumference, waist:hip ratio, fasting glucose, fasting insulin and fasting lipid levels) in 1644 individuals within these 261 families. Each SNP was also tested for association with insulin responsiveness using data obtained from a frequently sampled intravenous glucose tolerance test in 399 individuals (32 extended families). RESULTS A well characterized coding SNP in FAAH (rs324420) was associated with increased BMI, increased triglycerides, and reduced levels of high-density lipoprotein cholesterol. Mean (standard deviation) high-density lipoprotein cholesterol level was 40.5 (14.7) mg/dl for major allele homozygotes, 39.1 (10.4) mg/dl for heterozygotes, and 34.8 (8.1) mg/dl for minor allele homozygotes (p < 0.01, Family-Based Association Test). This SNP was not associated with insulin sensitivity, acute insulin response to intravenous glucose, glucose effectiveness or glucose disposition index. CONCLUSION Genetic variability in FAAH is associated with dyslipidemia, independent of insulin response.

Genotype-by-smoking interaction for leptin levels in the Metabolic Risk Complications of Obesity Genes project

RATIONALE: Recently, we identified a genotype-by-smoking status interaction with serum leptin levels in a sample of Mexican Americans. However, it is unknown whether this phenomenon occurs in other populations as well.OBJECTIVE: The goal of this study was to examine the genetic architecture of the response to smoking in leptin levels using data from Midwestern Caucasian subjects participating in the Metabolic Risk Complications of Obesity Genes project.METHODS: We employed a variance decomposition analysis using maximum likelihood methods to model genotype-by-smoking interactions for leptin levels and examined the impact of the exclusion of smokers in a subsequent linkage analysis.RESULTS: We found significant evidence (p-value=0.027) for a genotype-by-smoking status interaction for serum leptin levels. In the subsequent linkage analysis with smokers excluded, we obtained a maximum LOD score of 3.4 (P=0.00004) near D8S1128.CONCLUSIONS: These results suggest that a QTL on chromosome 8 may have a differential effect on the expression of leptin in smokers vs nonsmokers, as first identified in Mexican Americans.