Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers

doi:10.1016/j.numecd.2013.01.006

Nutrition, Metabolism and Cardiovascular Diseases

Volume 23, Issue 12, December 2013, Pages 1182-1187

https://doi.org/10.1016/j.numecd.2013.01.006 Get rights and content

Abstract

Background and aims

Nonalcoholic fatty liver disease (NAFLD) is linked with insulin resistance, however, if it is differentially associated with surrogate hepatic insulin resistance indexes is still undefined. We examined the relationship between these indexes, NAFLD and its related biomarkers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [GGT], alkaline phosphatase [ALK], high-sensitive C reactive protein [hsCRP], insulin-like growth factor-1 [IGF-1]).

Methods and results

473 Caucasians subjects underwent liver ultrasonography and oral glucose tolerance tests; homeostasis model assessment (HOMA), glucose_0–30 (area under the curve [AUC]) × insulin_0–30 (AUC) and liver insulin resistance (liver IR) indexes were computed. Liver IR index correlated more strongly than HOMA with GGT, ALK, hsCRP, ALT and AST and more strongly than glucose_0–30 (AUC) × insulin_0–30 (AUC) index with ALT, AST, GGT, ALK, hsCRP, and IGF-1. The ability of these indexes to identify NAFLD was evaluated by the area under the ROC curve; the ROC AUC for liver IR index was higher (0.733) than the ones for HOMA (0.685) and glucose_0–30 (AUC) × insulin_0–30 (AUC) (0.663) indexes. In a logistic regression model subjects in the highest quartile of the three indexes had a higher risk of having NAFLD than those in the lowest quartile (9.85-, 5.12- or 3.99-fold higher for liver IR index, HOMA, glucose_0–30 (AUC) × insulin_0–30 (AUC) index respectively).

Conclusions

we documented significant cross-sectional associations of NAFLD and liver biomarkers with three validated indexes of hepatic insulin resistance, with liver IR index showing the stronger correlation.

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease affecting 20–30% of adults in the general population in Western countries [1], [2]. NAFLD is strongly associated with obesity, metabolic syndrome, and type 2 diabetes mellitus [2], [3], [4], [5], and is becoming recognized as a condition possibly implicated in the pathogenesis of these metabolic disorders. This hypothesis is supported from studies demonstrating that NAFLD and its surrogate measures are independent predictors of incident type 2 diabetes [6], [7], [8]. NAFLD is tightly linked to hepatic insulin resistance, which is characterized by a selective impairment of the ability of insulin to suppress hepatic glucose production, in face of a preserved ability to enhance lipogenesis, eventually resulting in increased synthesis of fatty acids and triglycerides [9], [10]. Therefore, hepatic insulin resistance is thought to be a core component of NAFLD [2], [3], [4]. Increased endogenous glucose production (EGP) in the presence of elevated fasting plasma insulin (FPI) levels is suggestive of hepatic insulin resistance. Because EGP mostly occurs in the liver, EGP × FPI has been considered the gold-standard measure for hepatic insulin resistance [11]. However, the direct measure of hepatic insulin resistance by clamp combined with tracer techniques is invasive, complex, and expensive, and therefore not feasible in large epidemiological studies. Surrogate indexes of hepatic insulin resistance have thus been developed and validated versus gold-standard measurements of hepatic insulin resistance [12], [13], [14]. Whether these hepatic insulin resistance indexes are differentially associated with NALFD is still undefined.

The aim of this study was to examine the relationship of hepatic insulin resistance indexes with NAFLD diagnosed on ultrasonography, and with biomarkers/acute-phase reactants (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [GGT], alkaline phosphatase [ALK], high-sensitive C reactive protein [hsCRP], insulin-like growth factor-1 [IGF-1]) associated to NAFLD in a cohort of Caucasian individuals.

Section snippets

Methods

The study group consisted of 473 Caucasian subjects participating to the CATAnzaro MEtabolic RIsk factors (CATAMERI) Study, a cross-sectional study assessing cardio-metabolic risk factors in subjects carrying at least one risk factor including high blood pressure, dyslipidemia, dysglycemia, overweight/obesity, and family history for diabetes as previously described [15], [16]. Exclusion criteria included: known diabetes, history of any malignant disease, chronic gastrointestinal diseases or

Results

Of the 473 individuals examined (293 men and 180 women), 234 had NAFLD as assessed by ultrasonography (Table 1). After adjustment for age and gender, individuals with NAFLD had a worse metabolic risk profile exhibiting significantly higher BMI, waist circumference, fat mass, 2 h glucose, fasting insulin, triglycerides, hsCRP, ALT, AST, GGT, ALK levels, and lower HDL cholesterol and IGF-1 as compared with the non-NAFLD group (Table 1). In addition, as compared with the non-NAFLD group, a higher

Discussion

NAFLD, the most common chronic liver disease in Western countries, is strongly associated with obesity and metabolic syndrome [24]. Several studies have shown that NAFLD, liver biomarkers, and pro- and anti-inflammatory molecules predominantly produced by liver are associated with metabolic syndrome, and predict incident type 2 diabetes [2], [3], [4], [5], [6], [7], [8], [18], [23], [24], [25], [26], [27], thus suggesting common underlying pathophysiological mechanisms. NAFLD is closely

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Thus, it is conceivable that greater lipid accumulation in visceral and liver tissues during glucose tolerance deterioration owing to the exhaustion of the women capacity to store fat in the subcutaneous depot may allow to reach the same visceral fat deposition required in men to develop NAFLD. Then, the lipid accumulation in the liver may be facilitate both hepatic insulin resistance and hepatic inflammation, two key features of NAFLD [6,26,27]. These results suggest that sex differences in adiposity and other metabolic risk factors associated with worsening of glucose homeostasis are likely to contribute to sex differences in the driving force leading to NAFLD.
To characterize the prevalence of NAFLD among subjects with NGT, prediabetes and type 2 diabetes (T2DM) by sex in adults with one or more cardio-metabolic risk factors, and to assess whether cardio-metabolic factors explained sex-related differences in NAFLD prevalence.
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Prediabetic and diabetic women have higher OR of having NAFLD than men. Deterioration of glucose homeostasis in women is associated with a greater worsening in metabolic risk factors than men, which may explain the stronger impact of prediabetes and T2DM on NAFLD in women.
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Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers

Abstract

Background and aims

Methods and results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Nutr Metab Cardiovasc Dis

Cell Metab

Mol Cell

Nutr Metab Cardiovasc Dis

Gastroenterology

Lancet

Best Pract Res Clin Endocrinol Metab

Nutr Metab Cardiovasc Dis

Nonalcoholic fatty liver disease

N Engl J Med

Causes and metabolic consequences of fatty liver

Endocr Rev

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome

Diabetes

Fatty liver: a novel component of the metabolic syndrome

Arterioscler Thromb Vasc Biol

High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes

Diabetes

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study

Diabetes

Alanine aminotransferase, gamma-glutamyl-transferase, and incident diabetes: the British Women's Heart and Health Study and Meta-analysis

Diabetes Care