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1. Diabetes Mellitus (DM) Mezgebu S. MD Nov 2016

2. Outline Introduction Classification Epidemiology Diagnosis Type I DM Type II DM

3. Introduction DM refers to a group of metabolic disorders that share the phenotype of hyperglycaemia Hyperglycaemia results from: Reduced insulin secretion Decreased glucose utilization, and/or Increased glucose production The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems In the US, it’s the leading cause of ESRD, nontraumatic lower extremity amputations, and adult blindness

4. Classification Current classification is based on the basis of the pathogenic process leading to hyperglycaemia Age is no more the criterion in the classification system 5-10% of patients who develop DM after the age of 30 have type I DM Type II DM is now being diagnosed more frequently in children and young adults, particularly obese adolescents The terms insulin-dependent (IDDM) and non-insulin-dependent DM (NIDDM) are obsolete Many individuals with type II eventually require insulin for control of hyperglycaemia Both type I and II DM are preceded by a phase of abnormal glucose homeostasis as the pathogenic process progress

5. Etiologic classification of DM

6. Glucose homeostasis and diabetes

7. Epidemiology The worldwide prevalence of DM is increasing From 30 million cases in 1985 to 285 million in 2010 Estimated to affect 438 million individuals by 2030 The prevalence of type II is rising more rapidly than type I due to; Increasing obesity Reduced activity levels Aging of the population Dietary changes DM increases with aging The prevalence is similar in men and women

8. Worldwide prevalence of DM

9. Worldwide prevalence of DM

10. Diagnosis

11. Prediabetes is defined as; FPG- 100-125mg/dl 2hr postprandial glucose- 140-199 mg/dl, or HgbA1C- 5.7-6.4% FBG and A1C are the most reliable and convenient tests for identifying DM in asymptomatic patients Abnormalities on screening tests for DM should be repeated before making a definitive diagnosis of DM, unless acute metabolic derangements or a markedly elevated plasma glucose are present The diagnosis of DM should be withdrawn in situations when the glucose intolerance reverts to normal

12. Screening Screening for type II is indicated because; A large number of individuals who meet the current criteria for DM are asymptomatic, Type II DM may be present for up to a decade before diagnosis, Some pts with Type II have DM-specific complications at the time of their diagnosis Treatment of Type II DM may favourably alter the natural history of DM Use A1C or FBG for screening Indicated in all individuals >45yrs of age or younger individuals with overweight and one additional risk factor for DM In contrast to type II DM, a long asymptomatic period of hyperglycaemia is rare prior to the diagnosis of type I DM and thus, screening for type I DM is not indicated

13. Risk factorsfortype2 diabetes mellitus

14. Insulin synthesis and secretion Produced in the beta cells of the pancreatic islets Glucose is the key regulator of insulin secretion by the pancreatic beta cells Amino acids, ketones, various nutrients, GI peptides, and neurotransmitters also influence insulin secretion Insulin is co-secreted with C-peptide important markers of insulin secretion Also allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia Islet amyloid polypeptide (IAPP) The major component of amyloid fibrils found in the islets of patients with type II DM

15. Action of Insulin Carbohydrate Insulin is the most important regulator of homeostasis Neural input, metabolic signals, and other hormones contribute to the integrated control of glucose supply and utilization Facilitates the transport of glucose into muscle and adipose cells Facilitates the conversion of glucose to glycogen for storage in the liver and muscle Decreases the breakdown and release of glucose from glycogen by the liver Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla

16. Protein Stimulates protein synthesis Inhibits protein breakdown; diminishes gluconeogenesis Fat Stimulates lipogenesis- the transport of triglycerides to adipose tissue Inhibits lipolysis – prevents excessive production of ketones or ketoacidosis

17. Type I DM

18. Pathophysiology Is a result of lymphocytic infiltration and destruction of islet cells After 80-90% of the beta cells are destroyed, hyperglycaemia develops and diabetes may be diagnosed A result of interaction between genetic, environmental, and immunologic factors In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules About 85% of type I DM pts have circulating islet cell antibodies The prevalence of type I DM is increased in pts with other autoimmune diseases, such as Graves disease, Hashimoto thyroididtis, and Addison disease

19. Etiology Results from autoimmune destruction of the beta cells of the pancreas Involves both genetic and environmental factors Genetics Susceptibility to type I DM involves multiple genes Dizygotic twins have 5-6% concordance rate for type I DM Monozygotic twins will share the diagnosis more than 50% of the time by the age of 40 years The risk for the child if the parent has type I DM is 3-4%

20. Environmental factors- triggers for immunologically mediated destruction of the beta cells Viruses- enterovirus, mumps, rubella, and coxsackie virus Toxic chemicals Exposure to cow’s milk in infancy Increasing maternal age? Combination of factors may be involved None of the environmental factors have been conclusively linked with diabetes

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22. Clinical presentation History polyuria, polydypsia, and polyphagia- the most common symptoms Lassitude, nausea, and blurred vision Weight loss despite normal or increased appetite Abdominal pain and change in bowel movements The onset of symptomatic disease may be sudden DKA can be the initial presenting feature

23. Symptoms Hypoglycemia Tremor Headache, dizziness, confusion Pallor Paresthesia Loss of coordination Anxiety seizure Hyperglycemia Polyurea Polydipsia Polyphagia Dry mouth Ketoacidosis (shortness of breath, acidotic breathing pattern Blurring of vision

24. Physical examination Usually normal in newly diagnosed cases DKA Kussmaul respiration Hypotension and other signs of dehydration Altered mental status Vital signs Assess for orthostatic hypotension Fundoscopic examination For possible diabetic retinopathy Foot examination Palpate dorsalis pedis and posterior tibialis pulses

25. Complications Acute Diabetic ketoacidosis (DKA) Infection Hypoglycemia- after treatment of DM Chronic Microvascular Retinopathy Nephropathy Neuropathy Macrovascular Coronary artery disease Cerebrovascular disease Peripheral arterial disease

26. Workup Plasma glucose Fasting plasma glucose (FPG) Random blood glucose (RBG) 2hr post prandial glucose Hemoglobin A1 c CBC Blood and urine cultures Urinalysis WBC casts Ketones Glucose Protein Serum ketone and PH

27. Tests specific for type I DM C-peptide – level below 0.6ng/ml suggests type I DM Level >1ng/dl in a patient who has had diabetes for >1-2yrs is suggestive of type II DM Serum insulin levels Low or absent in type I Short half life Islet cell autoantibodies Anti-Glutamic acid decarboxylase (anti-GAD) Anti-insulin autoantibodies

28. Type-1 Vs Type-2 Type 1 Young age Normal BMI, not obese No immediate family history Short duration of symptoms (weeks) Can present with diabetic ketoacidosis Insulin required Type 2 Middle aged, elderly Usually overweight/obese Family history usual Symptoms may be present for months/years May present with HHS Insulin not necessarily required Previous diabetes in pregnancy These differences are not absolute

29. Management of DM The major components of the treatment of diabetes are:

30. A. Diet Diet is a basic part of management in every case Treatment cannot be effective unless adequate attention is given to ensuring appropriate nutrition Dietary treatment should aim at: Ensuring weight control Providing nutritional requirements Allowing good glycemic control with blood glucose levels as close to normal as possible Correcting any associated serum lipid abnormalities

31. Exercise Physical activity promotes weight reduction and improves insulin sensitivity, thus lowering blood glucose levels Together with dietary treatment, a programme of regular physical activity and exercise should be considered for each person Such a programme must be tailored to the individual’s health status and fitness People should, however, be educated about the potential risk of hypoglycaemia and how to avoid it

32. Nutritional Management for Type I Diabetes Consistency and timing of meals Timing of insulin Monitor blood glucose regularly

33. MANAGEMENT OF TYPE 1 DIABETES

34. Can we prevent type 1 DM? A number of interventions have prevented diabetes in animal models. None of these interventions have been successful in preventing type 1 DM in humans. Vaccines??

35. Type II DM

36. 46 Etiology of Type 2 Diabetes

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38. Risk Factors Type 2 DM Family History Obesity Habitual physical inactivity Previously identified impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) Hypertension Hyperlipidemia 48

39. MANAGEMENT OF TYPE 2 DIABETES

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

41. DIABETES – ORAL MEDICATIONS Sulfonylureas Biguanides Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides 5 Classes :

42. 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)

43. Oral Hypoglycaemic Medications

44. 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 Dose: 500mg daily increasing gradually to 500mg three times a day Max dose 2-2.5 gms daily

45. Metformin Reduces HbA1C by 1-2% Contraindications: Contraindicated with Renal impairment Liver & heart failure Severe dehydration Side effects Nausea, vomiting, diarrhoea, abdominal discomfort, impaired B 12 absorption

46. Sulphonylureas Stimulate beta cells to release insulin from functioning pancreatic cells Other drugs in the category are Glipizide,Glibinclamide etc. Glimepiride is a third generation sulphonylurea DOSE Glimepiride 1mg (OD) 10-15 minutes before breakfast for two weeks; can be titrated by 1mg doses till 8mg/day with two week intervals.

47. Sulphonylureas Reduces HbA1C by 1-1.5% 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

48. 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

49. Optimal Glycaemic Control One of the primary goals in treating diabetes is to ‘treat to target’ in terms of HbA 1 C With long term treatment, 75% of patients do not maintain optimal glycaemic control (<7% HbA 1c ) with monotherapy alone 1 Optimal combinations of oral therapy to treat diabetes need to be found to achieve this target Combination therapy used when monotherapy fails

50. COMPLICATIONS

51. Chronic Complications Systems Effected Disease Health   Concern Eyes Retinopathy Glaucoma Cataracts Blindness Blood Vessels Coronary artery disease Cerebral vascular disease Peripheral vascular disease Hypertension Heart attack Stroke Poor circulation in feet and   legs Heart attack, stroke, kidney   damage Kidneys Renal insufficiency Kidney failure Insufficient blood filtering Loss of ability to filter   blood Nerves Neuropathies Autonomic neuropathy Chronic pain Poor nerve signaling to organ   systems Skin,   Muscle, Bone Advanced infections Cellulitis Gangrene Amputation

52. Patient should check feet daily Wash feet daily Keep toenails short Protect feet Always wear shoes Look inside shoes before putting them on Always wear socks

53. Steps to lower risk of diabetes complications: A1C < 7, which is an estimated average glucose of 154mg/dl Blood pressure < 140/90 Cholesterol (LDL) < 100 Cholesterol (HDL) > 40 (men) and > 50 (women) Triglycerides < 150 Quitting smoking. Active life style. Healthy food choices.

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

55. Hyperglycemic Crises

56. Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) represent two extremes in the spectrum of decompensated diabetes. DKA and HHS remain important causes of morbidity and mortality

57. DKA Life-threatening condition in which severe insulinopenia resulting in metabolic acidosis, dehydration, and deficits in fluid and electrolyte HHS There is sufficient amount of insulin present in HHS to prevent lipolysis and ketogenesis but not adequate to cause glucose utilization Smaller increase in counter regulatory hormones

58. DKA is a far more characteristic feature of T1DM than of T2DM, but it may be seen in persons with T2DM under conditions of stress such as occur with serious infections, trauma, and cardiovascular or other emergencies.

59. PATHOGENESIS Reduced net effective action of circulating insulin as a result of decreased insulin secretion (DKA) or ineffective action of insulin in HHS Elevated levels of counter regulatory hormones: glucagon, catecholamines , cortisol , and growth hormone resulting in increased hepatic glucose production and impaired glucose utilization in peripheral tissues Dehydration and electrolyte abnormalities, mainly due to osmotic diuresis caused by glycosuria Diabetic ketoacidosis is also characterized by increased gluconeogenesis, lipolysis, ketogenesis , and decreased glycolysis  

60. Precipitating events

61. CLINICAL FEATURES Poly symptoms, weight loss Profound wasting, cachexia, and prostration Nausea, vomiting, and abdominal pain May mimic acute abdomen

62. Tachycardic , and tachypneic and have signs of mild to moderate volume depletion to hypotension Hypothermia Hyperventilation pattern with deep, slow breaths ( Kussmaul respirations) associated with the fruity odor of acetone Lethargy

63. laboratory evaluation Determination of plasma glucose, blood urea nitrogen, serum creatinine, serum ketones, electrolytes (with calculated anion gap), osmolality , Urinalysis, urine ketones by dipstick, Arterial blood gases Complete blood count with differential Electrocardiogram, blood, urine or sputum cultures and chest X-ray should also be performed HbA1c

64. Acidosis, the serum bicarbonate <10 mEq/l Two ketoacids (β- hydroxybutyrate and acetoacetate ) and the neutral ketone, acetone. Nitroprusside reaction on diagnostic strips at bedside Detects acetoacetate more effectively than acetone and does not detect β- hydroxybutyrate . Negative test in the presence of severe ketosis  Serum anion gap  =  Serum sodium  -  (serum chloride + bicarbonate) usually > 20 Glucose 250-600  mg/dL range Euglycemic DKA Pregnancy, decreased intake

65. . Serum electolytes Sodium Mildl hyponatremia Potassium deficit that averages 3 to 5 mg/kg  serum level potassium normal or elevated rise in plasma osmolality , insulin deficiency, GI and urinary losses

66. DDX Alcoholic ketoacidosis Starvation ketosis Lactic acidosis, advanced chronic renal failure Ingestion of drugs such as salicylate , methanol and ethylene glycol

67. Treatment Goals of therapy 1) improvement of circulatory volume and tissue perfusion, 2) gradual reduction of serum glucose and plasma osmolarity , 3) correction of electrolyte imbalance 4) identification and prompt treatment of co-morbid precipitating causes

68. Resolution of DKA Blood glucose is < 200 mg/dl Serum bicarbonate is 15 pH is > 7.30 Anion gap is < 12 Osmolarity is < 320 mOsm /kg Recovery to mental alertness

69. IV insulin should be continued for 2 hours after giving the subcutaneous insulin to maintain adequate plasma insulin levels Patients with known diabetes may be given insulin at the dose they were receiving before the onset of hyperglycaemic crises. In new onset diabetes, a multi-dose insulin regimen should be started at a dose of 0.5-0.8 U/kg per day, including regular or rapid-acting and basal insulin until an optimal dose is established

70. Complications of DKA Hypoglycemia and hypokalemia Overzealous treatment with insulin and bicarbonate Non-cardiogenic pulmonary edema

71. Cerebral edema Fatal complication of DKA, occurs in 0.7–1.0% of children Deterioration in the level of consciousness, lethargy, decreased arousal, and headache Prevention Avoidance of overenthusiastic hydration and rapid reduction of plasma osmolality Closed hemodynamic monitoring

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