Pathophysiology of Diabetes

1. Pathophysiology of Diabetes

2. Objectives • Review pathophysiology of Diabetes Mellitus. • Review dietary management for the treatment of Diabetes Mellitus. • Discuss the oral therapy medication options including mode of action, side effects, contra-indications and adverse reactions. • Outline the mono-therapy and combination therapy regimes available for Type 2 diabetes. • Outline the use of insulin therapy in management of Diabetes. • Review hypoglycaemia including management

3. Pancreas • The pancreas functions as both an exocrine and an endocrine gland • Exocrine function is associated with the digestive system because it produces and secretes digestive enzymes • Endocrine Function: produces two important hormones in Islets of Langerhans, insulin and glucagon • They work together to maintain a steady level of glucose, or sugar, in the blood and to keep the body supplied with fuel to produce and maintain stores of energy.

4. Pancreatic Hormones • Insulin (beta cells) • stimulates the uptake of glucose by body cells thereby decreasing blood levels of glucose • Glucagon (alpha cells) • stimulates the breakdown of glycogen and the release of glucose, thereby increasing blood levels of glucose • Glucagon and insulin work together to regulate & maintain blood sugar levels • Glycogen • Polysaccharide consisting of numerous monosaccharide glucoses linked together. Stored as an energy source in liver & muscles

5. Functions of insulin • Enables glucose to be transported into cells for energy for the body • Glucose is the preferred fuel of the body cells and the only fuel that the brain can use • Converts glucose to glycogen to be stored in muscles and the liver • Facilitates conversion of excess glucose to fat • Prevents the breakdown of body protein for energy

6. Diabetes Mellitus • After a meal, blood glucose levels rise, prompting the release of insulin • Causes cells to take up glucose, and liver & skeletal muscle cells to form the glycogen thus decreasing blood glucose • As glucose levels in the blood fall, further insulin production is inhibited • Glucagon production is stimulated when blood glucose levels fall • Glucagon causes the breakdown of glycogen into glucose, which in turn is released into the blood to maintain glucose levels within a homeostatic range • Glucagon is inhibited when blood glucose levels rise • Diabetes Mellitus results from inadequate levels of insulin

7. Diabetes Mellitus • Diabetes is a life-long disease marked by high levels of glucose in the blood • It can be caused by too little insulin, resistance to insulin, or both • There are three major types of diabetes: • Type 1 Diabetes • Type 2 Diabetes • Gestational Diabetes

8. Aetiology of Diabetes • Type One Diabetes (10-15%) • results when the body’s immune system destroys its own beta cells in the pancreas. No insulin production is then possible. • Type Two Diabetes (85-90%)results from either • Insulin resistance (overweight people) • Inadequate insulin production (lean people) • A combination of both

9. Gestational Diabetes • Diabetes diagnosed during pregnancy • Increased health risk to mother and baby • May require insulin injections • Goes away after birth, but increased risk of developing Type 2 DM for mother and child

10. Type One Diabetes • Usually under 30 yrs of age • Autoimmune disorder • Sudden onset of severe symptoms • Rapid weight loss • Total lack of insulin in the body • Insulin injections essential for life • Ketones produced • Genetic predisposition, though 80% have no relatives with the disease

11. Type Two Diabetes • Usually over 40 yrs of age though the age of diagnosis is getting younger • Gradual onset with mild symptoms • Most produce a normal amount of insulin but it is unable to work properly due to insulin resistance • Many have complications at diagnosis

12. What is Insulin Resistance? • condition in which the body does not utilise insulin efficiently • Insulin resistance is the decreased response of the liver and peripheral tissues (muscle, fat) to insulin • Insulin resistance is a primary defect in the majority of patients with Type 2 diabetes

13. Type 2 Diabetes Risk Factors • Increasing age • Obesity – especially abdominal • Women with BMI > 35 compared to 22 have a 93 fold increased risk • Men with BMI > 35 have 40 fold increased risk • Physical inactivity • Family history • Ethnic background • High blood pressure • High Cholesterol • Previous gestational diabetes

14. Characteristics of Diabetes Type 1 Type 2 • Usually under 30 • Rapid onset • Normal or underweight • Little or no insulin • Ketosis common • Make up 15% of cases • Autoimmune plus environmental factors • Low familial factor • Treated with insulin, diet and exercise • Usually over 40 • Gradual onset • 80% are overweight • Most have insulin resistance • Ketosis rare • 85% of diagnosed cases • Part of metabolic insulin resistance syndrome • Strongly hereditary • Diet & exercise, progressing to tablets, then insulin

15. Diabetes Mellitus Type 1 • Clinical Manifestations: • Polyuria – increased urine • Polydipsia – increased thirst • Polyphagia – increased hunger • 3 ‘Ps” • Weight loss • Fatigue • Nausea, vomiting • Ketoacidosis may be a presenting sign

16. Diabetes Mellitus Type 1 • Usually develop symptoms over a short period of time, and the condition is often diagnosed in an emergency setting • In addition to high glucose levels, acutely ill type 1 diabetics have high levels of ketones. • As cells cannot get glucose, they burn fats as an alternate energy source • Ketones are produced by the breakdown of fat and muscle, and are toxic at high levels • Ketones in the blood cause a condition called "acidosis” or “ketoacidosis" (low blood pH) • Urine testing detects ketones in the urine • Blood glucose levels are also high.

17. Diabetes Mellitus Type 2 • Type 2 Clinical Manifestations: • Polydipsia – increased thirst • Polyuria – increased urine • Polyphagia – increased hunger • Fatigue • Blurred vision • Slow healing infections • Impotence in men

18. Cornerstones of Diabetes Management • Healthy eating • Exercise • Monitoring • Medication/Insulin • Health Care Team

19. Management of Diabetes Type One: Insulin + Healthy Eating + Exercise Type Two: Healthy eating + exercise then Healthy eating + exercise + tablets then Healthy eating + exercise + tablets + insulin

20. Healthy eating

21. Glycaemic Index • Rates carbohydrate containing foods according to their effect on blood glucose levels ie. how long the food takes to get from the stomach to the blood • High GI quickly raises BGL’s to high level (70-100) • Moderate GI is in between (55-70) • Low GI gradually raises BGL’s and not as high (<55) • There is evidence that low GI foods can improve glycaemic control, insulin resistance, lipids and fibrinolysis • Best to include one low GI food at each meal – this helps to stabilise BGL’s by allowing BGL to increase gradually after the meal

22. Healthy Eating • Snacks for all? • People on sulphonyureas and conventional insulin therapies may need snacks to avoid hypos • Newer oral hypoglycaemic agents and insulins make snacks less necessary • Snack advice should be individualised and the person advised to blood glucose monitor

23. Exercise & Weight Loss • Benefits of a 10kg weight loss • Fall of 50% in fasting glucose • Fall of 10% total cholesterol • Fall of 15% LDL • Fall of 30% triglycerides • Rise of 8% HDL • Fall of 10 mmHg systolic, 20 mmHg diastolic SIGN guidelines

24. Blood Glucose Testing • Recommended for all people with diabetes. Urine testing for glucose no longer recommended • Assesses whether treatment is working or not • Frequency of testing depends on blood glucose control

25. Blood Glucose Testing LEVELS TO AIM FOR Before meals 4 – 6 ideal 4 – 7 OK > 7 unacceptable

26. Blood Glucose Testing • If no complications or symptoms are present, however, higher levels may be tolerated in an elderly person who lives alone. This is because the elderly are at risk of having a stroke or heart attack if they have hypoglycaemia (low blood glucose) • Higher blood glucose levels (BGL’s) are also appropriate in very young children

27. HbA1c • HbA1c is a measure of the average blood glucose level over the previous 2 – 3 months • Glycosylated Haemoglobin • It measures how much glucose is attached to the haemoglobin on red blood cells • It is expressed as a percentage, not mmol/l ie HbA1c and BGL are two different measurements • Normal HbA1c is 4 - 6% • with diabetes aim for ≤ 7%

28. Vascular Complications of Type 2 Diabetes • Vascular complications are the major cause of morbidity and mortality in Type 2 diabetes1 • Findings from UKPDS show that intensive glycaemic control in the treatment of Type 2 diabetes results in a decrease in diabetes-related microvascular complications • Microvascular • nephropathy • retinopathy • neuropathy • Macrovascular • cardiovascular disease • peripheral vascular disease • cerebrovascular disease

30. Vascular Complications Ways to reduce risks • Control cholesterol, blood pressure • No smoking • Maintain good blood glucose levels • Get regular exercise • Aim for healthy body weight • Medical checks including electrocardiograph (ECG)

31. Stepwise Management of Type 2 Diabetes Insulin ± oral agents Oral combination Oral monotherapy Diet & exercise

32. Oral Hypoglycaemic Agents

33. Oral Hypoglycaemics • Type 2 diabetes generally results from either a decrease in: • Insulin resistance (activity) • Insulin secretion • The use of oral medications with diet & exercise can manage the problem but oral hypoglycaemics are NOT insulin & therefore cannot replace insulin • Hypoglycaemics help the body better utilise or make insulin • Beta cells must make enough insulin to work, otherwise combination with insulin is necessary.

34. Classes of Oral Hypoglycaemic Agents • Target insulin secretion • Sulphonylureas (glibenclamide) • Meglitinides (repaglinide) • Target insulin resistance • Biguanides (metformin) • (Thiazolidinediones) (rosiglitazone) • Target glucose absorption from intestine • Alpha glucosidase inhibitors (ascarbase)

35. Oral Hypoglycaemics Acarbose Carbohydrate DIGESTIVE ENZYMES Glucose Glucose Insulin Sulphonylureas, Meglitinides Thiazolidinediones Metformin Metformin Thiazolidinediones

36. Administration • For treatment to be effective, tablets must be taken regularly and at appropriate times • Never stop medication without consulting doctor or diabetic consultant • If dose missed consult with doctor or pharmacist and monitor • If side effects present, consult with doctor and a possible alternative may be found.

37. Biguanides: Metformin Decreases hepatic glucose output Increases peripheral uptake of glucose into cells Monotherapy or adjunct Does not produce weight gain, useful in obese clients Diabex, Diaformin, Glucophage, Glucohexal Dose: 500mg daily increasing gradually to 500mg three times a day Max dose 3g – most only tolerate 2g daily

38. Metformin • Reduces HbA1C by 1-2% • Contraindications: • May provoke lactic acidosis • Contraindicated with Renal impairment • Liver & heart failure • Severe dehydration • Side effects • Nausea, vomiting, diarrhoea, abdominal discomfort, impaired B12 absorption

39. Sulphonylureas • Stimulate beta cells to release insulin from functioning pancreatic cells Examples: • Glibenclamide (Daonil, Glimel) • Widely used, long acting • Avoid in elderly, Renal impairment • Gliclazide (Diamicron, Nidem) • Glipizide (Minidiab, Melizide) • Glimepiride (Amaryl, Dimirel) • Dose: varies per drug • Drug interactions: multiple

40. Reduces HbA1C by 1-1.5% No lag in response Choice of agents available (dependent on onset, duration of action & elimination) 1st choice in lean patients Drugs broken down in liver so avoid in people with liver and renal impairment Adverse Effects: GI disturbances, headache; bone marrow depression Mild skin reactions, photosensitivity, mild alcohol intolerance. Hypoglycaemia Weight gain 5-10% secondary failure rate / year Sulphonylureas

41. Sulphonylurea • Long Term Side Effects • Beta cell exhaustion • Secondary failure of treatment • Therefore, use • Short-acting versions • Lowest effective doses • After many years of treatment • Secondary failure inevitable

42. Alpha Glucosidase Inhibitors • Reduces glucose absorption from the gut by inhibiting the breakdown of disaccharides to monosaccharides such as glucose. • Only effective if taken at same time as food, as drug needs to reach intestines at same time as food to work. • Example: • Acarbose (Glucobay) • Monotherapy or adjunct

43. Alpha Glucosidase Inhibitors • Dose: • 50mg daily increasing gradually to three times a day, if necessary up to 200mg three times a day • Take with or just prior to meal • Treat hypo with glucose • Side effects: • flatulence, diarrhoea, abdominal distension & pain • Contraindications • Pregnancy / breast-feeding • Liver and severe renal impairment • Inflammatory bowel disease & intestinal obstruction

44. Alpha Glucosidase Inhibitors • In therapy: • Add-on to treatment with metformin or sulphonylureas • Part of triple therapy • Monotherapy • With insulin in Type 1 diabetes • Reduces HbA1C by 0.5% • Safe • Weight neutral • Dose coupled with meals • Monitor LFTs during 1st 6-12mths

45. Meglitinides • Prandial Glucose Regulators (PGR’s) • Stimulate beta cells to release insulin, response however is glucose dependent • Following meals there is an early phase insulin release • In Type 2 diabetes, this is lost causing post prandial spikes • PGR mimic release of physiological insulin, as they are short acting and do not stimulate the beta cells constantly

46. The Biphasic Insulin Response Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.

47. Loss of Early-phase Insulin Release in Type 2 Diabetes Pattern of insulin release is altered early in Type 2 diabetes Normal Type 2 diabetes 120 100 80 60 40 20 0 120 100 80 60 40 20 0 20gglucose 20g glucose Plasma insulin (µU/ml) Plasma insulin (µU / ml) –30 0 30 60 90 120 –30 0 30 60 90 120 Time (minutes) Time (minutes) Adapted from Ward WK et al. Diabetes Care 1984; 7: 491–502.

48. Meglitinides • Repaglinide (NovoNorm) • Dose: initially 500mcg, up to 4mg as a single dose • Must be taken within 30 mins before a main meal • Contraindications • Diabetic ketoacidosis • Pregnancy & breast feeding • Type 1 diabetes • Severe hepatic impairment (repaglinide only) • Monitoring: LFTs periodically

49. Meglitinides • Quickly lowers post prandial glucose levels (no lag before response) • HbA1C 0.5-2% • Short half life • Meal time flexibility • Risk of weight gain

50. Thiazolidinediones • Improves insulin sensitivity skeletal muscle, adipose tissue & liver, thereby promoting uptake of fatty acids & glucose at these sites • Actions • Counteract insulin resistance • Reduces HbA1C by 1-2% • ? Alternative to insulin (Type 2 DM only) • Beneficial effect on lipids • Examples: • Pioglitazone(Actos), Rosiglitazone (Avandia) • Adjunct with either metformin or SU • Dose: varies per drug • Pioglitazone (Actos): 15-30mg once daily • Rosiglitazone (Avandia): 4 mg/day, or + metformin 8 mg/day