1. Question Make a scenario of an MCQ. Outline the signs and symptoms that you would expect in a Diabetic patient keeping in mind the actions of Insulin. Remember, Diabetes would have the same symptoms as that of Insulin deficiency. Give 4 options for the MCQ question.

2. (EFFECTS OF INSULIN DEFICIENCY) PATHOPHYSIOLOGY OF DIABETES MELLITUS

3. 1.Hyperglycemia

4. EFFECTS OF INSULIN DEFICIENCY: 2. Glucosuria

5. EFFECTS OF INSULIN DEFICIENCY: 3. Polyuria

6. EFFECTS OF INSULIN DEFICIENCY: 4. Polydipsia & Polyphagia (There is an extracellular glucose excess & an intracellular glucose deficiency- “starvation in the midst of plenty”)

7. EFFECTS OF INSULIN DEFICIENCY: 5. Weight Loss (For every gram of glucose excreted, 4.1 kcal is lost from the body. Increasing the caloric intake to cover this loss simply raises the plasma glucose further.)

8. EFFECTS OF INSULIN DEFICIENCY: 6. Increase in plasma Cholesterol & Phospholipid conc. (Role in the accelerated development of atherosclerosis that is a major complication)

10. COMPLICATIONS When Diabetes continues for a long time period (15-20 years) chronic complications occur. 1.Neuropathies 2.Peripheral vascular disease 3.Gangrene 4.Atherosclerosis 5.Ischemic heart disease 6.Renal disease 7.Early cataract 8.Retinopathy 9.Skin infections 10.Neuropathies affecting the ANS

11. Diabetic foot showing ulcer

12. Gangrene that must be treated with an amputation

14. KETOSIS AND COMA In severe form of Insulin deficiency, plasma levels of FFA is more than doubled. ↓ In the liver and other tissues, the fatty acids are catabolized to acetyl Co-A. ↓ Some of the acetyl-CoA enters into the citric acid cycle. ↓ When the supply exceeds the capacity of the citric acid cycle, the excess are converted into acetoacetate and β-hydroxybutyrate. ↓ These are ketone bodies that lead to progressive metabolic acidosis. ↓ Acidosis can depress the brain and if severe enough can lead to coma and death.

15. CHO, Fat & Protein Metabolism Disturbed Fluid and Acid- Base Balance Disturbed Diabetes Mellitus

16. DIABETES MELLTIUS

17. DIABETES MELLITUS Def: Diabetes mellitus is a syndrome of impaired carbohydrate, protein & fat metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin. The word “Diabetes Mellitus” literally means “excessive secretion of sweet urine”. Third leading cause of death Leading cause of blindness Diabetes is a very prevalent disease, has a huge economic toll, forces individuals to change their lifestyle thus affecting their quality of life & predisposes the affected to a variety of troublesome & even life threatening conditions.

18. Diabetes Mellitus Type I Juvenile onset/ Insulin Dependant 10% Lack of Insulin secretion Type II Adult onset/ Insulin Independent 90% Reduced sensitivity of target cells to insulin

19. TYPE I/ Juvenile Onset/ Insulin Dependent It is the more severe from of diabetes and more prevalent in children. DEFINITION: It is a catabolic disorder in which the circulating insulin is virtually absent, plasma glucose is elevated & the pancreatic beta cells fail to produce any insulin in response to all insulinogenic stimuli. Cause: Lack of insulin secretion from the beta cells of the islets of langerhans. It is an autoimmune disorder in which there is selective destruction of the pancreatic beta cells by T lymphocytes. Mostly it seems to have an immunological basis & circulating islet cell antibodies & anti-insulin antibodies may be demonstrated. Usually there is a genetic predisposition to this type of diabetes which may be triggered off by: - Viral infections e.g. rota virus, coxsackie virus - Environmental triggers.

21. TYPE II DIABETES/ Non-Insulin Dependant/ Adult Onset Diabetes It is further classified into: It is the most common type of diabetes, accounting for about 90% of all cases of diabetes mellitus. The age of onset is usually after 30, often b/w 50 & 60 years of age. It develops gradually & is the less severe form of diabetes. 1.Non-obese type II 2.Obese type II Cause: Decreased sensitivity of target tissues to the metabolic effects of insulin. This reduced sensitivity to insulin is often called INSULIN RESISTANCE.

23. TYPE II DIABETES Factors that can lead to Insulin resistance include: 1.Anti-insulin antibodies 2.Autoantibodies to the insulin receptor 3.Mutation of insulin receptor 4.Down-regulation of insulin receptors by sustained hyperinsulinism. 5.Primary hyperinsulinism (Beta cell adenoma). 6.Secondary hyperinsulinism (Cushing’s syndrome, acromegaly, pregnancy or diabetes mellitus) 7.Obesity/overweight especially excess fat deposits around the abdomen 8.Insulin resistance in peripheral tissues such as skeletal muscle, brain and liver.

24. PATHOPHYSIOLOGY Diabetes type I is far more rapid in onset occurring over a few days as compared to type II which has a more gradual onset. Type I also shows far more complications as compared to Type II which rarely shows complications Type I requires Insulin while Type II can usually be controlled by simple changes in lifestyle as diet, exercise & weight control Type I insulin is more prone to Ketoacidosis while Type II is not!

25. DIAGNOSIS OF DIABETES 1.Blood sugar random ( 80-120 mg/100ml) 2.Blood sugar fasting (80-90 mg/100ml) 3.GTT or Glucose Tolerance Test: When a normal fasting person is given 1g of glucose /kg body weight, his plasma glucose levels rise to 120-140 but fall back to normal within 2 hours In a prediabetic or diabetic, not only is the fasting plasma glucose on the higher side but also the post meal plasma glucose rises to as high as 140-200 & fails to come back to normal within 2 hours of giving conc. glucose solution. Even after 4-6 hours it rarely comes back to the normal range! NORMAL MEAN BLOOD GLUCOSE IS APP. 110 !

26. Glucose Tolerance Test

27. POINT TO REMEMBER! WHY IS ORAL GLUCOSE A MORE POWERFUL STIMULANT THAN INJECTABLE GLUCOSE FOR INSULIN SECRETION?

30. DIAGNOSIS OF DIABETES 4.Presence of glucose in urine (glucosuria) 5.Acetone breath 6.Lab test for assessing control of diabetes: HbA 1c is a minor component of Hb A & is normally present in small amounts.i.e. up to 6% of normal Hb. In the presence of long standing hyperglycemia, its concentration rises. When plasma glucose is episodically elevated over time, small amounts of Hb A are non-enzymatically glycated to form HbA 1c Careful control of diabetes with insulin reduces the amount formed and thus, HbA 1c levels give an index of diabetic control for past 4-6 weeks.

31. TREATMENT for Type I DIABETES WHY CANNOT INSULIN BE GIVEN BY MOUTH? WHY IS ONLY CHO RESTRICTION NOT VERY EFFECTIVE? Administer enough insulin so that metabolism of fat, proteins & CHO proceed as normally as possible! Insulin is available in various forms: 1.Insulin preparations are available with rapid (regular), intermediate & long durations of action: - regular: duration of action is 3-8 hours. - Intermediate (NPH): not used during - Long: duration of action is 10-48 hours Individualized insulin schedules which consist of one injection of longer acting insulin followed by regular insulin when the glucose level is expected to rise.i.e. at meals. Insulin is administered subcutaneously (s/c) except in the case of emergencies when it is given intravenously (i/v). The less soluble an insulin preparation is, the longer it acts!

32. INSULIN SYRINGES

33. Insulin Human insulin is absorbed more quickly from its site of action than are beef or pork insulins. Thus, duration of action of human Insulin is shorter & doses must be adjusted. Hypoglycemia is the most serious & common side effect of Insulin therapy! B/C long term diabetics do not produce counteracting hormones of Glucagon, EN, cortisol etc. that normally provide defense against Hypoglycemia!

34. TREATMENT for Type II DIABETES Diet Exercise: is useful in managing both types of Diabetes, because working muscles are not Insulin dependent. Exercising muscles take up some of the excess blood glucose, reducing the overall need for insulin. Weight loss Oral Hypoglycemic Drugs.

35. Oral Hypoglycemic Drugs There are many types of oral Hypoglycemic drugs, some of which are: Sulfonylureas: act by stimulating the β- cells to secrete more insulin than they do on their own. E.g: Glucotrol. Metformin: acts by suppressing liver output of glucose. E.g: Glucophage. Alpha-glycosidase Inhibitors: act by slowing CHO digestion and absorption from the digestive tract into the blood, thus reducing the glucose surge seen after a meal. E.g: Precose. Byetta (Glucagon-like peptide 1 mimic) mimics the incretin GLP-1. It suppresses glucagon secretion and slows gastric emptying. By promoting satiety, it decreases food intake and in the long term leads to weight loss. Because none of the drugs deliver new insulin to the body, they cannot replace insulin therapy for people with Type I Diabetes and later in Type II Diabetics as well.

36. SULFONYLUREAS! NIDDM patients above the age of 40 years & having h/o diabetes of less than 5 years are given Oral Hypoglycemics! Mechanism of Action: 1.Stimulate release of Insulin from beta cells of pancreas. 2.Reduction of serum Glucagon! 3.Increased binding of Insulin to target tissues & receptors. E.g. Tolbutamide Glyburide Glipizide

37. WHO NEEDS INSULIN? Type 1 Type 2 uncontrolled w/meds DKA Hyperosmolar hyperglycemic state (HHS) Surgery Illness/Infection Stress Those receiving parental/ enteral nutrition Pancreatitis /diseases that ↓ beta cell function

38. WHAT HAPPENS WHEN THERE IS INSULIN EXCESS?

39. Insulin Excess Insulin Shock When a diabetic takes an overdose of Insulin Reactive Hypoglycemia When there is a β- cell tumour or over- responsiveness

40. Symptoms Decreased blood supply to the brain, as the brain literally starves. Tremors Fatigue Sleepiness Inability to concentrate Unconsciousness Death

41. NOTE A diabetic can lose consciousness and die from either diabetic ketoacidotic coma caused by prolonged Insulin deficiency or acute hypoglycemia caused by Insulin excess. How do you differentiate between the two if a diabetic patient is brought to you unconscious?