Loading ...
Sorry, an error occurred while loading the content.

Fwd: NATAP: Insulin Resistance & Liver Disease

Expand Messages
  • claudine intexas
    NATAP http://natap.org/ _______________________________________________ Insulin resistance: A metabolic pathway to chronic liver disease Hepatology Volume 42,
    Message 1 of 1 , Nov 7 12:34 PM
    • 0 Attachment
      NATAP http://natap.org/
      Insulin resistance: A metabolic pathway to chronic liver disease
      Volume 42, Issue 5, Pages 987-1000
      Published Online: 25 Oct 2005

      Elisabetta Bugianesi 1, Arthur J. McCullough 2, Giulio Marchesini 3 *
      1Gastroenterology Department, University of Turin, Turin, Italy
      2Gastroenterology Department, Metro Health Medical Center, Case Western Reserve University, Cleveland, OH
      3Department of Medicine and Gastroenterology, Alma Mater Studiorum, University of Bologna, Bologna, Italy

      Insulin resistance is becoming a health concern in HIV. Fatty liver (NAFLD- non alcoholic fatty liver disease) may not yet be identified yet as a concern in HIV but I think it will be in the future. This article will inform you regarding aspects of these conditions. To facilitate getting the most from this article, I excerpted passages.

      Perhaps the strongest evidence supporting the importance of IR in the pathophysiology of NAFLD are the nascent data provided by recent clinical trials. Table 5 displays clinical strategies designed to improve insulin sensitivity in the liver[135-138] (metformin) and in the periphery[31][106][139-142] (thiazolidinediones) in patients with NAFLD. Although none of these studies had a double-blind randomized design, which is limiting,[143] the results certainly warrant additional carefully performed studies with these agents.

      Table 5. Clinical Trials Treating Insulin Resistance in NAFLD

      Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gammaglutamyltransferase; PPAR-, peroxisome proliferator-activated receptor agonists; LPL, lipoprotein lipase.
      * Compared with 6 noncompliant patients.
      Compared with dietary control group.
      Compared with either vitamin E (800 IU daily) or a prescriptive diet (all subjects received nutritional counseling).
      § Compared with pioglitazone used in combination with vitamin E (400 IU daily) vs. vitamin E alone.
      Compared with metformin (2 g) treatment group, which did not have improvement in the outcomes stated.

      In closing, two additional points warrant emphasis. First, this review has focused on the effect of IR on the liver. However, IR and its associated metabolic syndrome is a systemic disease affecting (likely via mitochondrial injury[40]) the nervous system,[144] muscles,[39] pancreas,[145] kidney,[146] heart,[115][147] and immune system.[148] Second, NAFLD is a disease of our generation. NAFLD has exploded onto the clinical landscape over the past 25 years. Its pathophysiology is complex (Fig. 3), and the available data suggest that environmental factors such as diet, exercise, and/or environmental toxins are likely important. The fact that the prevalence of NAFLD varies among different racial groups[149] and that there are variable rates of disease progression within individuals with similar risk factors[150] strongly suggests that fat genes also play a role in both prevalence and natural history, as indicated by recent studies.[151-153] However, determining the genetics of IR in
      NAFLD is not easy.[154][155] There are over 400 gene interactions involved in fat storage,[156] and even more involved in insulin action.[157] A recent study suggests that abnormalities in at least 23 genes may be involved in NAFLD.[157] However, as is the case for other common complex metabolic diseases, there is likely to be an interaction between the environment and genetics that will determine the influence of IR on the phenotypic expression of NAFLD in any individual patient.

      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.

      Clinical Aspects of Insulin Resistance in Relation to Metabolic Liver Disease

      IR is present in a variety of clinical conditions, most of which have NAFLD as an associated disease. The term metabolic syndrome[114] has been coined to indicate a cluster of diseases, strictly correlated with each other, having IR as the common pathogenic determinant, and carrying a high risk of cardiovascular disease.[115][116] Regulatory agencies and scientific societies have proposed different criteria to define the metabolic syndrome, all including data on obesity - namely visceral obesity, glucose regulation, dyslipidemia, and blood pressure.[114][117-120] The most commonly quoted proposals are given in Table 4. The Adult Treatment Panel III proposal produced from the National Cholesterol Education Program,[118] which defined the metabolic syndrome as a combination of five clinical and biochemical risk factors, is easily determined in individual patients using routine examination and biochemistry. It is also the basis for the most recent proposal of the International Diabetes
      Federation,[120] which focuses on abdominal obesity as a necessary feature. Other clinical conditions not included in the definition are strictly associated with IR - namely elevated uric acid, reduced fibrinolysis, endothelial dysfunction, and fatty liver, all of which might also be included. The metabolic syndrome also now has its own ICD9 code carrying the diagnosis of dysmetabolic syndrome X.

      Table 4. Criteria for the Definition of the Metabolic Syndrome According to the Most Commonly Quoted Proposals (the Amer Diabetes Ass takes issue with a blanket term "Metabolic Syndrome')

      Abbreviations: T2DM, type 2 diabetes mellitus; WHO, World Health Organization; NCEP, National Cholesterol Education Program; IDF, International Diabetes Foundation; OGTT, oral glucose tolerance test; M, male; F, female.

      Since it was first described, NAFLD has been consistently associated with obesity (60%-95%), diabetes (28%-55%), and dyslipidemia (27%-92%), and less clearly with raised arterial pressure.[121] The presence of any one of these conditions may be evidence of IR. Obesity - more specifically central obesity - characterized by abdominal fat accumulation is definitely associated with both IR and NAFLD. In the general population, obesity increases the risk of steatosis independent of alcohol intake.[122] In severe obesity, the prevalence of liver abnormalities is nearly the rule.[123] Body mass index is an independent predictor of the degree of fat infiltration of the liver,[124] and the likelihood of developing NASH increases with the severity of obesity: about 15%-20% of morbidly obese subjects have NASH.[125] The simple measurement of waist girth proposed by the World Health Organization to categorize visceral obesity[126] may be used as a guide to determine insulin sensitivity.[127]

      T2DM is the disease most commonly related to IR. Whereas overt disease also depends on decreased insulin secretion, impaired insulin sensitivity plays a primary role in the altered glucose regulation that heralds the onset of disease.[128] At any level of obesity, T2DM significantly increases the prevalence and severity of NAFLD.[129] It has been reported that up to 50% of T2DM patients have fatty liver.[129] Similarly, any category of altered glucose regulation is associated with NAFLD, and even a family history of T2DM increases the risk of NAFLD. In population studies, raised aminotransferase levels are associated with IR and predict the development of T2DM.[130]

      Both triglyceride and high-density lipoprotein cholesterol concentrations are regulated by insulin, and hyperinsulinemia with IR is characterized by hypertriglyceridemia and low high-density lipoprotein cholesterol concentrations. Mixed hyperlipidemia and hypertriglyceridemia are the lipid disorders most commonly associated with NAFLD, but the presence of low high-density lipoprotein cholesterol doubles the risk of NAFLD.[131]

      Finally, hypertension has been associated with IR.[132] The correlation of NAFLD with hypertension has been less clearly defined. When present, hypertension is usually associated with obesity and T2DM. However, nonobese hypertensive patients with normal liver enzymes also have an increased prevalence of fatty liver, which is related to IR.[133]

      The overall prevalence of metabolic syndrome in NAFLD patients is largely dependent on selection criteria. Most studies excluded patients with diabetes, where the metabolic syndrome is nearly the rule.[134] In a large NAFLD series, prevalence of the metabolic syndrome was higher in females and increased with increasing body mass index from 18% in normal-weight subjects to 67% in obese subjects.[19] The association of obesity with diabetes and/or altered lipid metabolism leads to a multiplicative effect on the final prevalence of metabolic syndrome, and significantly increases the risk of more severe stages of liver disease.[19]

      Article Text

      The liver plays a pivotal role in nutrient and hormone metabolism. Metabolic abnormalities are common in liver disease, hence the term hepatogenous diabetes, which is used to describe the hyperglycemia that develops in advanced cirrhosis. However, only recently has a direct effect of altered insulin metabolism been postulated in the pathogenesis of liver disease. Abnormalities in insulin action may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a condition that ranges from clinically benign fatty liver to its more severe form, nonalcoholic steatohepatitis (NASH). As a result, interest in insulin resistance (IR), its pathogenesis, and its quantitative measurement has increased. The aim of this review is to focus on the general aspects of IR and to summarize the present knowledge of the biochemical and clinical aspects that support the view of a metabolic mechanism involved in the pathogenesis of chronic liver disease mediated by IR.

      Insulin Resistance

      IR may be defined as a condition in which (1) higher-than-normal insulin concentrations are needed to achieve normal metabolic responses or (2) normal insulin concentrations fail to achieve a normal metabolic response. The first definition dates back to the 1960s, when a quantitative measurement of insulin concentrations was made available; the second was proposed by Kahn,[1] who also differentiated reduced insulin sensitivity (rightward shift of the insulin-response curve) from reduced insulin responsiveness (lower-than-normal maximal response).

      One limitation of this definition is a lack of clarity in the metabolic functions used to measure insulin activity. Historically, glucose metabolism has been the measured function of choice, but other metabolic pathways and/or different organs respond to insulin in nonuniform fashion.[2]

      Several dynamic[3-8] and static[9-12] methods have been proposed for the quantitative assessment of IR (Table 1). The glucose clamp technique remains the gold standard,[3] and the validity of different methods is usually measured against that of the clamp.[6][7][13-16] Simple indices based on the sole measurement of glucose and insulin - both in the fasting state and in response to an oral glucose tolerance test - provide data that may be confidently used in epidemiological surveys. The reproducibility of static methods depends largely on analytical and day-to-day variability of insulin concentrations, and small changes in insulin produce a large error in the estimate of IR. Nonetheless, these simple indices have greatly expanded our knowledge of insulin-resistant states.

      Since the first demonstration of IR in NAFLD,[17] homeostasis model assessment has been used in epidemiological studies to demonstrate the close association between NAFLD and the metabolic syndrome.[18][19] The glucose clamp technique was first used by Comert et al,[20] and subsequent studies showed that the increased IR of NAFLD also includes defective insulin-mediated suppression of lipolysis,[21-23] similar to that observed in type 2 diabetes (T2DM). IR is accompanied by higher total insulin secretion and normal hepatic insulin extraction[24] and predicts the presence of more severe disease.[25] However, it may be present even in lean, nondiabetic patients who do not exhibit the classical features of the metabolic syndrome.[23]

      Metabolic Effects of Insulin Resistance

      After an overnight fast (postabsorptive state), most of the total glucose disposal occurs in insulin-independent tissues, approximately 50% in the brain and 25% in the splanchnic area (liver plus gastrointestinal tissues). Glucose utilization, which averages approximately 2.0 mg/kg/min, is precisely matched by the release of glucose from the liver.[34] After the ingestion of a glucose-containing meal, the majority (approximately 80%-85%) of glucose disposal occurs in muscle tissue. The maintenance of normal glucose homeostasis is dependent on three tightly related processes: (1) insulin secretion by pancreatic ≤ cells, (2) stimulation of glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues, and (3) suppression of hepatic glucose output. Although fat tissue is responsible for only a small amount of total body glucose disposal (4%-5%), it plays a very important role in the maintenance of total body glucose homeostasis.

      Glucose Metabolism and Glucose Disposal.

      Muscle is the primary site of glucose disposal in humans. After glucose enters a cell, it can either be converted to glycogen (70% of glucose uptake) or enter the glycolytic pathway (90% glucose oxidation and 10% anaerobic glycolysis).

      In NAFLD patients, the main site of IR during euglycemic insulin clamp studies is muscle. Because obesity and diabetes are the two most common risk factors for the development of NAFLD, peripheral IR can be partially accounted for by the presence of each or both of them. However, an independent association of NAFLD with IR, as suggested by epidemiological studies,[17] has been confirmed through the use of the clamp technique. In nondiabetic NAFLD patients, glucose disposal is reduced by nearly 50% compared with normal subjects, to an extent similar to that observed in T2DM.[22] The lack of difference in glucose disposal between normal and overweight NAFLD suggests that the defect is not exclusively associated with abnormal glucose regulation and/or excess fat mass. Glucose utilization in muscle progressively deteriorates from fatty liver to NASH,[21] and IR and hyperinsulinemia are not secondary to a reduced hepatic insulin extraction.[24]

      When combined with the clamp, indirect calorimetry provides the rate of nonoxidative glucose disposal (i.e., glycogen synthesis) as the difference between whole-body glucose uptake (as determined by the insulin clamp) and glucose oxidation. Insulin-stimulated glycogen synthesis is reduced in insulin-resistant states, including obesity, diabetes, and the combination of obesity and diabetes.[34] Likewise, nonoxidative glucose disposal during insulin clamp is decreased in obese patients with NAFLD, and the defect is more pronounced in subjects with NASH than in those with fatty liver.[21] Glucose disposal is inversely related to the amount of body fat in obese patients,[21] but not in lean patients with NAFLD,[22] in whom insulin sensitivity more closely correlates with visceral adiposity indirectly assessed by waist circumference.[24] The reduced insulin sensitivity in NAFLD is compensated by an enhanced cell secretion,[24] which is necessary to maintain euglycemia. The relationship
      between these two parameters is hyperbolic.

      The independent association of NAFLD with IR has also been confirmed by studies showing that the presence of fatty liver influences the severity of IR in T2DM and obesity. In T2DM, insulin-stimulated glucose disposal is markedly diminished in relation to fatty liver[35] and correlates with the degree of fat infiltration (measured via CT) and visceral fat (determined via MRI). Intrahepatic lipids, together with intra-myocellular lipids, are increased in T2DM and are negatively associated with insulin sensitivity during a three-step hyperinsulinemic euglycemic clamp.[36] Similarly, impairment in whole-body insulin sensitivity is more pronounced in obese nondiabetic women with high liver fat.[37] Goto et al.[38] found a correlation between insulin sensitivity and liver fat in lean Japanese individuals without liver disease.

      In healthy lean elderly subjects, insulin-stimulated muscle glucose metabolism is reduced as compared with young controls and is associated with increased fat accumulation in muscle and liver tissue assessed via 1H nuclear magnetic resonance spectroscopy.[39] In the same group, mitochondrial oxidative and phosphorylation activity is reduced by approximately 40%; mitochondrial abnormalities are also observed in obese patients with fatty liver and NASH.[40]

      >From an anatomical perspective, mesenteric adipocytes might be a crucial source of fatty acids entering portal circulation. Even though FFAs released from the splanchnic bed account for only about 10% of the FFAs reaching the liver,[49] mesenteric adipocytes are less responsive to the antilipolytic action of insulin. Recent studies using selective catheterization of the hepatic vein have concluded that the major source of liver fat is not the visceral depot, but rather upper body nonsplanchnic subcutaneous tissue.[50] Nevertheless, visceral fat and fatty liver represent special depots of adiposity related to the pathogenesis of IR and may be part of an overall axis of central adiposity.[51]

      Organ-specific deposition of fat is a strong predictor of hyperinsulinemia and/or insulin resistance. Analogous to fat in the liver, increased intramyocellular triglyceride content as assessed via muscle biopsy[52] or magnetic resonance imaging/computed tomography[53][54] closely correlates with muscle IR and is a better predictor of impaired insulin action than visceral adiposity.[55] The importance of ectopic fat deposition in the pathogenesis of IR is further confirmed in inherited or HIV-related forms of lipodystrophy, where the selective loss of subcutaneous and visceral fat are associated with steatosis, hypertriglyceridemia, and severe IR.[56][57] The sequence of events leading to ectopic accumulation of triglycerides has been referred to as the overflow hypothesis,[58] according to which IR is the result of the inability of the adipose organ to expand to accommodate excess calories. Once the capacity of the fat cell to store triglycerides is exceeded, fat overflows to other
      tissues (muscle and liver), where the intracellular triglyceride metabolism interferes with insulin signaling, glucose transport/phosphorylation, and glycogen synthesis in muscle and augments hepatic gluconeogenesis.

      It is also now recognized that the hepatitis C virus (HCV) may contribute to both steatosis and IR, thus explaining the high prevalence of T2DM and steatosis observed in these patients. These aspects, at present largely unexplained, will not be analyzed in the present review.

      Cross-Talk Between Liver and Peripheral Tissues

      The complex network that regulates energy homeostasis implies a tightly regulated cross-talk between liver, muscle, and adipose tissue and the central nervous system. Recent studies have focused on the crucial role of adipose tissue, which is able to integrate signals from other organs and respond by secreting proteins termed adipocytokines.[59] In NAFLD, as well as in different metabolic diseases, the release of adipocytokines is altered. Because these adipocyte-specific proteins share energy-regulating and immune-regulating functions, a dysfunctional cross-talk between adipose tissue and the liver results in metabolic and inflammatory abnormalities.


      Adiponectin (Acrp 30 or AdipoQ) is expressed only in adipocytes. Low circulating levels of adiponectin have been linked to several components of the metabolic syndrome, including visceral adiposity, hyperlipidemia, and IR/T2DM,[49] and adiponectin administration reverses IR and exerts anti-inflammatory actions.[34] In the liver, it increases the sensitivity of insulin to inhibit gluconeogenesis[60] and regulates hepatic FFA metabolism in vivo via suppression of lipogenesis and activation of FFA oxidation.[61]

      Available evidence from cross sectional studies suggests that in humans adiponectin levels are tightly associated with the amount of centrally located fat. In healthy adults, a relationship is present between adiponectin deficiency and increased liver fat, and both are independent determinants of serum insulin.[62] Adiponectin levels correlate negatively with liver fat and hepatic IR in diabetic patients and in their healthy relatives.[63] In subjects with mild obesity, hypoadiponectinemia predicts the presence of hepatic steatosis on ultrasound.[64] In a cohort of NAFLD patients with a low prevalence of type 2 diabetes, low levels of circulating adiponectin were related to the amount of hepatic fat content and to increased hepatic insulin sensitivity, suggesting that hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.[65]

      Adiponectin has anti-inflammatory properties in the liver, and low adiponectin levels might increase liver cell necrosis and disease progression. In healthy subjects, low adiponectin levels are significantly associated with increased concentrations of liver enzymes (namely, aminotransferase and gamma-glutamyltransferase), in keeping with a possible contribution of adiponectin in maintaining liver integrity.[66] Similarly, low adiponectin levels are associated with increased fat content and more extensive necroinflammation in NAFLD patients.[67] Finally, in KK Ay-obese mice, pretreatment with adiponectin reduces mortality, aminotransferase elevation, and apoptosis induced by D-galactosamine/lipopolysaccharide.[68] The administration of recombinant adiponectin to ob/ob mice alleviates hepatomegaly and steatosis and attenuates inflammation in alcoholic and nonalcoholic fatty liver diseases.[69] These therapeutic effects are likely the result of the ability of adiponectin to enhance
      hepatic fatty acid oxidation and to reduce fatty acid synthesis, HGO and tumor necrosis factor (TNF-).

      Adiponectin may influence liver fibrosis. After carbon tetrachloride injections, adiponectin knockout mice develop more extensive liver fibrosis than wild-type mice.[70] In wild-type mice, injection of adenovirus-producing adiponectin prevents liver fibrosis induced by carbon tetrachloride, possibly via suppression of transforming growth factor-1, one of the cytokines that stimulate hepatic stellate cells (HSCs) to produce fibrosis. Adiponectin overexpression in activated HSCs reduces proliferation and increases apoptosis, suggesting that adiponectin may act to reverse HSC activation or to maintain HSC quiescence.[71]

      Adiponectin activity strongly depends upon the metabolic milieu and the inflammatory pattern, and adiponectin concentrations in the plasma and liver are not always correlated. In NASH, the messenger RNA expression of adiponectin receptors (AdipoRII) in the liver is negatively correlated with the histological grade of fibrosis but not with serum or hepatic adiponectin.[72] Similarly, no correlation is observed between circulating adiponectin levels and liver adiponectin expression.

      In patients with advanced liver fibrosis, adiponectin levels are normal or even higher than normal.[73] This phenomenon has been related to reduced hepatic extraction.

      Tumor Necrosis Factor a.

      TNF-a is an adipocyte-derived cytokine that plays a central role in IR. TNF-a impairs insulin signaling by inhibiting the function of IRS-1 through serine phosphorylation.[74] Circulating TNF-a levels are increased in obese[75] and diabetic subjects,[76] even if the correlation between IR and plasma TNF- levels is weak.

      Interestingly, although the three-dimensional structure of TNF-a closely resembles that of adiponectin,[77] these two proteins have completely opposite effects. Both in vivo and in vitro experiments have demonstrated that adiponectin and TNF-a suppress each other's production and also antagonize each other's action in their target tissues.[78] Overproduction of TNF-a in liver tissue has been proposed to play a key role in the pathogenesis of fatty liver.[79] Fatty liver disease in ob/ob mice is significantly improved by inhibition of hepatic TNF-a production or infusion of anti-TNF-a neutralizing antibodies.[80] Treatment with adiponectin significantly inhibits lipopolysaccharide-induced TNF-a production in cultured macrophages.[81] TNF-a stimulates leptin secretion in cultured adipocytes and in obese mice, and, as a feedback loop, leptin administration to rats decreases TNF-a expression.[82][83]


      Leptin is produced by adipose tissue in proportion to adipose tissue mass. It plays a role in modulating food intake and energy expenditure and exerts a proinflammatory influence regulating T cell response, enhancing cytokine production and phagocytosis by macrophages.[84] According to a recent proposal, leptin might also be an antisteatotic hormone, teleologically aimed at preventing FFA entry and fat accumulation in nonadipose tissues.[85]

      Chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients, and reduces hepatic and muscle triglyceride content.[56] It also improves hepatic histology in these patients.[86] Leptin is also directly involved in hepatic fibrogenesis through HSC activation.[87] Both quiescent and activated HSCs express the Ob-RL receptor for leptin, which is further expressed during the development of liver fibrosis and cirrhosis.[88] Finally, in animal models of NAFLD, leptin appears to be essential for developing fibrosis in response to chronic liver injury.[89] However, the importance of leptin in human NAFLD has recently been questioned.[90]

      Interleukin 6.

      One third of interleukin 6 (IL-6) in humans is produced by adipose tissue during noninflammatory conditions. It plays an important role in inflammation and the regulation of T cell and B cell function. Visceral adipose tissue produces three times more IL-6 than subcutaneous adipose tissue.[91] Circulating IL-6 is associated with IR in humans[92] and impairs insulin signaling in hepatocytes.[93] In T2DM, IL-6 levels are increased and correlate with the severity of glucose intolerance[94] and with the severity of inflammation, as indicated by the highly sensitive C-reactive protein serum concentration.[95] The close linear relationship between IL-6 and TNF- secretion from adipose tissue[59] suggests that IL-6 is part of the TNF-/leptin axis.


      Resistin is a novel protein found in preadipocytes undergoing differentiation into mature adipocytes.[96] It is a potent proinflammatory agent. In humans with T2DM, plasma resistin levels are elevated and correlate closely with hepatic IR but not muscle IR.[44] Infusion of resistin into normal animals causes severe hepatic IR but has no effect on muscle insulin sensitivity.[97] In diet-induced IR, treatment with an antisense oligodeoxynucleotide directed against resistin messenger RNA reduced the plasma resistin levels and completely reversed hepatic IR.[98]


      Angiotensinogen has also been found in adipocytes.[99][100] Nascent data suggest it may be important in NAFLD, because angiotensinogen II antagonists improve liver function tests in patients with NAFLD[100] and attenuate fibrosis in animal models.[101]

      Pathogenic Implications

      Several mechanisms may account for fatty liver in insulin-resistant states, but factors responsible for the progression from simple fatty liver to NASH remain obscure. Although the search for an additional cause of oxidative stress (the so-called second hit[102]) has been elusive, patients at risk for more severe disease are those with several features of the metabolic syndrome, indicating that IR itself might play a role in disease progression. An imbalance in cytokine activity produced by dysfunctional fat cells can provide a link between metabolic and liver disorders, and it has recently been reported that oxidative stress in accumulated fat may cause dysregulated adipocytokine production, thus being part of the first hit.[103] The excessive production of TNF-, IL-6, leptin, and FFAs versus the defective production of adiponectin may cause IR and inflammation.

      The recent proposal that the insulin resistance syndrome could be an inflammatory disorder appears particularly relevant.[104] As shown in Fig. 2, the balance between proinflammatory and anti-inflammatory cytokines derived from adipocytes and other tissue may determine the development of IR. Nascent data regarding the mechanism of actions and the beneficial effects of peroxisomes proliferator-activated receptor agonists[105][106] and long-chain polyunsaturated fatty acids[107] give credence to the inflammatory nature of IR. The recent report that salicylates or disruption of IKKB reversed obesity and diet-induced IR gives further support to this concept.[108] All insulin-resistant states are characterized by chronic subclinical inflammation.[59] In patients with T2DM and/or obesity, the serum concentration of C-reactive protein, fibrinogen, 1-acid glycoprotein, amyloid A, sialic acid, and orosomucoid are all increased[109] to a greater extent when fatty liver is also present.[35]

      Increased serum ferritin, another acute phase reactant, is a common finding in NAFLD as well as in other insulin-resistant states. When iron stores are not increased, ferritin levels predict the development of diabetes in epidemiological studies[110] and are strongly associated with the degree of liver damage in NAFLD.[25]

      To further strengthen this concept, the insulin-sensitizing agents of the thiazolidinedione class, currently being tested for the treatment of NASH, also have anti-inflammatory properties. Thiazolidinediones inhibit resistin and TNF- gene expression in adipocytes and decrease their circulating levels,[111][112] whereas they stimulate adiponectin gene expression in adipocytes and increase plasma adiponectin concentration.[48] In rats with liver fibrosis induced by dimethylnitrosamine or carbon tetrachloride, administration of pioglitazone or rosiglitazone reduces hepatic extracellular matrix deposition and activation of hepatic stellate cells.[113]

      [Non-text portions of this message have been removed]
    Your message has been successfully submitted and would be delivered to recipients shortly.