1. Diabetes Mellitus ENDO 412

2. Overview DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative deficiency of insulin DM is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose caused by absolute or relative deficiency of insulin Two types of DM: Two types of DM: Type 1 (insulin-dependent DM) Type 1 (insulin-dependent DM) Type 2 (noninsulin dependent DM Type 2 (noninsulin dependent DM) Prevalence of type 2 is increasing as: Prevalence of type 2 is increasing as: Aging (increase in rate of life-age of population) Aging (increase in rate of life-age of population) Increasing prevalence of obesity Increasing prevalence of obesity

3. Comparison between type 1 & type 2 DM

4. Type 1 Diabetes Mellitus

5. about 10% of diabetics (in USA) Onset: usually during childhood absolute deficiency of insulin : Caused by absolute deficiency of insulin : may be caused by autoimmune attack of  -cells of the pancreas, viral infection or toxin Destruction is enhanced by environmental factors as viral infection & a genetic element (that allows  -cells to be recognized as nonself) In identical twins if one sibling has type 1 DM, the other twin has only 30- 50% chance of developing DM Rapid symptoms appear when 80-90% of the  -cells have been destroyed Commonly complicated by diabetic ketoacidosis (DKA) only Treated only by insulin

6. Onset of type 1 DM

7. Metabolic changes of type 1 DM 1- Hyperglycemia 1- Hyperglycemia: increased glucose in blood Due to: Decreased glucose uptake by muscles & adipose tissues (by GLUT-4) & Increased hepatic gluconeogenesis 2- Ketoacidosis 2- Ketoacidosis: increased ketone bodies in blood (in untreated or uncontrolled cases) in 25 – 40% of newly diagnosed type 1 DM in stress states demanding more insulin (as during infection, illness or during surgery) no comply with therapy (intake of meals with no insulin medication) Biochemical causes of diabetic ketoacidosis (DKA) Absence of insulin leads to increased mobilization of FFA from adipose tissues in the liver, FFA are oxidized to yield excess acetyl CoA that will synthesize KETONE BODIES.

8. Metabolic changes of type 1 DM (cont.) 3- Hypertriacylglyceridemia: 3- Hypertriacylglyceridemia: increased TAG in blood adipose tissues Released fatty acids from adipose tissues are converted to triacylglycerol VLDL Triacylglycerol is secreted from the liver in VLDL to blood. Chylomicrons diet fat Chylomicrons (from diet fat) accumulates (low lipoprotein lipase in DM) VLDL & chylomicrons Increased VLDL & chylomicrons results in hypertriacylglyceridemia

9. Metabolic changes of type 1 DM

10. Diagnosis of type 1 DM Clinically: Age: during childhood or puberty (< 20 years of age) Abrupt appearance of : Polyuria (frequent urination) Polydepsia (excessive thirst) Polyphagia (excessive hunger) Fatigue Weight loss Complication as ketoacidosis (common, may be the cause of diagnosis) Laboratory diagnosis: Fasting blood glucose: > or equal 126 mg/dl Fasting blood glucose: > or equal 126 mg/dl 100 – 125 mg/dl is called impaired fasting blood glucose Insulin level in blood Insulin level in blood: low Circulating islet-cell antibodies detection

11. Treatment of type 1 DM AIM Exogenous insulin by subcutaneous injection to control hyperglycemia & ketoacidosis Strategies of treatment Strategies of treatment: 1- Standard treatment 2- Intensive treatment (tight control) 2- Intensive treatment (tight control)

12. 1- Standard treatment: by one or two injections of insulin/day AIMMean blood glucose level AIM: Mean blood glucose level 225-275 mg/dl (normal: 110 mg/dl) HbA1c level HbA1c level: 8-9 % of total Hb (normal: 6% of total HB) HbA1c: is proportional to average blood concentration over the previous several months So, it provides a measure of how proper treatment normalized blood glucose in diabetic over several months Treatment of type 1 DM Treatment of type 1 DM (cont.)

13. 2- Intensive treatment: 2- Intensive treatment: (tight control) Conducted by more frequent monitoring & subsequent injection of insulin (3 or more times / day). More closely normalize blood glucose to prevent complications of existence of hyperglycemia for a long period AIMMean blood glucose levels AIM: Mean blood glucose levels of 150 mg/dl HbA1c HbA1c : approximately 7% of total Hb Advantage: Reduction in chances of occurrence of complications of DM: e.g. retinopathy, nephropathy & neuropathy by about 60% Treatment of type 1 DM Treatment of type 1 DM (cont.)

14. Complications of treatment by insulin: Hypoglycemia Hypoglycemia is a common complication of insulin treatment (in more than 90% of patients) More Common with intensive treatment regimens Diabetics cannot depend on glucagon or epinephrine to avoid hypoglycemia as: No glucagon (early in the disease) No epinephrine (with progression of the disease diabetic autonomic neuropathy with inability to secrete epinephrine in response to hypoglycemia) So, patients with long-standing type 1 DM are particularly vulnerable to hypoglycemia Hypoglycemia can be caused by strenuous exercise Hypoglycemia can be caused by strenuous exercise. Exercise promotes glucose uptake into muscles & decrease the need for exogenous insulin. So, blood glucose level should be checked before & after exercise to avoid hypoglycemia. Treatment of type 1 DM Treatment of type 1 DM (cont.)

15. Contraindications of intensive treatment: Children Children: risk of episodes of hypoglycemia may affect the brain development Elderly people Elderly people: as hypoglycemia can cause strokes & heart attacks in older people Treatment of type 1 DM Treatment of type 1 DM (cont.)

16. Type 2 Diabetes Mellitus

17. 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 In type 2 DM: a combination of insulin resistance & dysfunctional  -cells Metabolic changes in type Metabolic changes in type 2: are milder than type 1 as insulin secretion restrain ketoacidiosis (although not adequate) Diagnosis Diagnosis: blood glucose concentration equal or more than 126 mg/dl Treatment Treatment : no requirement for insulin to sustain life BUT: insulin may be required to control hypoglycemia in some patients

18. Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue & muscle to respond properly to normal circulating insulin Obesity Obesity is the most common cause of insulin resistance Obesity causes insulin resistance as: Obesity causes insulin resistance as: substances produced by fat cells as leptin and resistin - substances produced by fat cells as leptin and resistin may contribute to development of insulin resistance Free fatty acids elevated in obesity - Free fatty acids elevated in obesity is involved in insulin resistance Causes of type 2 DM (cont.) Insulin resistance & dysfunctional  -cell

19. Most 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  -cell So, glucose levels in blood remain within normal range In late cases  -cell dysfunction occurs due to increased amounts of free fatty acids & other factors secreted by fat cells in addition to impaired glucose tolerance may end in development of type 2 DM (hyperglycemia). Causes of type 2 DM (cont.) Insulin resistance & dysfunctional  -cell

20. 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 & impaired glucose tolerance)  -cells fail to secrete enough insulin Increased blood glucose levels (hyperglycemia) Causes of type 2 DM (cont.) Insulin resistance & dysfunctional  -cell

21. Progression of type 2 DM

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

23. Metabolic changes in type 2 DM

24. Chronic effects of DM The long-standing hyperglycemia causes the chronic complications of DM : Atherosclerosis 1- Atherosclerosis : diabetic retinopathy diabetic nephropathy diabetic neuropathy cardiovascular diseases & stroke Sorbitol accumulation in certain cells with its complications 2- Sorbitol accumulation in certain cells with its complications Glycated proteins formation with microvascular complications 3- Glycated proteins formation with microvascular complications For avoiding these complications, lomg-term control og hyperglycemia is recommernded for all types of DM

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

26. Treatment of type 2 DM AIM 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: Lines of treatment: Weight reduction 1- Weight reduction (to control insulin resistance) Exercise 2- Exercise Dietary modification 3- Dietary modification Hypoglycemic agents 4- Hypoglycemic agents some 5- Insulin (required in some cases)