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Insulin Resistance, the Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease

IV Division of Internal Medicine, Department of Experimental Medicine and Pathology (F.A., M.D.B., S.Fr., K.F., S.Fi., C.A., F.V.) and Department of Clinics and Applied Medical Therapy (R.C., M.G.C.), University La Sapienza, 00161 Rome, Italy; and Department of Medical and Surgical Sciences (B.Z., F.L.), University of Padua, 35100 Padua, Italy

Address all correspondence and requests for reprints to: Prof. Francesco Angelico, IV Division of Internal Medicine, Policlinico Umberto 1, Via Antonio Nibby 8, 00161 Rome, Italy. E-mail: Francesco.angelico{at}uniroma1.it.

	Abstract

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Background/Aims: An association of nonalcoholic fatty liver disease with the insulin-resistant metabolic syndrome has been suggested. The aim of the study was to assess the association of fatty liver to different degrees of insulin resistance and secretion.

Methods and Results: The study was performed in 308 alcohol- and virus-negative consecutive patients attending a metabolic clinic, who underwent a complete clinical and biochemical work-up including oral glucose tolerance test and routine liver ultrasonography. Steatosis was graded as absent/mild, moderate, and severe.

In nondiabetic subjects, a progressive (P < 0.05) increase in mean homeostasis model of insulin resistance was recorded from the group without steatosis to the groups with mild/moderate and severe steatosis. Severe steatosis was associated with the clustering of the five clinical and biochemical features proposed for the clinical diagnosis of the metabolic syndrome.

Subjects with the metabolic syndrome with a more pronounced insulin resistance had a higher prevalence of severe steatosis (P < 0.01) compared with those with homeostasis model of insulin resistance below the median.

Conclusions: The findings stress the heterogeneous presentation of patients with the metabolic syndrome when the diagnosis is based on the broad Adult Treatment Panel III clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis.

	Introduction

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NONALCOHOLIC FATTY LIVER disease (NAFLD) is a common condition comprising a wide spectrum of liver damage strongly associated with type 2 diabetes, obesity, and hyperlipidemia (1, 2, 3, 4, 5, 6, 7, 8, 9). The pathogenesis of fatty liver is multifactorial, and it has been suggested that the presence of insulin resistance (IR) is an essential requirement for the accumulation of hepatocellular fat (10, 11).

IR syndrome is a frequent metabolic abnormality affecting approximately 20% of the nondiabetic population and occurring in association with many cardiovascular and metabolic abnormalities (12, 13, 14).

IR has been demonstrated to unify NAFLD to the metabolic syndrome, i.e. the clustering of glucose intolerance and/or diabetes, hyperinsulinemia, increased levels of triglycerides and decreased high-density lipoprotein (HDL)-cholesterol, hypertension, and central and overall obesity (15, 16, 17).

Recently, a broad clinical definition of the metabolic syndrome, which does not consider insulin sensitivity, has been proposed by the Adult Treatment Panel III (ATPIII) Report of the U.S. National Cholesterol Education program (18). However, using the ATPIII broad clinical criteria, the diagnosis of the metabolic syndrome is very common, and patients may have a different clustering of risk factors and present various degrees of IR and secretion (13, 18). In fact, the metabolic syndrome may have multiple clinical and pathophysiological presentations and among them, most important, its presentation with or without diabetes (19). The aim of the study was to assess the association of NAFLD to the metabolic syndrome and to the different degrees of IR and secretion.

	Patients and Methods

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The study has been performed in 308 consecutive patients referred to our metabolic outpatient clinic for suspected metabolic disorders. Clinical characteristics of the study population are reported in Table 1. Patients underwent a complete clinical and biochemical work-up, including a liver ultrasonographic scanning (US), as part of the routine clinical examination.

Subjects underwent routine biochemical evaluation including alanine aminotransferase (ALT), fasting total and HDL-cholesterol, triglycerides, glucose, and insulin; glucose and insulin levels were also recorded during a standard (75 g) oral glucose tolerance test.

Waist circumference, height, and weight were recorded, and body mass index (BMI) was calculated as weight (kilograms) divided by height (meters squared).

The homeostasis model of IR (HOMA-IR), based on serum fasting glucose and insulin levels, was used as a measure of IR (20, 21). The ratio of early insulin increment to early glucose increment (I_30-0/G_30-0) after oral glucose loading (75 g glucose) was obtained as a surrogate for insulin secretion (22). Nondiabetic subjects were simultaneously categorized by IR and insulin secretion status based on HOMA-IR and I_30-0/G_30-0 values above or below median in the nondiabetic group (3.96 and 100.5, respectively). Diabetes and impaired glucose tolerance (IGT) were diagnosed according to the World Health Organization (WHO) criteria (23). Subjects taking insulin or oral antidiabetic drugs were considered to have diabetes. ALT elevation was defined as values 1.5 or more times the upper normal values.

Following the criteria of the ATP III Expert Panel of the U.S. National Cholesterol Education Program (18), the metabolic syndrome was diagnosed on the concomitant presence of at least three of the following five clinical features: waist circumference (central obesity) more than 102 cm in men and more than 88 cm in women, fasting blood glucose 110 mg/dl or more, triglycerides 150 mg/dl or more, HDL-cholesterol less than 40 mg/dl in men and less than 50 mg/dl in women, and arterial systolic/diastolic blood pressure 130/85 mm Hg or more.

Liver US scanning was performed to assess the degree of steatosis. All US procedures were performed by the same operator, who was unaware of the aims of the study and blinded to laboratory values using an Esaote Medica apparatus equipped with a convex 3.5-MHz probe. Liver steatosis was assessed semiquantitatively on a scale of 0 to 3: 0, absent; 1, mild; 2, moderate; and 3, severe. Steatosis was graded on the basis of abnormally intense, high-level echoes arising from the hepatic parenchyma, liver-kidney difference in echo amplitude, echo penetration into deep portion of the liver, and clarity of liver blood vessel structure (24, 25).

Statistical analysis was performed by using the SPSS statistical software version 8.0 for Windows (SPSS, Inc., Chicago, IL). Data are expressed as the mean ± SD for continuous variables. Student’s t tests for unpaired data were used for the comparison of mean values. Group comparisons were performed by the use of ANOVA. Proportions and categorical variables were tested by the ² test and by the two-tailed Fisher’s exact method when appropriate. All P values are two-tailed; a P value of less than 0.05 was considered to indicate statistical significance. Multivariate analyses used the step-wise logistic regression analysis testing for the dichotomous response variable presence or absence of mild/severe steatosis and presence or absence of ALT elevation. The predictor variables entered in the two models were age, gender, BMI, triglycerides, glucose tolerance, IR (HOMA-IR), and the insulinogenic index (I_30-0/G_30-0).

Written consent was obtained from all patients before the study. The study was approved by the hospital ethics committee and conforms to the ethical guidelines of the 1975 Declaration of Helsinki.

	Results

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The main clinical features of the study population are reported in Table 1. In the group of 308 subjects who underwent liver US scanning, steatosis was absent in 5.1%, whereas 58.9% had mild/moderate steatosis and 36.0% severe steatosis.

According to WHO criteria, 193 subjects had a normal glucose tolerance test, 43 had IGT, and 72 had type 2 diabetes mellitus (48 with newly diagnosed diabetes).

As reported in Table 2, a progressive statistically significant increase in mean HOMA-IR (P < 0.001) and in the proportion of high HOMA-IR (above the median in the nondiabetic group) (P < 0.000) was observed in subjects with normal glucose tolerance to those with IGT and untreated patients with type 2 diabetes, whereas a negative nonsignificant trend was present for the insulin secretory response. In the same three groups, the prevalence of severe liver steatosis was 34.7, 41.9, and 40.8%, respectively.

When nondiabetic subjects were simultaneously categorized by IR and insulin secretion status (Table 3), prevalence of severe steatosis was 45.4% in nondiabetic subjects who had a predominant IR (high HOMA-IR and high I_30-0/G_30-0), 50.0% in subjects with IR but decreased insulin secretion (high HOMA-IR and low I_30-0/G_30-0), 43.2% in those with low HOMA-IR and high I_30-0/G_30-0, and 35.0% in those who had a predominant decrease in insulin secretion (low HOMA-IR and low I_30-0/G_30-0). Subjects who were insulin resistant had significantly higher BMI (P < 0.001), waist circumference (P < 0.005), and serum ALT levels (P < 0.01) compared with those with a predominant insulin-secretory defect (Table 3). Significant differences were primarily accounted for by either high/high or high/low groups and the low/low group.

The metabolic syndrome was diagnosed in 100 nondiabetic subjects fulfilling three minimal criteria in accordance with the recommendations of the ATPIII Expert Panel of the U.S. National Cholesterol Education Program. Ninety-five percent had IR (HOMA-IR higher than 1.64) (30). In this group, the prevalence of severe steatosis was 41.0%, compared with 34.8 and 19.0%, respectively, in 113 subjects with only one or two risk factors and in 23 with no risk factors (P < 0.01). A statistically significant positive trend was also observed between mean serum ALT values and the clustering of risk factors (P < 0.02) (Table 4).

Among nondiabetic subjects with the metabolic syndrome, those with a more pronounced IR (HOMA-IR above the median in the nondiabetic population) had a significantly higher prevalence of severe steatosis (P < 0.01) compared with those with HOMA-IR below the median (Table 5). A positive linear correlation (r = 0.259; P < 0.05) was observed between HOMA-IR and the severity of liver steatosis.

In the overall group of 72 subjects with type 2 diabetes, the prevalence of severe liver steatosis was 45.8% in 47 with the clinical features of the metabolic syndrome and 26.1% in 23 without the metabolic syndrome (P < 0.05).

	Discussion

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The metabolic syndrome is a very common clinical condition with approximately 40% of the population over 50 yr of age in Western countries meeting the ATPIII diagnostic criteria (12, 13). NAFLD is a clinical condition that comprises a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis in patients with normal or elevated serum ALT (1, 2, 3, 4, 5, 17). It is estimated that it affects 20% of the general population (26) and accounts for the vast majority of cases with elevated serum liver enzymes (27). Recent studies have shown that the metabolic syndrome is associated with an increased prevalence of NAFLD, although the precise sequence of events leading to the development of fatty liver is not yet fully understood. The metabolic syndrome is characterized by a cluster of major cardiovascular risk factors and by the presence of IR. IR is responsible for causing abnormalities of lipid storage and lipolysis in insulin-sensitive tissues, which may induce an increased fatty acid flux from adipose tissue to the liver and cause steatosis. IR may also cause lipid peroxidation, which in turn may activate inflammatory cytokines and promote the progression of innocent steatosis to nonalcoholic steato-hepatitis and liver fibrosis (28).

Although different clinical and biochemical criteria may be proposed for the diagnosis of the metabolic syndrome, in our study, the clinical diagnosis was performed in patients fulfilling three minimal criteria in accordance with the recommendations of the ATPIII Expert Panel of the U.S. National Cholesterol Education Program (18). However, when the diagnosis of the metabolic syndrome is based on the broad clinical criteria proposed in the ATPIII report, there may be multiple clinical and biochemical presentations depending on the different clustering of risk factors and on the interplay between genetic variation and environmental factors. As a consequence of such variability, patients may also have normal insulin sensitivity and secretion or normal insulin sensitivity and decreased insulin secretion in addition to high IR and secretion. Therefore, in the nondiabetic state, some patients with the metabolic syndrome (i.e. with three or more risk factors), besides hyperinsulinemia as a consequence of reduced insulin sensitivity, may also present a decrease in the insulin secretory response, which later becomes prominent in type 2 diabetes mellitus.

A considerable part of NAFLD patients may develop nonalcoholic steatohepatitis, which can develop fibrosis and further cirrhosis. Thus, liver biopsy followed by histological examination is in many cases a very important part of diagnosis. However, most patients with liver steatosis can be well managed without a need for liver biopsy, which cannot be performed at large in patients with no significant or trivial liver disease, mainly for ethical reasons. Yet, in our series, the majority of subjects had normal ALT and no clinical indication for histologic confirmation of NAFLD.

In our study, steatosis was assessed by liver ultrasonography, which has been demonstrated to have a sensitivity of 83% and a specificity of 100% using histological criteria as gold standard. Severe steatosis was evaluated on the basis of the concomitant presence of the four ultrasonographic findings reported in the methods (24, 25).

The homeostatic assessment model (HOMA-IR) has been used to evaluate IR. This approach, which provides a reasonable approximation of insulin sensitivity, has a good correlation with the measurement of insulin sensitivity obtained directly from the insulin clamp technique (29). The ratio of early insulin increment to early glucose increment (I_30-0/G_30-0) after 75-g oral glucose loading, which has been demonstrated to be a significant predictor of type 2 diabetes in the prediabetic stage, has been used as a surrogate for insulin secretory response. Both indexes may be used effectively for group comparisons.

When nondiabetic subjects were simultaneously categorized by IR and insulin secretion status, those with a predominant IR had a higher prevalence of severe liver steatosis, thus confirming the pathophysiological role of hyperinsulinemia in the events leading to the development of fatty liver. The same subjects had significantly higher BMI and waist circumference and similar blood pressure and serum lipids compared with those with a prevalent insulin secretory defect. The association between steatosis and IR was present even if our population was represented by patients attending a metabolic clinic, i.e. with a higher prevalence of obesity and other metabolic abnormalities, compared with the general population. This might have reduced or obscured some associations.

IR (HOMA-IR), the prevalence of severe liver steatosis, and mean ALT values were significantly higher in subjects with the metabolic syndrome compared with those with less than three of the five clinical features considered for its diagnosis. However, subjects fulfilling the ATPIII criteria for the diagnosis of the metabolic syndrome greatly differed with respect to insulin sensitivity; yet, the prevalence of fatty liver was significantly higher in those with HOMA-IR above the median in the nondiabetic population, compared with those below the median. Conversely, in this group, IR did not differentiate between the presence or absence of ALT elevation. This last finding does not support liver biopsy or a more aggressive therapeutic strategy in patients who present the clinical features of the metabolic syndrome and a more pronounced IR.

Moreover, IR was associated with severe steatosis independently from potentially confounding factors such as age, BMI, high fasting glucose, and high serum triglycerides.

Our findings stress the heterogeneous clinical and biochemical presentation of patients with the metabolic syndrome when the diagnosis is based on the broad ATPIII clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis. This last result further confirms a pathogenetic role of IR in the development of NAFLD, even when the diagnosis of fatty liver is based on routine ultrasound examination.

We conclude that in nondiabetic subjects and in those with the metabolic syndrome, IR but not reduced insulin secretion is associated to NAFLD, and we suggest that strategies to prevent fatty liver might focus on dietary and/or drug interventions that improve insulin sensitivity.

	Footnotes

 
First Published Online December 14, 2004

Abbreviations: ALT, Alanine aminotransferase; ATPIII, Adult Treatment Panel III; BMI, body mass index; HDL, high-density lipoprotein; HOMA-IR, homeostasis model of IR; I_30-0/G_30-0, ratio of early insulin increment to early glucose increment; IGT, impaired glucose tolerance; IR, insulin resistance; NAFLD, nonalcoholic fatty liver disease; US, ultrasonographic scanning.

Received June 1, 2004.

Accepted December 2, 2004.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Angelico, F. Articles by Violi, F. Search for Related Content PubMed PubMed Citation Articles by Angelico, F. Articles by Violi, F. Related Collections Diabetes and Insulin Metabolism