Ahmed H. Kissebah

Adiposity, Fat Distribution, and Cardiovascular Risk

STUDY OBJECTIVE To determine the relative importance of adiposity and fat distribution to cardiovascular risk profile. DESIGN A cross-sectional study. SETTING Clinical research center funded by the National Institutes of Health. PATIENTS Convenience sample of 33 healthy premenopausal women with a wide range of body weight who did not have diabetes mellitus, hirsutism and virilism, gynecologic disorder, cardiac disease, or hypertension. Women participating in exercise or dietary programs or taking medication were excluded. All subjects completed the study. INTERVENTIONS Total body fat mass was determined by hydrostatic weighting, and fat distribution was assessed by subscapular skinfold thickness, subscapular-to-triceps skinfold ratio, the waist-to-hip ratio, and computed tomography. Cardiovascular risk was assessed by the serum insulin response during oral glucose stimulation; levels of triglycerides and total cholesterol; high-density lipoprotein cholesterol to total cholesterol concentrations; and systolic and diastolic blood pressures. MEASUREMENTS AND MAIN RESULTS The anthropometric parameters chosen were significantly associated with the cardiovascular risk profile (P less than 0.001). Visceral fat distribution assessed by computed tomography accounted for a significantly greater degree of variance in the cardiovascular risk factors than the total body fat mass (P less than 0.05). The cumulative insulin response was the primary metabolic variable relating the anthropometric indices to cardiovascular risk. CONCLUSIONS Intra-abdominal fat deposition constitutes a greater cardiovascular risk than obesity alone. Hyperinsulinemia may constitute an important component of the increased cardiovascular risk of abdominal obesity.

Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women

The relationship of body fat distribution to metabolic profiles was determined in 80 healthy premenopausal white women of a wide range of obesity levels [percentage of ideal body weight (% IBW) 92-251]. Distribution of fat between the upper and lower body was assessed from the waist/hips girth ratio (WHR), which varied from 0.64 to 1.02. In 23 women, in vivo insulin sensitivity was also determined from the steady-state plasma glucose (SSPG) level at comparable insulin levels of approximately 100 microU/mL attained by the intravenous infusion of somatostatin, glucose, and insulin. Increasing WHR was accompanied by progressively increasing fasting plasma insulin levels (r = 0.47, P less than 0.001), insulin and glucose areas after glucose challenge (r = 0.53, P less than 0.001; r = 0.50, P less than 0.001, respectively) and fasting plasma triglyceride concentrations (r = 0.48, P less than 0.001). Obesity level was similarly correlated with these metabolic indices. Partial and multiple regression analysis and analysis of variance with a linear contrast model revealed that the effects of body fat topography were independent of, and additive to, those of obesity level. Within obese subjects alone (%IBW: 130), %IBW had no predictive value, but WHR remained a significant predictor of plasma glucose, insulin, and triglyceride concentrations. The WHR also correlated with the plasma cholesterol level, but this association was largely dependent on its relationship to %IBW. Both WHR and %IBW correlated with the insulin resistance index, SSPG (r = 0.60, P less than 0.01; r = 0.61, P less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Splanchnic insulin metabolism in obesity. Influence of body fat distribution.

The effects of obesity and body fat distribution on splanchnic insulin metabolism and the relationship to peripheral insulin sensitivity were assessed in 6 nonobese and 16 obese premenopausal women. When compared with the nonobese women, obese women had significantly greater prehepatic production and portal vein levels of insulin both basally and following glucose stimulation. This increase correlated with the degree of adiposity but not with waist-to-hip girth ratio (WHR). WHR, however, correlated inversely with the hepatic extraction fraction and directly with the posthepatic delivery of insulin. The latter correlated with the degree of peripheral insulinemia. The decline in hepatic insulin extraction with increasing WHR also correlated with the accompanying diminution in peripheral insulin sensitivity. Increasing adiposity is thus associated with insulin hypersecretion. The pronounced hyperinsulinemia of upper body fat localization, however, is due to an additional defect in hepatic insulin extraction. This defect is closely allied with the decline in peripheral insulin sensitivity.

Health risks of obesity.

Evidence implicating obesity as a risk-factor disease is critically reviewed. Possible reasons for the many conflicting findings are addressed. The classification of obesity, based upon the site of body fat distribution, and possible biologic mechanisms associating regional adiposity with morbidity, are discussed.

Genetic variation in selenoprotein S influences inflammatory response

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1β and TNF-α. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, −105G → A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-α. To investigate further the significance of the observed associations, we genotyped −105G → A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-α (P = 0.0049) and IL-1β (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Integrated Regulation of Very Low Density Lipoprotein Triglyceride and Apolipoprotein-B Kinetics in Non-insulin-dependent Diabetes Mellitus

Turnover rates of plasma very low density lipoprotein (VLDL) triglyceride (TG) and apolipoprotein-B (apo-B) were significantly increased in age- and weight-matched groups of normolipemic and hyperlipemic mild diabetics, and hyperlipemic moderately severe diabetics when compared with normolipemic controls. As in the normolipemic subjects, a significant correlation between VLDL TG and apo-B turnover rates was found in all diabetic groups, suggesting that integration of TG and apo-B production at synthetic and/or secretory sites is retained in diabetes, thus resulting in increased secretion of VLDL particles of normal composition. In normolipemic mild diabetic subjects, the fractional turnover rates of VLDL TG and apo-B were also significantly increased so that increased removal accompanied increased VLDL production. In the hyperlipemic diabetics, however, the fractional turnover rates were significantly reduced, hence the increased in VLDL removal was not sufficient to compensate for enhanced production. In normolipemic mild diabetic patients, low density lipoprotein (LDL) formation was increased, only a small fraction of VLDL apo-B being removed via a non-LDL pathway, presumably as remnant VLDL. In hyperlipemic mild diabetics, removal of VLDL apo-B via both the LDL and non-LDL pathways was increased. In hyperlipemic moderately severe diabetes, LDL formation was not increased; catabolism of VLDL apo-B through the non-LDL route was however, fivefold > normal. We conclude that increased VLDL secretion is a fundamental defect in non-insulin-dependent diabetes. In hyperlipemic individuals, VLDL removal is also impaired. The increase in LDL and/or VLDL remnant formation, regardless of prevailing plasma lipid levels or the severity of diabetes, provides a source of cholesterol which may account for the atherogeneity of this disorder.

Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography.

Skeletal muscle sensitivity and responsiveness to insulin and their relationship to overall glucose disposal and insulin binding were determined in 89 premenopausal women of varying body fat topography (waist/hips girth ratio [WHR] 0.64-1.02) and obesity level (percentage of ideal body weight 92-230). As a marker of insulin action, the percentage of total glycogen synthase present in the I form (glucose-6-phosphate independent) was measured in quadriceps muscle biopsies. The increase in percentage of synthase I 1 h after oral glucose loading was not significantly different between nonobese and obese weight-matched subgroups of increasing WHR, but this response was maintained at the expense of increasing plasma insulin levels as the WHR rose. The increase in percentage of synthase I in response to submaximal steady state plasma insulin (SSPI) of approximately 100 microU/ml achieved by the infusion of somatostatin, insulin, and glucose, however, was significantly lower in obese than in nonobese subjects, and was inversely correlated with WHR. The increase in percentage of synthase I correlated inversely with the steady state plasma glucose (SSPG) concentration, which is an index of the efficiency of overall glucose disposal, and directly with insulin binding to circulating monocytes. Insulin binding also correlated inversely with WHR and with fasting plasma insulin levels. When obese subjects were separated into three weight-matched subgroups on the basis of increasing WHR, significant trends to decreased percentage of synthase I response, increased SSPG, and decreased insulin binding were found. In women with predominantly upper body obesity (WHR greater than 0.85), the increase in percentage of synthase in response to submaximal SSPI was diminished, but there was no impairment of percentage of synthase I responsiveness to supramaximal SSPI of approximately 1,000 microU/ml. At supramaximal SSPI levels, SSPG in four obese women was normal, whereas in five women, SSPG concentrations were markedly increased. Our results suggest that in premenopausal women, impaired skeletal muscle insulin sensitivity that results in decreased glucose storage capacity may contribute to the diminished efficiency of glucose disposal and insulin resistance that are associated with upper body obesity. The impairment in skeletal muscle sensitivity may be overcome in vivo at the expense of increasing plasma insulin levels, with maximal responsiveness remaining unimpaired. This defect may result from a reduction in insulin receptor number which could, in turn, be secondary to persistently elevated fasting plasma insulin levels. In some upper body segment obese women, however, an additional defect affecting other insulin-sensitive pathways may also be present.

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.

Meta-analysis of genome-wide linkage studies in BMI and obesity

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI‐defined obesity using a nonparametric genome scan meta‐analysis.

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.