Biomedical subjects
Publications and source records attributed to Samuel Klein.
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The effect of relative body fat mass on exercise-induced stimulation of lipolysis and fatty acid oxidation was evaluated in 15 untrained men (5 lean, 5 overweight, and 5 obese with body mass indexes of 21 +/- 1, 27 +/- 1, and 34 +/- 1 kg/m2, respectively, and %body fat ranging from 12 to 32%). Palmitate and glycerol kinetics and substrate oxidation were assessed during 90 min of cycling at 50% peak aerobic capacity (VO2 peak) by use of stable isotope-labeled tracer infusion and indirect calorimetry. An inverse relationship was found between %body fat and exercise-induced increase in glycerol appearance rate relative to fat mass (r2 = 0.74; P < 0.01). The increase in total fatty acid uptake during exercise [(micromol/kg fat-free mass) x 90 min] was approximately 50% smaller in obese (181 +/- 70; P < 0.05) and approximately 35% smaller in overweight (230 +/- 71; P < 0.05) than in lean (354 +/- 34) men. The percentage of total fatty acid oxidation derived from systemic plasma fatty acids decreased with increasing body fat, from 49 +/- 3% in lean to 39 +/- 4% in obese men (P < 0.05); conversely, the percentage of nonsystemic fatty acids, presumably derived from intramuscular and possibly plasma triglycerides, increased with increasing body fat (P < 0.05). We conclude that the lipolytic response to exercise decreases with increasing adiposity. The blunted increase in lipolytic rate in overweight and obese men compared with lean men limits the availability of plasma fatty acids as a fuel during exercise. However, the rate of total fat oxidation was similar in all groups because of a compensatory increase in the oxidation of nonsystemic fatty acids.
BACKGROUND: Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy. METHODS: We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters. RESULTS: Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [+/-SD], -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight; P=0.001) and 6 months (-7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (-4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. CONCLUSIONS: The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.
OBJECTIVE: To evaluate the efficacy and safety of topiramate (TPM) for weight loss in healthy obese subjects. RESEARCH METHODS AND PROCEDURES: A randomized, double-blind, placebo-controlled, dose-ranging trial was conducted. Three hundred eighty-five subjects, 18 and 75 years of age, were randomized to receive either placebo or TPM at 64, 96, 192, or 384 mg daily. Dosing began at 16 mg once daily. In week 2, the dose was increased to 16 mg twice daily. Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. Twenty-four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. All participants received the same lifestyle program. RESULTS: Mean percent weight loss from baseline to week 24 was -2.6% in placebo-treated patients vs. -5.0%, -4.8%, -6.3%, and -6.3% in the 64, 96, 192, and 384 mg/d TPM groups, respectively. Greater percentages of TPM-treated patients lost at least 5% or 10% of body weight compared with placebo. The most frequent adverse events were related to the central or peripheral nervous system, including paresthesia, somnolence, and difficulty with memory, concentration, and attention. Most events were dose-related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving TPM withdrew due to adverse events compared with 11% on placebo. DISCUSSION: TPM produced significantly greater weight loss than placebo at all doses.
Roland L. Weinsier, M.D., Dr.P.H., devoted himself to the fields of nutrition and obesity for more than 35 years. He contributed outstanding work related to the treatment of obesity through dietary and lifestyle change; metabolic/energetic influences on obesity, weight loss, and weight regain; body composition changes accompanying weight loss and regain; the health benefits and risks of weight loss; nutrition education for physicians; and nutrition support of sick patients. He served on the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Task Force on Prevention and Treatment of Obesity, as Chair of the University of Alabama at Birmingham's Department of Nutrition Sciences, and as Founder and Director of its NIDDK-funded Clinical Nutrition Research Center. He was a long-time and active member of NAASO, serving in the roles of Councilor, Publications Committee Chair, Continuing Medical Education Course Director, Public Relations Committee Chair, and Membership Committee Co-Chair, to name just a few. He was well respected as a staunch defender of NAASO's scientific integrity in these roles. Sadly, Roland Weinsier died on November 27, 2002. He will be missed and remembered by many as a revered and beloved teacher, mentor, healer, and scholar.
BACKGROUND: Plasma fatty acid availability is a major regulator of VLDL-triacylglycerol production. Basal whole-body lipolysis is higher in women than in men and is higher in persons with abdominal obesity than in lean individuals. OBJECTIVE: Our goal was to determine whether sex and abdominal obesity affect VLDL-triacylglycerol kinetics. We hypothesized that basal VLDL-triacylglycerol production would be greater in women than in men and greater in obese than in lean subjects. DESIGN: VLDL-triacylglycerol kinetics were measured in 20 lean (10 men, 10 women; body mass index, in kg/m(2): 23 +/- 1) and 20 abdominally obese (10 men, 10 women; body mass index: 35 +/- 1) subjects by using a bolus injection of [(2)H(5)]glycerol and compartmental modeling analysis. RESULTS: The rate of VLDL-triacylglycerol secretion was greater in the lean women than in the lean men (5.1 +/- 0.7 and 2.6 +/- 0.3 micro mol x L plasma(-1) x min(-1), respectively; P < 0.002). Obesity was associated with increased VLDL-triacylglycerol secretion in the men (P < 0.001) but not in the women, which resulted in greater rates of VLDL-triacylglycerol secretion in the obese men than in the obese women (6.8 +/- 0.5 and 5.0 +/- 0.5 micro mol x L plasma(-1) x min(-1), respectively; P < 0.05). The clearance of VLDL-triacylglycerol from plasma was greater (P < 0.05) in the lean women than in the lean men (42 +/- 7 and 27 +/- 4 mL plasma/min, respectively) or in the obese men and obese women (28 +/- 3 and 20 +/- 4 mL plasma/min, respectively). The plasma VLDL-triacylglycerol concentration was directly related to the rate of VLDL-triacylglycerol secretion in the men (R(2) = 0.79, P < 0.001) and inversely related to VLDL-triacylglycerol clearance in the women (R(2) = 0.84, P<0.001). CONCLUSION: Sex and obesity have independent effects on basal VLDL-triacylglycerol kinetics.
Adipose tissue lipolysis supplies circulating FFAs, which largely meet lipid fuel needs; however, excess FFAs, can contribute to the adverse health consequences of obesity. Because "normal" FFA release has not been well defined, average (mean of 4 days) basal FFA release and its potential regulation factors were measured in 50 lean and obese adults (25 women). Resting energy expenditure (REE), but not body composition, predicted most of the interindividual variation in FFA release. There was a significant, positive linear relationship between palmitate release and REE; however, women released approximately 40% more FFA than men relative to REE. Neither plasma palmitate concentrations nor respiratory quotient by indirect calorimetry differed between men and women. Glucose release rates were not different in men and women whether related to REE or fat free mass. These findings indicate that nonoxidative FFA clearance is greater in women than in men. This could be an advantage at times of increased fuel needs. We conclude that "normal" adipose tissue lipolysis is different in men and women and that the fuel export role of adipose tissue in obesity will need to be reassessed.
Whether free fatty acid (FFA) rate of appearance (R(a)) is increased in type 2 diabetes is controversial. To characterize nocturnal and postprandial abnormalities in FFA kinetics and to determine the effects of treatment with insulin sensitizers on lipolysis, we measured palmitate R(a) in control subjects (n = 6) and individuals with poorly controlled, sulfonylurea-treated type 2 diabetes (HbA(1c) = 8.7 +/- 0.2%, n = 20), the latter before and at the end of 12 weeks of treatment with troglitazone (600 mg/day, n = 4), metformin ( approximately 2,000 mg/day, n = 8), or placebo (n = 8). Subjects consumed a standard breakfast at 0800 h. Results in control subjects and type 2 diabetic subjects were compared at baseline. Integrated nocturnal FFA R(a) (AUC(1:00-8:00 A.M.)) was approximately 50% higher in type 2 diabetic subjects than in control subjects (29.4 +/- 3.0 vs. 19.4 +/- 3.9 mmol. m(-2). 7 h(-1), respectively, P < 0.05), whereas postprandial palmitate R(a) (AUC(0-240 min)) was almost threefold higher in type 2 diabetic subjects than in control subjects (14.2 +/- 1.7 vs. 5.3 +/- 1.0 mmol. m(-2). 4 h(-1), respectively, P < 0.01). After troglitazone treatment, nocturnal palmitate R(a) did not change, but postprandial palmitate R(a) decreased by approximately 30% (P < 0.05). Palmitate kinetics did not change with metformin or placebo treatment. In summary, nocturnal and postprandial FFA R(a) is increased in type 2 diabetes. Postprandial lipolysis appears to be preferentially improved by thiazolidinediones compared with nocturnal lipolysis.
We evaluated the validity of using a single fatty acid tracer to assess total plasma long-chain free fatty acid (FFA) kinetics and the relationship between the rate of appearance (R(a)) of fatty acids in plasma and the fatty acid composition of adipose tissue triglyceride (TG). A mixture of [(13)C]-labeled myristate, palmitate, stearate, oleate, and linoleate was infused in healthy men during basal conditions and during conditions that stimulate (epinephrine infusion) and inhibit (insulin infusion) lipolysis of adipose tissue TGs. Calculated total FFA, R(a) based on palmitate, oleate, or linoleate tracers, was within 15% of the measured sum of the individual fatty acid R(a) under all conditions, whereas stearate and myristate tracers consistently underestimated and overestimated total FFA R(a), respectively. The fatty acid R(a) profile closely matched the fatty acid profile of subcutaneous adipose tissue TGs during epinephrine infusion, but not during basal conditions and insulin infusion. Our data support the common practice of using labeled palmitate or oleate as fatty acid tracers for assessing total plasma FFA kinetics and suggest that a source of lipids other than adipose tissue TG release fatty acids into the systemic circulation.
The effects of obesity and weight loss on lipoprotein kinetics were evaluated in six lean women [body mass index (BMI): 21 +/- 1 kg/m(2)] and seven women with abdominal obesity (BMI: 36 +/- 1 kg/m(2)). Stable isotope tracer techniques, in conjunction with compartmental modeling, were used to determine VLDL-triglyceride (TG) and apolipoprotein B-100 (apoB-100) secretion rates in lean women and in obese women before and after 10% weight loss. VLDL-TG and VLDL-apoB-100 secretion rates were similar in lean and obese women. Weight loss decreased the rate of VLDL-TG secretion by approximately 40% (from 0.41 +/- 0.05 to 0.23 +/- 0.03 micromol x kg fat-free mass(-1) x min(-1); P < 0.05). The relative decline in VLDL-TG produced from nonsystemic fatty acids, derived from intraperitoneal and intrahepatic TG, was greater (61 +/- 7%) than the decline in VLDL-TG produced from systemic fatty acids, predominantly derived from subcutaneous TG (25 +/- 8%; P < 0.05). Weight loss did not affect VLDL-apoB-100 secretion rate. We conclude that weight loss decreases the rate of VLDL-TG secretion in women with abdominal obesity, primarily by decreasing the availability of nonsystemic fatty acids. There is a dissociation in the effect of weight loss on VLDL-TG and apoB-100 metabolic pathways that may affect VLDL particle size.
We have previously shown that sex and obesity independently affect basal very low density lipoprotein (VLDL)-triglyceride (TG) kinetics. In the present study, we investigated the effect of hyperglycemia-hyperinsulinemia on VLDL-TG kinetics in lean and obese men and women (n = 6 in each group). VLDL-TG kinetics were measured during basal, postabsorptive conditions and during glucose infusion (5.5 mg x kg FFM(-1) x min(-1)) by using [(2)H(5)]glycerol bolus injection in conjunction with compartmental modeling analysis. Basal VLDL-TG secretion in plasma was greater in obese than in lean men (7.8 +/- 0.6 and 2.9 +/- 0.4 micromol x l plasma(-1) x min(-1); P < 0.001) but was not different in lean and obese women (5.0 +/- 1.1 and 5.9 +/- 1.1 micromol x l plasma(-1) x min(-1)). Glucose infusion decreased the VLDL-TG secretion rate by approximately 50% in lean and obese men and in lean women (to 1.5 +/- 0.4, 4.0 +/- 0.6, and 2.2 +/- 0.4 micromol x l plasma(-1) x min(-1), respectively; all P < 0.05) but had no effect on the VLDL-TG secretion rate in obese women (4.9 +/- 1.0 micromol x l plasma(-1) x min(-1)). These results demonstrate that both sex and adiposity affect the regulation of VLDL-TG metabolism. Glucose and insulin decrease VLDL-TG production in both lean men and lean women; obesity is associated with resistance to the glucose- and insulin-mediated suppression of VLDL-TG secretion in women, but not in men.
A combinatorial library approach was used to produce synthetic peptides mimicking the snake neurotoxin binding site of nicotinic receptors. Among the sequences, which inhibited binding of alpha-bungarotoxin to muscle and neuronal nicotinic receptors, HRYYESSLPWYPD, a 14-amino acid peptide with considerably higher toxin-binding affinity than the other synthesized peptides, was selected, and the structure of its complex with the toxin was analyzed by NMR. Comparison of the solution structure of the free toxin and its complex with this peptide indicated that complex formation induced extensive conformational rearrangements mainly at finger II and the carboxy terminus of the protein. The peptidyl residues P10 and Y4 seemed to be critical for peptide folding and complex stability, respectively. The latter residue of the peptide strongly interacted with the protein by entering a small pocket delimited by D30, C33, S34, R36, and V39 toxin side chains.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Type 2 diabetes mellitus is characterized by insulin-resistant glucose and lipid metabolism. Thiazolidinediones (TZDs) enhance insulin-mediated glucose disposal, but their effects on lipid kinetics are unknown. We evaluated the effect of the TZD troglitazone on insulin-mediated suppression of fatty acid and glycerol kinetics. Eight obese men and women (body mass index [BMI], 34.1 +/- 2.3 kg/m(2)) with insulin-requiring type 2 diabetes were studied before and after 12 weeks of troglitazone therapy (400 mg/d). Whole-body and abdominal fat masses were determined by dual-energy x-ray absorptiometry and magnetic resonance imaging, respectively. Palmitate and glycerol rates of appearance (R(a)) into plasma were evaluated during a 3-stage hyperinsulinemic euglycemic clamp, which spanned the physiologic range of plasma insulin concentrations that regulate lipolysis. Troglitazone therapy did not alter body composition. Palmitate and glycerol R(a) decreased progressively during each stage of hyperinsulinemia (P <.001). Suppression of palmitate R(a) by insulin was greater after than before troglitazone therapy (P <.001), whereas glycerol R(a) was unchanged. These results demonstrate that TZDs increase insulin-mediated suppression of fatty acid release into plasma in obese subjects with type 2 diabetes mellitus, which may contribute to their metabolic benefits. However, TZD therapy did not affect whole-body glycerol R(a), possibly because of upregulation of lipoprotein lipase action on plasma triglycerides.