Insulin resistance

Insulin resistance (IR) is the pathogenic foundation underlying metabolic syndrome, steatosis and cirrhotic-NASH, and possibly HCC. The interplay between genetic and environmental risk factors ultimately leads to the development of IR. Obesity is considered a major risk factor, with dysregulation of levels of secreted adipokines from distended adipose tissue playing a major role in IR. HCV-induced IR may be due to the HCV core protein inducing proteasomal degradation of IRS 1 and 2, impairing expression of IRS 1 and 2 and blocking intracellular insulin signalling. The latter is mediated by increased levels of both TNF-α and suppressor of cytokine signalling 3 (SOC-3). IR, through different mechanisms, plays a role in the development of steatosis and its progression to steatohepatitis, cirrhosis, and even HCC. In addition, it has a role in impairing IFN signalling cascade (JAK → STAT → IFN genes), as insulin activates PI3K thus blocking STAT-1 translocation, avoiding the antiviral effect of interferon. Introduction Insulin resistance is a condition in which a higher than normal insulin concentration is needed to achieve normal metabolic responses. The overall prevalence of IR is significant; some have reported that 10–25% of the population is affected by the condition [1] , others have reported that approximately 1/3 of the apparently healthy population are insulin resistant [2,3] . 30–70% of patients with CHC display some form of IR [4] . Worldwide, 47 million patients may have HCV-associated DM [5] . Calculation of IR • HOMA-IR = Fasting insulin (μU/L) × fasting glucose (mmol/L)/22.5. • Convert glucose in mg/dL → mmol/L, divide glucose by 18. Values >2 are consistent with IR. Types of insulin resistance Insulin resistance may be either peripheral (which refers to diminished insulin-mediated uptake of glucose by skeletal muscle and depends primarily on the failure of glucose transporter type 4 (GLUT4) expression and translocation to the plasma membrane) or hepatic insulin resistance (which describes impaired suppression of hepatic glucose production, and largely accounts for hyperglycemia and glucose intolerance). Phases of insulin resistance [6] 1. Prereceptor: due to abnormal insulin (mutations) or anti-insulin antibodies. 2. Receptor: due to – Decreased number of receptors and proteasomal degradation of insulin receptor substrate (IRS). – Abnormal insulin receptor (mutation). – Antibodies blocking insulin-receptor binding. – Activation of receptor on serine rather than tyrosine kinase. – Reactive oxygen species (ROS), which decreases tyrosine phosphorylation of IRS. 3. Postreceptor: – TNF-α, IL-6 and insulin inhibit insulin signalling via induction of SOCs 1, 3. – Mutations of GLUT4. 4. Combination of defects [6] . Risk factors of insulin resistance ( Fig. 1 ) • Gender : Increased visceral adiposity in men leads to a higher risk of IR than in women [7] . • Aging : Associated with increased levels of FFAs and TG, a decrease and mutation of GLUT4. • Obesity : Associated with decreased number and downregulation of insulin receptors and impairment of postreceptor signalling. Overflow of FFAs from adipose tissue interferes with intrahepatic insulin signalling pathway via increased levels of pro-inflammatory cytokines such as TNF-α [8,9] and proteasomal degradation of the insulin receptor substrate-1 and 2 (IRS-1 and 2) [10] . • Smoking : Induces the production of high levels of circulating catecholamines, which act as antagonists to insulin-action [11] . Smoking contributes to increased levels of TG and decreased HDL. • Alcohol : Doses higher than 50 g/day leads to higher risk of IR. • Increased production of insulin antagonists : Cushing syndrome, acromegaly, stress, diabetic ketoacidosis, severe infection, uremia, trauma, surgery, liver cirrhosis, etc. • Medications, particularly : Glucocorticoids, cyclosporine, growth hormones, thyroid hormones, sex hormones, protease inhibitors (HCV), nucleoside analogues (HBV), thiazides, β-blockers. • Exercise : Low physical activity and high energy intake leads to high risk of IR [12] . In addition it has been reported that IR improves after exercise [13] . • Cirrhosis : Induces IR due to diminished insulin extraction by the liver as well as portosystemic shunting of insulin, whilst increasing incontra-insulin hormones (glucogen, growth hormones, IGF, FFAs). Cirrhosis can downregulate insulin receptor or postreceptor function [14] . • HCV : Core proteins downregulate IRS and block intracellular insulin signalling. • Periodontal infection : Patients with severe periodontitis have six times greater risk of worsening glycaemic control over time than patients without periodontitis, a finding attributed to increased insulin resistance [15] . Recent findings suggest that pro-inflammatory proteins (e.g., Tumour Necrosis Factor TNF-α and Interleukin IL-1b) can induce insulin resistance by interfering with lipid metabolism. It appears that prevention and treatment of periodontal infections can have a beneficial effect on glycaemic control in diabetic patients [16] ( Fig. 1 ). Insulin resistance and metabolic syndrome MS is a set of risk factors that includes: abdominal obesity, a decreased ability to process glucose (increased blood glucose and/or insulin resistance), dyslipidaemia, and hypertension [17] . The functional defect in patients with MS is resistance to the cellular action of insulin, particularly to insulin stimulated glucose uptake [18] . Patients who have this syndrome have been shown to be at an increased risk of developing cardiovascular disease and/or type-2 diabetes. IR is the pathogenic foundation underlying metabolic syndrome (MS) [4] . IR may play an important role in the development of hyperinsulinemia, hyperglycemia (due to enhanced hepatic gluconeogenesis and glucose output), an increase in plasma FFAs, and dyslipidemia, which can further aggravate the degree of IR [19] . However, a substantial proportion of patients with MS do not exhibit evidence of IR. Role of adipokines in insulin resistance Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. Adipolines include Adiponectin, Leptin, Resistin, Retinol binding protein 4, Visfatin, Omentin, Vaspin, Chemerin, Apelin, TNF-α, IL-6, and Monocyte chemoattractant protein-1 (MCP-1) [20] . Adiponectin Acts as anti-inflammatory, hepatoprotective adipokine [21] . Some of its beneficial effects include suppression of TNF-α and IL-6 expression [22] , leading to increased insulin sensitivity [23] , glucose uptake, FA oxidation and activation of PPAR-α, which leads improved insulin sensitivity [24] . Finally, adiponectin prevent hepatic steatosis [25] . Deficiency of adiponectin is associated with: obesity, insulin resistance, glucose intolerance, TG accumulation and steatosis, and metabolic syndrome [20] . Leptin Upregulation of leptin has been found to be associated with regulation of food intake and body weight (anorexigenic), and limited accumulation of TG in the liver and skeletal muscles, thus inhibiting steatosis. In addition to stimulation of fatty acid oxidation, improved insulin sensitivity and stimulation of PI3K signalling can lead to increased glucose uptake by hepatocytes [26] . On the other hand, leptin insufficiency is associated with increased body weight, increased FA synthesis, decreased FA oxidation, decreased TG excretion, increased steatosis, and impaired insulin sensitivity and secretion [20] . TNF-α Impairs phosphorylation of IRS on tyrosine kinase [27] . Triggers secretion of FFAs from adipose tissue, causing proteasomal degradation of IRS. Inhibits P-R signalling via induction of SOCs, which leads to inactivation of PI3K and inhibition of translocation of GLUT4 to the cell membrane, thus blocking glucose entry [27] . Inactivation of both IRS and post receptor signalling generate IR, with subsequent development of hepatic steatosis and activation of HSCs, eventually leading to fibrosis. On the other hand, the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) has an anti-inflammatory role, involved in the regulation of glucose and lipid homeostasis and may have insulin sensitising effects. Upregulation of PPAR-γ regulates FA uptake by the liver. Control of TG and VLDL synthesis prevent hepatic steatosis. PPAR-α is known to be activated by insulin sensitisers (thiazolidinedione (TDZ)). Alternatively, downregulation of PPAR-γ occurs in cases of IR due to impaired expression of PPAR-γ, leading to retention of TG with subsequent development of fatty liver and upregulation of NFκ−β, which can accelerate HCV replication. HCV core protein also inhibits PPAR-α and γ promoting IRS-1 degradation, thereby generating IR [28] . HCV-induced insulin resistance HCV generates necroinflammation of cell membranes with consequent reduction of insulin receptors. HCV-Core protein induces IR by: proteasomal degradation of IRS 1 and 2, impairing expression of IRS 1 and 2, blocking intracellular insulin signalling mediated by increased levels of pro-inflammatory cytokine TNF-α [9,10] ; increased suppression of cytokine signalling 3 (SOC-3) [8] ; inhibition of phosphorylation of PI3K, leading to decreased translocation of GLUT4 to the cell membrane and glucose entry. HCV genotype non-3 induces IR via downregulation of IRS [29–31] through phosphorylation of the receptor on serine. HCV genotype-3 may induce a cytopathic effect and auto-immune aggression on b-cells of the pancreas [32] . Data suggest that either HCV per se or its inflammatory response in the liver plays a central role in the development of IR in patients with CHC [33] . Role of insulin resistance in steatosis development It is well known that insulin resistance causes impaired metabolic clearance of glucose. In addition, it also increases lipolysis, leading to increased plasma FFAs. Increased hepatic uptake of FFAs impairs b-oxidation and decreases excretion of TG-Apo B100 (VLDL), resulting in steatosis. IR impairs expression of anti-inflammatory PPAR-γ, resulting in TG retention. IR also reduces adiponectin and induces a loss of adiponectin receptors, resulting in TG retention with subsequent development of fatty liver [34–38] . The mechanisms leading NAFLD to NASH and cirrhosis Increased FFA flux to the liver is caused by excessive adipose tissue lipolysis, resulting from peripheral IR. In patients that fail to adequately incorporate FFAs into TG (“bad fat storers”) NASH develops as a result of direct lipotoxicity and generation of ROS. Individuals that efficiently store FFA as TG (“good fat storers”) have a benign course unless additional hepatic injury occurs (“second hit”). Progression to cirrhosis depends on fibrogenic factors [39] . Progression of metabolic cirrhosis to HCC Metabolic fibrosis or cirrhosis is associated with the following: oxidative stress, cell cycle stimulation, apoptosis inhibition, mutagenesis. Each is capable of developing hepatic cancer. Insulin-induced IFN resistance ( Fig. 2 ) IR-induced steatosis increases the risk of fibrosis and reduces antiviral activity. In addition, HCV-induces necroinflammation, with consequent reduction and malfunction of IFN receptors. Steatosis/NASH/fibrosis decreases the contact between IFN and receptor [40] , impairing IFN signalling cascade (JAK → STAT → IFN genes) [41] . Moreover, PI3K, activated by insulin, seems to be responsible for the block of STAT-1 translocation, eventually inhibiting production of ISG (Mx, 2′5′ OAS, PKR) ( Fig. 2 ). Insulin resistance can be improved by regulation of food intake and body weight, and exercise reduces peripheral IR. Pharmacological intervention with agents that target insulin resistance (metformin, thiazolidinedione (TDZ)) can also be used. In conclusion, IR plays a key role in the pathogenesis of metabolic syndrome, steatosis and cirrhotic-NASH, and perhaps HCC. Steatosis independently increases the risk of HCC. IR and steatosis reduce SVR to antiviral therapy. Diet control, exercise, and insulin sensitisers improve insulin sensitivity. Pentoxifylline also reduces TNF-α and may improve insulin sensitivity. References [1] E. Ferrannini A. Natali B. Capaldo M. Lehtovirta S. Jacob H. Yki-Jarvinen Insulin resistance, hyperinsulinemia, and blood pressure: role of age and obesity. European group for the study of insulin resistance (EGIR) Hypertension 30 5 1997 1144 1149 [2] F.S. Facchini N. Hua F. Abbasi G.M. Reaven Insulin resistance as a predictor of age-related diseases J Clin Endocrinol Metab 86 8 2001 3574 3578 [3] J. Yip F.S. Facchini G.M. 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