The study of renin–angiotensin–aldosterone in experimental diabetes mellitus

It is generally accepted that hypertension and other vascular pathologies increase in diabetes mellitus (DM) patients as a result of the renin–angiotensin–aldosterone (RAA) system. In this study, changes in the renin‐angiotensin‐aldosterone (RAA) system level was determined in Streptozotocin (STZ)‐injected rats. A total of 46 female Wistar albino rats (180–220 g body weight) was utilized in these experiments. STZ was given intraperitoneally to induce diabetes in rats. Streptozotocin (60 mg kg⁻¹ body weight) was dissolved in 0·1 m citrate–‐phosphate buffer (pH 4–5). The non‐diabetic rats were injected with sterilized buffer alone to act as a control group. Blood glucose levels were 398±8·2 mg dl⁻¹, 488±11·75 mg dl⁻¹ and 658±29·6 mg dl⁻¹ at days 3, 12 and 30 respectively. The level of plasma renin activity (PRA) was measured as 7·69±1·07 ng ml⁻¹ h⁻¹; 1·82±0·22 ng ml⁻¹ h⁻¹ and 0·67±0·12 ng ml⁻¹ h⁻¹ at days 3, 12 and 30, respectively. These values showed that the PRA levels are decreased with increased time period. Serum angiotensin converting enzyme (ACE, E.C. 3.4.15.1) levels were increased at days 12 and 30 (p<0·05 and p<0·005), whereas serum aldosterone levels were increased at days 3 and 12 (p<0·05). The level of urea and creatinine increased at days 12 and 30 (p<0·05 and p<0·005, respectively) when compared to the control group. The data from these experiments indicate that the PRA level decreased whereas ACE activity level increased in diabetic rats compared with the control. Aldosterone levels increased at the first stage of the experiment, but then decreased by the end of the experiment as a result of changes in renin and ACE levels. Copyright © 1999 John Wiley & Sons, Ltd.     

Insulin Resistance in Nondiabetic Morbidly Obese Patients: Effect of Bariatric Surgery

Objective: To evaluate insulin action on substrate use and insulinemia in nondiabetic class III obese patients before and after weight loss induced by bariatric surgery. Research Methods and Procedures: Thirteen obese patients (four men/nine women; BMI = 56.3 ± 2.7 kg/m²) and 13 lean subjects (five men/eight women; BMI = 22.4 ± 0.5 kg/m²) underwent euglycemic clamp, oral glucose tolerance test, and indirect calorimetry. The study was carried out before (Study I) and after (～40% relative to initial body weight; Study II) weight loss induced by Roux‐en‐Y Gastric bypass with silastic ring surgery. Results: The obese patients were insulin resistant (whole‐body glucose use = 19.7 ± 1.5 vs. 51.5 ± 2.4 μmol/min per kilogram fat‐free mass, p < 0.0001) and hyperinsulinemic in the fasting state (332 ± 86 vs. 85 ± 5 pM, p < 0.0001) and during the oral glucose tolerance test compared with the lean subjects. Fasting plasma insulin normalized after weight loss, whereas whole‐body glucose use increased (35.5 ± 3.7 μmol/min per kilogram fat‐free mass, p < 0.05 vs. Study I). The higher insulin clearance of obese did not change during the follow‐up period. Insulin‐induced glucose oxidation and nonoxidative glucose disposal were lower in the obese compared with the lean group (all p < 0.05). In Study II, the former increased slightly, whereas nonoxidative glucose disposal reached values similar to those of the control group. Fasting lipid oxidation was higher in the obese than in the control group and did not change significantly in Study II. The insulin effect on lipid oxidation was slightly improved (p = 0.01 vs. Study I). Discussion: The rapid weight loss after surgery in obese class III patients normalized insulinemia and improved insulin sensitivity almost entirely due to glucose storage, whereas fasting lipid oxidation remained high.     

Modest Lifestyle Intervention and Glucose Tolerance in Obese African Americans

Objective: Previous studies have demonstrated the benefit of short‐term diets on glucose tolerance in obese individuals. The purpose of this study was to evaluate the effectiveness of modest lifestyle changes in maintaining improvements in glucose tolerance induced by short‐term energy restriction in obese African Americans with impaired glucose tolerance or type 2 diabetes mellitus. Research Methods and Procedures: An intervention group (n = 45; 47 ± 1 year [mean ± SE]), 105 ± 4 kg; body mass index: 39 ± 1 kg/m²) received an energy‐restricted diet (943 ± 26 kcal/d) for 1 week, followed by a lifestyle program of reduced dietary fat (?125 kcal/d) and increased physical activity (+125 kcal/d) for 1 year. Body weight and plasma concentrations of glucose, insulin, and C‐peptide during an oral glucose tolerance test were measured at baseline, 1‐week, and 4‐month intervals. A control group (n = 24; 48 ± 1 year; 110 ± 5 kg; body mass index: 41 ± 2 kg/m²) underwent these measurements at 4‐month intervals. Results: No changes in weight or glucose tolerance were observed in the control group. The intervention group had significant (p < 0.05) improvements in body weight and glucose tolerance in response to the 1‐week diet, which persisted for 4 months (p < 0.001 vs. control for change in weight). A total of 19 subjects (42%) continued the intervention program for 1 year, with sustained improvements (weight: ?4.6 ± 1.0 kg; p < 0.001 vs. control; oral glucose tolerance test glucose area: ?103 ± 44 mM · min; p < 0.05 vs. control). Discussion: A modest lifestyle program facilitates weight loss and enables improvements in glucose tolerance to be maintained in obese individuals with abnormal glucose tolerance. However, attrition was high, despite the mild nature of the program.     

Effect of Gastric Banding on Aminoterminal Pro‐brain Natriuretic Peptide in the Morbidly Obese

Objective: Aminoterminal pro‐brain natriuretic peptide (NT‐proBNP), like brain natriuretic peptide, might have diagnostic utility in detecting left ventricular hypertrophy and/or left ventricular dysfunction. The aim of the study was to investigate the relationship between morbid obesity and NT‐proBNP and the effect of weight reduction on this parameter. Research Methods and Procedures: A total of 34 morbidly obese patients underwent laparoscopic adjustable gastric banding (LAGB). NT‐proBNP levels were measured before and 12 months after the surgery. Results: Metabolic features and systolic and diastolic blood pressure were significantly decreased (p < 0.00001 for both) after a cumulative weight loss of 19.55 kg 1 year after LAGB. NT‐proBNP concentration was significantly higher in morbidly obese patients before LAGB than in normal‐weight control subjects (341.15 ± 127.78 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p < 0.00001). After bariatric surgery, NT‐proBNP concentration decreased significantly from 341.15 ± 127.78 fmol/mL to 204.87 ± 59.84 fmol/mL (p < 0.00, 001) and remained statistically significantly elevated (204.88 ± 59.84 fmol/mL vs. 161.68 ± 75.78 fmol/mL; p = 0.04) compared with normal‐weight subjects. Discussion: This investigation demonstrates higher levels of NT‐proBNP in morbidly obese subjects and a significant decrease during weight loss after laparoscopic adjustable gastric banding. In obesity, NT‐proBNP might be useful as a routine screening method for identifying left ventricular hypertrophy and/or left ventricular dysfunction.     

Improvement of Insulin Resistance and Early Atherosclerosis in Patients after Gastric Banding

Objective: To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS). Research Methods and Procedures: Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose‐tolerance test model analysis. In addition, soluble intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, leptin, high‐sensitivity C‐reactive protein, plasminogen activating factor‐1 (PAI‐1), and tissue plasminogen activator were measured. Results: BMI dropped from 45.22 ± 5.62 to 36.99 ± 4.34 kg/m² after 6 months and 33.72 ± 5.55 kg/m² after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C‐peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E‐selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule‐1 and PAI‐1 were only seen after 6 months. Subclinical inflammation, measured by high‐sensitivity C‐reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule‐1 and tissue plasminogen activator levels. Discussion: Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI‐1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.     

Serum Leptin Concentrations and Weight Gain in Postobese,Postmenopausal Women

Objective : This study was designed to determine if serum leptin concentrations (adjusted for fat mass) after weight loss on a low-calorie diet predict subsequent weight gain. Research Methods and Procedures : Body composition and serum leptin concentrations were determined on 14 moderately obese, postmenopausal, nondiabetic women with a familial predisposition to obesity. Assessments were obtained under tightly controlled metabolic ward conditions of macronutrient intake and weight maintenance both before (obese state) and after a mean weight loss of 12.0 kg to normal body weight (postobese state). Four years later, without intervention, body weight and body composition were reassessed. Results : Weight loss resulted in significant decreases in fat mass (29.7 ± 5.4 vs. 20.3 ± 4.7; kg), body mass index (27.7 ± 1.6 vs. 23.0 ± 1.5; kg/m2), percent body fat (40.7 ± 4.3 vs. 33.1 ± 5.0), and serum leptin concentrations (31.8 ± 16.0 vs. 11.5 ± 5.4; ng/mL). Serum leptin concentrations were positively correlated (p<<0.05) with fat mass in both the obese and postobese states (r = 0.67 and r = 0.56, respectively). However, residual serum leptin concentrations (adjusted for fat mass) in the obese and postobese states were not related to changes in body weight (p<= 0.61 and 0.52), fat mass (p = 0.72 and 0.42), body mass index (p = 0.59 and 0.33), or percent body fat (p = 0.84 and 0.46) over the follow-up period. Discussion : These finding do not support the hypothesis that relatively low concentrations of leptin predict weight regain after weight loss. However, because the number of subjects in this study was limited, further studies are warranted.     

Weight Loss Reduces Tissue Factor in Morbidly Obese Patients

Objective: To investigate the tissue factor (TF) pathway in clinical obesity and associated metabolic syndrome. Research Methods and Procedures: Thirty‐seven morbidly obese patients (4 men; BMI, 48 ± 7 kg/m²; range, 42 to 53 kg/m²), undergoing elective gastroplasty for the induction of weight loss, were examined for hemostatic, metabolic, and inflammatory parameters at baseline and 14 ± 5 months postoperatively. Results: Weight loss significantly reduced circulating plasma TF (314 ± 181 vs. 235 ± 113 pg/mL, p = 0.04), coagulation factor VII (130 ± 22% vs. 113 ± 19%, p = 0.023), and prothrombin fragment F1.2 (2.4 ± 3.4 vs. 1.14 ± 1.1 nM, p = 0.04) and normalized glucose metabolism in 50% of obese patients preoperatively classified as diabetic or of impaired glucose tolerance. The postoperative decrease in plasma TF correlated with the decrease of F1.2 (r = 0.56; p = 0.005), a marker of in vivo thrombin formation. In subgroup analysis stratified by preoperative glucose tolerance, baseline circulating TF (402.6 ± 141.6 vs. 176.2 ± 58.2, p < 0.001) and TF decrease after gastroplasty (ΔTF: 164.7 ± 51.4 vs. ?81 ± 31 pg/mL, p = 0.02) were significantly higher in obese patients with impaired glucose tolerance than in patients with normal glucose tolerance. Discussion: Procoagulant TF is significantly reduced with weight loss and may contribute to a reduction in cardiovascular risk associated with obesity.     

Correlation between Serum Resistin Level and Adiposity in Obese Individuals

Objective: Resistin is associated with insulin resistance in mice and may play a similar role in humans. The aim of our study was to examine the relationship of serum resistin level to body composition, insulin resistance, and related obesity phenotypes in humans. Research Methods and Procedures: Sixty‐four young (age 32 ± 10 years), obese (BMI 32.9 ± 5.6), nondiabetic subjects taking no medication, and 15 lean (BMI 21.1 ± 1.3) volunteers were studied cross‐sectionally. Thirty‐five of the subjects were also reevaluated after 1.5 years on a weight reduction program entailing dieting and exercise; changes of serum resistin were compared with changes of BMI, body composition, fat distribution, and several indices of insulin sensitivity derived from plasma glucose and serum insulin levels measured during 75‐g oral glucose tolerance test. Results: In a cross‐sectional analysis, serum resistin was significantly higher in obese subjects than in lean volunteers (24.58 ± 12.93 ng/mL; n = 64 vs. 12.83 ± 8.30 ng/mL; n = 15; p < 0.01), and there was a correlation between resistin level and BMI, when the two groups were combined (ρ = 0.35, p < 0.01). Although cross‐sectional analysis in obese subjects revealed no correlation between serum resistin and parameters related to adiposity or insulin resistance, longitudinal analysis revealed change in serum resistin to be positively correlated with changes in BMI, body fat, fat mass, visceral fat area, and mean glucose and insulin (ρ = 0.39, 0.40, 0.44, 0.50, 0.40, and 0.50; p = 0.02, 0.03, 0.02, <0.01, 0.02, and <0.01, respectively). Discussion: Resistin appears to be related to human adiposity and to be a possible candidate factor in human insulin resistance.     

Effect of Lifestyle Modification on Adipokine Levels in Obese Subjects with Insulin Resistance

Objective: To study the effect of weight loss in response to a lifestyle modification program on the circulating levels of adipose tissue derived cytokines (adipokines) in obese individuals with insulin resistance. Research Methods and Procedures: Twenty‐four insulin‐resistant obese subjects with varying degrees of glucose tolerance completed a 6‐month program consisting of combined hypocaloric diet and moderate physical activity. Adipokines [leptin, adiponectin, resistin, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6)] and highly sensitive C‐reactive protein were measured before and after the intervention. Insulin sensitivity index was evaluated by the frequently sampled intravenous glucose tolerance test. Results: Participants had a 6.9 ± 0.1 kg average weight loss, with a significant improvement in sensitivity index and reduction in plasma leptin (27.8 ± 3 vs. 23.6 ± 3 ng/mL, p = 0.01) and IL‐6 (2.75 ± 1.51 vs. 2.3 ± 0.91 pg/mL, p = 0.012). TNF‐α levels tended to decrease (2.3 ± 0.2 vs. 1.9 ± 0.1 pg/mL, p = 0.059). Adiponectin increased significantly only among diabetic subjects. The reductions in leptin were correlated with the decreases in BMI (r = 0.464, p < 0.05) and with changes in highly sensitive C‐reactive protein (r = 0.466, p < 0.05). Discussion: Weight reduction in obese individuals with insulin resistance was associated with a significant decrease in leptin and IL‐6 and a tendency toward a decrease in circulating TNF‐α, whereas adiponectin was increased only in diabetic subjects. Further studies are needed to elucidate the relationship between changes of adipokines and the health benefits of weight loss.     

Body Weight Modulates Cholesterol Metabolism in Non‐Insulin Dependent Type 2 Diabetics

Objective: Cholesterol metabolism was studied in 64 subjects with type 2 diabetes who had body weight ranging from normal to obese, to find out whether weight interferes with cholesterol metabolism in diabetes. Research Methods and Procedures: Cholesterol absorption was measured with peroral isotopes and by assaying serum plant sterol and cholestanol to cholesterol ratios, cholesterol synthesis with sterol balance, and measuring serum cholesterol precursor ratios. Results: The study population was divided into normal‐weight (body mass index, 24.1 ± 0.4 kg/m²; mean ± SEM; n = 20) and obese (31.0 ± 0.5 kg/m²; n = 44) groups. Despite similar serum cholesterol and blood glucose values, fecal neutral sterol excretion, cholesterol and bile acid synthesis, cholesterol turnover (1649 ± 78 vs. 1077 ± 52 mg/d; p < 0.001), and serum cholesterol precursors were higher, and cholesterol absorption % (32 ± 1 vs. 40 ± 2%; p < 0.05), serum cholestanol, and plant sterols were lower in the obese vs. the non‐obese groups. Serum sex hormone‐binding globulin was positively associated with variables of cholesterol absorption, whereas blood glucose, serum insulin, and body mass index were associated with variables of cholesterol synthesis. In multiple stepwise regression analysis, cholesterol absorption percentage (R² = 24%) and body mass index (R² = 15%) were the only variables explaining the variability of cholesterol synthesis. Discussion: Body weight, through its entire range, regulates cholesterol metabolism in type 2 diabetes such that with increasing insulin resistance, cholesterol absorption is lowered and cholesterol synthesis increased.     

Peptide YY levels are elevated after gastric bypass surgery

Objective: Mechanisms that promote effective and sustained weight loss in persons who have undergone Roux‐en‐Y gastric bypass surgery are incompletely understood but may be mediated, in part, by changes in appetite. Peptide YY (PYY) is a gut‐derived hormone with anorectic properties. We sought to determine whether gastric bypass surgery alters PYY levels or response to glucose. Research Methods and Procedures: PYY and ghrelin levels after a 75‐gram oral glucose tolerance test were measured in 6 morbidly obese patients 1.5 ± 0.7 (SE) years after gastric bypass compared with 5 lean and 12 obese controls. Results: After substantial body weight loss (36.8 ± 3.6%) induced by gastric bypass, the PYY response to an oral glucose tolerance test was significantly higher than in controls (p = 0.01). PYY increased ～10‐fold after a 75‐gram glucose load to a peak of 303.0 ± 37.0 pg/mL at 30 minutes (p = 0.03) and remained significantly higher than fasting levels for all subsequent time‐points. In contrast, PYY levels in obese and lean controls increased to a peak of ～2‐fold, which was only borderline significant. Ghrelin levels decreased in a symmetric but opposite fashion to that of PYY. Discussion: Gastric bypass results in a more robust PYY response to caloric intake, which, in conjunction with decreased ghrelin levels, may contribute to the sustained efficacy of this procedure. The findings provide further evidence for a role of gut‐derived hormones in mediating appetite changes after gastric bypass and support further efforts to determine whether PYY_3–36 replacement could represent an effective therapy for obesity.     

Visceral Obesity and Insulin Resistance Are Associated with Plasma Aldosterone Levels in Women

GOODFRIEND, THEODORE L., DAVID E. KELLEY, BRET H. GOODPASTER, AND STEPHEN J. WINTERS. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res. Objective: Both obesity and insulin resistance increase the risk of hypertension and other cardiovascular diseases, but the mechanisms linking these abnormalities are unknown. The current study was undertaken to examine the effects of obesity, fat distribution, and insulin resistance on plasma levels of aldosterone and other adrenal steroids that might contribute to sequelae of obesity. Research Methods and Procedures: Twenty-eight normo-tensive premenopausal women and 27 normotensive men with a wide range of body fat underwent measurements of visceral adipose tissue by CT scan, total fat mass by dual energy X-ray absorptiometry, blood pressure, insulin sensitivity, and plasma levels of three adrenal steroid hormones. Results: Plasma aldosterone in women correlated directly with visceral adipose tissue (r = 0. 66, p<0. 001) and inversely with insulin sensitivity (r = ?0. 67, p<0. 001), and these associations were independent of plasma renin activity. There were no corresponding correlations in men. Plasma aldosterone was significantly correlated with plasma cortisol and dehydroepiandrosterone sulfate in women. Seventeen women and 15 men completed a weight-reduction regimen, losing an average of 15. 1±1. 2 kg. After weight loss, plasma aldosterone was significantly lower and insulin sensitivity higher; however, the correlations of aldosterone with visceral adipose tissue and insulin sensitivity in women persisted (p = 0. 09 and 0. 07, respectively). Although none of the women were hypertensive, blood pressure correlated with plasma aldosterone both before and after weight loss. Discussion: We conclude that visceral adiposity and insulin resistance are associated with increased plasma aldosterone and other adrenal steroids that may contribute to cardiovascular diseases in obese women.     

Decreased Glucagon‐like Peptide 1 Release after Weight Loss in Overweight/Obese Subjects

Objective: Postprandial glucagon‐like peptide 1 (GLP‐1) release seems to be attenuated in obese subjects. Results on whether weight loss improves GLP‐1 release are contradictory. The aim of this study was to further investigate the effect of weight loss on basal and postprandial GLP‐1 release in overweight/obese subjects. Research Methods and Procedures: Thirty‐two overweight/obese subjects participated in a repeated measurement design before (BMI, 30.3 ± 2.8 kg/m²; waist circumference, 92.6 ± 7.8 cm; hip circumference, 111.1 ± 7.4 cm) and after a weight loss period of 6 weeks (BMI, 28.2 ± 2.7 kg/m²; waist circumference, 85.5 ± 8.5 cm; hip circumference, 102.1 ± 9.2 cm). During weight loss, subjects received a very‐low‐calorie diet (Optifast) to replace three meals per day. Subjects came to the laboratory fasted, and after a baseline blood sample, received a standard breakfast (1.9 MJ). Postprandially, blood samples were taken every one‐half hour relative to intake for 120 minutes to determine GLP‐1, insulin, glucose, and free fatty acids from plasma. Appetite ratings were obtained with visual analog scales. Results: After weight loss, postprandial GLP‐1 concentrations at 30 and 60 minutes were significantly lower than before weight loss (p < 0.05). Glucose concentrations were also lower, and free fatty acids were higher compared with before weight loss. Ratings of satiety were increased, and hunger scores were decreased after weight loss (p < 0.05). Discussion: In overweight/obese subjects, GLP‐1 concentrations after weight loss were decreased compared with before weight loss, and nutrient‐related stimulation was abolished. This might be a response to a proceeding negative energy balance. Satiety and GLP‐1 seem to be unrelated in the long term.     

Leptin Responses to Weight Loss in Postmenopausal Women: Relationship to Sex‐Hormone Binding Globulin and Visceral Obesity

Objective: Leptin concentrations increase with obesity and tend to decrease with weight loss. However, there is large variation in the response of serum leptin levels to decreases in body weight. This study examines which endocrine and body composition factors are related to changes in leptin concentrations following weight loss in obese, postmenopausal women. Research Methods and Procedures: Body composition (DXA), visceral obesity (computed tomography), leptin, cortisol, insulin, and sex hormone‐binding globulin (SHBG) concentrations were measured in 54 obese (body mass index [BMI] = 32.0 ± 4.5 kg/m²; mean ± SD), women (60 ± 6 years) before and after a 6‐month hypocaloric diet (250 to 350 kcal/day deficit). Results: Body weight decreased by 5.8 ± 3.4 kg (7.1%) and leptin levels decreased by 6.6 ± 11.9 ng/mL (14.5%) after the 6‐month treatment. Insulin levels decreased 10% (p < 0.05), but mean SHBG and cortisol levels did not change significantly. Relative changes in leptin with weight loss correlated positively with relative changes in body weight (r = 0.50, p < 0.0001), fat mass (r = 0.38, p < 0.01), subcutaneous fat area (r = 0.52, p < 0.0001), and with baseline values of SHBG (r = 0.38, p < 0.01) and baseline intra‐abdominal fat area (r = ?0.27, p < 0.06). Stepwise multiple regression analysis showed that baseline SHBG levels (r² = 0.24, p < 0.01), relative changes in body weight (cumulative r² = 0.40, p < 0.05), and baseline intra‐abdominal fat area (cumulative r² = 0.48, p < 0.05) were the only independent predictors of the relative change in leptin, accounting for 48% of the variance. Discussion: These results suggest that obese, postmenopausal women with a lower initial SHBG and more visceral obesity have a greater decrease in leptin with weight loss, independent of the amount of weight lost.     

Weight Loss Reduces Liver Fat and Improves Hepatic and Skeletal Muscle Insulin Sensitivity in Obese Adolescents

Obesity in adolescents is associated with metabolic risk factors for type 2 diabetes, particularly insulin resistance and excessive accumulation of intrahepatic triglyceride (IHTG). The purpose of this study was to evaluate the effect of moderate weight loss on IHTG content and insulin sensitivity in obese adolescents who had normal oral glucose tolerance. Insulin sensitivity, assessed by using the hyperinsulinemic–euglycemic clamp technique in conjunction with stable isotopically labeled tracer infusion, and IHTG content, assessed by using magnetic resonance spectroscopy, were evaluated in eight obese adolescents (BMI ≥95th percentile for age and sex; age 15.3 ± 0.6 years) before and after moderate diet‐induced weight loss (8.2 ± 2.0% of initial body weight). Weight loss caused a 61.6 ± 8.5% decrease in IHTG content (P = 0.01), and improved both hepatic (56 ± 18% increase in hepatic insulin sensitivity index, P = 0.01) and skeletal muscle (97 ± 45% increase in insulin‐mediated glucose disposal, P = 0.01) insulin sensitivity. Moderate diet‐induced weight loss decreases IHTG content and improves insulin sensitivity in the liver and skeletal muscle in obese adolescents who have normal glucose tolerance. These results support the benefits of weight loss therapy in obese adolescents who do not have evidence of obesity‐related metabolic complications during a standard medical evaluation.     

Low Plasma Leptin Concentration and Low Rates of Fat Oxidation in Weight‐Stable Post‐Obese Subjects

Objective: A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, low levels of physical activity, and low plasma leptin concentrations are all risk factors for body weight gain. The aim of the present investigation was to compare resting metabolic rate (RMR), respiratory quotient (RQ), levels of physical activity, and plasma leptin concentrations in eight post‐obese adults (2 males and 6 females; 48.9 ± 12.2 years; body mass index [BMI]: 24.5 ± 1.0 kg/m²; body fat 33 ± 5%; mean ± SD) who lost 27.1 ± 21.3 kg (16 to 79 kg) and had maintained this weight loss for ≥2 months (2 to 9 months) to eight age‐ and BMI‐matched control never‐obese subjects (1 male and 7 females; 49.1 ± 5.2 years; BMI 24.4 ± 1.0 kg/m²; body fat 33 ± 7%). Research Methods and Procedures: Following 3 days of weight maintenance diet (50% carbohydrate and 30% fat), RMR and RQ were measured after a 10‐hour fast using indirect calorimetry and plasma leptin concentrations were measured using radioimmunoassay. Levels of physical activity were estimated using an accelerometer over a 48‐hour period in free living conditions. Results: After adjustment for fat mass and fat‐free mass, post‐obese subjects had, compared with controls, similar levels of physical activity (4185 ± 205 vs. 4295 ± 204 counts) and similar RMR (1383 ± 268 vs. 1430 ± 104 kcal/day) but higher RQ (0.86 ± 0.04 vs. 0.81 ± 0.03, p < 0.05). Leptin concentration correlated positively with percent body fat (r = 0.57, p < 0.05) and, after adjusting for fat mass and fat‐free mass, was lower in post‐obese than in control subjects (4.5 ± 2.1 vs. 11.6 ± 7.9 ng/mL, p < 0.05). Discussion: The low fat oxidation and low plasma leptin concentrations observed in post‐obese individuals may, in part, explain their propensity to relapse.     

Short‐Term Effects of Gastric Bypass Surgery on Circulating Ghrelin Levels

Objective: To prospectively evaluate the short‐term effects of Roux‐en‐Y gastric bypass (RYGBP) on ghrelin secretion and its relevance on food intake and body weight changes. Research Methods and Procedures: Ghrelin response to a standardized test meal was evaluated in eight obese patients (BMI, 43.5 to 59.1 kg/m²) before and 6 weeks after RYGBP. Ghrelin response was compared with that of an age‐matched group of six normal weight individuals (BMI, 19.6 to 24.9 kg/m²). Results: Fasting serum ghrelin levels were lower in obese subjects compared with controls (p < 0.05). Meal ingestion significantly suppressed ghrelin concentration in controls (p < 0.05) and obese subjects (p < 0.05), albeit to a lesser degree in the latter group (p < 0.05). Despite a 10.3 ± 1.5% weight loss, fasting serum ghrelin levels were paradoxically further decreased in obese subjects 6 weeks after RYGBP (p < 0.05). Moreover, at this time‐point, food intake did not elicit a significant ghrelin suppression. The changes in ghrelin secretion after RYGBP correlated with changes in insulin sensitivity (p < 0.05) and caloric intake (p < 0.05). Discussion: This study showed that the adaptive response of ghrelin to body weight loss was already impaired 6 weeks after RYGBP. Our study provides circumstantial evidence for the potential role of ghrelin in the negative energy balance in RYGBP‐operated patients.     

Metabolic Response to a Mixed Meal in Obese and Lean Women from Two South African Populations

Objective: Lower lipid and insulin levels are found during a glucose-tolerance test in obese black than obese white South African women. Therefore, β-cell function and lipid metabolism were compared in these populations during a mixed meal. Research Methods and Procedures: Blood concentrations of glucose, free fatty acids (FFAs), insulin, lipograms, and in vivo FFA oxidation were determined at fasting and for 7 hours after oral administration of a mixed emulsion containing glucose-casein-sucrose-lipid and [1-¹³C] palmitic acid in 8 lean black women (LBW), 10 obese black women (OBW), 9 lean white women (LWW), and 10 obese white women (OWW). Subcutaneous and visceral fat mass was assessed by computerized tomography. Results: Visceral fat area was higher in OWW (152.7 ± 17.0 cm²) than OBW (80.0 ± 6.7 cm²; p < 0.01). In OBW, 30-minute insulin levels were higher (604.3 ± 117.6 pM) than OWW (311.0 ± 42.9 pM; p < 0.05). Total triglyceride was higher in OWW (706.7 ± 96.0 mM × 7 hours) than OBW (465.7 ± 48.2 mM × 7 hours; p < 0.05) and correlated with visceral fat area (β = 0.38, p = 0.05). Palmitate oxidation was higher in lean than obese women in both ethnic groups and correlated negatively with fat mass (β = −0.58, p < 0.005). Discussion: The higher 30-minute insulin response in OBW may reflect a higher insulinotropic effect of FFAs or glucose. The elevated triglyceride level of OWW may be due to their higher visceral fat mass and possibly reduced clearance by adipose tissue.     

Weight Loss and Leptin Changes in Individuals with Type 2 Diabetes

WILLIAMS, KATHERINE V., MONICA MULLEN, WE1 LANG, ROBERT V. CONSIDINE, AND RENA R. WING. Weight loss and leptin changes in individuals with type 2 diabetes. Obes Res. Objective To identify variables associated with leptin change in subjects with type 2 diabetes after 3 weeks and 20 weeks of weight loss. Research Methods and Procedures Subjects with type 2 diabetes treated with diet or sulfonylureas (n = 54) were enrolled in a 20-week behavioral weight control program. Sulfonylureas were stopped ≥2 weeks before study entry. Seven subjects who restarted sulfonylureas after week 3 had their data analyzed separately after this point. Results Leptin, fasting plasma glucose, and insulin levels were measured at baseline and at 3, 10, and 20 weeks. After 3 weeks, subjects lost 2.7±2.0 kg (p<0.001), and had significant decreases in leptin (5.2±7.0 ng/mL, p<0.001), fasting plasma glucose (1.8±1.8 mmol/L, p<0.001), and insulin (23±60 pmol/L, p<0.03). Between week 3 and week 20, subjects lost an additional 6.3±4.4 kg (P<0.001), but had no further changes in leptin. The primary determinants of leptin change at all time-points were weight loss and initial leptin level. Changes in insulin were not related to changes in leptin after controlling for the effects of weight loss. At week 20, more recent weight loss (week 10 to week 20) was as strong a predictor of overall change in leptin as overall weight loss (baseline to 20 week). Subjects who restarted sulfonylureas had an increase in both leptin levels (+1.9±9.0 ng/mL, p<0.05) and insulin levels (+23±65 pmol/L, p<0.05), despite significant overall weight loss (-7.4±4.0 kg, p<0.01). Initial changes in leptin (0 weeks to 3 weeks) did not affect subsequent ability to lose weight. Discussion Both short- and long-term changes in weight had an effect on leptin changes in individuals with type 2 diabetes. Although physiological insulin changes did not independently influence changes in leptin concentration with weight loss, increases in insulin levels with sulfonyl-urea therapy were associated with increases in leptin levels despite weight loss.