► The pathophysiological link between NAFLD and hepatic insulin resistance is unknown. ► We studied the effect of postprandial lipoproteins on hepatic insulin sensitivity. ► Postprandial lipoproteins cause liver steatosis and hepatic insulin resistance. ► We characterize the underlying molecular mechanisms. ► Postprandial lipoproteins are a link between NAFLD and hepatic insulin resistance.
Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD.
BMI, body mass index; DAPI, 4′,6-diamidino-2-phenylindole; DMEM, dulbeccos minimal essential media; FCS, fetal calf serum; GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; HL, hepatic lipase; HOMA-IR, homeostasis model assessment of insulin resistance; HSPG, heparan sulfate proteoglycans; LPL, lipoprotein lipase; LRP, LDL-receptor-related protein; NAFLD, non-alcoholic fatty liver disease; PBS, phosphate buffered saline; RAP, receptor-associated protein; ROS, reactive oxygen species; Sf, Svedberg flotation rate; TGRL, triglyceride-rich lipoproteins; THL, tetrahydrolipstatin; Glucose metabolism; Hepatic insulin resistance; Insulin signaling; Liver steatosis; Postprandial lipemia
Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a marker of Insulin Resistance (IR). Euglycemic-hyperinsulinemic clamp is the gold standard for measuring whole body IR (hepatic + peripheral IR). However, it is an invasive and expensive procedure. Homeostasis Model Assessment Index for Insulin Sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) for hepatic IR and Insulin Sensitivity Index (ISI0,120), and Whole Body Insulin Sensitivity Index (WBISI) for whole body IR are the indices calculated after Oral Glucose Tolerance Test (OGTT). We used these indices as noninvasive methods of IR (inverse of insulin sensitivity) estimation and compared hepatic/peripheral components of whole body IR in NAFLD. Methods. 113 morbidly obese, nondiabetic subjects who underwent gastric bypass surgery and intraoperative liver biopsy were included in the study. OGTT was performed preoperatively and the indices were calculated. Subjects were divided into closely matched groups as normal, fatty liver (FL) and Non-Alcoholic Steatohepatitis (NASH) based on histology. Results. Whole body IR was significantly higher in both FL and NASH groups (NAFLD) as compared to Normal, while hepatic IR was higher only in NASH from Normal. Conclusions. FL is a manifestation of peripheral IR but not hepatic IR.
Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), and progressive liver fibrosis is considered the most common liver disease in western countries. Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance. Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients. Besides liver biopsy no diagnostic tools to identify patients with NASH are available, and no effective treatment has been established. Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage, insulin resistance, and progressive liver damage. Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage. Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH. Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis. This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin.
Hepatic steatosis; Non-alcoholic steatohepatitis; Adiponectin; Obesity; Adipose tissue
Background & Aims
Nonalcoholic fatty liver disease is associated with insulin resistance and diabetes. The purpose of this study was to determine the relationship between intrahepatic triglyceride (IHTG) content and insulin action in liver (suppression of glucose dioduction), skeletal muscle (stimulation of glucose uptake) and adipose tissue (suppression of lipolysis) in non-diabetic, obese subjects.
A euglycemic-hyperinsulinemic clamp procedure and stable isotopically labeled tracer infusions were used to assess insulin action, and magnetic resonance spectroscopy was used to determine IHTG content, in 42 non-diabetic, obese subjects (BMI 36±4 kg/m2) who had a wide range of IHTG content (1%−46%).
Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration, was inversely correlated with IHTG content (r=−0.599; P<0.001). The ability of insulin to suppress the release of fatty acids from adipose tissue and to stimulate glucose uptake by skeletal muscle were also inversely correlated with IHTG content (adipose tissue: r=−0.590; P<0.001; skeletal muscle: r=−0.656; P<0.001). Multivariate linear regression analyses found that IHTG content was the best predictor of insulin action in liver, skeletal muscle and adipose tissue, independent of BMI and percent body fat, and accounted for 34%, 42%, and 44% of the variability in these tissues, respectively (P< 0.001 for each model).
These results demonstrate that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle and adipose tissue in non-diabetic, obese subjects. Therefore, NAFLD should be considered part of a multi-organ system derangement in insulin sensitivity.
Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity, insulin resistance, and abnormal hepatic lipid metabolism; however, the precise regulation of these processes remains poorly understood. Here we examined genes and proteins involved in hepatic oxidation and lipogenesis in 14-week-old leptin-deficient Ob/Ob mice, a commonly studied model of obesity and hepatic steatosis. Obese Ob/Ob mice had increased fasting glucose, insulin, and calculated HOMA-IR as compared with lean wild-type (WT) mice. Ob/Ob mice also had greater liver weights, hepatic triglyceride (TG) content, and markers of de novo lipogenesis, including increased hepatic gene expression and protein content of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), as well as elevated gene expression of PPARγ and SREBP-1c compared with WT mice. While hepatic mRNA levels for PGC-1α, PPARα, and TFAM were elevated in Ob/Ob mice, measures of mitochondrial function (β-HAD activity and complete (to CO2) and total mitochondrial palmitate oxidation) and mitochondrial OXPHOS protein subunits I, III, and V content were significantly reduced compared with WT animals. In summary, reduced hepatic mitochondrial content and function and an upregulation in de novo lipogenesis contribute to obesity-associated NAFLD in the leptin-deficient Ob/Ob mouse.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.
Insulin resistance; Fatty acid; Lipid metabolism
Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD.
Free fatty acids; De novo lipogenesis; Fatty acid beta oxidation; TG secretion
Nonalcoholic fatty liver disease (NAFLD) is the most common initial presentation of obesity and insulin resistance. Uninterrupted progression of hepatic lipid accumulation often leads to fatty liver disease and eventually cirrhosis. Insulin resistance is one of the characteristics of type 2 diabetes. Several types of treatment have been employed against type 2 diabetes some of which ameliorate NAFLD. The frequent line of treatment to improve insulin sensitivity is the use of thiazolidinediones (TZD) which activate the nuclear receptor, peroxisome proliferator activated receptor gamma (Pparγ). Although TZDs are proven to be very effective in promoting insulin sensitivity, its actions on Pparγ have been complicated, specifically on NAFLD. According to studies in different models, Pparγ manifests both beneficial and undesirable effects on NAFLD. This paper will focus on the current knowledge of Pparγ and its effect on NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of insulin resistance (IR) syndrome. The effect of insulin sensitizers on liver function tests and metabolic indices in NAFLD patients is a matter of debate.
The aim of study was to compare the effects of two different insulin sensitizers, pioglitazone, and metformin, on liver function tests (LFT), lipid profile, homeostasis model assessment-IR (HOMA-IR) index, and liver fat content (LFC) in NAFLD patients.
Materials and Methods
This double blind clinical trial was performed on patients who were referred to a gastroenterology clinic with evidence of fatty liver in ultrasonography. After excluding other causes, participants with persistent elevated alanine aminotransferase (ALT) levels and “NAFLD liver fat score” greater than -0.64 were presumed to have NAFLD and were enrolled. They were randomly assigned to take metformin (1 g/day) or pioglitazone (30 mg/day) for four months. Fasting serum glucose (FSG), ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride, cholesterol (CHOL), high and low density lipoprotein (HDL, LDL), HOMA-IR, and LFC were checked at the baseline, two and four months post-treatment. LFC was measured by a validated formula.
Eighty patients (68 males) with mean age of 35.27 (± 7.98) were included. After 2 months, LFT was improved significantly in the pioglitazone group and did not change in the metformin group. After four months, both medications significantly decreased serum levels of LFT, FSG, CHOL, LDL, HOMA-IR, and LFC, and increased serum level of HDL. No statistically significant differences were seen between the two treatment groups with regard to the changes of laboratory parameters and LFC from baseline to four months post-treatment.
During the four months, the use of metformin (1 g/day) and pioglitazone (30 mg/day) were safe and might have equally affected LFT, HOMA-IR, lipid profile, and LFC in NAFLD patients.
Fatty Liver; Insulin Resistance; Metformin; Pioglitazone
Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Steatosis, the hallmark feature of NAFLD, occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and export (as triglyceride within VLDL). Therefore, an excessive amount of intrahepatic triglyceride represents an imbalance between complex interactions of metabolic events. The presence of steatosis is associated with a constellation of adverse alterations in glucose, fatty acid and lipoprotein metabolism. It is likely that abnormalities in fatty acid metabolism, in conjunction with adipose tissue, hepatic, and systemic inflammation, are key factors involved in the development of insulin resistance, dyslipidemia and other cardiometabolic risk factors associated with NAFLD. However, it is not clear whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for IHTG accumulation, or possibly both. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD will provide important insights into the mechanisms responsible for the cardiometabolic complications of obesity.
Background & Aims
Hepatic steatosis is associated with insulin resistance, but it is not clear whether increased intrahepatic triglyceride (IHTG) content causes the resistance or is a marker. Subjects with familial hypobetalipoproteinemia (FHBL) have high levels of IHTG because of a genetic defect in hepatic export of triglycerides, and provide a unique cohort to study the relationship between steatosis and insulin sensitivity.
One group of lean subjects with normal IHTG content (2.2%±0.6% of liver volume) (n=6), and 3 groups of overweight and obese subjects, matched for body-mass index, were studied: 1) normal IHTG content (3.3%±0.5%; n=6), 2) high IHTG content (21.4%±2.6%) due to nonalcoholic fatty liver disease (NAFLD; n=6), and 3) high IHTG content (18.1%±2.2%) due to FHBL (n=3). A hyperinsulinemic-euglycemic clamp procedure, in conjunction with glucose tracer infusion, was used to determine multi-organ insulin sensitivity.
Hepatic insulin sensitivity (reciprocal of glucose rate of appearance [μmol · kgFFM−1 · min−1] × insulin [mU · L−1]) was greatest in the lean group (2.0±0.4); it was the same among subjects with FHBL (0.8±0.1) and the group with normal IHTG content, matched for body-mass index, (0.7±0.1), but greater than the NAFLD group (0.3±0.1) (P<.01). Muscle insulin sensitivity (percent increase in glucose uptake during insulin infusion) was greatest in the lean group (576%±70%). Muscle insulin sensitivity was similar in subjects with FHBL and those with normal IHTG (319%±77%, 326%±27%, respectively), but greater than the NAFLD group (145%±18%) (P<.01).
Steatosis is dissociated from insulin resistance in FHBL, which suggests that increased IHTG content is a marker, not a cause, of metabolic dysfunction.
steatosis; insulin sensitivity; obesity; clamp
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.
Nonalcoholic fatty liver disease; Metabolic syndrome; Cardiovascular risk; Children
Non-alcoholic fatty liver disease (NAFLD) is an escalating health problem that is frequently associated with obesity and insulin resistance. The mechanistic relationship between NAFLD, obesity, and insulin resistance is not well understood. A nonsynonymous variant in PNPLA3 (rs738409; I148M) is reproducibly associated with increased hepatic triglyceride content (HTGC), yet not associated with either body mass index (BMI) or indices of insulin resistance. Conversely, two sequence variants in APOC3 that have been linked to hypertriglyceridemia (rs2854117 C>T and rs2854116 T>C) were recently reported to be associated with both hepatic fat content and insulin resistance. Here we examined the association between these two APOC3 variants and HTGC as well as homeostatic model assessment of insulin resistance (HOMA-IR) in 1228 African-Americans, 843 European-Americans and 426 Hispanics from a multiethnic population-based study, the Dallas Heart Study. We also examined the relationship between these two variants and HOMA-IR in the Atherosclerosis Risk in Communities Study (ARIC). No significant difference in hepatic fat content was found between carriers and noncarriers in the Dallas Heart Study. Neither APOC3 variant was associated with HOMA-IR in the Dallas Heart Study; this lack of association was confirmed in the Atherosclerosis Risk in Communities Study, even after the analysis was restricted to lean (BMI < 25 kg/m2) individuals (n=4,399).
Our data do not support a causal relationship between these two variants in APOC3 and either HTGC or insulin resistance in middle-aged men and women.
APOC3; PNPLA3; fatty liver; hepatic steatosis; insulin resistance
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.
exenatide; insulin resistance; metformin; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; pioglitazone; rosiglitazone; sitagliptin; thiazolidinediones; vitamin E
Nonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents.
The purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m2), and Tanner stage.
Stable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 ± 1.3) adolescents with NAFLD (IHTG = 28.4 ± 3.4%) and 10 overweight (BMI = 36.6 ± 31.5) adolescents with a normal IHTG content (3.3 ± 0.5%).
The baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 ± 1.2 mg/dL, 16.2 ± 1.1 μmol · kg fat-free mass−1 · min−1) or high (89.2 ± 2.5 mg/dL, 16.3 ± 1.2 μmol · kg fat-free mass−1 · min−1) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had a lower hepatic insulin sensitivity index, based on baseline glucose kinetics and insulin concentrations (4.0 ± 0.5 compared with 2.4 ± 0.4; P < 0.05) and an impaired increase in glucose uptake during insulin infusion (169 ± 28.1% compared with 67 ± 9.6% above baseline; P < 0.01). In addition, the plasma triglyceride concentration was greater and the plasma HDL-cholesterol concentration was lower in subjects with NAFLD than in those with a normal IHTG content.
An elevated IHTG content in overweight adolescents is associated with dyslipidemia and with insulin-resistant glucose metabolism in both liver and skeletal muscle.
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries. Insulin resistance is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of insulin resistance or obesity. Adiponectin is the most abundant adipose-specific adipokine. There is evidence that adiponectin decreases hepatic and systematic insulin resistance, and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and the severity of NAFLD; however, to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.
Non-alcoholic fatty liver disease; Obesity; Adiponectin; Visceral fat; Adipokines
Metabolic syndrome contributes to pathogenesis of Type-2 diabetes and CAD. Insulin Resistance is the key factor of metabolic syndrome implicated in development of Non Alcoholic Fatty Liver Disease (NAFLD). In present study we have investigated the prevalence of NAFLD in metabolic syndrome and contribution of metabolic risk factors in causation of NAFLD in non-diabetic North Indian male population. The study was conducted on 495 non-diabetic, nonalcoholic subjects (age 30–65 years). Metabolic Syndrome was assessed by using ATP III and ADA (2005) criteria. Anthropometric factors-Waist circumference and blood pressure were measured. Fasting serum samples were analyzed for Glucose, Triglycerides, Cholesterol and its fractions, Insulin, Alanine transaminase, Aspartate transaminase, Gamma glutamyl transferase and free fatty acids. Insulin resistance was estimated by Homeostasis Model and Insulin sensitivity by QUICKI Index. Liver ultrasonographic scanning was used for assessing fatty liver. The prevalence of metabolic syndrome and NAFLD was 24% and 14.8% respectively in non-alcoholic population and 27% of metabolic syndrome had NAFLD which was associated with hyperinsulinemia, insulin resistance, insulin insensitivity along with elevated levels of waist circumference, blood pressure, triglyceride, FFA and decreased HDL-Cholesterol. The prevalence of NAFLD increased with insulin resistance and clustering of metabolic risk factors.
Hyperinsulinemia; Insulin resistance; NAFLD; Obesity; Metabolic Syndrome
The clinical implications of non-alcoholic fatty liver diseases (NAFLD) derive from their potential to progress to fibrosis and cirrhosis. Inappropriate dietary fat intake, excessive intake of soft drinks, insulin resistance and increased oxidative stress results in increased free fatty acid delivery to the liver and increased hepatic triglyceride (TG) accumulation. An olive oil-rich diet decreases accumulation of TGs in the liver, improves postprandial TGs, glucose and glucagon-like peptide-1 responses in insulin-resistant subjects, and upregulates glucose transporter-2 expression in the liver. The principal mechanisms include: decreased nuclear factor-kappaB activation, decreased low-density lipoprotein oxidation, and improved insulin resistance by reduced production of inflammatory cytokines (tumor necrosis factor, interleukin-6) and improvement of jun N-terminal kinase-mediated phosphorylation of insulin receptor substrate-1. The beneficial effect of the Mediterranean diet is derived from monounsaturated fatty acids, mainly from olive oil. In this review, we describe the dietary sources of the monounsaturated fatty acids, the composition of olive oil, dietary fats and their relationship to insulin resistance and postprandial lipid and glucose responses in non-alcoholic steatohepatitis, clinical and experimental studies that assess the relationship between olive oil and NAFLD, and the mechanism by which olive oil ameliorates fatty liver, and we discuss future perspectives.
Liver steatosis; Fatty liver; Olive oil; Fatty acids; Monounsaturated; Non-alcoholic steatohepatitis; Lipids; Oleic acid; Non-alcoholic fatty liver disease
Niaspan® (extended-release niacin) is a nicotinic acid formulation used to treat dyslipidemia in obese subjects. Niaspan binds to the GPR109A receptor in adipose tissue and stimulates adiponectin secretion, which should improve insulin sensitivity. However, Niaspan therapy often causes insulin resistance. The purpose of this study was to evaluate whether Niaspan-induced changes in plasma adiponectin concentration are associated with a blunting of Niaspan's adverse effect on insulin action in obese subjects with non-alcoholic fatty liver disease (NAFLD).
A hyperinsulinemic-euglycemic clamp procedure was used to assess muscle insulin sensitivity before and after 16 weeks of Niaspan therapy in 9 obese subjects with NAFLD [age 43 ± 5 years; BMI 35.1 ± 1.3 (means ± SEM)].
Niaspan therapy did not affect body weight (99.1 ± 4.2 vs. 100 ± 4.4 kg) or percent body fat (37.8 ± 2.5 vs. 37.0 ± 2.5%). However, Niaspan therapy caused a 22% reduction in insulin-mediated glucose disposal (p < 0.05). The deterioration in glucose disposal was inversely correlated with the Niaspan-induced increase in plasma adiponectin concentration (r = 0.67, p = 0.05).
These results demonstrate that Niaspan causes skeletal muscle insulin resistance, independent of changes in body weight or body fat, and the Niaspan-induced increase in plasma adiponectin concentration might partially ameliorate Niaspan's adverse effect on insulin action in obese subjects with NAFLD.
Adiponectin; Insulin sensitivity; Obesity; Nicotinic acid; Glucose uptake
Obesity is an important risk factor for non-alcoholic fatty liver disease (NAFLD); however, NAFLD does occur in lean subjects. This study was aimed to evaluate the magnitude, clinical, pathological, and metabolic profiles of NAFLD in normal body mass index (BMI) subjects (defined as lean NAFLD) in comparison to overweight or obese NAFLD and lean healthy control.
Materials and Methods:
336 subjects (205 consecutive NAFLD, and 131 healthy controls) were studied.
Among 205 NAFLD patients, 27 (13.2%) were lean, while 141 (68.8%) and 37 (18%) patients were obese and overweight, respectively. The lean NAFLD compared to obese NAFLD had significantly lesser degree of fasting hyperinsulinemia (P < 0.001), homeostasis model assessment insulin resistance (HOMA-IR, P < 0.001), and lower prevalence of diabetes mellitus (P = 0.01) and metabolic syndrome (P < 0.001). The profiles of serum lipids were similar between all 3 BMI categories, and 89% of lean NAFLD were dyslipidemic. Compared to obese subjects, patients with lean NAFLD had less hepatic necro-inflammation (P = 0.05) and fibrosis (P < 0.001). However, the proportion of steatohepatitis and advanced fibrosis were similar between all BMI categories. The profiles of overweight NAFLD were similar to those of lean NAFLD, except for higher HOMA-IR, uric acids and male gender in overweight group. Despite being lean, the mean BMI of lean NAFLD were still higher than unselected lean healthy controls (P = 0.02).
Lean NAFLD patients have less severe disease, minor, or no insulin resistance, but are frequently dyslipidemic and have BMI higher than lean healthy control.
Dyslipidemia; insulin resistance; lean non-alcoholic fatty liver disease
Nonalcoholic fatty liver disease (NAFLD) is associated with abnormalities in basal glucose and free fatty acid (FFA) metabolism, multi-organ insulin resistance, and alterations in lipoprotein kinetics. These metabolic outcomes can be evaluated in vivo by using stable isotopically-labeled tracer methods. An understanding of the reproducibility of these measures is necessary to ensure adequate statistical power in studies designed to evaluate metabolic function in subjects with NAFLD.
We determined the degree of intra-individual variability of skeletal muscle, adipose tissue, and hepatic insulin sensitivity and basal plasma glucose, FFA, and very-low-density lipoprotein (VLDL) triglyceride (TG) and apolipoprotein B-100 (apoB-100) kinetics in 8 obese subjects with NAFLD (age: 44±3 yr; body mass index: 38.2±1.7 kg/m2; intrahepatic triglyceride content: 24.5±3.9%), by using the hyperinsulinemic-euglycemic clamp technique and stable isotope-labeled tracer methods and mathematical modeling on two separate occasions ~2 months apart.
The intra-individual variability (coefficient of variation) ranged from 6% for basal glucose production to 21% for insulin-stimulated glucose disposal (% increase from basal). We estimated that a 25% difference in any outcome measure can be detected with a sample size of ≤8 subjects for paired studies and ≤15 subjects per group for unpaired studies, assuming an α value of 0.05 and a β value of 0.20 (i.e., 80% power).
These results demonstrate that only a small number of subjects are needed to detect clinically relevant effects in insulin sensitivity and hepatic lipoprotein metabolism in obese subjects with NAFLD, and will be useful to determine appropriate sample size for future metabolic studies.
NALFD; insulin resistance; tracers; VLDL kinetics; repeatability; reliability
With the increasing prevalence of obesity, research has focused on the molecular mechanism(s) linking obesity and skeletal muscle insulin resistance. Metabolic alterations within muscle, such as changes in the cellular location of fatty acid transporter proteins, decreased mitochondrial enzyme activity and defects in mitochondrial morphology, likely contribute to obesity and insulin resistance. These defects are thought to play a role in the reduced skeletal muscle fatty acid oxidation (FAO) and increased intramuscular lipid (IMCL) accumulation that is apparent with obesity and other insulin resistant states, such as type 2 diabetes. Intramuscular triacylglycerol (IMTG) does not appear to be a ubiquitous marker of insulin resistance, although specific IMCL intermediates such as long-chain fatty acyl-CoAs (LCFA-CoAs), ceramide and diacylglycerol (DAG) may inhibit insulin signal transduction. In this review, we will briefly summarize the defects in skeletal muscle lipid metabolism associated with obesity, and discuss proposed mechanisms by which these defects may contribute to insulin resistance.
Prediabetes and type 2 diabetes mellitus (T2DM) are believed to be common and associated with a worse metabolic profile in patients with nonalcoholic fatty liver disease (NAFLD). However, no previous study has systematically screened this population.
RESEARCH DESIGN AND METHODS
We studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 patients with NAFLD. The control group comprised 20 subjects without NAFLD matched for age, sex, and adiposity. We measured 1) plasma glucose, insulin, and free fatty acid (FFA) concentration during an oral glucose tolerance test; 2) liver fat by magnetic resonance spectroscopy (MRS); 3) liver and muscle insulin sensitivity (euglycemic insulin clamp with 3-[3H]glucose); and 4) indexes of insulin resistance (IR) at the level of the liver (HIRi= endogenous glucose production × fasting plasma insulin [FPI]) and adipose tissue (Adipo-IRi= fasting FFA × FPI).
Prediabetes and T2DM was present in 85% versus 30% in controls (P < 0.0001), all unaware of having abnormal glucose metabolism. NAFLD patients were IR at the level of the adipose tissue, liver, and muscle (all P < 0.01–0.001). Muscle and liver insulin sensitivity were impaired in patients with NAFLD to a similar degree, whether they had prediabetes or T2DM. Only adipose tissue IR worsened in T2DM and correlated with the severity of muscle (r = 0.34; P < 0.001) and hepatic (r = 0.57; P < 0.0001) IR and steatosis by MRS (r = 0.35; P < 0.0001).
Patients with NAFLD may benefit from early screening for T2DM, because the prevalence of abnormal glucose metabolism is much higher than previously appreciated. Regardless of glucose tolerance status, severe IR is common. In patients with T2DM, adipose tissue IR appears to play a major role in the severity of NAFLD.
Obesity is a risk factor for metabolic diseases. Intramuscular lipid accumulation of ceramides, diacylglycerols, and long chain acyl-CoA is responsible for the induction of insulin resistance. These lipids are probably implicated in obesity-associated insulin resistance not only in skeletal muscle but also in fat tissue. Only few data are available about ceramide content in human subcutaneous adipose tissue. However, there are no data on DAG and LCACoA content in adipose tissue. The aim of our study was to measure the lipids content in human SAT and epicardial adipose tissue we sought to determine the bioactive lipids content by LC/MS/MS in fat tissue from lean non-diabetic, obese non-diabetic, and obese diabetic subjects and test whether the lipids correlate with HOMA-IR. We found, that total content of measured lipids was markedly higher in OND and OD subjects in both types of fat tissue (for all p < 0.001) as compared to LND group. In SAT we found positive correlation between HOMA-IR and C16:0-Cer (r = 0.79, p < 0.001) and between HOMA-IR and C16:0/18:2 DAG (r = 0.56, p < 0.001). In EAT we found a strong correlation between C16:0-CoA content and HOMA-IR (r = 0.73, p < 0.001). The study showed that in obese and obese diabetic patients, bioactive lipids content is greater in subcutaneous and epicardial fat tissue and the particular lipids content positively correlates with HOMA-IR.
Obesity; Diabetes; Ceramide; Diacylglycerols; Long-chain acyl-CoA
MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.