Diabetes Mellitus

1. Reporters: JI Tabajonda, Jennifer M. JI Vio, Rachel Louise S. Diabetes Mellitus

2. Gross Anatomy

3. Microscopic Anatomy

4. Physiology • Glucagon • single-chain polypeptide that contains 29 amino acid residues and has a molecular weight of 3483 • increases blood glucose and relaxes smooth muscle of the gastrointestinal tract.  • potent stimulator of hepatic glycogenolysis, gluconeogenesis, and ketogenesis

5. Insulin Preproinsulin (86 aa) proteolytic processing Proinsulin site specific peptide cleavage C-peptide Insulin

8. Effects of Insulin

9. Diabetes Mellitus • Refers to a group of metabolic disorders that share the phenotype of hyperglycemia • With several distinct types • Interaction of genetics and environment • Reduced Insulin secretion • Decreased glucose utilization • Increased glucose production

10. Classic Symptoms of Diabetes • Polyuria • Polydipsia • Unexplained weight loss

11. Levels of Glycemia

12. Criteria for the Dx of DM • Fasting Plasma Glucose (FPG) ≥126 mg/dl (7.0 mmol/L) - Must be repeated on a separate day to confirm diagnosis OR • Postprandial Plasma Glucose (2h PG) ≥200 mg/dl (11.1 mmol/L) -Measured with Oral Glucose Tolerance Test (OGTT) -Must be repeated on a separate days to confirm diagnosis OR

13. Classic Symptoms + Casual Plasma Glucose (CPG) > 200 mg/dl (> 11.1 mmol/L). -Considered diagnostic of diabetes but should be confirmed on a separate day with FPG or 2hPG. - Casual plasma glucose ( plasma glucose taken without regard to the last meal)

14. Algorithm for Diagnosing Diabetes Classic Symptoms of DM RBS 140-200 mg/dl (<11.1 mmol/L ≥200 mg/dl (≥11.1 mmol/L) 20PGBS DM <140 mg/dl 140-199 mg/dl ≥200 mg/dl Repeat 20PGBS NORMAL IGT ≥200 mg/dl UERMMC-ISDFI

15. Asymptomatic Patients Categorize Patients Low Risk High Risk Risk Factors: • BMI > 23kg/m2(w to h ratio >1) or • Waist cir >80 cm F,>90 cm for M • Family Hx of Type 2 diabetes • Age >45 yo • HPN (130/85 mmhg) Risk Factors: • BMI > 23kg/m2(w to h ratio >1) or • Waist cir >80 cm F,>90 cm for M • Family Hx of Type 2 diabetes • Age • HPN (130/85 mmhg)

16. High risk- Screen as early as 20 years of age FBS <100 mg/dl 100-125 mg/dl (IFG) >/= 126mg/dl NORMAL IFG Rpt FBS <126 mg/dl Check 2hPGBS 2hPGBS Check 2hPGBS <140 mg/dl 140-199 mg/dl >/= 200mg/dl ≥126 mg/dl NORMAL IGT Diabetes

17. Classification • Type 1 • Complete or near total insulin deficiency • Type 2 • Insulin resistance • impaired insulin secretion • Increased glucose production • Preceded by IFG and IGT

18. DM Type 3 and 4 • DM type 3 • Other specific types of Diabetes • DM type 4 • Gestational Diabetes Mellitus

19. Pathophysiology • DM Type I • Complete or near total insulin deficiency • circulating insulin is very low or absent • plasma glucagon • and the pancreatic beta cells fail to respond to all insulin-secretory stimuli.

20. Pathophysiology of DM Type I • Autoimmune • islet cell antibodies • anti-insulin antibodies • genetic susceptibility • HLA markers • Infectious and/or environmental agents ? •  viruses (eg, mumps, rubella, Coxsackie B4), toxic chemicals, exposure to cow's milk in infancy, and cytotoxins

21. Dm Type 2 • Predominantly insulin resistance with relative insulin deficiency to predominantly insulin deficiency with insulin resistance • Excessive hepatic glucose production • Abnormal fat metabolism *Insulin resistance, is the decreased ability of insulin to act effectively on target tissues (especially muscle, liver, and fat)

22. GDM • Any degree of glucose intolerance with the onset or first recognition during pregnancy • Does not exclude the possibility that undiagnosed glucose intolerance may have occurred prior to pregnancy • Usually 24-48 weeks

23. Pathophysiology • Placental hormones causing insulin resistance • Estrogen, progesterone, cortisol, HPL • Decreased insulin secretion • Borderline pancreatic function, cannot produce insulin levels to meet metabolic needs

24. Pre-Diabetes • Impaired Fasting glucose • FBS of 100-125 mg/dL • IGT • 2HPGBS 140-199 mg/dL • Associated withthe metabolic syndrome, which includes obesity (especially abdominalor visceral obesity), dyslipidemia of the high-triglycerideand/or low-HDL type, and hypertension.

25. Complications of Diabetes Mellitus ACUTE Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar State (HHS) CHRONIC: Macrovascular (CAD,CVD,PVD) Microvascular (retinopathy, nephropathy, neuropathy) Others (e.g. GI, GU, Dermatologic, Infectious)

26. Acute Complications of DM DKA and HHS are medical emergencies • associated with potentially serious complications if not promptly diagnosed and treated. • associated with absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities.

27. DKA vs HHS

28. DKA • Can occur in both type 1 and type 2 DM • Signs & symptoms develop over 24hrs • results from relative or absolute insulin deficiency combined with counterregulatory hormone excess

29. DKA Diagnostic Criteria: • Glucose >250mg/dl • pH <7.3 • High anion gap • Positive ketones

30. Clinical Features of DKA Precipitating events: • Inadequate insulin administration • Infection • Infarction • Drugs • Pregnancy

31. Clinical Features of DKA Symptoms: • Nausea / vomiting • Thirst / polyuria • Abdominal pain • Shortness of breath

32. Clinical Features of DKA Physical Findings: • Tachycardia • Dehydration / Hypotension • Tachypnea / Kussmaul respirations/ respiratory distress • Abdominal tenderness (may resemble acute pancreatitis or surgical abdomen) • Lethargy / obtundation / cerebral edema/ possibly coma

33. Diagnosis DKA Anion Gap = Na – (Cl + HCO3) Normal: 8 - 12

34. Management of DKA • Hydration • Insulin administration • Glucose monitoring • Electrolyte correction

35. HHS • Prototype case is an elderly type 2 DM patient with several week history of polyuria, weight loss, ↓oral intake that culminates in mental confusion, lethargy or coma.

36. Clinical features of HHS Precipitating events: • serious, concurrent illness (e.g. MI, CVA) • Sepsis, pneumonia, and other serious infections • debilitating condition (prior stroke or dementia) or social situation that compromises water intake

37. Clinical features of HHS Physical findings: • Profound dehydration • Hypotension • Tachycardia • Altered mental status

38. Clinical features of HHS Symptoms: • Notable absence of nausea, vomiting, and abdominal pain and the Kussmaul respirations

39. HHS Diagnostic criteria: • Glucose >600mg/dl • Total serum osmolality >300mOsm/kg • Absence of severe ketoacidosis

40. Management of HHS • Hydration • Insulin administration • Glucose monitoring • Electrolyte correction

41. Chronic Complications of DM • Macrovascular (CAD, CVD, PVD) • Microvascular (retinopathy, nephropathy, neuropathy) • Others (e.g. GI, GU, dermatologic, infectious)

42. Macrovascular Complications • Largest cause of morbidity and mortality • Risk of CVD increased 2 to 4 fold • Reduced survival post-MI. post-CABG, and particularly PTCA • Risk of stroke and PVD substantially increased

43. Clinical Manifestations Heart • Angina pectoris • Acute MI • Silent MI • Arrhythmias

44. Clinical Manifestations Brain • TIA (Transient ischemic attack) • RIND (Reversible Ischemic Neurological Deficits) • Stroke in evolution • Completed stroke (infarction,embolism, hge) • Lacunar infarcts

45. Clinical Manifestations Limbs • Peripheral vascular disease (claudication; pain relieved by rest; pain does not go away with continued walk; primarily affects calves) • Poor wound healing, foot ulcers, gangrene

46. Microvascular Complications DIABETES AGE’s Reactive oxygen species Diacyglycerol • protein cross-linking • accelerate atherosclerosis • promote glomerular dysfxn • ↓ NO synthesis • Induce endothelial dysfxn • Alter ECM composition & structure PKC activation MICROVASCULAR DAMAGE Retinopathy Neuropathy Nephropathy

47. DM Retinopathy • DM is the leading cause of blindness in ages 20-74 in the US • Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema. • Incidence: • Found in almost all individuals with DM for > 20yrs and 25% incidence with 5 years, and 80% incidence with 15 years of type 1 DM

48. Pathophysiology of DM Retinopathy loss of retinal pericytes ↑ retinal vascular permeability altered retinal blood flow abnormal retinal microvasculature Retinal Ischemia Neovascularization • Vitreous hemorrhage • Fibrosis Retinal Detachment

49. Classifications of DM Retinopathy Stage I – Non-proliferative • Thickening of capillary endothelial BM • Reduction of pericytes • Microaneurysms • Multiple hemorrhages • Macular edema • Microvascular occlusion and ischemia

50. Classifications of DM Retinopathy Stage II – Proliferative • Hallmark – Neovascularization in response to retinal hypoxia • newly formed vessels appear near the optic nerve and/or macula and rupture easily • vitreous hemorrhage, fibrosis • retinal detachment