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DOI: 10.1530/eje.1.01960
European Journal of Endocrinology, Vol 153, Issue 2, 283-290
Copyright © 2005 by European Society of Endocrinology
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CLINICAL STUDY

Relationship between leptin, insulin, body composition and liver steatosis in non-diabetic moderate drinkers with normal transaminase levels

Silvia Valtueña, Filippo Numeroso, Diego Ardigò, Mario Pedrazzoni, Laura Franzini, Pier Marco Piatti1, Lucilla Monti1 and Ivana Zavaroni

Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy and 1 Metabolic and Cardiovascular Rehabilitation Unit, IRCCS San Raffaele Hospital, Milan, Italy

(Correspondence should be addressed to S Valtueña, Department of Internal Medicine and Biomedical Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy; Email: valtuena{at}libero.it)


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Objective: Obesity and insulin resistance play a major role in the development of liver steatosis (LS), but also relative leptin resistance has been reported to correlate with LS in humans. Our objective was to investigate the relationship between serum leptin, insulin, obesity and LS in non-diabetic males (n = 74) and postmenopausal females (n = 50) with normal transaminase levels and low-to-moderate alcohol intake.

Methods: A medical history to retrieve information about health status, current medications, alcohol consumption and history of viral or toxic hepatitis; a physical examination including height, weight, waist circumference and blood pressure; a fasting blood draw for the determination of glucose, insulin, leptin, lipid profile, transaminases and uric acid; an oral glucose tolerance test to exclude type 2 diabetes; a dual-energy X-ray absorptiometry scan to assess fat mass (FM) and lean body mass (LBM), and an echography of the liver to assess LS.

Results: Fasting leptin and insulin were highly correlated with FM in men (R = 0.767 and R = 0.495 respectively, P < 0.001) and women (R = 0.713 and R = 0.526 respectively, P < 0.001). After correction for FM, leptin showed a significant negative correlation with LBM in men (R = –0.240, P = 0.039), but not in women (R = –0.214, P = 0.132). The positive relationship observed between leptin, insulin and LS persisted after adjustment of leptin and insulin for body composition only in men (R = 0.415, P < 0.001 and R = 0.339, P = 0.003 respectively for leptin and insulin vs LS). Adjusted means (95% confidence intervals) of leptin increased significantly across categories of LS in men even when insulin was considered in the model (absent = 7.1 ng/ml (5.6–8.5), mild = 8.2 ng/ml (7.2–9.2), moderate/severe = 12.1 ng/ml (10.3–14.0); P < 0.001), whereas no significant relationship was observed between insulin and LS after leptin was accounted for.

Conclusion: Serum concentrations of leptin and insulin are positively correlated in men independently of body composition, but not in postmenopausal women. In men, the steatogenic effect of hyperinsulinemia/insulin resistance in the context of low-to-moderate alcohol consumption appears to be mediated by high concentrations of serum leptin, whereas body fat alone could identify postmenopausal women at high risk for LS.


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Non-alcoholic fatty liver disease (NAFLD) is common in the presence of obesity and other associated features of the insulin resistance syndrome such as hypertriglyceridemia, low high-density lipoprotein (HDL) concentrations, postprandial hyperlipemia and hypertension. Once considered a benign finding, now it is known that a minority of subjects with liver steatosis (LS) of metabolic origin can progress to non-alcoholic steatohepatitis (NASH) and liver failure (1–5). Only recently has it been suggested that the adipocyte-derived anti-obesity hormone leptin may prevent fat accumulation in the liver. Leptin deficiency in transgenic mice and in humans with lipodistrophies induces severe LS and insulin resistance that are responsive to the administration of exogenous leptin (6–8). In addition, hyperleptinemia, a feature suggestive of resistance to the action of endogenous leptin, has been observed to correlate with LS in subjects with NASH and chronic hepatitis C (9–11), but the exact role of hyperleptinemia in the pathogenesis of human NAFLD remains controversial (12).

The accumulation of triglycerides in the hepatocyte is very likely the result of an increased flux of fat to the liver, of a decreased mitochondrial fat oxidation, or both. It is well known that peripheral insulin resistance increases plasma triglycerides and circulating free fatty acids, but also obesity, a condition that is usually associated with relative hyperleptinemia/leptin resistance, promotes fat mobilization from peripheral stores to be used as preferential fuel (13). As far as fat oxidation in the hepatocyte is concerned, leptin increases mitochondrial beta-oxidation by downregulating the stearoyl-CoA desaturase-1 (SCD-1) gene, as do the insulin-sensitizing agents metformin and thiazolidinediones (TZDs) through the activation of hepatic AMP-activated protein kinase. All of leptin, metformin and TZDs have been shown to reverse LS in animals and humans to a certain degree (4, 6, 14). However, the independent role of obesity, insulin resistance and hyperleptinemia in the development of LS has been scarcely investigated in humans, probably because of methodological reasons. First, these three variables are intimately associated among them and all represent strong individual predictors of LS (15, 16). Secondly, hormonal risk factors for LS may be different for men and women, since men have a higher prevalence of central obesity and insulin resistance, but lower plasma levels of leptin for a given fat mass (FM) (17). In addition, the FM and the lean body mass (LBM) compartments seem to affect differently serum leptin levels in men and women, and the relationship between body composition, insulin resistance and leptin may further change in women depending on menopausal status due to the fat redistribution observed after menopause (18–20). Therefore, we have investigated the relationship among serum leptin, insulin, obesity and LS in a relevant group of non-diabetic males and postmenopausal females using an appropriate body composition technique (dual-energy X-ray absorptiometry (DXA)) for the determination of the FM and the LBM compartments.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Subjects

Subjects were selected from a population of apparently healthy factory workers surveyed in 1981 for a variety of risk factors for cardiovascular disease who had returned for a follow-up in 2002. Exclusion criteria were diagnosis of diabetes, menses in the last 12 months, hormone replacement therapy in the last 12 months, treatment with cholesterol-lowering medications, alcohol consumption >60 g/day for men and >40 g/day for women, levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >40 U/L, evidence of hepatitis B virus and/or hepatitis C virus (HCV) infection, chronic liver diseases and/or nephropathies, and autoimmune diseases. Subjects with a body mass index (BMI) >35 kg/m2 were excluded from the study because leptin concentrations appear to be unrelated to FM and to other features of the metabolic syndrome in morbidly obese females (21). All subjects gave their written informed consent at enrollment. The protocol was approved by the Ethics Committee for Human Research of the University of Parma.

Experimental procedures

All subjects completed a medical history to retrieve information about health status, current medications, alcohol consumption and history of viral or toxic hepatitis; had a physical examination including height, weight, waist circumference and blood pressure; had blood drawn after a 12 h fast for biochemical analyses; underwent an oral glucose tolerance test with 75 g of glucose with blood draws at 0, 60 and 120 min for determination of glucose and insulin to exclude type 2 diabetes (22); and had a DXA scan to assess body composition, and an echography of the liver to assess LS.

Alcohol intake

Mean daily alcohol intake was estimated by means of a frequency questionnaire in which individuals were asked specifically about their regular consumption of white and red wine, beer and spirits on week and weekend days on a weekly basis. We considered one serving of alcoholic beverage as a glass of wine (150 ml = 12 g ethanol), a can of beer (330 ml = 13 g ethanol) or a small glass of spirits (30 ml = 13 g ethanol). If subjects reported drinking one type of beverage, but not on a weekly basis, this was coded as half a serving per week.

Body composition measurements

Height was measured with a wall-mounted Holtain stadiometer to the nearest 0.1 cm. Weight was measured without shoes and in light clothes to the nearest 0.01 kg. BMI was calculated as weight divided by height squared (kg/m2). Waist circumference was measured to the nearest 0.1 cm at the iliac crests while the subject was standing, after a moderate expiration (23). Total body FM and LBM were measured by DXA (DXA QDR 4500A; Hologic, Inc., Bedford, MA, USA; software version 11.2.1 for analysis) and reported as subtotals which do not include the contribution from the head of the patient. Total percentage body fat was calculated on the same basis.

Blood pressure measurements

Blood pressure was measured twice using a mercury cuff sphygmomanometer on two different occasions. After the patient had been sitting quietly for at least 5 min, blood pressure was repeatedly measured until the last two measurements varied by less than 5 mmHg in both systolic and diastolic. The mean of these last two values was used as the experimental variable. Hypertension was defined as active treatment with blood pressure-lowering medications or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on the two occasions on which blood pressure was measured.

Ultrasonography

Liver ultrasonography scanning was performed to assess the degree of steatosis. All ultrasonographies were performed by the same operator, who was blinded to laboratory values, using an Hitachi AU 600 ecographer equipped with a convex 3.5 MHz transducer. LS was graded on a scale of 0–3 (0, absent; 1, mild; 2, moderate; 3, severe) according to Saverymuttu et al. (24) on the basis of abnormally bright echoes arising from the hepatic parenchyma, liver–kidney difference in echo amplitude, echo penetration into the deep portion of the liver and clarity of the liver blood vessel structure.

Biochemical analysis

Serum leptin concentrations were measured in duplicate using an ELISA kit (Linco Research, Inc., St Louis, MO, USA). The minimum concentration detectable with the use of this assay is 0.05 ng/ml. Normal ranges are 3.8±1.8 ng/ml in lean men. Intra- and interassay coefficient of variation (CV) values were 3.1 and 7.1% respectively. Serum insulin levels were assayed with a microparticle enzyme immunoassay (IMX; Abbott Laboratories, Abbott Park, IL, USA), with intra- and interassay CV values of 3.0 and 5.3% respectively. Fasting plasma glucose, total cholesterol, HDL-cholesterol, triglycerides, AST, ALT, folic acid and vitamin B12 concentrations were assessed by a central laboratory using standard methodologies.

Statistical analysis

All continuous variables were checked for normality using the Kolmogorov–Smirnoff test. Variables not normally distributed were log-transformed for correlation and regression analysis. Differences between categories of LS in men were tested using ANOVA for variables with a normal distribution and homogeneity of variances, the H of Kruskal–Wallis for variables non-normally distributed and {chi}2 statistics for categorical variables. The Bonferroni correction was used for post-hoc comparisons between pairs of categories. In women, differences between categories of LS were tested using a t-test for normally distributed variables, the Mann–Whitney U-test for variables non-normally distributed and {chi}2 statistics for categorical variables. The association between single continuous and ordinal variables was explored by Pearson or Spearman correlations as appropriate. Serum leptin and insulin were adjusted for body composition variables as described by Ravussin & Bogardus (25) for energy expenditure. Adjusted means of leptin and insulin by category of LS in men were calculated using the General Linear Model (GLM) procedure in SPSS version 12.0. Models were adjusted for body composition (FM and LBM by DXA), regional distribution of fat (waist circumference), and other covariates identified as risk factors for fat storage in the liver: age, alcohol consumption and serum concentrations of triglycerides. To assess the independent effects of leptin and insulin on LS in men, means of leptin and insulin by category of LS were also calculated by including insulin and leptin respectively as covariates in the adjusted models. Polynomial regression techniques were used to assess non-linearity between leptin, insulin and categories of LS and to calculate linear P per trend. Stepwise General Discriminant Analysis (GDA) models were constructed to identify independent predictors of LS in men. Stepwise multiple regression analysis was used to investigate the biological determinants of serum leptin in our population, including age, FM, LBM, waist circumference, fasting insulin and the degree of LS as independent variables. GLM and stepwise multiple regression analysis models were re-assessed using the homeostasis model assessment (HOMA) index instead of fasting insulin as a surrogate of insulin resistance (26). All tests of significance were two-sided and a P value <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Out of the 121 males and the 75 females who underwent all experimental procedures programmed in the follow-up, 145 (83 males and 62 women) were eligible for this study, but only 74 men and 50 women had complete data for all study variables. Since only two men presented severe LS, cases of moderate and severe steatosis were combined in a unique category. In women, no cases of severe steatosis were found and only four women presented with moderate LS. Therefore, LS was defined as present or absent in this population subgroup by combining cases of mild and moderate LS. Tables 1Go and 2Go show the demographics, clinical characteristics and alcohol consumption of men and postmenopausal women respectively, by category of LS. All anthropometric variables but height, and serum concentrations of leptin, insulin, ALT, and the HOMA index significantly increased across categories of LS in men, whereas no differences were observed between groups for AST, total and HDL-cholesterol, triglycerides, alcohol intake or indirect markers of alcohol consumption (mean corpuscular volume, folic acid and vitamin B12). Twenty-two men consumed <20 g of alcohol daily, 42 between 20 and 40 g/day and 10 between 41 and 60 g/day. In women, comparable results were obtained for all anthropometric variables, but only serum leptin, uric acid and the prevalence of hypertension increased across LS groups and no significant differences were recorded for either insulin, the HOMA index as a surrogate of insulin resistance, triglycerides or transaminase levels. Thirty-six women consumed <20 g of alcohol daily and 14 between 20 and 40 g/day. Table 3Go depicts simple correlations between categories of LS, body composition variables, leptin and insulin in men and women. Serum insulin, leptin and LS were positively and significantly correlated with LBM and with all indicators of body fatness (BMI, FM, %FM and waist circumference) in men. Since insulin and leptin were better correlated with total FM assessed by DXA than with any other body composition parameter, both were adjusted for FM first (insulin[FM] and leptin[FM] respectively). Insulin[FM] no longer correlated with any body composition variable, but leptin[FM] was further adjusted for LBM (leptin[FM+LBM]) because the association between leptin and LBM remained significant after controlling for FM. LS, insulin[FM] and leptin[FM+LBM] were all correlated with each other. As in men, insulin, leptin and LS correlated positively and significantly with all body composition variables in women. However, insulin and leptin adjusted for FM no longer correlated with any body composition parameter, nor with categories of LS. Furthermore, no relationship was observed between insulin and leptin, once FM was accounted for. To rule out the effect of body composition on the association between hormone levels and LS in men, GLM-adjusted means of serum leptin and insulin across categories of LS were calculated. We considered as relevant covariates only body composition variables (FM, LBM and waist circumference as marker of fat distribution highly correlated with LS) in the first model (data not shown). A second model was constructed (Table 4Go) by including also as covariates the subjects’ age, plasma concentrations of triglycerides and daily alcohol intake, all known risk factors for LS. In both models, mean concentrations of insulin and leptin increased across categories of LS with a significant linear trend but, interestingly, the association between insulin and LS was no longer significant when models were further adjusted for serum leptin. Conversely, mean leptin concentrations showed a trend across categories of LS even when fasting insulin was included as covariate. Similar data were obtained when the HOMA index was used instead of fasting plasma insulin as a surrogate of insulin resistance (data not shown). Indeed, stepwise GDA identified serum leptin and LBM as independent predictors of LS in men (step 1 = leptin, F = 24.205, P < 0.001 and step 2 = LBM, F = 14.678, P < 0.001), whereas FM was the only independent predictor of LS in postmenopausal women (F = 17.291, P < 0.001). Finally, in a stepwise multiple regression analysis model, FM, fasting insulin, LBM and the degree of LS accounted for 72% of the inter-individual variability of fasting leptin levels in men (59%, + 6%, + 3% and + 4% respectively), whereas FM (48%) and LBM (+8%) were the only predictors of leptin concentrations in postmenopausal women. Results were substantially identical when the HOMA index was used instead of fasting insulin.


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  		Table 1 Baseline characteristics of male subjects by category of Ls. Data are means (S.D.), unless otherwise noted.
 

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  		Table 2 Baseline characteristics of female subjects by category of Ls. Data are means (S.D.), unless otherwise noted.
 

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  		Table 3 Simple correlations between categories of Ls, leptin, insulin and anthropometric variables. Data are expressed as Pearson correlation coefficients or Rho of Spearman, as appropriate.
 

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  		Table 4 Adjusted mean values for serum leptin and plasma insulin by category of LS in male subjects.
 

   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Relationship among leptin, insulin and body composition

Our group and others have already observed a close association between serum leptin levels and plasma insulin independent of the level of fatness in adolescents and middle-age men and women (27–28). In this study, we confirm such a relationship in men, but not in postmenopausal women, in which the correlation between leptin and insulin appears to be almost completely mediated by the FM compartment. This is consistent with the study by Kennedy et al. (17), who reported an association between hyperleptinemia and insulin resistance (assessed by the hyperinsulinemic–euglycemic clamp technique) only in men. As first published by Fernandez-Real et al. (20) using less-reliable techniques of body composition assessment (anthropometry and bioelectrical impedance analysis), the LBM compartment was positively correlated with leptin levels in men and, together with FM, insulin (or the HOMA index) and the degree of LS, was an independent predictor of serum leptin. However, we observe a negative relationship between leptin and LBM after correction for the FM compartment, suggesting that greater LBMs for a given FM would not promote leptin synthesis, but the opposite. Indeed, after adjustments for FM are made, higher LBMs identify leaner individuals, who are likely to be less insulin- and leptin-resistant. In this study, LBM was also positively correlated with leptin levels in postmenopausal women, and together with the FM compartment was an independent predictor of serum leptin. As in men, the relationship between LBM and leptin became negative (although not statistically significant) after adjustment for FM. Fernandez-Real et al. (20) did not find an association between LBM and leptin in their women, who were about 20 years younger than ours and probably mostly premenopausal. This, and the fact that no influence of hyperinsulinemia/insulin resistance was observed on leptin levels in our postmenopausal women, suggests that metabolic factors controlling serum concentrations of leptin may be affected by hormonal changes taking place after menopause.

Relationship among leptin, insulin and LS

The primary role of hyperinsulinemia/insulin resistance in the development of LS has been extensively documented (4, 29–31). In the population of low-to-moderate alcohol drinkers considered in the present study, the degree of hyperinsulinemia/insulin resistance increases across categories of LS in men after controlling for body composition variables and other risk factors for hepatic fat accretion, but this relationship appears to be mediated by increased serum concentrations of leptin. Serum leptin has been reported to increase with alcohol consumption in a dose-dependent manner (32), and to correlate with the degree of LS in subjects with normal transaminase levels, in NASH and in chronic hepatitis C, but not with transaminase concentrations, inflammation or fibrosis (4, 7, 32–35). This suggests that hyperleptinemia and leptin resistance may be involved in the first steps of the pathogenesis of LS, but not necessarily on its progression to steatohepatitis. Indeed, relative hypoleptinemia has been described in advanced forms of liver disease, probably as an index of poor nutritional status (34, 36). Our data indicate that hyperleptinemia, an indirect index of resistance to the action of endogenous leptin, could mediate the accumulation of triglycerides in the liver observed in insulin-resistant states in the context of low-to-moderate alcohol intake, a model of LS that is likely to represent the vast majority of non-HCV fatty livers identified in our environment since regular alcohol consumption is widespread in the Parma area. The plausibility of this hypothesis comes from the following observations: (i) short-term administration of metformin decreases plasma concentrations of leptin without altering body weight or body fat content in healthy men (37); (ii) leptin-deficient individuals build up fat in non-adipose locations such as muscle and liver (lipotoxicity), and secondarily develop severe insulin resistance and NAFLD, a metabolic scenario commonly seen in obese, leptin-resistant subjects (38); and (iii) leptin and some antidiabetic medications appear to share a common anti-steatogenic pathway in the liver (4, 6). Briefly, leptin represses specifically the gene coding for SCD-1, an enzyme involved in the synthesis of triglycerides and very-low-density lipoprotein in the liver. SCD-1 deficiency limits hepatic fat storage by increasing the available pool of saturated fatty acyl-CoAs, which in turn inhibits acetyl-CoA carboxylase and reduces malonyl-CoA formation, the primary inhibitor to the influx and oxidation of fatty acids in the mitochondria (6). Metformin and TZDs (rosiglitazone, poliglitazone) dowregulate SCD-1 as well through the activation of AMP-activated protein kinase (4). As far as postmenopausal women are concerned, LS was a function of the level of fatness and no relationship with either leptin or insulin was observed after correcting for FM. Moreover, leptin and insulin were not significantly correlated after FM was accounted for, suggesting that the degree of obesity per se may be a reliable marker of LS in postmenopausal women. Finally, in our population selected by defining upper limits for alcohol consumption (up to moderate), BMI (<35 kg/m2) and transaminase levels (normal), the incidence of severe LS was very low. This is not surprising since alcohol consumption and obesity are major risk factors for LS, whereas transaminase elevation reflects hepatic damage, which is most commonly seen in severe LS.

In conclusion, serum concentrations of leptin and insulin are positively correlated independently of body composition in men, but not in postmenopausal women. In men, the steatogenic effect of hyperinsulinemia/insulin resistance in the context of low-to-moderate alcohol consumption appears to be mediated by high concentrations of serum leptin, whereas body fat could be enough to identify postmenopausal women at high risk for LS.


   Acknowledgements
 
We acknowledge financial support from the European Community IST-2001-33 204 ‘Healthy Market’ and the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00 923.CT26 research projects. We thank Corrado Cavalli for his valuable help in the performance of DXA scans.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received 22 March 2005
Accepted 10 May 2005




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