Metabolic Syndrome Insulin Resistance

1. 1 Metabolic Syndrome Insulin Resistance Dr Faiza . A. Qari Associated professor

2. 2 Background Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect

3. 3 Cause of Insulin Resistance The underlying causes of insulin-resistant states can be categorized as follows: Prereceptor Abnormal insulin (mutations) Anti-insulin antibodies Receptor Decreased number of receptors (mainly, failure to activate tyrosine kinase) Reduced binding of insulin Insulin receptor mutations Insulin receptor–blocking antibodies

4. 4 Cause of Insulin Resistance Postreceptor Defective signal transduction Mutations of GLUT4 (In theory, these mutations could cause insulin resistance, but polymorphisms in the GLUT4 gene are rare.)

5. 5 Path physiology of MS insulin resistance syndromes Mechanism include genetic or primary target cell defects, autoantibodies to insulin, and accelerated insulin degradation. Obesity, the most common cause of insulin resistance, is associated with a decreased number of receptors and with postreceptor failure to activate the tyrosine kinase. Insulin resistance plays a major pathogenic role in the development of the metabolic syndrome, which may include any or all of the following:

6. 6 Path physiology of MS INSULIN RESISTANCE Hyperinsulinemia Type 2 diabetes or glucose intolerance Central obesity Hypertension Dyslipidemia that includes high TG levels Low HDL-C level and small, dense low-density lipoprotein (LDL) particles Hypercoagulability characterized by an increased plasminogen activator inhibitor 1 (PAI-1) level

7. 7 Frequency A quarter of the world's adults are considered to have the metabolic syndrome.

8. 8 Race / Sex / Age Race :- all races , commoner among nonwhite populations. Acanthosis nigricans, a common physical sign of insulin resistance syndrome, occurs in all ethnic groups, but the prevalence is higher in Hispanics and blacks than in whites. Sex The metabolic syndrome is more evident in middle-aged men. PCOD is a disease limited to women.

9. 9 AGE The strongest relation between insulin resistance and the cardiovascular risk factors are observed in middle-aged rather than older persons, although cardiovascular morbidity and mortality increase with age. Women with PCOD usually present in their mid twenties.

10. 10 Mortality / Morbidity Insulin resistance is a common basis for development of glucose intolerance, including diabetes and coronary artery disease (CAD).

11. 11 Mortality / Morbidity twice as likely to die from, and 3 times as likely to have, a myocardial infarction or stroke compared with people without the syndrome. 5-fold increased risk of developing type 2 diabetes. DM -----cardiovascular disease. end-stage renal disease and blindness, heart disease and a higher risk of stroke; neuropathy and gangrene. Diabetes is also associated with acute metabolic complications.

12. 12 Mortality / Morbidity CAD is the leading cause of death in the United States and in most developed countries. CAD is responsible for 500,000 deaths annually in the United States. Nearly 1.5 million myocardial infarctions occur annually, of which approximately one third are fatal. The total annual economic cost of CAD in the United States is nearly $60 billion.

13. 13 Clinical criteria of MS BMI of 25 kg/m2 or higher TG 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

14. 14 Clinical criteria of MS Additional risk factors include the following: Family history of type 2 diabetes Hypertension Coronary heart disease (CHD) Polycystic ovary disease Sedentary lifestyle Advanced age Ethnic groups at high risk for type 2 diabetes or for CHD

15. 15 Mortality / Morbidity PCOD - Infertility, menstrual irregularity, androgen excess Rare conditions - Lipodystrophic states (fatty liver [Liver cirrhosis is a major cause of morbidity and mortality.]) Leprechaunism - Growth retardation, abnormal glucose homeostasis (especially occurrence of hypoglycemia), early death

16. 16 History Presentation depends on the type and stage of the insulin-resistant state. Most patients have one or more clinical features of the insulin-resistant state. Many patients do not develop overt diabetes despite extreme insulin resistance. Other patients present with cases of severe hyperglycemia that require large quantities of insulin (>200 units); these people may manifest the classic symptoms of diabetes mellitus, such as polyuria, polydipsia, polyphagia, and weight loss.

17. 17 Clinical Presentation Hypoglycemia sweating, tremulousness, irritability, and altered level of consciousness. Hypoglycemia results from interaction between insulinomimetic antibodies and the insulin receptor. Some patients have insulin-binding antibodies directed against insulin, which, upon dissociation, can cause hypoglycemia.) Metabolic syndrome (syndrome X) Obesity Type 2 diabetes mellitus History of biochemical abnormalities, such as dyslipidemia, detected during routine screening or workup for a cardiovascular disease History of hypertension

18. 18 Clinical Presentation Symptoms of CAD Symptoms related to other macrovascular disease (eg, stroke, peripheral vascular disease) PCOD infertility associated with anovulation; menstrual irregularity, typically chronic; and symptoms related to androgen excess, such as frontal baldness and deepening of the voice.

19. 19 Physical Examination Blood pressure (hypertension) Anthropometry Waist or waist-to-hip ratio, height, weight, and BMI. Central obesity, not peripherally distributed fat, is a strong marker of insulin resistance syndrome.

20. 20 Physical Examination Cardiovascular system Signs of heart disease Peripheral vascular disease - Abnormalities in pulses and arterial wall Stigmata of lipid disorders -arcus cornealis -Xanthelasma - Lipemia retinalis - Retinal vessels with milky chylomicron-rich plasma commonly observed in acute uncontrolled diabetes Skin xanthomata - Eruptive xanthomas found most commonly on buttocks Tendon xanthomata - Usually over the patellar and Achilles tendon

21. 21 Physical Examination Type A syndrome hirsutism(a thin or a muscular body build. Acral enlargement, a form of pseudoacromegaly, is not uncommon.

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30. 30 Physical Examination Acanthosis nigricans. . . These eruptions have been reported in nearly one tenth of women evaluated for PCOD. PCOD: Patients may have masculine habitus, such as coarse or greasy skin and acne, frontal alopecia, breast atrophy, hypertrophy of clitoris, and obesity; varying degrees of hirsutism or virilization may be present. These manifestations are due to hyperandrogenism.

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33. 33 Physical Examination Type B insulin resistance (autoantibodies to the insulin receptor): Patients usually have symptomatic diabetes mellitus, although ketoacidosis is unusual. Patients occasionally present with hypoglycemia.

34. 34 Lab Investigations In clinical practice, no single laboratory test is used to diagnose insulin resistance syndrome. Diagnosis is based on clinical findings corroborated with laboratory tests. Individual patients are screened based on the presence of comorbid conditions.

35. 35 Lab Investigations Plasma glucose level Glycohemoglobin level – Used to assess chronic hyperglycemia Fasting insulin level - A measure of the degree of insulin resistance in many patients with insulin resistance syndrome Lipid profile (Chol , TG , LDL ,HDL ) Electrolyte levels (BUN, creatinine, and uric acid levels - Hyperuricemia is common and is often considered a component of the metabolic syndrome.) Urinalysis (Microalbuminuria)

36. 36 Other Tests Other cardiac tests include echocardiography and stress testing, depending on the presentation. A risk-assessment calculator based on data from the Framingham Heart Study for estimating 10-year cardiovascular risk is available.

37. 37 Complications Acute metabolic complications, including severe hyperglycemia and hypoglycemia Angina Myocardial infarction Stroke Transient ischemic attack Peripheral vascular disease Renal disease Ocular complications