1. Newsweek, September 4, 2000 Time, September 4, 2000

2. PRESENATATION BY DR MISBAHUL FERDOUS MBBS(USTC) FMD (USTC) PGT (CARDIOLOGY) NICVD.DHAKA PUBLICATION- 1 (ORIGINAL ARTICLE) METABOLIC SYNDROME AND ACUTE ST ELEVATION MI IN HOSPITAL OUTCOME. PUBLISHED IN B.H.J. JANUARY-2008 MD (CARDIOLOGY), COURSE SHANDONG UNIVERSITY, CHINA.

3. Key words Insulin resistance Metabolic syndrome Leptin Adiponectin resistin

4. Histological slide of pancreatic islets cell

5. 5 Electron micrograph showing release of insulin from  cell

7. History os insulin resistance Insulin resistance may be the underlying cause of diabetes mellitustype 2 was first advanced by Prof. Wilhelm Faltaand published in Vienna in 1931 THIS theory confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936.

8. Definition: Insulin resistance is defined as a failure of target organs to respond normally to the action of insulin. Insulin resistance is a condition in which cells, particularly those of muscle, fat, and liver tissue, display "resistance" to insulin by failing to take up and utilize glucose for energy and metabolism .

10. Factors Contributing to Insulin Resistance Acquired: • Central obesity • Sedentary lifestyle • High fat diet • Medications Genetics & Aging Acquired ©2006 General Mills, Inc.

11. DRUGS and GENETIC CAUSES OF INSULIN RESISTANCE Drugs : rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids, Genetic causes 1.Insulin receptor mutations (Donohue Syndrome)

13. Glucose transporter

15. Inactivity

16. Over eating

17. Aging

18. Medications

19. Obesity

21. Energy Balance Positive NegativeeE Weight Loss Fat Accumulation Fatty Acids Adipose Tissue Liver & Muscle Insulin Resistance “Adipokines” Robust B-cells Weak B-cells Hyperinsulinemia Hyperglycemia Preventing Type 2 Diabetes Three Levels of Opportunity

22. Hyperinsulinemia/hyperproinsulinemia Insulin resistance Glucoseintolerance Increasedtriglycerides DecreasedHDL cholesterol Increased BP Endothelial dysfunction IncreasedPAI-1 Small, denseLDL Atherosclerotic cardiovascular disease Metabolic Syndrome, Insulin Resistance, and Atherosclerosis MacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.

23. Metabolic Syndrome Also known as: Insulin Resistance Syndrome Dysmetabolic Syndrome Syndrome X The Deadly Quartet metabolic risk factors associated with Type 2 diabetes (5-fold higher risk) Cardiovascular disease (2-fold higher risk) Underlying risk factors are abdominal obesity and insulin resistance Grundy et al., 2005; Kahn et al., 2005 ©2006 General Mills, Inc.

24. Glucose Intolerance, Diabetes Dyslipidemia Visceral Obesity Hypertension The ‘Metabolic Syndrome’ Also known as: Syndrome X Insulin Resistance Syndrome The Deadly Quartet The Dysmetabolic Syndrome

25. Prevalence of Metabolic Syndrome Affects nearly ¼ of adults 24%- 50% with coronary heart disease 50% with hypertension 85% with low HDL and high TG 87% with type 2 diabetes Ford et al. 2002; Alexander et al., 2003; Duncan et al., 2004 ©2006 General Mills, Inc.

26. Lifestyle Genetic AbdominalObesity Insulin Resistance GlucoseIntolerance Dyslipidemia Hypertension MetabolicSyndrome Type 2 Diabetes & CVD ©2006 General Mills, Inc. Grundy et al., 2005; Kahn et al., 2005 Metabolic Syndrome

28. Diagnosis of metabolic syndrome The American Association of Clinical Endocrinologists (AACE) clinical criteria for diagnosis of insulin resistance syndrome include the following: BMI of 25 kg/m2 or higher Triglyceride level of 150 mg/dL or higher HDL-C level of less than 40 mg/dL in men or less than 50 mg/dL in women Blood pressure of 130/85 mm Hg or higher Glucose level of more than 140 mg/dL 2 hours after administration of 75 g of glucose Fasting glucose level of 110-126 mg/dL

30. Adipose tissue act as an endocrine organ (1) Adipose tissue is secrete free fatty acids (FFA) ,which have well described physiological and pathophysiological effects on glucose homeostasis (2) secrets proteins, termed adipocytokines, that act in an autocrine, paracrine, or endocrine fashion to control various metabolic functions

31. Adipose tissue -Adipose tissue is an anatomical term for loose connective tissue composed of adipocytes (or fat cells). -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. Adipose tissue Adipocyte + capillary

32. adipose tissue -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 subcutaneous adipose tissue 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). mouse adipocytes

33. Normal Tabetes Courtesy of Wilfred Y. Fujimoto, MD. Visceral Fat Distribution:Normal vs Type 2 Diabetes

34. LEPTIN Product of the obese gene (ob) , conserved residues in purple colour (receptor binding sites not yet determined) Four-helix bundle Size 2,0x2,5x4,5 nm Cys-96 <-> cys-146 PDB : 1ax8

35. LEPTIN Greek word leptos meaning thin . First discover in 1994 . Leptin is a 167-amino acid protein secreted by adipocytes in proportion to adipocyte tissue mass . The Ob(Lep) gene [Ob for obese, Lep for leptin] is located on chromosome 7 in humans.

36. Synthesis of Leptin 1. White adipose tissue :major source of leptin brown adipose tissue, placenta (syncytiotrophoblasts) ovaries, skeletal muscle stomach (lower part of fundic glands) mammary epithelial cells, bone marrow liver.

38. Member of helical cytokine familyPrimary structure of leptin

39. FUNCTION OF LEPTIN key role in regulating energy intake and energy expenditure, including appetite and metabolism. Leptin circulates at levels proportional to body fat. It controls food intake and energy expenditure by acting on receptors in the mediobasalhypothalamus There are five Ob-R isoforms; the best characterized one is Ob-Rb, which activates the Jak-Stat signal transduction pathway

40. Leptinreceptor(s) Synonym: receptor for obesity facto, Ob-R

41. focus on leptinsignalling

42. focus on leptinsignalling

43. Appetite is suppressed CNS MSH Periphery Metabolic activity increases to burn fat Leptin + Hypothalamus arcuate nucleus  JAK-STAT Leptin receptor MSH POMC: pro-opiomelanocortin (from peptide-amine hormone biosynthesis lecture) Adipose Adipose stores are HIGH Figure 2. The leptin signaling system and its effects when adipose stores are "high"

44. Appetite is enhanced JAK-STAT CNS Periphery Metabolic activity decreases limiting fat burning Leptin + Leptin receptor Hypothalamus  AGRP from hunger neurons Block MSH binding MSH Adipose Adipose stores are low Figure 2. The leptin signaling system and its effects when adipose stores are “low"

45. congenitalleptindeficiencyhuman) - voraciousappetite - morbidobesity - immunosuppression - hypothalamichypogonadism

46. LEPTIN AND INSULIN RESISTANCE Mice that are deficient in leptin (ob/ob) exhibit hyperphagia, obesity,hypercortisolemia,infertility,and diabetes. Exogenous leptin administration reverses these abnormalities Leptin may also improve insulin sensitivity by directly acting on peripheral tissues such as skeletal muscle and liver

47. ADIPONECTIN Adiponectin is a 247-amino acid It has multiple name, like-AcrP30,AdipoQ, apM1, and gelatin binding protein. 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 . Adiponectin knockout mice showed high levels of TNF-αand increased insulin resistance.

48. Low plasma adiponectin was an independent risk factor for future development of type 2 diabetes . Adiponectin may play a causative role in the development of insulin resistance and the metabolic syndrome. The mechanisms by which adiponectin may ameliorate insulin resistance have not been fully elucidated. 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

49. KEY MESSAGE ABOUT ADIPONECTIN Adiponectin is an adipocyte-derived plasma protein with insulin sensitizing, antiinflammatory, and antiatherogenic properties. Although its physiological and pathophysiological role has not been fully elucidated. its low levels in insulin resistance states suggest that therapeutic modulation of adiponectin may provide a novel treatment modality for insulin resistance.

50. RESISTIN Crystallographic structure of a hexamer of mouse resistin (rainbow colored, N-terminus = blue, C-terminus = red).

51. RESISTIN Resistin is a adipocyte-secreted polypeptide. first described in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine Resistin is a member of a family of tissue-specific signaling molecules,calledresistin-like molecules . The resistin mRNA encodes a 114-amino acid polypeptide with a 20-amino acid signal sequence. Resistin is secreted as a disulfide-linked dimmer.

52. Resistin, a novel 12.5 kDa cysteine-rich protein, is secreted by adipocytes. Serum resistin levels are significantly increased in insulin-resistant mice and genetic or diet-induced obese mice In addition, neutralization of endogenous resistin with antibodies significantly suppresses hyperglycaemia in diet-induced obese mice by improving insulin sensitivity.

53. TNF-α TNF-α is a proinflammatory cytokine that has been implicated in the pathogenesis of insulin resistance. Increased TNF- α production has been observed in adipose tissue derived from animal models of obesity and insulin resistance as well as human subjects

54. probable mechanisms by which adipose tissue TNF- α increases insulin resistance is- 1. increased release of FFA by adipocytes 2. reduction in adiponectin synthesis 3. impairment of insulin signaling Additional human studies are needed to understand its role in the pathogenesis of insulin resistance in humans.

55. LIPODYSTROPHY AND INSULIN RESISTANCE in the absence of adipose tissue,excess calories cannot be diverted to normal storage depots(adipocytes) Than they accumulate, insteadas triglyceride stores in liver, skeletal muscle, cardiac muscle, and pancreatic islet cells. Abnormal intracellular TG accumulation leads to impaired insulin secretion and action, leading to diabetes

56. leptin levels are very low in generalized lipodystrophy. low leptinlevels correlate significantly with markers of insulin resistance. ∙ In lipodystrophic patients, leptinreplacement therapy improved glycemic control and decreased TG levels . Leptin treatment improved insulin-stimulated hepatic and peripheral glucose metabolism and was associated with a reduction in hepatic and muscle TG content.

57. SUMMURY The mechanisms by which adipocytokines promote insulin resistance are still complex, and our understanding incomplete. 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.

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.

61. The END!Thank You! Oh, sorry, not the END, just the beginning! 53 Email: misbahul_ferdous@yahoo.com house no: 26. house name:TAKHDIR. SUGANDHA. R/A ,CHITTAGONG BANGLADESH