Kenneth Cusi

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic β cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican–American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPARγ coactivator 1-α and-β (PGC1-α/PPARGC1 and PGC1-β/PERC), coactivators of NRF-1 and PPARγ-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Insulin resistance differentially affects the PI 3-kinase– and MAP kinase–mediated signaling in human muscle

The broad nature of insulin resistant glucose metabolism in skeletal muscle of patients with type 2 diabetes suggests a defect in the proximal part of the insulin signaling network. We sought to identify the pathways compromised in insulin resistance and to test the effect of moderate exercise on whole-body and cellular insulin action. We conducted euglycemic clamps and muscle biopsies on type 2 diabetic patients, obese nondiabetics and lean controls, with and without a single bout of exercise. Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance.

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology NAGA CHALASANI, MD, FACG,* ZOBAIR YOUNOSSI, MD, FACG, JOEL E. LAVINE, MD, PhD, ANNA MAE DIEHL, MD, ELIZABETH M. BRUNT, MD, KENNETH CUSI, MD, MICHAEL CHARLTON, MD,** and ARUN J. SANYAL, MD

Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 +/- 3 yr; body mass index, 29.0 +/- 1.1 kg/m(2)), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m(2).min) with [(3)H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 +/- 10 to 140 +/- 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 +/- 13 to 233 +/- 14 mg/dl; P < 0.01), and hemoglobin A(1c) (8.6 +/- 0.4% to 7.2 +/- 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 +/- 38 to 569 +/- 31 microEq/liter; P < 0.05) and mean plasma FFA (539 +/- 20 to 396 +/- 29 microEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 +/- 7 to 25 +/- 3 mg/kg fat-free mass (FFM).min x microU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 +/- 0.1 to 0.6 +/- 0.2 mg/kg FFM.min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 +/- 0.5 to 4.4 +/- 0.4 ml/kg FFM.min (P < 0.05); second MCR, 8.7 +/- 1.0 to 11.3 +/- 1.1 ml/kg FFM(.)min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 +/- 4 to 85 +/- 4 kg; P < 0.05) and fat mass (27 +/- 2 to 30 +/- 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4-5 (301 +/- 44 to 342 +/- 44 cm(2); P < 0.01) increased, whereas visceral fat area at L4-5 (144 +/- 13 to 131 +/- 16 cm(2); P < 0.05) and the ratio of visceral to sc fat (0.59 +/- 0.08 to 0.44 +/- 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

Role of Obesity and Lipotoxicity in the Development of Nonalcoholic Steatohepatitis: Pathophysiology and Clinical Implications

As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients.

Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes.

Aims/hypothesisThe recent discovery of two adiponectin receptors (AdipoR1 and AdipoR2) will improve our understanding of the molecular mechanisms underlying the insulin-sensitising effect of adiponectin. The aim of this study was to determine for the first time whether skeletal muscle AdipoR1 and/or AdipoR2 gene expression levels are associated with insulin resistance.MethodsUsing RT-PCR and northern analysis we measured AdipoR1 and AdipoR2 gene expression in skeletal muscle from healthy Mexican Americans with normal glucose tolerance who had (n=8) or did not have (n=10) a family history of Type 2 diabetes.ResultsGene expression profiling indicated that the AdipoR1 and AdipoR2 isoforms are highly expressed in human skeletal muscle, unlike in mice where AdipoR2 expression was highest in the liver, and AdipoR1 was highest in skeletal muscle. In the study subjects, the expression levels of AdipoR1 (p=0.004) and AdipoR2 (p=0.04), as well as plasma adiponectin concentration (p=0.03) were lower in people with a family history of Type 2 diabetes than in those with no family history of the disease. Importantly, the expression levels of both receptors correlated positively with insulin sensitivity (r=0.64, p=0.004 and r=0.47, p=0.048 respectively).Conclusions/interpretationCollectively, these data indicate that both isoforms of the adiponectin receptor play a role in the insulin-sensitising effect of adiponectin.

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-γ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ± 0.02 to 1.73 ± 0.43 mm and decreased insulin-stimulated glucose disposal from 8.82 ± 0.69 to 6.67 ± 0.66 mg/kg·min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation.

The Role of Adipose Tissue and Lipotoxicity in the Pathogenesis of Type 2 Diabetes

The widespread epidemics of obesity and type 2 diabetes mellitus (T2DM) suggest that both conditions are closely linked. An increasing body of evidence has shifted our view of adipose tissue from a passive energy depot to a dynamic “endocrine organ” that tightly regulates nutritional balance by means of a complex crosstalk of adipocytes with their microenvironment. Dysfunctional adipose tissue, particularly as observed in obesity, is characterized by adipocyte hypertrophy, macrophage infiltration, impaired insulin signaling, and insulin resistance. The result is the release of a host of inflammatory adipokines and excessive amounts of free fatty acids that promote ectopic fat deposition and lipotoxicity in muscle, liver, and pancreatic β cells. This review focuses on recent work on how glucose homeostasis is profoundly altered by distressed adipose tissue. A better understanding of this relationship offers the best chance for early intervention strategies aimed at preventing the burden of T2DM.

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association