Insulin resistance: a metabolic pathway to chronic liver disease

Insulin resistance (IR) is the pathophysiological hallmark of nonalcoholic fatty liver disease (NAFLD), one of the most common causes of chronic liver disease in Western countries. We review the definition of IR, the methods for the quantitative assessment of insulin action, the pathophysiology of IR, and the role of IR in the pathogenesis of chronic liver disease. Increased free fatty acid flux from adipose tissue to nonadipose organs, a result of abnormal fat metabolism, leads to hepatic triglyceride accumulation and contributes to impaired glucose metabolism and insulin sensitivity in muscle and in the liver. Several factors secreted or expressed in the adipocyte contribute to the onset of a proinflammatory state, which may be limited to the liver or more extensively expressed throughout the body. IR is the common characteristic of the metabolic syndrome and its related features. It is a systemic disease affecting the nervous system, muscles, pancreas, kidney, heart, and immune system, in addition to the liver. A complex interaction between genes and the environment favors or enhances IR and the phenotypic expression of NAFLD in individual patients. Advanced fibrotic liver disease is associated with multiple features of the metabolic syndrome, and the risk of progressive liver disease should not be underestimated in individuals with metabolic disorders. Finally, the ability of insulin-sensitizing, pharmacological agents to treat NAFLD by reducing IR in the liver (metformin) and in the periphery (thiazolidinediones) are discussed.     

The metabolic syndrome: Insulin resistance

Insulin resistance is the most accepted unifying theory explaining the pathophysiology of the metabolic syndrome. However, epidemiologic studies indicate that a substantial proportion of patients with the metabolic syndrome do not have evidence of insulin resistance, and the correlation between insulin resistance and individual components of the syndrome is weak to moderate. Insulin resistance may play an important role in the development of hyperglycemia and dyslipidemia, which can further aggravate insulin resistance. The implication of insulin resistance in hypertension appears to be less strong than its role in causing hyperglycemia and dyslipidemia. Obesity may be another pathogenic factor in the metabolic syndrome that may help initiate or worsen insulin resistance. However, like insulin resistance, obesity is not universal in the metabolic syndrome, and many obese subjects do not have metabolic abnormalities. This review provides an update on the relationship between insulin resistance and main components of the metabolic syndrome: hyperglycemia, dyslipidemia, hypertension, and obesity.     

Insulin resistance and metabolic syndrome

The metabolic syndrome represents a complex combination of the symptoms obesity, insulin resistance, dyslipoproteinemia, hypertension, and type 2 diabetes. These components have a heterogeneous genetic basis and appear to be closely linked. Obesity is determined by a polygenic constellation and produces insulin resistance, hypertension and dyslipidemia. In addition, defects in the signal transduction of insulin appear to aggravate the insulin resistance independent of obesity. Type 2 diabetes is produced by a third genetic predisposition and is precipitated by the failure of pancreatic beta-cell to compensate insulin resistance. Because prevalence and course of the diabetes markedly depend on the extent of obesity and insulin resistance, these symptoms of the metabolic syndrome represent crucial targets for preventive and therapeutic strategies.     

Insulin resistance in liver diseases

Coexistence of hyperinsulinemia and normal or impaired carbohydrate tolerance indicates insulin resistance which is frequently observed in patients with liver diseases such as liver cirrhosis, fatty liver, acute and chronic hepatitis and idiopathic haemochromatosis. Insulin resistance in liver diseases can be due to circulating insulin antagonists or a target tissue defect in insulin action, either due to changes in the state of the insulin receptor or due to a postreceptor defect, that means any abnormality in the insulin action sequence following the initial binding step. High insulin levels in liver diseases are caused by diminished degradation of insulin by the liver whereas hypersecretion only plays a minor role under basal conditions. High levels of glucagon, free fatty acids and growth hormone are well known in liver diseases but until now there is no evidence of the pathogenetic importance of these factors. Conflicting results on insulin binding, methodological criticism on binding data and the question whether or not diminished insulin binding on peripheral blood cells plays any physiological role make it unlikely that studies on insulin receptors of peripheral blood cells contribute to the revelation of insulin resistance in liver diseases. The clamp technique allows to quantify the sensitivity of the body to exogenous insulin. The results on liver cirrhosis in connection with studies on glucose metabolism show that under basal conditions insulin insensitivity is due to peripheral resistance (primarily muscle) according to a postreceptor defect. Finally the causes of insulin resistance in liver diseases are still not known.     

Insulin resistance/hyperinsulinemia associated diseases not included in the metabolic syndrome

In the past years, in Brazil and in developed countries, obesity has become a major public health problem. It was identified that besides DM2 and metabolic syndrome other clinical entities were associated with insulin resistance. In this review we describe some of these alterations emphasizing nonalcoholic fatty liver disease, but also including polycistic ovary disease, hyperuricemia, chronic renal failure, heart failure, cognitive decline and cancer.     

Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease

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.     

Insulin resistance and chronic liver disease

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes.Distinctive factors including hepatic parenchymal cell damage,portalsystemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes.Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes,retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure,hepatocellular carcinoma and gastrointestinal hemorrhage.Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes.Moreover,exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis.Thus,pathogenesis,cause of death,assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes.In this article,we review features of insulin resistance in relationship to chronic liver disease.We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.     

Insulin resistance and lichen planus in patients with HCV-infectious liver diseases

Background and Aim: Hepatitis C virus (HCV) causes liver diseases and extrahepatic manifestations, and also contributes to insulin resistance and type 2 diabetes mellitus (DM). The aims of the present study were to examine the incidence of extrahepatic manifestations including lichen planus in HCV‐infected patients and to evaluate the relationship between lichen planus and insulin resistance. Methods: Of 9396 patients with liver diseases presenting to the study hospital, 87 patients (mean age 60.0 ± 11.5 years) with HCV‐related liver diseases were identified and examined for the incidence of extrahepatic manifestations. Insulin resistance and the presence of Helicobacter pylori antibodies were also measured. Results: The prevalence of DM was 21.8% (19/87), hypertension was 28.7% (25/87), thyroid dysfunction was 20.7% (18/87), and extrahepatic malignant tumor was 9.2% (8/87). The prevalence of lichen planus at oral, cutaneous, pharyngeal, and/or vulval locations was 19.5% (17/87). Characteristics of 17 patients with lichen planus (group A) were compared with 70 patients without lichen planus (group B). Prevalence of smoking history, presence of hypertension, extrahepatic malignant tumor, and insulin resistance (HOMA‐IR) were significantly higher in group A than in group B. Significant differences were not observed for age, sex, body mass index, diagnosis of liver disease, alcohol consumption, presence of DM, thyroid dysfunction, liver function tests, or presence of H. pylori infection between the two groups. Conclusions: Infection with HCV induces insulin resistance and may cause lichen planus. It is necessary for an HCV‐infected patient to be assayed for insulin resistance, and to be checked for different extrahepatic manifestations of this infection, particularly lichen planus.     

Insulin resistance and the metabolic syndrome in obese French children

OBJECTIVE: To estimate the frequency of the metabolic syndrome (MS) and of the insulin resistance syndrome (IRS) in overweight or obese French children and to determine the risk factors. DESIGN, PATIENTS AND METHODS: A total of 308 overweight and obese children [166 girls, 142 boys, aged 7-17 years; median body mass index (BMI) 4.7 standard deviation (SD) (Q1-Q3: 3.9-5.8) adjusted for age and sex] were included. The frequency of the MS was assessed with the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria and the frequency of the IRS with World Health Organization (WHO) criteria. RESULTS: The overall frequency of MS and IRS was 15.9% and 42.5%, respectively. The most common component, after abdominal obesity (95.8%) and IR (71.8%), was elevated systolic blood pressure (28.6%). The frequency of glucose tolerance disorders was low (3.6%). The frequency of MS was independently influenced by homeostatic model assessment (HOMA) (P = 0.06) and waist-to-hip ratio (P = 0.09), whereas the frequency of IRS was influenced by adiposity (degree of obesity: P = 0.02; waist-to-hip ratio: P = 0.05), puberty (P = 0.05) and mother's BMI (P = 0.01). Ethnicity had no effect on either MS or IRS. CONCLUSIONS: Metabolic complications and IR are frequent in overweight and obese children whereas the frequency of glucose tolerance disorders is very low. IRS is more prevalent than MS, indicating a major role of IR, which could precede the other metabolic complications in obese children. IRS is a relevant marker for the risk of type 2 diabetes (T2D) and cardiovascular complications in obese European children.     

Insulin resistance and metabolic syndrome in type 1 diabetes mellitus

Insulin resistance (IR) plays a larger role in the type 1 diabetes mellitus (T1DM) disease process than commonly recognized. Overweight and physical inactivity have increased steadily for the last 20-30 years in children and adolescents in many populations, concurrently with a rising incidence of T1DM. The role of IR in T1DM has only recently been gaining acceptance. This review will focus on how IR influences our current understanding of disease development and metabolic syndrome (MS) in T1DM. Increases in IR by weight gain and sedentarism, associated to decreased beta cell mass by autoimmune process, may disrupt normoglycemia in pre-T1DM individuals. IR may reflect a more aggressive form of autoimmune disease mediated by immuno-inflammatory factors that also mediate beta cell destruction (TNF-alpha and IL-6). These concepts are included in the "accelerator hypothesis". Moreover, family history of T2DM and chronic hyperglycemia (glucotoxicity), occurring after T1DM diagnosis, contribute to decrease peripheral glucose uptake. The onset of diabetic nephropathy (DN) might also contribute to IR and metabolic syndrome (MS) via low-grade inflammation and increased oxidative stress. MS is found between 12 to 40% in T1DM, especially in patients with advanced DN and poor glycemic control. These findings have therapeutic and cardiovascular prognostic implications as children make the transition toward adolescence and young adulthood T1DM.     

��л�ۺ�����β�

以不良生活方式、中心性肥胖、胰岛素抵抗(IR)为纽带构成了代谢综合征(MS)和非酒精性脂肪肝病(NAFLD)的密切联系,尽管NAFLD未纳入MS组分中,但其作为IR的早期标志,与MS在代谢应激上的交互影响,引发了心血管危险因素聚集和肝细胞损伤的双重危机。另外,MS对其他类型肝病的影响也值得高度重视。     

Insulin resistance, inflammation, and nonalcoholic fatty liver disease in non-obese adults without metabolic syndrome components

Purpose

The purpose of the present study was to examine the association of insulin resistance and inflammation with nonalcoholic fatty liver disease (NAFLD) in non-obese adults without metabolic syndrome components.

Methods

This was a cross-sectional study of 759 subjects aged 50 years and older. Diagnosis of NAFLD was based on sonographic evidence of fatty liver without significant alcohol consumption and another cause of chronic liver disease. Subjects without metabolic syndrome components were defined as having none of the following: high blood pressure (≥130/85 mmHg), elevated fasting glucose (≥100 mg/dl), hypertriglyceridemia (≥150 mg/dl), low high-density lipoprotein-cholesterol (men <40 mg/dl; women <50 mg/dl), and abdominal obesity measured by waist circumference ≥90 cm for men and ≥80 cm for women. The subjects were divided into quartile groups according to levels of high-sensitivity C-reactive protein (hs-CRP), homeostasis model assessment of insulin resistance (HOMA-IR), and uric acid. Odds ratios (ORs) were computed for each quartile relative to the lowest quartile group.

Results

After adjustment for age, sex, smoking status, regular exercise, hs-CRP, HOMA-IR, and uric acid, a significant association was found between NAFLD and higher levels of hs-CRP, HOMA-IR, and uric acid. After adjustment for age, sex, smoking status, regular exercise, hs-CRP, HOMA-IR, and uric acid, the Ors (95 % confidence interval) of NAFLD with the highest quartile of hs-CRP, HOMA-IR, and uric acid compared with the lowest quartile were 2.58 (1.03–6.50), 2.55 (1.08–6.05), and 5.15 (1.78–14.89), respectively.

Conclusions

Insulin resistance and inflammation are independently associated with NAFLD in non-obese adults without metabolic syndrome components.     

Insulin resistance and plasma glucose tolerance abnormalities in Nigerians with chronic liver disease

AimsGlucose tolerance abnormalities are frequently observed in patients with chronic liver disease (CLD). Insulin resistance (IR) has been suggested to be a major factor responsible for these abnormalities in CLD. However studies relating IR with severity of CLD are scarce in Nigeria. This study assessed insulin resistance and glucose tolerance abnormalities in CLD and their relationship with the severity of CLD in a tertiary hospital in South-West, Nigeria.MethodsThis cross sectional study involved 100 subjects with CLD. Ethical clearance was obtained and informed consent was granted by participants. Participants were interviewed using a structured proforma; physical examination and relevant investigations were performed. Insulin resistance was measured using the homeostasis model assessment (HOMA-IR) Data was analysed using Statistical Package for Social Sciences version 20.0 and p value of <0.05 was considered significant.ResultsMean age of the study participants was 51.9 ± 11.9 years, and mean duration of CLD was 15.9 ± 5.8 months. Glucose tolerance abnormalities were present in 66 subjects (66%) and increased from 16.1% in Child Pugh's class A to 90.0% in class C.HOMA-IR positively correlated with age, body mass index, serum blood glucose, duration and severity of CLD. Increasing age, presence of hepatocellular carcinoma, Child Pugh's class B and class C were associated with glucose tolerance abnormalities.ConclusionGlucose tolerance abnormalities and insulin resistance were highly prevalent among chronic liver disease subjects studied and seemed to parallel the severity of CLD, determined by the Child Pugh's score.     

Insulin resistance and metabolic syndrome criteria in lean,normoglycemic college-age subjects

Aims

The goal of this study was to determine insulin sensitivity in a fasted state and during an oral glucose tolerance test (OGTT), in normoglycemic (NGT), lean (L) (n?=?35) and, for comparison, overweight/obese (OW/O) (n?=?9) college-aged subjects.