1. Diabetes Mellitus (Lecture 2)

2. Type 2 DM 90% of diabetics (in USA) Develops gradually may be without obvious symptoms may be detected by routine screening tests BUT: many type 2 diabetics have symptoms of polyuria & polydepsia Polyphagia is less common In type 2 DM: a combination of insulin resistance & dysfunctional  -cells Metabolic changes in type 2: are milder than type 1 as insulin secretion restrain ketoacidiosis (although not adequate) Diagnosis: blood glucose concentration equal or more than 126 mg/dl Treatment : no requirement for insulin to sustain life BUT: insulin may be required to control hypoglycemia in some

4. Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin Examples of metabolic effects of insulin resistance: - increased gluconeogenesis (liver synthesis of glucose) - decreased glucose uptake by muscles & adipose tissues

5. Causes of insulin resistance Insulin resistance increases with weight gain & diminishes with weight loss So, fat accumulation (OBESITY) causes insulin resistance as: - substances produced by fat cells as leptin and resistin may contribute to development of insulin resistance - Free fatty acids elevated in obesity is involved in insulin resistance

6. Insulin resistance & obesity Obesity is the most common cause of insulin resistance However, most people with obesity & insulin resistance do not develop DM ?? in the absence of defect in  -cell function, nondiabetic, obese individuals can compensate for insulin resistance by: increasing levels of secretion of insulin from  -cells So, glucose levels in blood remain within normal range

8. Insulin resistance & type 2 DM Insulin resistance alone will not lead to type 2 DM. BUT: type 2 DM will develop in individuals with: insulin resistance + impaired  -cells function This is common to occur in: - elderly - obese - physically inactive - 3-5% of pregnant women (develop gestational DM) All these are unable to sufficiently compensate by increasing insulin release

9. Dysfunctional  -cells In type 2 DM Initially (In early stages) the pancreas retains  -cell capacity insulin is secreted (may be higher than normal) normal blood glucose levels ________________________________________________ With time (late stages)  -cells become dysfunctional (fat cells substances, FFA & hyperglycemia)  -cells fail to secrete enough insulin Increased blood glucose levels (hyperglycemia)

11. Progression of type 2 DM

12. Metabolic changes in type 2 DM metabolic abnormalities of type 2 DM are the results of insulin resistance (in liver, muscle & adipose tissue) 1- hyperglycemia (BUT: ketosis is minimal or absent) 2- hypertriacylglyceridemia

13. Metabolic changes in type 2 DM Hyperglycemia in type 2 DM Causes: as a result of insulin resistance 1- increased gluconeogenesis (glucose production) by liver 2- diminished peripheral use of glucose _______________________________________________ Ketosis: usually minimal or absent because of the presence of insulin (even with resistance) is sufficient to prevent liver ketogenesis

14. Metabolic changes in type 2 DM Hypertriacylglyceridemia in type 2 DM insulin resistance (in adipose tissues) active hormone sensitive lipase Lipolysis free fatty acids in liver VLDL synthesis in liver hypertriacylglyceridemia

16. Treatment of type 2 DM AIM: 1- to maintain blood glucose concentrations within normal limits 2- to prevent the development of long-term complications occurring due to prolonged hyperglycemia Lines of treatment: 1- weight reduction (to control insulin resistance) 2- exercise 3- dietary modification 4- hypoglycemic agents 5- insulin (required in some cases)

17. Chronic effects of DM The long-standing elevation of blood glucose (hyperglycemia) causes the chronic complications of DM some complications of DM for long durations: 1- Atherosclerosis : retinopathy nephropathy neuropathy cardiovascular diseases & stroke 2- Sorbitol accumulation in certain cells ----- complications 3- Glycated proteins formation---- microvascular complications

18. Chronic effects of DM (cont.) in cells where entry of glucose is not dependent on insulin (eye lens, retina, kidney, neurones) intracelluar levels of glucose SORBITOL Cataract diabetic retinopathy diabetic nephropathy diabetic neuropathy

19. Chronic effects of DM (cont.) Cellular glycated proteins formation: Hyperglycemia promotes condensation of glucose with many cellular proteins Glycated prioteins mediate some early microvacular changes of DM

20. Prevention of DM For prevention of DM occurrence 1- type 1: no preventive measures available 2- type 2: combined regimen of medical nutritional therapy & exercise For prevention of occurrence complications type 1 DM: tight control of may prevent complications (may prevent complications in DM type 2 also)