Insulin Resistance and Obesity

Orla Mahony Sept 2013

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: TNFα, adiponectin, leptin• Veterinary literature

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

Insulin resistance

• Insulin resistance is defined as a subnormal glucose response to both endogenous and exogenous insulin

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

Consequences

• Type 2 DM• Cardiovascular disease• Neoplasia (colon, breast and endometrial

cancers associated with obesity and IR)

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

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 TNFα and IL6, and activation of PKC’s and serine phosphorylation of IRS1

• Changes in adipokines and lipokines

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

• In obesity, delivery of fatty acids overwhelm capacity of cells to oxidize them or convert DAG’s to TG’s (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

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

• Exercise increases DAGT1 expression in muscle and is associated with increased TG’s, reduced DAG and improved insulin sensitivity

• Reductions in DAG also occur with thiazolidinedione therapy

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

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

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

Hepatic steatosis

• Non alchoholic fatty liver disease• Most common cause of chronically inc LE’s• 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

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 PKC’s, 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

Omega 3 Fatty Acids

• Not all fats are bad• Docosahexaenoic acid and eicosapentaenoic acid

bind to GPR120 , 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 FA’s may promote FA oxidation through activation of PPAR’s, increasing adiponectin, and preventing DAG accumulation

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

Other theories of Insulin Resistance

• Proinflammatory state associated with release of TNFα and IL6, activation of PKC and increased serine phosphorylation of IRS1

• Effects of adipokines centrally and peripherally

TNF-α

• 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 α

• Causes localized insulin resistance by activating PKC and serine phosphorylation of IRS1

TNF-α

• Impairs TG storage, induces fat lipolysis• High conc’s of serum FFA’s diminish insulin

sensitivity in perhipheral tissues• TNF-α is inversely correlated with adiponectin

and alters its gene expression

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, TNFα best

known

Lusby et al JAVMA 2009:325;518-522

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)

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

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-α 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

Adionectin cont.

• Anti-inflammatory and cardioprotective• Insulin sensitizer• Lower TG levels in muscle and liver by moving

them to adipose tissue

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)

• 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

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

Hypothyroidism and IR

• 16 anestrous female dogs, 8 w expt hypothyr• Insulin-modified frequently sampled IV GGT

and minimal model analysis used to determine basal insulin, gluc conc., acute insulin response to gluc, insulin sensitivity, glucose effectiveness, and disposition index

• Showed that insulin sensitivity lower, and acute insulin response to glu higher in hpoTh

Hofer-Inteeworn et al. AJVR 2012;73;529-538

Hypothyroidism and IR

• Hypothyroidism induces insulin resistance, but glucose tolerance preserved by increased insulin secretion

• May be due to high GH and IGF-1 conc in hypoth dogs and increased abdominal fat

• Relevance for poorly regulated DM and concurrent hypothyroidism

Assoc of inc. TG’s with IR in schnauzers

• 28 min schn’s w hyperlipidemia, 31 controls• Healthy for prior 3 months• Single fasting blood sample, for serum insulin

and gluc and the homeostasis model assessment (HOMA) score was calculated; basal serum insulin X basal glu conc (mmol/L)/ 22.5

• Basal insulin conc higher and % of dogs with higher HOMA scores and higher insulin conc.’s was greater in hyperlipidemic dogs

Xenoulis et al JAVMA 2011:238:1011-1016

• Authors conclude that IR is often present in min Schnauzers with hypertriglyceridemia

• May make concurrent DM more difficult to control• IR may play role in vacuolar hepatopathy and gall

bladder disease• Limitation; no body scores included and obesity

important cause of IR• Hypothyroidism and DM not ruled out although

57/59 had normal BG’s and 8 had normal TT4

Insulin resistance and obesitySummary

• Accumulation of intramyocellular lipid, (DAG), activates novel PKC’s causing serine phosphorylation of IRS1, preventing it from, interacting with insulin receptor and moving GLUT4 to plasma membrane, for glucose uptake

• Proinflammatory state (IL6 and TNFα)• Increased leptin, decreased adiponectin