Insulin resistance

The condition in which normal amounts
of insulin are inadequate to produce a
normal insulin response from fat,
muscle and liver cells.

1. INSULIN RESISTANCE Mr.Tapeshwar Yadav. P.G Final Year Dept. of Biochemistry Mamata Medical College 6 th April 2012

2. TYPE 2 DM PCOS IGT CENTRAL OBESITY DYSLIPIDEMIA HYPERTENSION INFERTILITY WHAT IS BEHIND ALL THESE PROBLEMS ? INSULIN RESISTANCE

3. Insulin polypeptide hormone Langerhans —clusters of cells Normal blood insulin level: 5-15µU/ml

4. Pancreas: Only 2% of the pancreas weight is beta cell. 1 unit/kg of body weight. Over 80% of beta cells should be lost before diabetes develops. GLUCAGON INSULIN

5. Glu Thr Lys Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Le Tyr Leu Ala Val Leu His Ser Gly Cys Leu His Gln Asn Val Phe Asn Cys Tyr Asn Glu Leu Gln Tyr Leu Ser Cys Ile Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Insulin Structure Alpha chain Beta chain Disulfide bridges The hormone is protein with high molecular weight. Unstable if taken orally. Metabolized by the kidney.

6. Structure of insulin

7. Synthesis of insulin

8. Proinsulin Centr- omere CAT CAL PTH c-Ha-ras INS IGF-2  -globin Short arm of chromosome 11 C peptide Insulin A chain Insulin B chain Proinsulin Insulin A chain Insulin B chain C peptide Insulin Production

9. Insulin Resistance Definition The condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells.

10. Etiology of IR Genetic factor Medication : steroid, glucosamine etc Conditions : Obesity, Metabolic syndrome, pregnancy, infection or severe illness, stress etc

11. Insulin resistance and obesity

12. Insulin resistance and Type 2 diabetes :

13. Dysfunctional β cells Fig:-Typical progression of Type 2 diabetes

14. MEASUREMENT OF INSULIN RESISTANCE Hyperinsulinemic euglycemic clamp INSULIN TOLERANCE TEST MINIMAL MODEL TEST HOMEOSTATIC MODEL TEST Quantitative insulin sensitivity check index (QUICKI)

15. Hyperinsulinemic Euglycemic Clamp A measure of peripheral insulin sensitivity High insulin infusion rate: 80 mU /m 2 body surface area Variable infusion rate of dextrose to keep blood glucose levels in the range of 90-100 mg/dl. A higher glucose infusion rate (GIR) indicates better insulin sensitivity

16. Insulin Tolerance test First method developed to measure in vivo insulin sensitivity GTT with Insulin tolerance test BMI is to be considered

17. Homeostatic Model test Fasting plasma glucose and fasting plasma insulin concentrations are used to estimate IR Used to assess hepatic insulin sensitivity a lower score indicates better insulin sensitivity

18. Who is a risk for IR Overweight (BMI > 25) A man with a waist > 40 inches or a woman with a waist > 35 inches > 40 years of age Latino, African American, Native American or Asian American have family history with type 2 diabetes, Hypertension or arteriosclerosis have had gestational diabetes Have high BP, high blood TG, low HDL-C

19. OBESITY 50-80% of PCOS are obese Obesity induced hyperinsulinemia contributes to obesity specific insulin resistance Insulin resistance in PCOS is genetic and obesity worsens it.

20. Some Medical Condition are associated with IR Metabolic syndrome Abnormally sedentary lifestyle (aging and obesity) Type 2 diabetes Fatty liver Arteriosclerosis Skin lesions or skin tags : Achanthosis nigricans Reproductive abnormalities in woman (PCOS) Hyperandrogens Growth abnormalities

21. INSULIN RESISTANCE The vicious cycle of insulin resistance Insulin Resistance Overeating Truncal obesity High blood sugar Hunger Craving carbohydrates Excessive insulin production by reduced number of beta cells Beta cell burnout

22. OBESITY DIABETES MELLITUS INSULIN RESISTANCE INSULIN SECRETION DEFECT GENETIC PREDISPOSITION ENVIRONMENTAL FACTORS GLUCO- AND LIPO- TOXICITY Low physical activity High energy intake Genes Vicious circle IGT FFA TNF-a, resistin , leptin , adiponectin … Liver Muscles

23. Treatment of IR Weight reduction, Exercise and Dietary modifications

24. IR & OBESITY Weight Loss Reduces insulin levels Improves status – Clinical - Metabolic - Endocrinal Androgen level falls by 44% Weight loss is first line therapeutic option

25. Dietary Components Which May Affect Insulin Resistance ↓ IR Whole grains Fruits and vegetables Low fat dairy products Magnesium Calcium Dietary fiber Omega-3 fatty acids Low GI foods ↑ IR Saturated fat Salt (deficiency or excess) Alcohol (>30g/day)

26. Increased intake of fruits, vegetables, and low fat dairy products is associated with: ↑ ed insulin sensitivity ↓ ed risk of metabolic syndrome ↓ ed risk of Type 2 diabetes ↓ ed risk of hypertension High intakes of calcium and magnesium are associated with: ↑ ed insulin sensitivity ↓ ed risk of metabolic syndrome ↓ ed risk of Type 2 diabetes The Diet: Epidemiologic Studies

27. Insulin Resistance At A Glance:- Insulin resistance is a condition in which the cells of the body become resistant to the hormone, insulin. Insulin resistance may be part of the metabolic syndrome, and associated with the development of heart disease . Insulin resistance precedes the development of type 2 diabetes. Insulin resistance is associated with other medical conditions including fatty liver, arteriosclerosis, acanthosis nigricans , skin tags, and reproductive abnormalities in women .

28. Individuals are more likely to have insulin resistance if they have any of the associated medical conditions listed above. They also are more likely to be insulin resistant if they are obese or are Latino, African-American, Native American, and Asian-American. While there is a genetic component, insulin resistance can be managed with diet, exercise, and medication. Contd …….

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