Insulin Resistance
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Insulin Resistance Insulin Resistance Presentation Transcript

  • Newsweek, September 4,
    2000
    Time, September 4, 2000
  • 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.
  • Key words
    Insulin resistance
    Metabolic syndrome
    Leptin
    Adiponectin
    resistin
  • Histological slide of pancreatic islets cell
  • 5
    Electron micrograph showing release of insulin
    from  cell
  • 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.
  • 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 .
  • Factors Contributing to Insulin Resistance
    Acquired:
    • Central obesity
    • Sedentary lifestyle
    • High fat diet
    • Medications
    Genetics
    & Aging
    Acquired
    ©2006 General Mills, Inc.
  • DRUGS and GENETIC CAUSES OF INSULIN RESISTANCE
    Drugs :
    rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids,
    Genetic causes
    1.Insulin receptor mutations (Donohue Syndrome)
  • Insulin Resistance: Inherited and Acquired Influences
    12
    Inherited
    Acquired
    Rare Mutations
    • Insulin receptor
    • Glucose transporter
    • Signaling proteins
    Common Forms
    • Largely unidentified
    • Inactivity
    • Over eating
    • Aging
    • Medications
    • Obesity
    • Elevated FFAs
  • How Is Insulin Resistance Measured?
    Determination of insulin resistance is difficult
    Generally measured in terms of the glucose-lowering effects of insulin
    Two common methodologies:
    Hyperinsulinemic, euglycemic clamp (EHC): gold standard: insulin and glucose infused; steady state when glucose infusion equals rate of glucose disposal rate (GDR)
    Homeostasis Model of Assessment (HOMA): fasting glucose and insulin measured for calculation of insulin sensitivity
    McClenaghan, 2005
    ©2006 General Mills, Inc.
  • 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
  • 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.
  • 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.
  • Glucose
    Intolerance,
    Diabetes
    Dyslipidemia
    Visceral
    Obesity
    Hypertension
    The ‘Metabolic Syndrome’
    Also known as:
    Syndrome X
    Insulin Resistance Syndrome
    The Deadly Quartet
    The Dysmetabolic Syndrome
  • 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.
  • 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
  • Diagnosing Metabolic Syndrome
    Waist Circumference
    • Greater than 35 inches in women and 40 inches in men (abdominal obesity)
    Triglyceride
    • Levels of 150 milligrams per deciliter (mg/dl) or higher
    Blood Pressure
    • 130/85 millimeters of mercury or higher
    Fasting blood glucose
    • Level of 110 mg/dl or higher
    High-density lipoprotein cholesterol (HDL)
    • Lower than 50 mg/dl in women and 40 mg/dl for men
    PBRC 2009
    According to the National Cholesterol Education Program (NCEP), the presence of three or more of the following traits indicates metabolic syndrome:
  • 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
  • Treatment of metabolic syndrome
    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:
    Lose weight
    • 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.
    Exercise
    • Walking just 30 minutes a day or engaging in other aerobic activities can help prevent the serious diseases associated with MS.
    Stop smoking
    • Smoking cigarettes increases insulin resistance and worsens health consequences associated with MS.
    Eat fiber-rich foods
    • 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.
    PBRC 2009
  • 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
  • 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
  • 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
  • Normal
    Tabetes
    Courtesy of Wilfred Y. Fujimoto, MD.
    Visceral Fat Distribution:Normal vs Type 2 Diabetes
  • 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
  • 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.
  • 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.
  • Leptin structure
    • 146 a.a residue non glycosylated polypeptide
    • Member of helical cytokine family
    Primary structure of leptin
  • 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
  • Leptinreceptor(s)
    Synonym: receptor for obesity facto, Ob-R
  • focus on leptinsignalling
  • focus on leptinsignalling
  • 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"
  • 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"
  • congenitalleptindeficiencyhuman)
    - voraciousappetite
    - morbidobesity
    - immunosuppression
    - hypothalamichypogonadism
  • 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
  • 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.
  • 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
  • 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.
  • RESISTIN
    Crystallographic structure of a hexamer of mouse resistin
    (rainbow colored, N-terminus = blue, C-terminus = red).
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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