Insulin resistance causes and consequences


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Insulin resistance causes and consequences

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Insulin resistance causes and consequences

  2. 2. INSULIN  RESISTANCE Decreased biological response to normal concentration of circulating insulin.  Insulin (endogenous) or administered (exogenous).  Beta cells in the pancreas subsequently increase their production of insulin, further contributing to hyperinsulinaemia
  3. 3. INSULIN RESISTANCE IS OFTEN SEEN WITH THE FOLLOWING CONDITIONS DM,  Metabolic syndrome,  Obesity ,  Pregnancy ,  Infection or severe illness,  Stress ,  Inactivity and excess weight. 
  4. 4. SIGNS AND SYMPTOMS  Inability to focus.  Increased hunger.  Intestinal bloating (cannot digest and absorb).  Sleepiness (after meals).  Weight gain, difficulty losing weight ( around abdominal organs in both males and females).   Increased blood pressure  Increased pro-inflammatory  . Acanthosis nigricans.   Depression. Increased blood triglyceride levels.
  5. 5. ACANTHOSIS NIGRICANS  brown to black, poorly defined, velvety hyperpigmentation of the skin.  found in body folds  ↑insulin activates keratinocyte insulin-like growth factor receptors, particularly IGF-1.  At high concentrations, insulin may also displace IGF-1 from IGFBP.  Increased circulating IGF may lead to keratinocyte and dermal fibroblast proliferation
  6. 6. CAUSES AND CONSEQUENCES PKB mutation  Mutation in IRS  Increased in serine phosporylation of IRS protein  PI3 Kinase Activity  Metabolic syndrome.  Type 2 Diabetes mellites.  Obesity/ Inactivity and excess weight 
  7. 7. Protein Kinase B PKB MUTATION  The serine/threonine kinase Akt (also called PKB), triggers insulin effects on the liver  Akt1 --inhibiting apoptotic processes, induce protein synthesis pathways, key signaling protein in cellular that lead to skeletal muscle hypertrophy, general tissue growth  Akt2 is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane
  8. 8.  Phosphorylation of the serine stimulates Akt phosphorylation at a T308 residue.  Glycogen synthase kinase 3 (GSK-3) inhibited upon phosphorylation by Akt, which results in increase of glycogen synthesis  Suppression of hepatic glucose , PEPCK inhibition. Glycogen synthase kinase
  9. 9. Insulin receptor substrate 1 MUTATION IN IRS  Most of the metabolic and antiapoptotic effects of insulin are mediated by the signaling pathway involving the phosphorylation of the insulin receptor substrate (IRS) proteins, IRS-1, IRS- 2  Mutation of IRS 1 results in IR in muscles and adipose tissue.  Mutation of IRS 2 results in IR in liver.
  10. 10. INCREASED IN SERINE PHOSPORYLATION OF IRS PROTEINS  Serine phosphorylation of IRS proteins can reduce the ability of IRS proteins to attract PI3-kinase, minimizing its activation.  Serine phosphorylation in turn ↓ IRS-1 tyrosine phosphorylation, impairing downstream effectors.  serine phosphorylation may lead to dissociation between insulin receptor/IRS-1 &/or IRS-1/PI3-kinase, preventing PI3-kinase activation or increased degradation of IRS-1  circulating FFA & adipokine tumour necrosis factor (TNF) may ↑ serine phosphorylation of IRS proteins, causing impaired insulin signal transduction
  11. 11. CAUSES OF SERINE PHOSPHORYLATION OF IRS-1 PROTEINS ARE Obesity  Stress  Hyperinsulinemia   PKC θ • hyperglycemia • Diacylglycerol • inflammation
  12. 12. PI3 KINASE ACTIVITY  class 1a  Consisting of a regulatory subunit p85, tightly associated with a catalytic subunit, p110.  p85 monomer & p85-p110 heterodimer compete for same binding sites on tyrosine-phosphorylated IRS proteins, Imbalance could cause either ↑ or ↓PI3kinase activity  Human placental growth hormone causes severe insulin resistance by specifically ↑ expression of p85α subunit  Subsequently affecting the ability of insulin to stimulate the association of the p85-p110 heterodimer with IRS-1  Reducing the PI3-kinase insulin signaling resistant states induced by obesity, type 2 diabetes
  13. 13. PKC Ca2+ cPKCs (α, βⅠ, βⅡ, γ) DAG + + nPKCs (δ, ε, θ, η) aPKCs (ζ, λ) + No response No response
  14. 14. FATTY ACID INDUCED IR defective insulin-stimulated glucose transport activity ↑intramyocellular lipid metabolites (fatty acyl CoAs & diacylglycerol) Activating PKC activate a serine/threonine kinase cascade Defect insulin signaling through the Ser/Thr phosphorylation IRS-1 Reduced IRS 1 associated PI3K activity Defective regulation of GLUT4
  15. 15. DIABETES  The primary defects in insulin action appear to be in muscle cells and adipocytes, with impaired GLUT 4 translocation resulting in impaired insulin-mediated glucose transport.  β cells fail to compensate for the prevailing insulin resistance leading impaired glucose tolerance.  As glucose levels rise, β cell function deteriorates further, with diminishing sensitivity to glucose and worsening hyperglycemia and diabetes develops.
  16. 16. PREGNANCY  Due to the combined effects of human placental lactogen, progesterone, oestradiol and cortisol, which act as counterregulatory hormones to insulin mainly in 3rd trimester of pregnancy.  Exaggeration of the insulin resistance normally seen in pregnancy is associated with gestational diabetes mellitus and gestational hypertension
  17. 17. PCOS  In 2003 Rotterdam- indicated PCOS   excess androgen activity   Oligoovulation &/or anovulation polycystic ovaries (ultrasound) The ovarian dysfunction relates to the effects of compensatory hyperinsulinaemia increasing pituitary LH secretion & androgen production by the theca cells of the ovary.  Aromatization of androgens in setting of obesity ↑production of oestrogens, further impairing function of the HPA axis.  Hyperinsulinaemia also suppresses SHBG production by liver, ↑ free androgens. Elevated androgens in turn further aggravate insulin resistance.
  18. 18. Hyperinsulinemia abnormalities of hypothalamic-pituitary-ovarian axis ↑ GnR pulse frequency, ↑ovarian androgen production ↑ LH/FSH ratio, ↓follicular maturation,↓ SHBG binding.  PCOS
  19. 19. INSULIN RESISTANCE SYNDROME  Constellation of associated clinical and laboratory findings consisting of Insulin resistance, Hyperinsulinemia dyslipidemia (↓HDL,↑ TG), Hypertension  Clinical syndromes associated with insulin resistance include type 2 diabetes, cardiovascular disease, essential hypertension, polycystic ovary syndrome, non-alcoholic fatty liver disease, certain forms of cancer and sleep apnoea.
  21. 21. HYPERTENSION  Insulin is a vasodilator with secondary effects on Na+2 reabsorption.  Hyperinsulinemia may result in enhanced sodium reabsorption and increased sympathetic nervous system (SNS) activity and contribute to the hypertension.
  22. 22. INSULIN RESISTANCE ROLE IN DEVELOPMENT OF ATHEROSCLEROSIS AND HYPERTENSION  Compensatory hyperinsulinaemia is associated higher levels of plasminogen activator inhibitor-1 (PAI-1) and ↑ fibrinogen levels  Dyslipidaemia with ↑ LDL, ↓ HDL are also found in insulin resistant states.  Again, lower levels of testosterone in men have been associated with a proatherogenic lipid profile (high total and LDL cholesterol)  Testosterone is an L-channel calcium blocker acting directly at the level of the ion pore serve as systemic vasodilator improve cardiac index and functional capacity.
  23. 23.  Endothelin 1, a potent vasoconstrictor also inhibits insulin signalling via PIP-3 kinase & competes with NO resulting in endothelial dysfunction.  Mitogenic properties, mediated via MAP (mitogen activated protein) kinase pathway, remain intact.  These mitogenic effects of insulin on endothelial smooth muscle cell proliferation probably contribute to atherosclerosis.
  24. 24. UNCOMMON GENETIC DISORDERS ASSOCIATED WITH INSULIN RESISTANCE              Down’s Syndrome Turner’s Syndrome Klinefelter’s Syndrome Thalassaemia Haemochromatosis Lipodystrophy Progeria Huntington’s Chorea Myotonic dystrophy Friedrich’s ataxia Laurence-Moon-Biedel syndrome Glycogen storage diseases type I & III Mitochondrial disorders
  25. 25. MEASUREMENT OF INSULIN RESISTANCE Research Methods  HOMA IR = Fasting Glucose(mmol/L) x Fasting Insulin(mU/L) 22.5  Quantitative Insulin Sensitivity Check Index (QUICKI ) = 1 / [log(fasting insulin µU/mL) + log(FBG mg/dL)]
  26. 26.  Functional Measures of Insulin Resistance  McLoughlin et al were able to identify insulin resistant individuals from an overweight-obese cohort  plasma triglyceride concentration,  ratio of triglyceride to high-density lipoprotein  cholesterol concentrations  insulin concentration.  Using cut points of    1.47 mmol/L for TG, 1.8 mmol/L for the TG-HDL - cholesterol ratio 109 pmol/L (16 mIU/L) for insulin
  27. 27. TREATMENT
  28. 28. REFERENCES  Review Article -Insulin and Insulin Resistance-Gisela WilcoxMelbourne Pathology, Collingwood, VIC 3066, Monash University Department of MUnit, C/- Body Composition Laboratory, Monash Medical Centre, Clayton, VIC 316  Willams Endocrinology12TH EDN  Teitz Clinical Chemistry 5TH EDN  Text book of biochemistry 3rd EDN lby dr.dinesh puri