Leptin concentrations during oral glucose tolerance test (OGTT) in obese and normal weight women.

OBJECTIVE: To examine possible changes of leptin concentrations after the acute administration of glucose orally (OGTT). DESIGN: Seventy-five grams of glucose were administered per os in one group of obese and normal weight individuals and concentrations of glucose, insulin and leptin were measured at 0, 30, 60, 90 and 120 min. In an age matched control group of individuals with similar BMI water was given and leptin concentrations were measured before and after 30, 60, 90 and 120 min. SUBJECTS: Twenty-seven obese women aged 34+/-1.57 y with BMI 37.1+/-0.8 kg/m2 and 16 normal weight women, aged 32+/-1.13 y with BMI 23.6+/-0.3 kg/m2 formed the experimental group, while 10 obese and 10 normal weight females with similar age and BMI were used as controls. MEASUREMENTS: Weight, height, BMI, body fat, glucose, insulin and leptin at baseline and during OGTT. Variations of the above parameters were calculated from the area under the curve (AUC). RESULTS: Fasting leptin concentrations and AUC were higher in obese than in normal weight women. In obese women, leptin increased significantly in comparison to its basal concentrations 30 and 60 min after the glucose loading. Insulin was also increased, as expected. No correlation was found between insulin and leptin concentrations after glucose loading. Basal concentrations of leptin did not correlate with those of glucose and insulin. No changes in leptin concentrations were found in normal weight women after OGTT. However, a significant positive correlation was found between insulin and basal leptin. Finally, leptin concentrations did not change in obese and normal weight controls after water administration. CONCLUSION: A significant increase in leptin concentrations was found 30 and 60 min after glucose loading in obese individuals. No such increase was found in normal-weight women.     

Changes in plasma,erythrocyte, and platelet magnesium levels in normotensive and hypertensive obese subjects during oral glucose tolerance test

We evaluated the 75-g oral glucose tolerance test (OGTT)-induced modifications in glucose, insulin, and norepinephrine plasma concentrations, and in plasma, erythrocyte, and platelet magnesium levels in two groups of obese subjects (normotensive obese, NT-Ob, N = 19; hypertensive obese, HT-Ob, N = 15), and in a group of healthy control subjects (N = 12). During OGTT we detected a reduction in plasma magnesium concentrations and an increase in erythrocyte and platelet magnesium levels in the controls, whereas in both normotensive and hypertensive obese subjects, there was a reduction in plasma, erythrocyte, and platelet magnesium levels. Furthermore, no statistically significant difference was detected among the groups studied as regards Δ-plasma magnesium. On the other hand, Δ-erythrocyte magnesium and Δ-platelet magnesium were negative in the NT-Ob (Δ-erythrocyte magnesium: −0.24 ± 0.08 mmol/L; Δ-platelet magnesium: −0.49 ± 0.09 μmol/10⁸cells) and HT-Ob (Δ-erythrocyte magnesium: −0.20 ± 0.10 mmol/L; Δ-platelet magnesium: −0.50 ± 0.11 μmol/10⁸cells) groups, and positive in control subjects (Δ-erythrocyte magnesium: 0.40 ± 0.08 μmol/L; Δ-platelet magnesium: 0.47 ± 0.09 mmol/10⁸ cells). Finally, a direct correlation was found between Δ-norepinephrine and Δ-erythrocyte magnesium (r = 0.80, P < .01) in the control group, and a negative correlation was detected between Δ-norepinephrine and Δ-platelet magnesium (r = −0.58, P < .05) in the HT-Ob group. Our results seem to indicate that the insulin resistance status, the hyperglycemia, and the disregulation of the adrenergic system in obese subjects could be involved in the pathogenesis of the magnesium homeostasis impairment observed in the obese subjects.     

Effects of sodium supplementation during energy restriction on plasma norepinephrine levels in obese women

We tested whether sodium restriction would counteract the decrease in sympathetic nervous system activity usually associated with marked energy restriction. The effects of two levels of energy restriction, with different sodium intakes, on plasma norepinephrine (NE) levels while supine and in response to standing were studied. Twenty-two healthy normotensive obese female subjects (body mass index, 34 +/- 1 kg/m2; weight, 90 +/- 2 kg) followed one of three 3-week protocols: 1) total fasting with 80 mmol/day NaCl, 2) a very low energy diet (VLED) containing 1.7 MJ, 93 g protein, and 90 mmol Na/day, with an additional 60 mmol/day NaCl supplement, or 3) total fasting without NaCl (0 Na fast). At the end of the baseline isocaloric diet and of total fasts or VLED, pulse, blood pressure, and plasma NE were measured after 4 h of recumbency and 5 and 10 min after assuming the upright posture. These measurements were repeated after 1 L physiological saline was infused into the 0 Na fast subjects. Cumulative negative sodium balance was observed only in the 0 Na fasting subjects. Supine blood pressure decreased from baseline with fasting, but not with the VLED. The decreases in systolic pressure and increases in heart rate on standing observed with all diets were greatest with the 0 Na fast. Supine plasma NE (vs. baseline value) declined (P less than 0.05) with the VLED, remained unchanged with the Na supplemented fast, but increased with the 0 Na fast (P less than 0.05). The upright plasma NE values were highest in the 0 Na fast subjects, but lower after the saline infusion as well as in the subjects on the VLED. Thus, the decrease in NE due to energy restriction with normal sodium intake was counteracted by moderate sodium restriction, and levels increased with zero sodium intake. Therefore, sodium depletion can override the suppressive effect of energy restriction and, instead, increase the activity of the sympathetic nervous system, as reflected by plasma NE.     

Changes in overall plasma norepinephrine turnover and lymphomonocyte beta-adrenoceptor number during combined caloric and sodium restriction in normotensive obese subjects

The aim of the study was to evaluate in eight normotensive obese patients the influence of low sodium intake (9 mEq/day) on the sympathetic activity modifications induced by caloric restriction (2511 kJ/day). As compared to the isocaloric salt balanced diet, 7 days of normosodic underfeeding induced a decrease in the overall norepinephrine turnover (clearance and appearance rate) and 24 hours urinary output, whereas the combined caloric and salt restriction significantly increased the norepinephrine appearance rate and even more the norepinephrine clearance but, on the other hand, decreased the beta-adrenergic receptor number on the lymphomonocyte surface, suggesting a reduced peripheral sensitivity to catecholamines. Therefore, the utility of the combined sodium and caloric restriction in the treatment of the normotensive obese patients remains still questionable.     

Forearm haemodynamics in obese normotensive and hypertensive subjects

Forearm haemodynamics using pulsed Doppler flowmetry were studied in 83 men: 15 non-obese and eight obese normotensive subjects; 30 non-obese and 30 obese hypertensive patients. Mean ages were similar in the four subgroups. The blood pressure of normotensives and hypertensives was identical in obese and non-obese subjects. Blood flow, expressed in ml/min, was significantly higher in obese subjects, whether normotensive or hypertensive. However, when blood flow was expressed per unit litre of forearm volume, it was similar in the four subgroups. Forearm vascular resistance, whether expressed as absolute or normalized values, was significantly higher (P less than 0.001) in non-obese hypertensives. When obese and non-obese hypertensives were compared, the former were characterized by higher values of blood flow velocity and blood flow, and lower values of vascular resistance, whether absolute or normalized values were used. This study shows firstly that forearm vascular resistance in hypertensives is increased exclusively in non-obese subjects, and secondly that obese hypertensives, when compared with non-obese hypertensives, are characterized by a hyperkinetic forearm circulation.     

Leptin response to oral glucose tolerance test in obese and nonobese premenopausal women

The objective of this study was to investigate the serum leptin response to oral glucose stimulation in a group of obese and nonobese normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese (BMI: 37.7 +/- 6.3 kg/m2) and 14 nonbese (BMI: 21.5 +/- 1.0 kg/m2) age-matched, healthy premenopausal women were included in the study. Serum glucose, insulin, and leptin levels were measured at 30 min intervals during the 120 min of an oral glucose tolerance test (OGTT). Mean serum glucose, insulin, and leptin levels were significantly higher in the obese group compared to nonobese subjects during OGTT. Except for a 120 min decrement noted in obese women, no changes occurred in serum leptin levels during oral glucose stimulation in both groups. As a conclusion, absence of a significant elevation in serum leptin levels during OGTT in our obese subjects compared to nonobese subjects may be related to their normal metabolic variables despite being abdominally obese and insulin resistant.     

Leptin plasma concentrations are dependent on body fat distribution in obese patients

AIM: To evaluate whether fat distribution plays a role in determining serum leptin concentrations. PATIENTS AND METHODS: One-hundred and forty-seven obese patients, 77 males and 70 females, aged 45.1 +/- 13.2 y (mean +/- s.d.; range 21-73 y), with body mass index (BMI) ranging from 30 to 55 kg/m2 (mean 42.3 +/- 5.9). Ultrasound assessment of the thickness of subcutaneous and preperitoneal fat was carried out and calculation of their ratio as abdominal fat index (AFI), waist-hip ratio (WHR), body composition by bioelectrical impedance to evaluate the percentage of fat mass (FM%) and total amount of fat (FMKg) were also determined. Plasma leptin was measured by radio immuno assay (RIA). RESULTS: In the whole group of patients, serum leptin concentrations were 37.2 +/- 18.4 ng/ml (range 6-101.3 ng/ml); in spite of BMI values not being significantly different, women had leptin values significantly higher (47.4 +/- 17.4 ng/ml) (P < 0.01) than males (28.1 +/- 15.1 ng/ml), also after correction for fat mass. The mean thickness of abdominal subcutaneous fat was 33.7 +/- 12.9 mm and it was significantly (P < 0.001) higher in female (40.9 +/- 10.6 mm) than in male (27.1 +/- 11.2 mm) patients; preperitoneal thickness was 22.9 +/- 7.1 mm, with significantly (P < 0.05) higher values in males (24.2 +/- 6.8 mm) than in females (21.7 +/- 7.3 mm). Accordingly, AFI (in all patients 0.84 +/- 0.6) was significantly higher in males (1.09 +/- 0.6) than in females (0.56 +/- 0.2). In the overall population, leptin concentrations were directly and significantly related to subcutaneous but not preperitoneal fat; they showed a strong inverse relationship with AFI and WHR. When the results were evaluated dividing the patients according to gender, subcutaneous fat thickness showed a stronger association with leptin levels in males than in females, whereas no association was found with preperitoneal fat thickness. Leptin and AFI values were significantly related only in men. WHR values were not correlated with leptin concentrations in either sex. When fat mass was added to the model, subcutaneous fat thickness, AFI and WHR remained independently associated with leptin concentrations. Age and diabetes did not influence these measures. CONCLUSIONS: Fat distribution contributes to the variability in serum leptin in obese patients. In particular, subcutaneous abdominal fat is a determinant of leptin concentration, also independently of the amount of fat mass, whereas the contribution of preperitoneal visceral fat is not significant.     

Increased plasma norepinephrine concentrations and metabolic rates following glucose ingestion in man

The effects of glucose ingestion on plasma levels of norepinephrine (NE), epinephrine (E), immunoreactive insulin (IRI), and glucose, and the resting metabolic rate (RMR) were examined in six normal males. Ingestion of the glucose (100 g) solution significantly increased all of these measures except E levels, compared with changes observed during a control experiment in which an equal volume of water was ingested. The initial (0–60 min) increase in plasma NE levels and the increase in the RMR following glucose was significantly greater than the smaller increases that occurred during the control experiment. Plasma IRI and glucose levels peaked 30–60 min after glucose consumption, then declined toward basal values. These data show that glucose intake causes an elevation of the RMR and sympathetic nervous system activity greater than that caused by other aspects of the testing solution, and are consistent with the possibility that the increase in RMR following glucose ingestion is related to elevated sympathetic nervous system activity.     

High plasma leptin concentrations in hypertensive men but not in hypertensive women.

OBJECTIVE: Previous studies on humans have reported higher leptin levels in women than in men, independent of body fat, and leptin has been correlated with insulin resistance in men but not in women. Since insulin resistance is thought to play a role in raising blood pressure, we investigated sex differences in leptin concentrations between hypertensive and normotensive individuals. METHODS: Ninety-two nondiabetic hypertensive patients (48 men and 44 women) and 92 age, body mass index (BMI)-matched normotensive control individuals were studied. Fasting plasma glucose, insulin, leptin and lipoprotein concentrations, glucose and insulin responses to 75 g oral glucose tolerance test (OGTT) and insulin suppression tests were determined. RESULTS: Fasting plasma leptin concentrations were higher in hypertensive men than in normotensive men (5.1 +/- 0.5 versus 3.9 +/- 0.4 ng/ml, P = 0.015). However, fasting plasma leptin concentrations were not significantly different between hypertensive and normotensive women (11.8 +/- 1.0 versus 10.9 +/- 1.0 ng/ml, P = 0.440). Fasting plasma leptin concentrations showed good correlation with BMI, body fat, fasting plasma insulin concentrations, and insulin area to OGTT in both men and women (all P < 0.001). However, fasting plasma leptin concentrations were related to steady-state plasma glucose (SSPG) concentrations, a measure of insulin sensitivity by insulin suppression test, in men only (P < 0.001). After adjustment for body fat amount, age and duration of hypertension, fasting plasma leptin levels still correlated significantly with SSPG concentrations in men. These four variables together accounted for a 67.9% variation in fasting plasma leptin levels in men. In women, body fat amount was the only significant determinant for plasma leptin levels. These four variables accounted for a 78.2% variation in plasma leptin levels in women. CONCLUSIONS: Our study confirmed a sex difference in leptin levels both in hypertensive and normotensive subjects. Higher plasma leptin concentrations in hypertensive men but not in hypertensive women when compared with normotensive control individuals was also demonstrated. These observations are consistent with the findings that plasma leptin is correlated with insulin sensitivity in men but not in women. Further studies are needed to understand the causes and consequences of sex effects on leptin in blood pressure regulation.     

Leptin plasma levels as a marker of sparing-energy mechanisms in obese women.

OBJECTIVE: To investigate possible relationships between leptin and energy expenditure (EE), both in the condition of stable body weight and during weight loss. SUBJECTS: Seventy four Caucasian, adult obese women with stable body weight (including 10 obese women studied before and during a body weight-reducing program). MEASUREMENTS: Resting EE (REE) and substrate oxidation rates by indirect calorimetry; plasma leptin concentrations by radioimmunoassay (RIA). RESULTS: In conditions of stable body weight, leptin values showed a significant, negative relationship with REE, as expressed in absolute values (P = 0.030) and as adjusted for the variation in lean body mass (LBM) (P = 0.017). This negative relationship was independent of both LBM and fat mass (FM). Linear regression analysis was used to obtain the equation linking REE and LBM; then both predicted REE and the percent deviation from predicted REE were calculated for each subject. Leptin values were negatively related (P < 0.0001) to the deviation from predicted REE. During active body weight loss, the modifications of both REE (delta REE) and lipid oxidation (delta lipid oxidation) were significantly negatively related to leptin concentrations, which were measured before the dieting period (P < 0.03 for both). CONCLUSION: In obese women, high plasma leptin concentrations are associated with a low rate of REE, when body weight is stable, and with a reduction of REE and lipid oxidation, in response to a hypocaloric diet. This suggests that, in severely obese women, leptin is a marker of sparing energy mechanisms operating in both basal and reducing weight conditions.     

Differential blood pressure effects of oral glucose and intravenous L-arginine in healthy lean normotensive and obese hypertensive subjects

We investigated the role of insulin and glucose in the pathophysiology of hypertension associated with obesity. The comparative effects of an oral glucose load and of an L-arginine infusion on plasma glucose, plasma insulin and blood pressures (BP) were assessed in lean normotensive and in obese hypertensive males. Oral glucose (75 g in 1-2 min) induced a small but significant lowering of BP in lean normotensives, but failed to modify BP in obese hypertensives. L-arginine infusion (30 min, 500 mg/kg total dose) reduced BP; significantly greater reductions in systolic and diastolic BP were observed in obese hypertensives than in the control group. Both oral glucose and L-arginine induced greater increases in plasma insulin in obese hypertensives than in lean normotensives. Endothelial dysfunction which accompanies the insulin resistant state of obesity, glucose intolerance and hypertension, may account for the different BP effects induced by glucose and L-arginine in obese hypertensives and lean normotensives.     

Renal interstitial Ca2+ during sodium loading of normotensive and Dahl-salt hypertensive rats

It is now established that cells in many tissues including renal epithelial cells and perivascular sensory nerves have mechanisms that monitor and respond to the concentration of Ca²⁺ in the interstitial compartment [Ca²⁺_ISF]. We tested the hypothesis that high Na⁺ intake alters renal [Ca²⁺_ISF] and that the response is altered in salt-sensitive hypertensive versus normotensive rats. Male Wistar (W), Dahl salt-resistant (DR), and Dahl salt-sensitive (DS) rats were fed diets containing 0.45% or 8% NaCl for 7 days beginning at 8 to 10 weeks of age. Systolic blood pressure (BP) was measured before and at the end of the 7-day period. During the last 12 h the animals were placed in metabolic cages for urine collection. They were then anesthetized and renal [Ca²⁺_ISF] was determined using in situ microdialysis. Feeding 8% NaCl caused a significant increase in systolic BP only in DS. The 8% NaCl also caused a significant increase in renal urinary Na⁺ excretion in all groups, had no effect on renal Ca²⁺ excretion in W or DS and significantly increased urinary Ca²⁺ excretion in DR. When fed 0.45% NaCl, renal [Ca²⁺_ISF] was lower in W and DR compared with DS. Feeding 8% NaCl significantly increased [Ca²⁺_ISF] in W, had no effect on this parameter in DR, and significantly decreased [Ca²⁺_ISF] in DS ([Ca²⁺_ISF] for DS on 0.45% NaCl = 1.89 ± 0.15 v 8% NaCl = 1.08 ± 0.07 mmol/L, n = 6 to 12, P < .05). These results indicate that Na⁺ loading significantly alters renal [Ca²⁺_ISF]; that the response of DS is disturbed relative to controls, and are consistent with the hypothesis that Na⁺ loading can alter cell function by modulating [Ca²⁺_ISF].     

Intracellular partition of plasma glucose disposal in hypertensive and normotensive subjects with type 2 diabetes mellitus

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.     

氯沙坦和氨氯地平对肥胖高血压患者血浆瘦素、去甲肾上腺素浓度影响的对比研究

目的 观察血管紧张素Ⅱ受体拮抗剂氯沙坦和钙离子拮抗剂氨氯地平对肥胖高血压患者血浆瘦素和血浆去甲肾上腺素浓度的影响,寻找肥胖相关高血压治疗的最佳药物.方法 采用放射免疫法测定血浆瘦素水平,采用高效液相色谱分析检测血浆去甲肾上腺素水平.结果 氯沙坦组血浆瘦素治疗前后有明显差异（P＜0.05）,然而氨氯地平组在治疗前后没有明显的差异（P＞0.05）;血浆去甲肾上腺素水平在氨氯地平组治疗后较前明显增加（P＜0.01）,氯沙坦组治疗前后没有明显差异（P＞0.05）,两组之间比较差异有统计学意义（P＜0.01）.结论 虽然血管紧张素Ⅱ受体拮抗剂氯沙坦和钙离子拮抗剂氨氯地平有等同的降压效应,但氯沙坦尚能改善肥胖相关代谢紊乱,因此肥胖高血压患者用氯沙坦比氨氯地平治疗可能会获得更多益处.     

B cell secretion and insulin sensitivity in hypertensive and normotensive obese subjects

To test the hypothesis that in obesity hypertension is associated with more pronounced hyperinsulinaemia and insulin resistance we compared plasma insulin levels and insulin sensitivity in a group of 6 obese subjects with untreated hypertension and in a group of 6 obese subjects with normal blood pressure. The two groups were similar for sex, age, body mass index and glucose tolerance. Six nonobese subjects served as controls. The study consisted of a 2-h hyperglycaemic clamp (steady-state plasma glucose = 11 mmol/l) and a 15-min insulin tolerance test (0.1 U/kg body wt). During hyperglycaemic clamp, insulin and C-peptide plasma levels were similar in normotensive and hypertensive obese subjects: the area under the plasma insulin curve was 36,000 +/- 3000 pmol/l X 120 min in the former and 34,000 +/- 1000 pmol/l X 120 min in the latter; the area under the plasma C-peptide curve was 298,000 +/- 26,000 pmol/l X 120 min in the former and 246,000 +/- 26,000 pmol/l X 120 min in the latter (P = n.s.). The ratio M/I between the amount of glucose metabolized (M) and the mean plasma insulin levels (I) during hyperglycaemic clamp was similar in the two groups: 0.59 +/- 0.09 in normotensive and 0.58 +/- 0.08 mg/min X m2 per pmol/l in hypertensive obese subjects (P = n.s.). Also the rate coefficient of glucose disappearance from plasma (K(itt)) after i.v. insulin injection was similar in the two groups (4.08 +/- 0.51 vs. 3.87 +/- 0.53 per cent/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Leptin receptor gene polymorphisms are associated with insulin in obese women with impaired glucose tolerance.

Leptin receptors are present on beta-cells as well as on muscle and fat cells, thus enabling leptin to modulate both insulin secretion and insulin action. Leptin inhibits especially the glucose-stimulated insulin secretion from pancreatic cells. The leptin receptor (LEPR) gene could thus play a role in the regulation of glucose and insulin after an oral glucose load. Therefore, the relationship between LEPR polymorphisms and glucose and insulin response to an oral glucose tolerance test (OGTT) was investigated. Three LEPR polymorphisms (Lys(109)Arg, Gln(223)Arg, and Lys(656)Asn) were typed on genomic DNA of 358 overweight and obese women, aged 18-60 yr. Based on an OGTT, 269 subjects were defined with normal glucose tolerance, and 89 with impaired glucose tolerance (IGT). Associations between genotypes and glucose metabolism were analyzed with a general linear models procedure in pre- and postmenopausal women separately, after adjusting the data for age and fat mass. In postmenopausal women with IGT (n = 24), associations were found with Lys(109)Arg and Lys(656)Asn for fasting insulin (P = 0.05) and with Lys(109)Arg and Gln(223)Arg for the insulin response to an OGTT (P < 0.02). In the same group, trends were found with Lys(656)Asn for fasting glucose as well as in response to the OGTT. In premenopausal women with IGT (n = 65), associations were found with Lys(109)Arg and Lys(656)Asn for overall glucose response to the glucose load. In contrast, no associations with insulin or glucose were found in women with normal glucose tolerance. In conclusion, these data indicate that LEPR polymorphisms are associated with insulin and glucose metabolism in women with impaired glucose homeostasis.