Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic steatosis, inflammation, and fibrosis. Leptin is an adipocyte-derived antiobesity hormone that in rodents prevents "lipotoxicity" by limiting triglyceride accumulation and also regulates matrix deposition (fibrosis) during wound healing. We therefore determined serum leptin levels in patients with NASH to determine whether relationships existed between leptin levels and severity of hepatic steatosis or fibrosis. We used a radioimmunoassay to determine serum [total] leptin concentrations in 27 men and 20 women with NASH and 47 controls matched for gender and body mass index (BMI; and partly for age). Serum leptin values were correlated with hepatic steatosis, fibrosis, and inflammation (each categorized semiquantitatively on liver histology), and with anthropometric indices, serum lipids, glucose, insulin, c-peptide, and alanine aminotransferase (ALT) levels. Compared with the controls, mean serum leptin levels were raised in both men and women with NASH (men 14 +/- 11 ng/mL vs. 7.2 +/- 4.1 ng/mL, P =.003; women 35 +/- 16 ng/mL vs. 15 +/- 8.2 ng/mL, P <.001). Leptin values correlated with serum c-peptide levels but not with BMI. In a multivariate analysis, serum leptin (P =.027), serum c-peptide (P =.001), and age (P =.027) were selected as independent predictors of the severity of hepatic steatosis. However, serum leptin was not an independent predictor of hepatic inflammation or fibrotic severity. In conclusion, hyperleptinemia occurs in NASH and is not explained simply by gender, obesity, or the presence of type 2 diabetes. Furthermore, leptin levels correlate directly with the severity of hepatic steatosis but not with inflammation or fibrosis. We propose that the relationship between leptin and steatosis reflects a pathogenic role of leptin in hepatic insulin resistance and/or a failure of the antisteatotic actions of leptin ("peripheral leptin resistance").     

Associations of leptin with body fat distribution and metabolic parameters in non-insulin-dependent diabetic patients: no effect of apolipoprotein E polymorphism

Leptin levels have been shown previously to be associated with anthropometric parameters such as the body mass index (BMI), total body fat, and subcutaneous fat. Since apolipoprotein E (apoE) polymorphism is known to be a genetic marker affecting the relationship between certain anthropometric and metabolic parameters, we evaluated whether the leptin level and/or associations between the leptin level and body composition in non-insulin-dependent diabetic patients could be determined by apoE polymorphism. In 171 type 2 diabetic patients (105 male and 66 female), body composition (BMI, waist to hip ratio [WHR], fat mass, and visceral fat) was measured and fasting blood samples were obtained to determine the apoE genotype, leptin, glucose, and insulin levels, and the lipid profile. The mean leptin level for the whole group was 11.7 +/- 9.3 ng/mL, with a significant difference (P < .001) between men (7.1 +/- 4.9 ng/mL) and women (19.0 +/- 10.1 ng/mL). No difference was found for leptin levels or anthropometric variables between the 3 different apoE genotypes (E3/E3 homozygotes, E2 carriers, and E4 carriers). Only low-density lipoprotein (LDL) cholesterol was significantly different between the 3 apoE subgroups. The correlations of leptin with anthropometric variables, especially visceral fat, tended to be different between the 3 apoE groups, but this was not independent and no effect was found after controlling for the other parameters in the model. A multiple regression model containing gender, subcutaneous fat, fasting glucose, triglycerides, and high-density lipoprotein (HDL) cholesterol explained 81% of the variance in leptin levels. We conclude that apoE polymorphism has no effect on the leptin level or its associations with other anthropometric and metabolic parameters.     

Increased leptin concentrations and lack of gender difference in Type 2 diabetic patients with nephropathy

Leptin plays an important role in the regulation of body weight and energy balance. Women have higher circulating leptin level than men. In this study, we examined serum leptin concentrations in Type 2 diabetic men and women with or without nephropathy. Fasting plasma glucose (FPG), lipid profile, and serum leptin concentrations were measured in 34 Type 2 diabetic patients with nephropathy (DMN), 12 normoalbuminuric Type 2 diabetic subjects (DM) and 34 non-diabetic control subjects, all matched for age and body mass index (BMI). RESULT: Patients with diabetic nephropathy had lower high-density lipoprotein cholesterol and higher triglyceride, FPG, urinary albumin/creatinine ratio (ACR) and serum creatinine than the other two groups. There was a significant trend in serum leptin concentrations (P<0.001, analysis of variance ANOVA) across the three groups with the main difference being detected between DMN and control subjects (DMN: 17.5 +/- 16.8 ng/ml, DM: 14.6 +/- 10.5 ng/ml and control: 9.1 +/- 7.1 ng/ml). Women had higher serum leptin concentration than men in the control group (12.5 +/- 7.3 ng/ml versus 4.2 +/- 2.0 ng/ml, P=0.001) and in the DM group (18.9 +/- 11 ng/ml versus 8.6 +/- 5.9 ng/ml, P=0.07) whereas this gender difference was not observed in the DMN group (18.6 +/- 17.0 ng/ml versus 16.8 +/- 17.0 ng/ml, P=0.754). On multivariate analysis, ACR (=0.411, P<0.001) and BMI (=0.240, P=0.002) were independently associated with serum leptin concentrations (R2=0.194, F=22.1, P<0.001) in the whole group. In the DMN group, ACR (=0.370, P=0.016) was the only independent determinant of serum leptin concentrations (R2=0.159, F=11.4, P=0.016). Serum leptin concentrations were higher in Type 2 diabetic patients with nephropathy than normoalbuminuric diabetic patients and controls. Diabetic men with nephropathy had proportionally higher serum leptin such that the gender difference in leptin observed in non-nephropathic individuals was abolished.     

Effect of exercise training on serum leptin levels in type 2 diabetic patients

To evaluate the effect of exercise training on serum leptin levels 50 sedentary subjects with type 2 diabetes were enrolled in either 6 weeks of aerobic exercise training with diet therapy (n = 23) or diet therapy alone (n = 27). The training program consisted of walking and cycle ergometer exercise for 1 hour at least 5 times per week, with the intensity of exercise maintained at 50% of maximum oxygen uptake. Serum leptin levels decreased significantly in the exercise training (TR) group (7.2 +/- 3.6 to 4.6 +/- 2.5 ng/mL, P <.05), but not in the sedentary (SED) group (6.9 +/- 3.4 to 5.6 +/- 2.9 ng/mL). Leptin levels standardized for percentage body fat (dividing serum leptin level by percentage body fat) after treatment were lower in the TR subjects compared with the SED subjects. Body weight and percentage body fat decreased in all patients; however, no significant changes were observed in either group. Fasting concentrations of plasma insulin and cortisol and the urinary excretion of 17-hydroxycorticosteroid (17-OHCS) did not differ between the groups either before or after treatment. Fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) improved significantly in both groups, although no significant differences were observed between the groups either before or after treatment. Ventilatory threshold increased significantly in the exercise training subjects. This study demonstrates that exercise training in type 2 diabetic subjects reduces serum leptin levels independent of changes in body fat mass, insulin, or glucocorticoids.     

Elevated serum leptin concentrations in type 2 diabetic patients with microalbuminuria and macroalbuminuria.

Leptin levels are elevated in end-stage renal disease, suggesting an impairment of renal leptin degradation. The present study aimed to determine whether leptin levels are also elevated in patients with earlier stages of renal disease, ie, microalbuminuric and macroalbuminuric nephropathy. A total of 60 subjects were assigned to two study groups. Group A contained 10 type 2 diabetics with macroalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy control subjects. Group B contained 10 type 2 diabetics with microalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy controls. The subgroups of both study groups were matched for sex and body fatness. In group A, macroalbuminuric diabetic patients had higher serum leptin levels than the normoalbuminuric diabetics (11.90 +/- 2.98 v 4.13 +/- 0.92 ng/mL, P < .002) and control subjects (4.78 +/- 1.37 ng/mL, P < .006). In group B, microalbuminuric diabetics had higher serum leptin levels than the normoalbuminuric diabetics (21.16 +/- 5.80 v8.74 +/- 1.89 ng/mL, P < .04) and control subjects (10.06 + 3.00 ng/mL, P < .06). In both groups A and B, creatinine clearance was inversely correlated with the serum leptin level after adjusting for body fat. In conclusion, serum leptin levels are elevated in type 2 diabetic patients with microalbuminuria and macroalbuminuria, suggesting that renal leptin degradation is already impaired in the early stages of renal disease.     

Serum leptin levels in diabetic patients on hemodialysis: the relationship to parameters of diabetes metabolic control

Leptin is a protein hormone produced predominantly by adipocytes that affects food intake and energy expenditure. Its serum levels are significantly higher in patients with chronic renal failure compared to healthy subjects. The aim of this study was to compare serum leptin levels in hemodialyzed patients with type II diabetes mellitus (n=26) with body content-matched hemodialyzed patients without diabetes (n=26) and to explore the relationship between parameters of the long term diabetes metabolic control and serum leptin levels. Serum leptin levels in diabetic patients did not significantly differ from those of non-diabetic patients (25.3+/-8.8 vs 25.7+/-8.7 ng/ml). Serum leptin levels in diabetic patients positively correlated with body fat content, body mass index and predialysis serum insulin levels. No significant relationship were observed between serum leptin levels and blood glucose, glycated hemoglobin, glycated protein, serum urea, creatinine, leukocyte count and total hemoglobin respectively. The multiple stepwise regression analysis revealed that body fat content together with body mass index accounted for 77.8% of variations in predialysis serum leptin levels, while insulin levels and the parameters of diabetes metabolic control had only slight prediction value for leptin concentrations. We conclude that serum leptin levels in hemodialysed patients with type III diabetes mellitus do not significantly differ from those of hemodialysed non-diabetic patients. The body fat content and body mass index are the strongest predictors of serum leptin levels, while parameters of long term diabetes metabolic control play probably only minor direct role in its regulation.     

Effects of anabolic-androgenic steroid use or gonadal testosterone suppression on serum leptin concentration in men.

OBJECTIVE: Serum leptin concentration shows a sexual dimorphism that is not accounted for by gender differences in adiposity. A strong inverse association exists between serum leptin and testosterone concentrations in men, pointing to a likely influence of gonadal sex steroids on serum leptin concentration. The aim of this study was to investigate whether manipulation of sex steroid hormones in men would alter serum leptin concentration independently of changes in fat mass. DESIGN AND METHODS: The effects of sex steroid suppression on serum leptin concentration were investigated in nine healthy men in whom testosterone had been reversibly suppressed for 5 weeks after treatment with intramuscular triptorelin. The effects of sex steroid supplementation were investigated in nine male bodybuilders who self-administered anabolic--androgenic steroids (AAS) for a mean period of 6.5 weeks. A control group received no hormonal treatment. RESULTS: Testosterone concentration was significantly reduced by triptorelin administration (7.32+/- 1.92ng/ml at baseline compared with 1.15+/-0.57ng/ml at 5 weeks, P=0.002). High-dose AAS use was confirmed by urine analysis. Body fat percentage was unaffected by the AAS or triptorelin intervention (P>0.19). Leptin concentration was significantly reduced after one cycle of AAS use (2.40+/-0. 98ng/ml off cycle compared with 1.63+/-0.37ng/ml on cycle, P=0.012), and was significantly increased by triptorelin administration (2. 96+/-1.50ng/ml at baseline compared with 6.63+/-4.67ng/ml at five weeks, P=0.004). No significant change occurred in the control group. CONCLUSION: Androgenic sex hormone supplementation decreases serum leptin concentration, whereas suppression increases serum leptin concentration, independently of changes in body fat mass in healthy men. The sexual dimorphism evident in serum leptin concentration is likely to be due to a suppressive effect of testosterone on serum leptin concentration in males.     

Serum lipid and leptin concentrations in hypopituitary patients with growth hormone deficiency

OBJECTIVE: To investigate the effects of growth hormone (GH) deficiency on serum lipid and leptin concentrations in hypopituitary patients taking conventional replacement therapy and to determine the relations between leptin and gender and anthropometric and metabolic variables. SUBJECTS: Twenty-one GH deficient adult hypopituitary patients (15 women, six men) and 21 (14 women, seven men) age, sex and body mass index (BMI) matched healthy controls. MEASUREMENTS: After an overnight fast, anthropometric parameters were measured and body composition was determined by a bioelectrical impedance analyser. Venous blood samples were obtained for the measurements of glucose, total cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, intact insulin, insulin-like growth factor 1 (IGF-1) and leptin concentrations. Serum leptin and hormones were analysed by radioimmunoassay. RESULTS: Hypopituitary patients with GH deficiency showed significantly higher triglyceride, total and low density lipoprotein (LDL) cholesterol and lower HDL cholesterol concentrations on conventional replacement therapy. The unfavourable lipid profile was particularly evident in women. Significantly higher leptin concentrations were found in patients compared with healthy controls with similar body fat content (23. 5+/-11.8 ng/ml vs 11.7+/-6.9 ng/ml, P=0.01). This difference remained significant even when leptin values were expressed in relation to fat mass percentage (0.79+/-0.40 vs. 0.42+/-0.17 ng/ml%, P<0.05) and fat mass kg (1.32+/-0.81 vs 0.66+/-0.30 ng/ml kg, P<0. 05). Significant positive correlations were observed between leptin concentrations and body fat percentage and age in the control group. In patients the sole significant relation between leptin and study parameters was the positive correlation observed between leptin and total cholesterol concentrations. Serum leptin concentrations were significantly higher in women than men in the control group, but not in the patients. No significant gender difference was observed when leptin concentrations were expressed in relation to fat mass (percentage and kg). CONCLUSION: Growth hormone deficient hypopituitary patients (particularly women) on conventional replacement therapy have a more atherogenic lipid profile. Leptin concentrations are increased in GH deficient adults even after adjustment for percentage body fat and body fat mass (kg). Although the nature of our data does not allow us to draw any conclusions on the mechanism(s) of increased leptin concentrations in GH deficiency, decreased central sensitivity to leptin and increased leptin production from per unit fat mass, or alterations in leptin clearance, might be operative.     

Serum leptin level as an indicator to predict the clinical efficacy of troglitazone in patients with type 2 diabetes mellitus

Troglitazone is effective in approximately 50% in patients with type 2 diabetes (NIDDM). In this study, we investigated the relations between serum leptin levels and clinical efficacy of troglitazone. Forty-five type 2 diabetic patients (23 men and 22 women) from our outpatient clinic were treated with troglitazone 400 mg daily for 12 weeks. Fasting plasma glucose (FPG), HbA1c, body weight, serum insulin and leptin concentrations were measured before and after troglitazone treatment. After 12 weeks of troglitazone treatment, FPG (before versus after, 179+/-33 vs. 138+/-26 mg/dl, mean+/-SD), HbA1c (7.8+/-1.3 vs. 6.9+/-1.0%), IRI (8.3+/-4.3 vs. 6.3+/-3.4 microU/ml) and HOMA-R index (homeostasis model assessment of insulin resistance) (3.8+/-2.4 vs. 2.2+/-1.3) decreased significantly, while body mass index (BMI) slightly increased (26.3+/-3.5 vs. 26.6+/- 3.6 kg/m(2)), and serum leptin remained unchanged (8.5+/-7.2 vs. 9.1+/-8.7 ng/ml). Reduction in FPG (DeltaFPG) after troglitazone treatment were correlated with reduction in HOMA-R (DeltaHOMA-R) (r=0.721, P<0.0001). DeltaFPG was correlated with serum leptin (r=0.441, P<0.01), HOMA-R (r=0.460, P<0.01) and FPG (r=-0.781, P<0.0001) at baseline, but not with BMI and serum IRI at baseline. Furthermore, serum leptin at baseline was significantly correlated with DeltaHOMA-R (r=0.634, P<0.01). Leptin concentration before treatment therefore, can be used as an predictor for clinical efficacy of troglitazone in patients with type 2 diabetes.     

Effect of orlistat on plasma leptin levels and risk factors for the metabolic syndrome

Background: The aim of this research was to assess the impact of treatment with Orlistat 120 mg three times daily on serum leptin levels, weight loss, glycemic control, and cardiovascular risk factors involved in the metabolic syndrome. Methods: A 3-month open-labeled prospective study was conducted on 40 patients with the clinical features of the metabolic syndrome divided into two groups-with and without type 2 diabetes mellitus. Twenty type 2 diabetic obese patients (group A) were studied, with BMI of 35.4 +/- 0.9 kg/m(2), as were 20 obese patients without diabetes (group B), with BMI of 36.2 +/- 0.7 kg/m(2). Weight, serum leptin levels, insulin resistance, and cardiovascular risk factors were measured at baseline and at the end of each month. Results: Patients reduced weight at 8.5 +/- 2.3 kg for men and 5.7 +/- 2.6 kg for women in group A against 7.9 +/- 1.9 kg for men and 5.6 +/- 2.0 kg for women in group B. Plasma leptin levels decreased at 4.5 +/- 1.9 ng/mL for men and 1.9 +/- 0.9 ng/mL for women in group A against 3.8 +/- 2.0 ng/mL for men and 2.8 +/- 1.4 ng/mL for women in group B. The level of insulin resistance measured with HOMA-IR decreased from 4.54 +/- 2.35 to 2.69 +/- 0.86 in group A against 3.98 +/- 1.89 to 2.87 +/- 0.93 in group B. In the lipid parameters, the highest decrease was found in triglycerides levels: 6.1 +/- 2.3 mmol/L for men and 3.5 +/- 2.6 mmol/L for women in group A against 2.1 +/- 1.9 mmol/L for men and 1.8 +/- 0.7 mmol/L for women in group B (all p < 0.05). Conclusions: Orlistat beneficially enhances weight loss, contributing to a decrease of serum leptin, insulin resistance level, and cardiovascular risk factors in both groups. An additional beneficial pleotropic effect of Orlistat could be proposed through a reduction of plasma leptin and lipid levels.     

Levels of leptin in plasma of patients with type 2 diabetes

Leptin, the product of ob gene is secreted by adipose tissue. It is believed that leptin plays an important role in energy balance. The secretion of leptin by adipose tissue is influenced by insulin. The aim of the present study was the estimation of plasma leptin concentrations in patients with type 2 diabetes mellitus. The study was carried out in 21 diabetic obese patients (BMI > 27.5), 8 diabetic patients with BMI < 27.5, 24 obese patients with normal glucose tolerance (BMI > 27.5) and 10 patients from the control group (BMI < 27.5). The mean leptin concentration in obese diabetic patients was 22.5 + 6.5 ng/ml and was not significantly different from that in obese patients without diabetes (24.1 + 10.3 ng/ml) but differed markedly in comparison to the normal weight diabetic patients (7.9 + 4.3 ng/ml, p < 0.01). Plasma leptin concentration correlated significantly and positively with BMI and fasting insulin in all studied groups. There was no significant correlation between leptin and glycated hemoglobin, total cholesterol and triglycerides. We conclude that serum leptin concentrations in patients with type 2 diabetes depends mainly on the amount of body fat.     

Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors

OBJECTIVE: To study clinical, anthropometric and metabolic determinants of serum leptin concentrations in a series of patients with a wide range of obesity. SUBJECTS: 400 patients, 116 males and 284 females, aged 44+/-12.3 years with body mass index (BMI) ranging from 31 to 82 kg/m2 (mean 41.4+/-7.1). MEASUREMENTS: Energy intake by 7-day recall, resting energy expenditure (REE) by indirect calorimetry, body composition determined by bioelectrical impedance; C index, an anthropometric index of abdominal fat distribution, and waist-hip ratio (WHR), blood glucose serum leptin concentrations, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, and insulin concentrations HOMA IRI (homeostastis model assessment of insulin resistance index). RESULTS: Leptin concentrations were higher in obese than in normal subjects and in females than in males without differences between diabetic and non-diabetic patients; leptin concentrations were not related to age and showed a strong negative association with energy intake only in the group of women with BMI less than 40. Leptin concentrations showed a direct correlation with BMI and body fat values (expressed either as percentage of total body mass or absolute fat mass) independent of age and sex. After adjustment for fat mass, leptin values higher than predicted were found in women whereas concentrations lower than predicted were found predominantly in men. Leptin showed an inverse correlation with WHR and C-index, the latter persisting also after correction for gender and fat mass. REE, but not REE/kg fat-free mass (FFM) was inversely related to leptin also after correction for sex and absolute fat mass. Leptin concentrations were directly associated with HOMA IRI, insulin and HDL cholesterol and inversely associated with triglycerides and uric acid. The relationship of leptin with HOMA IRI was still evident after adjusting for sex but was lost when absolute fat mass was added to the model; HDL cholesterol and triglycerides appeared to be variables independent of leptin concentrations even when both sex and fat mass were added to the model. CONCLUSIONS: In a large group of obese patients (half of whom had severe obesity, gender, BMI and fat mass accounted for the largest proportion of serum leptin concentrations variability. We found that in obese subjects there is an effect of fat distribution on leptin concentrations and that, after excluding variability due to absolute fat mass, patients with a greater amount of abdominal fat have relatively low leptin concentrations which in turn relates to a metabolic profile compatible with an increased cardiovascular risk. Women with milder obesity may retain some degree of control of food intake by leptin.     

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.     

Relative hypoleptinemia in patients with type 1 and type 2 diabetes mellitus

OBJECTIVE: To determine the relation between plasma leptin concentrations and metabolic control in human diabetes mellitus. DESIGN AND SUBJECTS: Cross sectional study consisting of 156 patients with diabetes mellitus type 1 (n=42), type 2 (n=114), and non-diabetic subjects (n=74). RESULTS: Plasma leptin concentrations were lower (P<0.05) in type 1 (8.3+/-1.7 ng/ml) and type 2 diabetic (14.9+/-1.8 ng/ml) than in non-diabetic humans (18.3+/-1.9 ng/ml). Only female type 1 and type 2 diabetic subjects also had decreased leptin/BMI ratios (P<0.05 vs non-diabetic females). The log rank test identified age-adjusted correlation of plasma leptin concentration with sex (P<0.0004) and body mass index (P<0.0218), but not with glycosylated haemoglobin A1c (P>0.5) in all groups. Plasma leptin was correlated with age (P<0.0058) and serum triglycerides (P<0.0199) in type 1 diabetic patients, and with serum cholesterol (P<0.0059) and LDL (P<0.0013) in type 2 diabetic patients. CONCLUSIONS: Defective leptin production and/or secretion might be present independently of metabolic control in female patients with type 1 or type 2 diabetes mellitus.     

Effect of age, gender, and body fat distribution on serum leptin concentrations

The aim of this study was to clarify the relationship between serum leptin concentration and age, gender and body fat distribution. Serum leptin concentrations were determined 267 subjects (138 men and 129 women), aged 30 to 91. The thicknesses of the preperitoneal fat layer (Pmax) and subcutaneous fat layer (Smin) in the abdomen were measured by ultrasonography. Fat mass and percent fat were measured by the bioelectrical impedance analysis method. Women had higher leptin and leptin/fat mass values than men in all BMI groups (BMI < 20, 20-23.9, 24-25.9, > or = 26). The leptin concentration correlated significantly with BMI, fat mass, percent fat, waist, hip, waist/hip ratio (W/H), Pmax, Smin and serum Cr in both men and women. The leptin concentration correlated significantly with age in men only and P/S in female only. Leptin/fat mass values significantly correlated with age, fat mass, and percent fat, but not with BMI, waist, hip, W/H, Pmax, Smin and P/S in men. In women, leptin/fat mass values significantly correlated with BMI, fat mass, percent fat, waist, hip, Pmax, Smin and P/S, but not with age or W/H. Multiple regression analysis showed that fat mass and serum creatinine were significant determinants of the leptin and leptin/fat mass values both in men and women, but that age was a significant determinant of these values only in men. These results suggest that the influence of aging on serum leptin concentration exists only in men.     

Association between serum leptin concentrations and bone mineral density, and biochemical markers of bone turnover in adult men.

Leptin, the product of the ob gene, has been shown to inhibit bone formation in mice. We addressed whether leptin has any role in the regulation of bone mineral density (BMD) in humans. Subjects were 221 adult men with a mean (+/-SD) age and body mass index of 52.1 +/- 8.7 yr and 23.6 +/- 2.8 kg/m2. Serum leptin, carboxyterminal propeptide of type 1 procollagen (PICP; a marker of bone formation), and cross-linked carboxyterminal teleopeptide of type 1 collagen (a marker of bone resorption) were measured by RIA. BMD was assessed by single photon absorptiometry, and total fat mass was determined by bioimpedance analysis. BMD was inversely associated with serum leptin concentrations and total fat mass after adjustment for body weight. PICP, but not cross-linked carboxyterminal teleopeptide of type 1 collagen, was inversely correlated with serum leptin. These results may suggest that an increase in serum leptin reduces bone formation and decreases BMD in adult men. Leptin may be a regulator of BMD in humans.     

Gender differences in the effect of type 2 diabetes on serum lipids, pre-heparin plasma lipoprotein lipase mass and other metabolic parameters in Japanese population

DESIGN: Cross-sectional study of fasting serum lipid and lipoprotein levels, pre-heparin lipoprotein lipase (LPL) mass, several other metabolic parameters, and intra-abdominal fat areas in 26 Japanese poorly controlled type 2 diabetic men and 23 women when matched for age, body mass index (BMI), and HbA1c between genders. SUBJECTS: Study subjects were Japanese type 2 diabetic patients who were admitted to our hospital between Jun 2001 and Aug 2002 because of their poorly controlled diabetes. A total of 49 subjects [40-79 years of age, average age 61.5 +/- 8.7; mean BMI 23.2 +/- 3.7 kg/m2] with fasting plasma glucose (PG) and HbA1c levels being 251 +/- 76.5 mg/dl and 10.8 +/- 2.2%, respectively, were involved in this study. METHODS: Pre-heparin LPL mass was determined by enzyme linked immunosorbent assay. Remnant like particle cholesterol (RLP-C) level was measured using an immunoaffinity mixed gel containing anti-apolipoprotein (apo) A-I and anti-apo B monoclonal antibodies. Serum leptin level was determined by radioimmunoassay. Intra-abdominal fat area was determined by computerized tomography analysis at the umbilical level. RESULTS: The men group showed a higher serum triglycerides (TG) and RLP-C levels, and lower high density lipoprotein-cholesterol levels and pre-heparin plasma LPL mass than did women. Serum leptin level was higher in women than in men counterparts. The intra-abdominal subcutaneous fat areas were significantly larger in women than in men counterparts, whereas the visceral fat areas did not differ. CONCLUSION: In Japanese population, poorly controlled type 2 diabetic men had more unfavorable lipid profile than did women counterparts, which may be associated with decreased lipolysis of plasma TG-rich lipoproteins by LPL.     

The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress-related (acute-phase) reaction

OBJECTIVE: Leptin is produced by adipose tissue and controls food intake and body weight. Although blood levels of leptin reflect energy stores, cytokines also stimulate leptin production from fat. Because we have proposed that type 2 diabetes mellitus is associated with a cytokine-mediated acute-phase or stress response, part of the innate immune system, we sought evidence that leptin is increased in type 2 diabetes partly as a stress response, independently of obesity and sex. DESIGN: We selected two groups of type 2 diabetic patients with either a low acute-phase response (< 2.30 mmol/l serum concentration of the acute-phase marker sialic acid) or high response (> 2.30 mmol/l sialic acid), but pair-matched for body mass index (BMI) and sex. PATIENTS: Twenty type 2 diabetic subjects (11 male, 9 female) in each group, whose body mass index (BMI) and age were comparable (mean +/- SD: 28.8 +/- 3.8 vs. 28.9 +/- 3.8 kg/m2, and 60.7 +/- 8.9 vs. 61.9 +/- 12.3 years, low vs. high acute-phase responders, respectively). The glycaemic control was also similar in each group (glycated haemoglobin: 9.1 +/- 2.2 vs. 8.9 +/- 1.9%). MEASUREMENTS: Serum concentrations of sialic acid, leptin, interleukin-6 (IL-6) (the major cytokine mediator of the acute-phase response) and cortisol were assayed in fasting venous blood samples from patients and the results compared. RESULTS: Serum leptin concentration was increased in the high compared to the low acute-phase group (median 13.2 (range 3.6-55) vs. 8.1 (2.0-22.5) microg/l, P = 0.004). IL-6 and cortisol concentrations were also higher in the high-stress group (1.9 (1.0-6.4) vs. 1.4 (0.4-7.5) ng/l, P = 0.02; and 409 (180-875) vs. 290 (157-705) nmol/l, P = 0.02, respectively). Leptin was strongly correlated with BMI (r = 0.61, P < 0.001), but also with sialic acid (r = 0.40, P = 0.01) and IL-6 (r = 0.38, P = 0.04). CONCLUSIONS: Serum leptin concentrations in type 2 diabetes are partly related to an acute-phase or stress response, independent of BMI and sex. The association of hyperleptinaemia with elevated serum cortisol provides a mechanism for leptin resistance in type 2 diabetes (glucocorticoids inhibit the central action of leptin). This study provides further support for the theory that type 2 diabetes is asociated with chronic innate immune activation.     

Changes in serum leptin levels during GnRH agonist therapy

The purpose of the present study was to investigate changes in serum leptin levels during GnRH agonist therapy. Twenty regularly menstruating women with uterine leiomyomas were enrolled. These subjects were given GnRH agonist (leuprorelin acetate, 3.75 mg) monthly for 4 months. Serum leptin and estradiol (E2) levels were measured at the two time points of day 1 or 2 of the menstrual cycle and the end of GnRH agonist therapy. Weight, total body fat mass, percentage of body fat, and total body lean mass were measured by whole body scanning with dual-energy X-ray absorptiometry. The ratio of serum leptin levels to total body fat mass (leptin-fat mass ratio), and the ratio of serum leptin levels to total body lean mass (leptin-lean mass ratio) were calculated. All subjects became amenorrheic after the initial administration of GnRH agonist. Baseline E2 levels were 45.4 +/- 21.0 pg/mL, which significantly decreased after GnRH agonist therapy (13.3 +/- 4.2 pg/mL, p<0.01). Baseline leptin levels were 8.7 +/- 8.1 ng/mL, which did not differ from the values after 4 months of GnRH agonist administration (8.9 +/- 6.8 ng/mL). Total body fat mass significantly increased from 20.0 +/- 10.4 to 21.0 +/- 9.4 kg (p<0.05), while total body lean mass significantly decreased (34.5 +/- 4.2 kg to 33.3 +/- 3.9 kg, p<0.01). However, leptin-fat mass ratio after GnRH agonist therapy did not differ from the baseline values (0.39 +/- 0.16 ng/mL/kg vs 0.38 +/- 0.16 ng/mL/kg). Hypogonadism does not have a major impact on circulating leptin levels.     

Reduced leptin concentrations in subjects with type 2 diabetes mellitus in Sudan

Differences have been observed in the relationship between leptin and metabolic perturbations in glucose homeostasis. Because no information is available from indigenous African populations with diabetes, the purpose of this study was to investigate the possible associations between leptin and different clinical and biochemical characteristics of a large group of subjects with type 2 diabetes mellitus in Sudan. A total of 104 (45 men and 59 women) consecutive type 2 diabetes patients and 75 control subjects (34 men and 41 women) were studied. The body mass index (BMI), blood glucose, serum insulin, and proinsulin were measured and related to serum leptin concentrations. Leptin was higher in females than in males and correlated significantly to BMI. The main novel finding was that serum leptin was significantly lower in diabetic subjects compared with controls in both females (P =.0001) and males (P =.019), although BMI did not differ between diabetic and nondiabetic subjects. Diabetic subjects treated with sulphonylurea (n = 81) had lower BMI than those treated with diet alone or other hypoglycemic drugs (n = 23) (P =.0017), but there was no difference in leptin levels between the 2 groups after adjustment for BMI (P =.87). In diabetic subjects, serum leptin correlated positively with the homeostatic assessment (HOMA) of both beta-cell function (P =.018) and insulin resistance (P =.038), whereas in control subjects, leptin correlated with insulin resistance (P =.0016), but not with beta-cell function. Diabetic subjects had higher proinsulin levels (P =.0031) and higher proinsulin to insulin ratio (P =.0003) than nondiabetic subjects. In univariate analysis, proinsulin showed a weak correlation to leptin (P =.049). In conclusion, we show in a large cohort of Sudanese subjects with type 2 diabetes that circulating leptin levels are lower in diabetic subjects than in controls of similar age and BMI. The lower serum leptin in diabetic subjects may be a consequence of differences in fat distribution.