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Insulin Resistance


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Insulin Resistance

  1. 1. Newsweek, September 4,<br /> 2000<br />Time, September 4, 2000<br />
  3. 3. Key words<br />Insulin resistance<br />Metabolic syndrome<br />Leptin<br />Adiponectin<br />resistin<br />
  4. 4. Histological slide of pancreatic islets cell<br />
  5. 5. 5<br />Electron micrograph showing release of insulin <br />from  cell<br />
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  7. 7. History os insulin resistance<br />Insulin resistance may be the underlying cause of diabetes mellitustype 2 was first advanced by Prof. Wilhelm Faltaand published in Vienna in 1931<br /> THIS theory confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936.<br />
  8. 8. Definition:<br /> Insulin resistance is defined as a failure of target organs to respond normally to the action of insulin.<br />Insulin resistance is a condition in which cells, particularly those of muscle, fat, and liver tissue, display &quot;resistance&quot; to insulin by failing to take up and utilize glucose for energy and metabolism .<br />
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  10. 10. Factors Contributing to Insulin Resistance<br />Acquired:<br />• Central obesity<br />• Sedentary lifestyle<br />• High fat diet<br />• Medications<br />Genetics <br />& Aging<br />Acquired<br />©2006 General Mills, Inc.<br />
  11. 11. DRUGS and GENETIC CAUSES OF INSULIN RESISTANCE<br />Drugs : <br />rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids, <br />Genetic causes <br />1.Insulin receptor mutations (Donohue Syndrome) <br />
  12. 12. Insulin Resistance: Inherited and Acquired Influences<br />12<br />Inherited<br />Acquired<br />Rare Mutations<br /><ul><li> Insulin receptor
  13. 13. Glucose transporter
  14. 14. Signaling proteins</li></ul>Common Forms<br /><ul><li> Largely unidentified
  15. 15. Inactivity
  16. 16. Over eating
  17. 17. Aging
  18. 18. Medications
  19. 19. Obesity
  20. 20. Elevated FFAs</li></li></ul><li>How Is Insulin Resistance Measured?<br />Determination of insulin resistance is difficult<br />Generally measured in terms of the glucose-lowering effects of insulin <br />Two common methodologies:<br />Hyperinsulinemic, euglycemic clamp (EHC): gold standard: insulin and glucose infused; steady state when glucose infusion equals rate of glucose disposal rate (GDR)<br />Homeostasis Model of Assessment (HOMA): fasting glucose and insulin measured for calculation of insulin sensitivity<br />McClenaghan, 2005<br />©2006 General Mills, Inc.<br />
  21. 21. Energy Balance<br />Positive<br />NegativeeE<br />Weight Loss<br />Fat Accumulation<br />Fatty Acids<br />Adipose Tissue<br />Liver & Muscle<br />Insulin Resistance<br />“Adipokines”<br />Robust B-cells<br />Weak B-cells<br />Hyperinsulinemia<br />Hyperglycemia<br />Preventing Type 2 Diabetes<br />Three Levels of Opportunity<br />
  22. 22. Hyperinsulinemia/hyperproinsulinemia<br />Insulin resistance<br />Glucoseintolerance<br />Increasedtriglycerides<br />DecreasedHDL cholesterol<br />Increased BP<br />Endothelial dysfunction<br />IncreasedPAI-1<br />Small, denseLDL<br />Atherosclerotic<br />cardiovascular<br />disease<br />Metabolic Syndrome, Insulin Resistance, and Atherosclerosis<br />MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.<br />
  23. 23. Metabolic Syndrome<br />Also known as:<br />Insulin Resistance Syndrome<br />Dysmetabolic Syndrome<br />Syndrome X<br />The Deadly Quartet<br />metabolic risk factors associated with<br />Type 2 diabetes (5-fold higher risk)<br />Cardiovascular disease (2-fold higher risk)<br />Underlying risk factors are abdominal obesity and insulin resistance<br />Grundy et al., 2005; Kahn et al., 2005<br />©2006 General Mills, Inc.<br />
  24. 24. Glucose<br />Intolerance,<br />Diabetes<br />Dyslipidemia<br />Visceral<br />Obesity<br />Hypertension<br />The ‘Metabolic Syndrome’<br />Also known as:<br />Syndrome X<br />Insulin Resistance Syndrome<br />The Deadly Quartet<br />The Dysmetabolic Syndrome<br />
  25. 25. Prevalence of Metabolic Syndrome<br />Affects nearly ¼ of adults <br />24%- 50% with coronary heart disease<br />50% with hypertension<br />85% with low HDL and high TG<br />87% with type 2 diabetes<br />Ford et al. 2002; Alexander et al., 2003; Duncan et al., 2004<br />©2006 General Mills, Inc.<br />
  26. 26. Lifestyle<br />Genetic<br />AbdominalObesity<br />Insulin Resistance<br />GlucoseIntolerance<br />Dyslipidemia<br />Hypertension<br />MetabolicSyndrome<br />Type 2 Diabetes & CVD<br />©2006 General Mills, Inc.<br />Grundy et al., 2005; Kahn et al., 2005<br />Metabolic Syndrome<br />
  27. 27. Diagnosing Metabolic Syndrome<br />Waist Circumference <br /><ul><li>Greater than 35 inches in women and 40 inches in men (abdominal obesity)</li></ul>Triglyceride<br /><ul><li>Levels of 150 milligrams per deciliter (mg/dl) or higher</li></ul>Blood Pressure<br /><ul><li>130/85 millimeters of mercury or higher</li></ul>Fasting blood glucose<br /><ul><li>Level of 110 mg/dl or higher</li></ul>High-density lipoprotein cholesterol (HDL)<br /><ul><li>Lower than 50 mg/dl in women and 40 mg/dl for men</li></ul>PBRC 2009<br />According to the National Cholesterol Education Program (NCEP), the presence of three or more of the following traits indicates metabolic syndrome:<br />
  28. 28. Diagnosis of metabolic syndrome<br />The American Association of Clinical Endocrinologists (AACE) clinical criteria for diagnosis of insulin resistance syndrome include the following: <br />BMI of 25 kg/m2 or higher <br />Triglyceride level of 150 mg/dL or higher <br />HDL-C level of less than 40 mg/dL in men or less than 50 mg/dL in women <br />Blood pressure of 130/85 mm Hg or higher <br />Glucose level of more than 140 mg/dL 2 hours after administration of 75 g of glucose <br />Fasting glucose level of 110-126 mg/dL<br />
  29. 29. Treatment of metabolic syndrome<br />Although metabolic syndrome creates a real risk for developing diabetes, stroke or heart disease, these conditions can be prevented. Metabolic syndrome can be controlled by the following:<br />Lose weight<br /><ul><li>Losing as little as 5 to 10% of your body weight can reduce insulin levels and high blood pressure, thus reducing your risk of diabetes.</li></ul>Exercise<br /><ul><li>Walking just 30 minutes a day or engaging in other aerobic activities can help prevent the serious diseases associated with MS.</li></ul>Stop smoking<br /><ul><li>Smoking cigarettes increases insulin resistance and worsens health consequences associated with MS.</li></ul>Eat fiber-rich foods<br /><ul><li>Whole grains, beans, fruits and vegetables are high in dietary fiber. These are important foods to eat since dietary fiber is known to lower insulin levels.</li></ul>PBRC 2009<br />
  30. 30. Adipose tissue act as an endocrine organ<br />(1) Adipose tissue is secrete free fatty acids (FFA) ,which have well described physiological and pathophysiological effects on glucose homeostasis<br />(2) secrets proteins, termed adipocytokines, that act in an autocrine, paracrine, or endocrine fashion to control various metabolic functions <br />
  31. 31. Adipose tissue<br />-Adipose tissue is an anatomical term for loose connective tissue composed of adipocytes (or fat cells). <br />-Its main role is to store fatty acids in the form of triglycerides, thus providing the organism with effective fuel storage-besides that it cushions and thermally insulates the body. <br />Adipose tissue<br />Adipocyte + capillary<br />
  32. 32. adipose tissue<br />-adipose tissue has an important endocrine function as it produces adipokines and inflammatory mediators, amongst others, leptin, adiponectin, resistin , adipsin, TNFα, IL-6 and PAI-1<br />subcutaneous<br />adipose tissue<br />Because of the production of inflammatory mediators, an excess of adipose tissue leads to a chronic mild inflammatory-state that may play a role in late onset diabetes (insulin resistance).<br /> mouse adipocytes<br />
  33. 33. Normal<br />Tabetes<br />Courtesy of Wilfred Y. Fujimoto, MD.<br />Visceral Fat Distribution:Normal vs Type 2 Diabetes<br />
  34. 34. LEPTIN<br />Product of the obese gene (ob) , conserved residues in purple colour (receptor binding sites not yet determined)<br />Four-helix bundle<br />Size 2,0x2,5x4,5 nm<br />Cys-96 &lt;-&gt; cys-146<br />PDB : 1ax8<br />
  35. 35. LEPTIN<br /> Greek word leptos meaning thin .<br />First discover in 1994 .<br />Leptin is a 167-amino acid protein <br /> secreted by adipocytes in proportion to adipocyte tissue mass .<br /> The Ob(Lep) gene [Ob for obese, Lep for leptin] is located on chromosome 7 in humans.<br />
  36. 36. Synthesis of Leptin<br />1. White adipose tissue :major source of leptin<br />brown adipose tissue,<br />placenta (syncytiotrophoblasts)<br />ovaries, <br />skeletal muscle<br />stomach (lower part of fundic glands)<br />mammary epithelial cells, <br />bone marrow<br /> liver.<br />
  37. 37. Leptin structure<br /><ul><li>146 a.a residue non glycosylated polypeptide
  38. 38. Member of helical cytokine family</li></ul>Primary structure of leptin<br />
  39. 39. FUNCTION OF LEPTIN<br />key role in regulating energy intake and energy expenditure, including appetite and metabolism. <br />Leptin circulates at levels proportional to body fat. <br />It controls food intake and energy expenditure by acting on receptors in the mediobasalhypothalamus<br />There are five Ob-R isoforms; the best characterized one is Ob-Rb, which activates the Jak-Stat signal transduction pathway<br />
  40. 40. Leptinreceptor(s)<br />Synonym: receptor for obesity facto, Ob-R<br />
  41. 41. focus on leptinsignalling<br />
  42. 42. focus on leptinsignalling<br />
  43. 43. Appetite is<br />suppressed<br />CNS<br />MSH<br />Periphery<br />Metabolic activity increases to burn fat<br />Leptin<br />+<br />Hypothalamus<br />arcuate nucleus<br /><br />JAK-STAT<br />Leptin<br />receptor<br />MSH<br />POMC: <br />pro-opiomelanocortin<br />(from peptide-amine hormone biosynthesis lecture)<br />Adipose<br />Adipose stores are HIGH<br />Figure 2. The leptin signaling system and its effects when adipose stores are &quot;high&quot; <br />
  44. 44. Appetite is<br />enhanced<br />JAK-STAT<br />CNS<br />Periphery<br />Metabolic activity decreases limiting fat burning<br />Leptin<br />+<br />Leptin<br />receptor<br />Hypothalamus<br /> AGRP from hunger neurons<br />Block MSH binding<br />MSH<br />Adipose<br />Adipose stores are low<br />Figure 2. The leptin signaling system and its effects when adipose stores are “low&quot; <br />
  45. 45. congenitalleptindeficiencyhuman)<br />- voraciousappetite<br />- morbidobesity<br />- immunosuppression<br />- hypothalamichypogonadism<br />
  46. 46. LEPTIN AND INSULIN RESISTANCE<br />Mice that are deficient in leptin (ob/ob) exhibit hyperphagia, obesity,hypercortisolemia,infertility,and diabetes.<br />Exogenous leptin administration reverses these abnormalities<br />Leptin may also improve insulin sensitivity by directly acting on peripheral tissues such as skeletal muscle and liver<br />
  47. 47. ADIPONECTIN<br />Adiponectin is a 247-amino acid<br />It has multiple name, like-AcrP30,AdipoQ, apM1, and gelatin binding protein.<br />In human cross-sectional studies, plasma adiponectin levels are negatively correlated with obesity ,adiposity, and waist to hip ratio, diabetic dyslipidemia,CVD, and insulin resistance .<br />Adiponectin knockout mice showed high levels of <br /> TNF-αand increased insulin resistance.<br />
  48. 48. Low plasma adiponectin was an independent risk factor for future development of type 2 diabetes .<br />Adiponectin may play a causative role in the development of insulin resistance and the metabolic syndrome.<br />The mechanisms by which adiponectin may ameliorate insulin resistance have not been fully elucidated. <br />One proposed mechanism is that adiponectin decreases circulating FFA by increasing fatty acid oxidation in skeletal muscle This results in decreased triglyceride content in muscle that has been associated with improved insulin sensitivity<br />
  49. 49. KEY MESSAGE ABOUT ADIPONECTIN<br />Adiponectin is an adipocyte-derived plasma protein with insulin sensitizing, antiinflammatory, and antiatherogenic properties. <br />Although its physiological and pathophysiological role has not been fully elucidated.<br />its low levels in insulin resistance states suggest that therapeutic modulation of adiponectin may provide a novel treatment modality for insulin resistance.<br />
  50. 50. RESISTIN<br />Crystallographic structure of a hexamer of mouse resistin<br />(rainbow colored, N-terminus = blue, C-terminus = red).<br />
  51. 51. RESISTIN<br />Resistin is a adipocyte-secreted polypeptide.<br />first described in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine<br />Resistin is a member of a family of tissue-specific signaling molecules,calledresistin-like molecules . <br />The resistin mRNA encodes a 114-amino acid polypeptide with a 20-amino acid signal sequence. <br />Resistin is secreted as a disulfide-linked dimmer.<br />
  52. 52. Resistin, a novel 12.5 kDa cysteine-rich protein, is secreted by adipocytes.<br />Serum resistin levels are significantly increased in insulin-resistant mice and genetic or diet-induced obese mice <br />In addition, neutralization of endogenous resistin with antibodies significantly suppresses hyperglycaemia in diet-induced obese mice by improving insulin sensitivity.<br />
  53. 53. TNF-α<br />TNF-α is a proinflammatory cytokine that has been implicated in the pathogenesis of insulin resistance.<br />Increased TNF- α production has been observed in adipose tissue derived from animal models of obesity and insulin resistance as well as human subjects<br />
  54. 54. probable mechanisms by which adipose tissue TNF- α increases insulin resistance is-<br /> 1. increased release of FFA by adipocytes<br /> 2. reduction in adiponectin synthesis <br /> 3. impairment of insulin signaling<br />Additional human studies are needed to understand its role in the pathogenesis of insulin resistance in humans.<br />
  55. 55. LIPODYSTROPHY AND INSULIN RESISTANCE<br />in the absence of adipose tissue,excess calories cannot be diverted to normal storage depots(adipocytes)<br />Than they accumulate, insteadas triglyceride stores in liver, skeletal muscle, cardiac muscle, and pancreatic islet cells.<br />Abnormal intracellular TG accumulation leads to impaired insulin secretion and action, leading to diabetes<br />
  56. 56. leptin levels are very low in generalized lipodystrophy.<br />low leptinlevels correlate significantly with markers of insulin resistance.<br /> ∙ In lipodystrophic patients, leptinreplacement therapy improved glycemic control and decreased TG levels .<br />Leptin treatment improved insulin-stimulated hepatic and peripheral glucose metabolism and was associated with a reduction in hepatic and muscle TG content.<br />
  57. 57. SUMMURY<br />The mechanisms by which adipocytokines promote insulin resistance are still complex, and our understanding incomplete.<br />the presence of adipose tissue is vital in the prevention of insulin resistance, at least in part, via secretion of the following cytokines: leptin and adiponectin.<br />
  58. 58. Finally, determining the relative contribution of adipocytokines to glucose homeostasis and insulin resistance and elucidating the dynamic interactions between adipocytokines should be a focus of our research in the future.<br />
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  61. 61. The END!Thank You!<br /> Oh, sorry, not the END, just the beginning!<br />53<br />Email: house no: 26. house name:TAKHDIR.<br />SUGANDHA. R/A ,CHITTAGONG BANGLADESH <br />