insulin resistance and obesity orla mahony sept 2013

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  • Slide 1
  • Insulin Resistance and Obesity Orla Mahony Sept 2013
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  • Insulin resistance and obesity Insulin signaling Definitions; insulin resistance, T2DM Hypotheses for why IR develops in obesity Unifying hypothesis Measuring insulin resistance IR in the liver/hepatic steatosis Metabolic syndrome Other theories of IR: TNF, adiponectin, leptin Veterinary literature
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  • Insulin Signaling In muscle insulin binds to R, activates tyrosine kinase, phosphorylates and activates IRS1 (insulin receptor substrate 1) IRS1 activates PI3K (1 phosphatidylinositol 3- kinase), which activates Akt2, which phosphorylates and inactivates AS160, a protein that prevents translocation of GLUT4 Insulin thus promotes docking and fusion of GLUT4 vesicles to the plasma membrane
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  • Insulin resistance Insulin resistance is defined as a subnormal glucose response to both endogenous and exogenous insulin
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  • Insulin resistance in people has been seen in association with Inherited disorders e.g. lipodystrophy Secondary to obesity, drugs, stress, infection, acromegaly, glucocorticoid excess, pregnancy Impaired glucose tolerance and type 2 DM Hypertension, hyperlipidemia, polycystic ovary disease, coronary heart disease; MOA of insulin resistance unknown
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  • Consequences Type 2 DM Cardiovascular disease Neoplasia (colon, breast and endometrial cancers associated with obesity and IR)
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  • T2DM T2DM is characterized by hyperglycemia, impaired insulin secretion and insulin resistance It can arise through genetic and environmental influences IR is characterized by impairment of insulin- mediated translocation of GLUT4 to the muscle sarcolemmal membrane
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  • Hypotheses for why IR develops in obesity Accumulation of fatty acid metabolites (DAG) within insulin-responsive tissues Obesity is a proinflammatory state with increases in TNF and IL6, and activation of PKCs and serine phosphorylation of IRS1 Changes in adipokines and lipokines
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  • Link between lipid and IR Tyrosine phosphorylation of IRS1 and activation of PI3K impaired in rodent models of IR and in muscles of volunteers given lipid infusions, implying a lipid-induced reduction in insulin-stimulated glucose transport is due to a defect in insulin signaling PKC serine threonine kinases are the link between lipid accumulation and impaired insulin action
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  • In obesity, delivery of fatty acids overwhelm capacity of cells to oxidize them or convert DAGs to TGs (via diacylglycerol acyl transferase 1, DAGT1) DAG activates protein kinase C serine- threonine kinases which lead to serine phosphorylation of IRS1, preventing it from interacting with insulin R and GLUT4 and taking up glucose
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  • Defect in insulin signaling Unifying hypothesis for IR in obesity, lean healthy offspring of T2DM parents, ageing, and disorders such as congenital and acquired lipodystrophy Increases in intramyocellular lipid content occurs in lean offspring of T2DM patients, and in elderly, maybe because of decreased lipid oxidation and a reduction in mitochondrial content
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  • Exercise increases DAGT1 expression in muscle and is associated with increased TGs, reduced DAG and improved insulin sensitivity Reductions in DAG also occur with thiazolidinedione therapy
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  • Measuring insulin resistance Euglycemic insulin clamp technique is gold standard IV glucose tolerance test and the insulin tolerance test/insulin suppression test also used most frequently in research setting Impractical for clinical use Glucose to insulin ratios and homeostasis model assessment of insulin resistance (HOMA) used in large population epidemiologic studies
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  • Limitations to HOMA & insulin ratios Changes in beta cell function over time Lack of standardized insulin assay No data demonstrating that markers of IR predict response to treatment
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  • IR estimation In nondiabetic, normotensive overweight individuals, serum TG concentration, ratio of TG to HDL cholesterol concentration and fasting insulin concentration used clinically to identify people who may be insulin resistant
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  • Hepatic steatosis Non alchoholic fatty liver disease Most common cause of chronically inc LEs Closely assoc with obesity, IR, T2DM In liver, insulin binds R, activates TK, phosphorylates IRS1 and IRS2, activates PI3K and Akt2, promoting glycogen synthesis and inhibiting gluconeogenesis
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  • Effect of IR on the liver IR in muscle, impairs storage of CHO as glycogen, CHOs redirected to liver for use in de-novo lipogenesis Increases in DAG activates PKCs, leading to impaired tyrosine phosphorylation of IRS1 and IRS2 by the insulin R, ultimately impairing ability of insulin to activate hepatic glycogen synthesis and suppress hepatic glucose production
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  • Omega 3 Fatty Acids Not all fats are bad Docosahexaenoic acid and eicosapentaenoic acid bind to GPR 120, a cell surface receptor abundant on adipocytes. GPR influences metabolism and reduced activity is assoc. w inflammation, weight gain and poor glucose control Omega 3 FAs may promote FA oxidation through activation of PPARs, increasing adiponectin, and preventing DAG accumulation
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  • Metabolic syndrome/ insulin resistance syndrome Metabolic syndrome is the co-occurrence of risk factors for T2DM and CVD Genetic predisposition, lack of exercise and body fat distribution determine whether an obese individual will develop T2DM or CVD Diagnosed based on Overall obesity (increased BMI) Abdominal obesity Increased BP Increased fasting glucose and TG levels, Low HDL
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  • Other theories of Insulin Resistance Proinflammatory state associated with release of TNF and IL6, activation of PKC and increased serine phosphorylation of IRS1 Effects of adipokines centrally and peripherally
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  • TNF- Inflammatory cytokine secreted by macrophages, mast cells, neuronal cells, fibroblasts, and adipocytes Necrosis and apotosis of adipocytes attracts monos and macs leading to inc. TNF Causes localized insulin resistance by activating PKC and serine phosphorylation of IRS1
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  • TNF- Impairs TG storage, induces fat lipolysis High concs of serum FFAs diminish insulin sensitivity in perhipheral tissues TNF- is inversely correlated with adiponectin and alters its gene expression
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  • The role of key adipokines in obesity and insulin resistance in cats Adipose tissue is an endocrine organ Adipokines are proteins, hormones and cytokines derived from adipose tissue Of over 100, leptin, adiponectin, TNF best known Lusby et al JAVMA 2009:325;518-522
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  • Leptin Leptin regulates body fat through satiety and energy metabolism As fat increases, leptin secretion from adipocytes increases Leptin acts on arcuate nucleus of the hypothalamus, inhibits neurotransmitters that increase food intake and lower energy expenditure and activate neurons that suppress appetite and increase energy expenditure (this may indirectly improve insulin sensitivity)
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  • Leptin Obese animals have highest leptin levels because of leptin resistance (may be from defects in signaling or transport across BBB) Leptin also has effects on immune, cardiovascular and reproductive systems
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  • Adiponectin Released from adipocytes, yet more fat assoc with lower adiponectin levels As adipocytes increase in size become more IR and secrete less adiponectin Also TNF- decrease adiponectin 30-kDa monomers form low molecular wt forms, middle molecular wt and HMW forms HWF (12 or more) more closely assoc with DM and IR
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  • Adionectin cont. Anti-inflammatory and cardioprotective Insulin sensitizer Lower TG levels in muscle and liver by moving them to adipose tissue
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  • IR in cats and dogs Mori et al, Japan, compared insulin signaling pathways between a cat and dog to see if any differences since IR more common in cats Measured IRS1, IRS2, PIK3 mRNA from liver, muscle, abdom fat and leukocytes by qRT-PCR Also measured enzymes involved in CHO and fat metabolism, MDH (malate dehydrogenas), FAS (fatty acid synthase) and G6PDH (glu 6 phos dehydrogenase)
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  • Higher levels of gene expression in dogs Implying that cats have a lower metabolic rate than dogs and cats may have underlying low insulin sensitivity level and be predisposed to developing insulin resistance Limitations; 2 animal study Mori et al Vet Res Commun 2009;33:211-226
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  • Decreased gene expression of insulin signaling genes in insulin sensitive tissues of obese cats 4 normal cats, 4 moderately obese cats Decreased levels of IRS2 and PI3K in obese cats and MDH and HSL mRNA indicating insulin signaling gene alterations occurring No studies of glucose tolerance performed Mori et al. Vet Res Commun 2009:33;315-329
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  • Hypothyroidism and IR 16 anestrous female dogs, 8 w expt hypothyr Insulin-modified frequently sampled IV GGT and minimal model analysis used to d