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INSULIN RESISTANCE IN CHILDHOOD Dr Abdullah Al Fares Pediatric endocrinology Consultant Security Forces Hospital Riaydh.KSA PANCREAS Only 2% of the pancreas weight is beta cell. Those cell produce insulin in the rate of one unit per each kilogram of body weight INSULIN STRUCTURE A Chain B Chain INSULIN Insulin Degradation: Chromosome 11 2 main organs: liver – 60% kidney – 35-40% has a half-life of approximately 3-5 minutes once it is released into the general circulation stimulated – glucose, amino acids, FFA, GIT hormones early phase (ready insulin) late phase (synthesis de novo) HOW INSULIN IS RELEASED? Insulin secretion is continuous BASAL INSULIN SECTRETION Increases after carbohydrate consumption BIPHASIC 1) Food enters the system and is digested in to simpler units, [one being glucose] 2) Glucose enters the blood stream 3) Insulin is produced by the pancreas and is released into the blood stream. 4) Insulin binds to the cell allowing glucose to enter 1) Food enters the system and is digested in to simpler units, [one being glucose] 2) Glucose enters the blood stream 3) Insulin is produced by the pancreas and is released into the blood stream. 4) Insulin binds to the cell allowing glucose to enter REGULATION OF INSULIN SECRETION Glucose rapidly increase the translation of the insulin mRNA and slowly increases transcription of the insulin gene No insulin is produced when plasma glucose below 50 mg/dI Threshold of glucose-stimulated insulin secretion is 100 mg/dl. Half-maximal insulin response occurs at 150 mg/dl A maximum insulin response occurs at 300 mg/dl above 300 mg/dl platue CCK G G GLUT 2 Secretin G G G G GLUT 2 Amino acids Acetylcholine G gastrin Fatty acids GIP Glycolysis SU K+ K+ K+ K+ K+ ATP BETA CELL Ca++ Ca++ Ca++ Ca++ ++ Ca++ Ca Ca++ Ca++ FACTORS AFFECTING INSULIN SECRETION Stimulatory agents or conditions ChemicalHyperglycemia Amino acids, Fatty acids Hormonal GIT hormones GIP-GLP1-Gastrin-Secretin, CCK Acetylcholine Neural Sulfonylureas Inhibitory agents or conditions Somatostatin Norepinephrine Epinephrine GLUCOSE TRANSPORTERS Name Tissue Function GLUT1 (erythrocyte) wide distribution, esp. brain, kidney, colon, fetal tissues Basal glucose transport GLUT2 (liver) Liver, b-cells of pancreas, small intestine, kidney Non-rate-limiting glucose transport GLUT3 (brain) Wide distribution, esp. neurons, placenta, testis Glucose transport in neurons GLUT4 (muscle) Skeletal muscle, cardiac muscle, adipose tissue Insulin-stimulated glucose transport* GLUT5 (small intestine) Small intestine, kidney, skelatal muscle, brain, adipose tissue Fructose transport Many individuals with insulin resistance are deficient in a glucose transporter GLUT-4 MECHANISM OF ACTION Tyrosine Kinase P Tyrosine Kinase P IRS-1 Insulin binds to the α subunits of the insulin receptor, so increases glucose transport and causes autophosphorylation of the β subunit of the receptor, that induces tyrosine kinase activity. Tyrosine phosphorylation, in turn, activates a cascade of intracellular signaling proteins that mediate the effects of insulin on glucose, fat, and protein metabolism. Ins ECF Ins G Tyrosine Kinase ICF P MAP-K G Tyrosine Kinase P GLUT-4 IRS-1 Grb2&SOS Phospho Kinase RAS RAF G G G G INSULIN ACTIONS Intermediate Rapid Increased transport of Glucose, Amino Acids and K+ into insulin Sensitive Cells Skeletal Ms Cardiac Ms Adipose Tissue • Stimulation of Protein Synthesis • Activation of Glycolysis & Glycogen Synthesis • Inhibition of Gluconeogenesis Delayed Increase in mRNAs for lipogenic and other enzymes HORMONE OF ABUNDANCE INSULIN RESISTANCE Diminishe the ability of the cells to respond to the action of insulin in transporting glucose from the bloodstream into muscle and other tissues Cells become less responsive to insulin high plasma insulin Compensatory hyperinsulinemia causes down regulation of insulin receptor Defects in insulin receptor Reduction of glucose uptake/use by cells hyperglycemia OBESITY the most common cause of insulin resistance, is associated mainly with postreceptor abnormality but is also associated with a decreased number of insulin receptors. Hi TG’s Hi FFA’s Intramuscular Subcutaneous Intrahepatic Intraabdominal FFA* TNF-alpha* Leptin* IL-6 (CRP)* Tissue Factor* PAI-1* Angiotensinogen* Role of Free Fatty Acids in Hyperglycemia Adipose tissue insulin resistance ADIPOSE TISSUE MUSCLE Muscle insulin resistance Lipolysis LIVER FFA mobilization Liver insulin resistance FFA oxidation FFA oxidation Gluconeogenesis Glucose utilization Hyperglycemia Boden G. Proc Assoc Am Physicians. 1999;111:241-248. NORMAL • Loss of the first phase result in elevation of the postprandial glucose. • Delayed second phase- can result in postmeal hypoglycemia. %%%%%%%%%%%% Plasma Insulin (uU/ml) INSULIN RELEASED IN DM 2 TYPE 2 DM 0 5 10 15 20 25 30 35 40 Time (Minutes) 45 50 55 60 CLINICAL SPECTRUM POSSIBLE MECHANISMS BY WHICH INSULIN RESISTANCE LEADS TO THE CLINICAL MANIFESTATIONS OF THE ACANTHOSIS NIGRICANS AND POLYCYSTIC OVARY SYNDROME PCOS – INSULIN RESISTANCE IR and Obesity Endocrine Liver SHBG Ovary Androgen Metabolic Adrenal Androgen PCOS, Infertility, Irr. Menses, Hirsutism MS, DM CVD GENETIC CAUSES OF INSULIN RESISTANCE The key feature of all insulin resistance Rabson-Mendenhall syndrome syndromes are Lipoatropic diabetes acanthosis nigricans, (Lorens syndrome) androgen excess and massively raised insulin Type A Ins resistance concentrations in the absence of obesity Leprechaunism LEPRECHAUNISM –DONAHUE SYNDROME Congenital Abnormal faces Large genitalia SGA and growth retardation fasting hypoglycemia Rarely survive infancy Death within the first 1 to 2 years of life Acanthosis Nigricans Gene involved Insulin receptor & GHresistence Recessive RABSON-MENDENHALL Congenital Extreme Growth retardation Mental retardation Abnormal dentition Acanthosis Nigricans Androgen Excess & Hypertrichosis Gene involved Insulin receptor Recessive LIPODYSTROPHY LORENS SYNDROME Congenital or Adolescence Loss of subcutaneous fat – partial or total Acanthosis Nigricans Androgen Excess & Hypertrichosis Insulin resistance,high TG,large fatty liver Gene involved Total: Seipin & AGPAT2 (A.recessive) Partial :Lamin AC & PPARG (dominant) TYPE A INS RESISTANCE Adolescence Ins-resistance in absence of obesity Acanthosis Nigricans Androgen Excess & Hypertrichosis Gene involved Insulin receptor Recessive Metabolic Syndrome CHILDREN AND ADOLESCENTS The International Diabetes Federation (IDF) definition of metabolic syndrome in children 10 to 16 years old is similar to that used by the IDF for adults For children 16 years and older, the adult criteria can be used For children younger than 10 years of age, metabolic syndrome cannot be diagnosed, but vigilance is recommended if the waist circumference is ≥90 percentile. CRITERIA FOR DIAGNOSIS World Health Organization (WHO) International Diabetes Federation (IDF) - European Association for the Study of Diabetes (EASD) National Cholesterol Education Project, Adult Treatment Panel (NCEP-ATP III) Others NECESSARY CRITERIA TO MAKE DIAGNOSIS IDF: Require central obesity plus two of the other abnormalities WHO: Also requires microalbuminuria - Albumen/ creatinine ratio >30 mg/gm creatinine ATP III: Require three or more of the five criteria OBESITY IDF: Central obesity - waist circumference >94 cm for men, >80 cm women with ethnicity specific values for other groups WHO: Waist-hip ratio >0.9 - men or >0.85 – women ATP III: Waist circumference >101.6 cm in men and 88.9 cm in women GLUCOSE ABNORMALITIES IDF: FPG >100 mg/dL (5.6 mmol.L) or previously diagnosed type 2 diabetes WHO: Presence of diabetes, IGT, IFG, insulin resistance ATP III: FBS >110 mg%, <126 mg (ADA: FBS >100) DYSLIPIDEMIA IDF: Triglycerides - >150mg/dL (1.7 mmol/L) HDL - <40 mg/dL (men), <50 mg/dL (women) WHO: Triglycerides - >150 mg/dL (1.7 mmol/L) HDL - <35 mg/dL (men),- <39 mg/dL) women ATP III: Same as IDF HYPERTENSION IDF: BP >130/85 or on Rx for previously Dxed hypertension WHO: BP >140/90 NCEP ATP III: BP >130/80 BIOCHEMICAL MARKERS In nondiabetic, normotensive overweight individuals : serum triglyceride concentration, the ratio of triglyceride to high density lipoprotein (HDL) cholesterol concentrations fasting insulin concentration CRP ,TSH ,LFT ,Fasting glucose,GTT,HBA1C, and uric acid. Reduced serum levels of adiponectin (a hormone made by fat tissue) and elevated leptin concentration are also features of conditions associated with the metabolic syndrome or cardiovascular disease. are useful markers for identifying those who may be insulin resistant THERAPY MULTIPLE RISK FACTOR MANAGEMENT Obesity Glucose Intolerance Insulin Resistance Lipid Disorders Hypertension Goals: Minimize Risk of Type 2 Diabetes and Cardiovascular Disease Lifestyle modification Diet Exercise Prevention of type 2 diabetes Oral hypoglycemic agents Cardiovascular risk reduction Prevention LIFE-STYLE MODIFICATION: IS IT IMPORTANT? Abdominal obesity Year 1: reduce body weight 7 to 10 percent Continue weight loss thereafter with ultimate goal BMI <25 kg/m2 Exercise Improves CV fitness, weight control, sensitivity to insulin, reduces incidence of diabetes Atherogenic diet Reduced intake saturate fat, trans fat, cholesterol Weight loss Improves lipids, insulin sensitivity, BP levels, reduces incidence of diabetes Goals: Brisk walking - 30 min./day 10% reduction in body wt. DIABETES CONTROL - HOW IMPORTANT? For every 1% rise in Hb A1c there is an 18% rise in risk of cardiovascular events & a 28% increase in peripheral arterial disease Evidence is accumulating to show that tight blood sugar control in both Type 1 and Type 2 diabetes reduces risk of CVD Prothrombotic state Low dose aspirin for high risk patients Goals;low CRP Proinflammatory state Lifestyle therapies; no specific interventions BP CONTROL - HOW IMPORTANT? MRFIT and Framingham Heart Studies: - Conclusively proved the increased risk of CVD with long-term sustained hypertension - Demonstrated a 10 year risk of cardiovascular disease in treated patients vs non-treated patients to be 40% - 40% reduction in stroke with control of HTN • Goal: BP <130/80 LIPID CONTROL - HOW IMPORTANT? Multiple major studies show 24 - 37% reductions in cardiovascular disease risk with use of statins and fibrates in the control of hyperlipidemia Goals: LDL <100 mg/dL (<3.0 mmol /l) (high risk <70 mg/dL- <2.6 mmol/L) TG <150 mg% (<1.7 mmol /l) HDL >40 mg% (>1.1 mmol /l) Medications Hypertension: ACE inhibitors, ARBs Others - thiazides, calcium channel blockers, beta blockers, alpha blockers Hyperlipidemia: Statins, Fibrates, Niacin Platelet inhibitors: ASA Insulin Resistance/Diabetes Insulin Sensitizers: - Biguanides - metformin - PPAR α, γ & δ agonists - Glitazones, Glitazars Can be used in combination Insulin Secretagogues: - Sulfonylureas - glipizide, glyburide, glimeparide, glibenclamide - Meglitinides - repaglanide, netiglamide prevention