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Diabetes mellitus

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  • 1. DIABETES MELLITUS
  • 2. DEFINITION • A metabolic syndrome characterized by hyperglycemia • ADA definition of DM: 1. FPG(FBS) ≥126 mg/dl, 2. NPG(RBS) ≥200 mg/dl, or 3. OGTT ≥200 mg/dl in the 2-hr sample • Upper limit of normal FBS=100 mg/dl • FBS= 100 to 126 mg/dl  IFG • OGTT=110 mg/dl and 200 mg/dl IFG
  • 3. Type 1 Type 2 Age of Onset Usually <30 yr, particularly childhood and adolescence, but any age Usually >40 yr, but any age Genetic predisposition Moderate; environmental factors required for expression: 35%-50% concordance in monozygotic twins; several candidate genes proposed Strong; 60%-90% concordance in monozygotic twins; many candidate genes proposed; some genes identified in MODY HLA Associations Linkage to DQA and DQB, influenced by DRB (3 and 4) (DR2 protective) None known
  • 4. Type 1 Type 2 Other Associations Autoimmune; Graves' disease, Hashimoto's thyroiditis, vitiligo, Addison's disease, pernicious anemia Heterogenous group, ongoing subclassification based on identification of specific pathogenic processes and genetic defects Precipitating and Risk Factors Largely unknown; microbial, chemical, dietary, other Age, obesity (central), sedentary lifestyle, previous gestational diabetes Findings at diagnosis 85%-90% of patients have one and usually more autoantibodies to ICA512/IA-2/IA-2β, GAD65, insulin (IAA) Possibly complications (microvascular and macrovascular) caused by significant preceding asymptomatic period
  • 5. Type 1 Type 2 Endogenous Insulin Levels Low or absent Usually present (relative deficiency), early hyperinsulinemia Insulin Resistance Only with hyperglycemia Mostly present Prolonged Fast Hyperglycemia, DKA Euglycemia Stress, withdrawal of insulin DKA HNKS, occasionally DKA
  • 6. EPIDEMIOLOGY • Prevalence: U.S. population vs. Pima Indians DM= 5% to 7% vs. 35% • Incidence: 2% in 20 to 44 yr olds vs. 18% in 65 to 74 yr olds • 8% of all legal blindness • Leading cause of ESRD in the US • CVS- disease: 2x the risk in non- DM patients
  • 7. CLINICAL PRESENTATION - Hx • Type-1-Poly symptoms ± DKA • Type-2-Asymptomatic • Sometimes weight loss; occasionally poly symptoms • Often- chronic complications • Paresthesias (feet > hands); • Symmetric, bilateral, intense burning pain (more at night)
  • 8. CLINICAL PRESENTATION- P/E • Normal in early stages • Diabetic retinopathy: a. Non-proliferative (background diabetic retinopathy): 1. Initially: micro-aneurysms, capillary dilation, waxy or hard exudates, dot and flame hemorrhages, AV shunts
  • 9. CLINICAL PRESENTATION- P/E 2. Advanced stage: micro-infarcts with cotton wool exudates, macular edema b. Proliferative retinopathy: formation of new vessels, vitreal hemorrhages, fibrous scarring, and retinal detachment • Cataracts and glaucoma
  • 10. CLINICAL PRESENTATION- P/E… • Peripheral neuropathy: a. Mononeuropathies- CN- III, IV, and VI  Diplopia, abnormalities of visual fields -intercostal nerves, and femoral nerves b. Sensation c. Motor- DTR, weakness and atrophy of interossei muscles
  • 11. CLINICAL PRESENTATION- P/E… • Autonomic neuropathy: a. GI disturbances: esophageal motility abnormalities, gastroparesis, diarrhea (usually nocturnal) b. GU disturbances: neurogenic bladder (hesitancy, weak stream, and dribbling), impotence
  • 12. CLINICAL PRESENTATION- P/E… c. Orthostatic hypotension: postural syncope, dizziness, light- headedness • Nephropathy: pedal edema, pallor, weakness, uremic appearance • DFU: 15% of DM pts (incidence 2%/yr), leading cause of hospitalization
  • 13. CLINICAL PRESENTATION- P/E… • Neuropathic arthropathy (Charcot's joints) • Necrobiosis lipoidica diabeticorum: - plaque like reddened areas - central area that fades to white- yellow - on anterior surfaces of the legs; - very thin; can ulcerate readily
  • 14. ETIOLOGY • Type 1 DM • Hereditary factors: 1. ICA (in 90% of pts in the 1st yr of dx) 2. Higher incidence of HLA types DR3, DR4 3. 50% concordance in identical twins 4. Environmental factors: viral infection (possibly coxsackie virus, mumps virus)
  • 15. ETIOLOGY… • Type 2 DM • Hereditary factors: 90% concordance in identical twins • Environmental factor: obesity • DIABETES 2° TO OTHER FACTORS: • Hormonal excess: Cushing's syndrome, acromegaly, glucagonoma, pheochromocytoma • Drugs: glucocorticoids, diuretics, oral contraceptives
  • 16. ETIOLOGY… • DIABETES 2° TO OTHER FACTORS: • Insulin receptor unavailability (with or without circulating Ab) • Pancreatic disease: pancreatitis, pancreatectomy, hemochromatosis • Genetic syndromes: hyperlipidemias, myotonic dystrophy, lipoatrophy • Gestational diabetes
  • 17. The Clinical Pattern of DM in Ethiopians Diabetes Care. 1984 Jan-Feb;7(1):6-11, Lester FT. • Among 849 Ethiopians with DM • 171 -type I, 462 type II nonobese, 210 type II obese, and 4 drug-induced • Undernutrition (BMI less than 18 kg/m2)- 12.9% • DKA- 7.8% • 73%- ≤10 yr of DM, 11% - ≥15 yr, and none >32 yr
  • 18. The Clinical Pattern of DM in Ethiopians • During 7 yr, 66 (7.8%) are known to have died (CRF 30.3%, and DKA 3%) • ~4% with 6-10 yr DM- clinically significant complication • “Diabetic triopathy" at 16-20 yr - 27.7% had nephropathy, 27.7% neuropathy, and 33.3% retinopathy • Cataracts- 1.4% of new DM patients, 40.7% in >20 y DM
  • 19. DIFFERENTIAL DIAGNOSIS • Diabetes insipidus • Stress hyperglycemia • Diabetes secondary to hormonal excess, drugs, pancreatic disease
  • 20. LABORATORY TESTS 1. Fasting glucose ≥126 mg/dl 2. Nonfasting plasma glucose ≥200 mg/dl • DM- nephropathy- microalbuminuria - 2 to 3 elevated levels within 3- to 6- months • Yearly fasting serum lipid panel, serum creatinine, and electrolytes
  • 21. NONPHARMACOLOGIC THERAPY • Diet - Calories - 15 cal/lb of ideal body weight; - 20 cal/lb for an active person and - 25 cal/lb for heavy physical labor - 50% to 60% carbohydrates, <30% fat, 15% to 20% protein
  • 22. NONPHARMACOLOGIC THERAPY… • Glycemic index • Fibers: delay glucose absorption and attenuate the postprandial serum glucose peak • Lower the elevated triglyceride level often present in uncontrolled diabetics(20 to 35 g/day of soluble and insoluble fiber)
  • 23. NONPHARMACOLOGIC THERAPY… • Sodium restriction: -2400 to 3000 mg/d - <2400 mg/d- If hypertensive - <2000 mg/d- nephropathy and htn • Exercise • Weight loss • Screening for nephropathy, neuropathy, and retinopathy
  • 24. OHA’s • OHA’s (metformin, sulfonylureas, repaglinide & acarbose , miglitol, pioglitazone & rosiglitazone ) • Sitagliptin- inhibits the enzyme DPP-4 (inactivates and degrades GLP-1 & GIP) ↑insulin synthesis and release and decrease glucagon production • ↓HbA1c of 0.5% vs. 1.5% for metformin
  • 25. INSULIN • Injectable/Inhaled insulin • ~50% to 60%- long-acting insulin- 1-2x/d, • 40% to 50%- short/rapid acting (aspart, lispro> regular) • Bedtime insulin glargine -↓risk of nocturnal hypoglycemia and less weight gain • Insulin detemir - long-acting insulin analog • not associated with weight gain
  • 26. THERAPY • Pramlintide (Symlin), synthetic analog of human amylin • Exenatide (Byetta), synthetic peptide , stimulates release of insulin • CSII, or insulin pump- DM presenting in childhood/adolescence /pregnancy • ASA- 81 mg/d • Strict lipid control (LDL<70 mg/dl)
  • 27. CHRONIC COMPLICATIONS • Diabetic retinopathy is - ~15% at 15 yr, increases 1%/yr after diagnosis • Neuropathy in type 2 DM- ~70% to 80% • Nephropathy- 35% to 45% in type 1 DM and 20% in type 2 DM
  • 28. PREVENTION • DCCT- intensive treatment- ↓risk of retinopathy, nephropathy, and neuropathy by 35% to 90% • Annual ophthalmologic examination • Podiatric care • HbA1C- twice yearly • Microalbumin - yearly • Creatinine and serum-lipid panel - yearly
  • 29. DKA • Severe dehydration and alterations in sensorium resulting from severe insulin deficiency • Mortality: ~ 2-4 % in adults; ↑as age > 50 (5% to 10%) • ~ 0.2-0.4% in children; mostly 2⁰ to cerebral edema • Children <10 yr, DKA  70% of DM related deaths • Cerebral edema occurs in 1% of episodes of DKA in children; mortality rate of 40% to 90%.
  • 30. EPIDEMIOLOGY • INCIDENCE/PREVALENCE: 46 episodes /10,000 diabetics; cause of 14% of all hospital admissions of diabetic patients • PREDOMINANT AGE: 1 to 25 yr
  • 31. ETIOLOGY-“The Four I’s”
  • 32. Pathophysiology Insulin Deficiency/Resistance Counter Regulatory Hormone Excess
  • 33. Pathophysiology... • Insulin action in normal host –Decrease blood glucose via decreasing hepatic glucose production –Decrease ketone production via decrease in lipolysis and glucagon secretion –Peripheral tissue utilization of glucose
  • 34. Pathophysiology... • The antilipolytic action of insulin occurs at much lower concentrations of insulin than does it’s glucose lowering effects –Any dose of insulin that corrects sugars should correct ketoacid production –No ketoacid production in Type II as these diabetics have small amounts of endogenous insulin
  • 35. Pathophysiology... • Presence of ketones GI symptoms stop drinking and get sick faster –1-2 days in DKA VS 1 week in HHS • 3 Ketones –Acetoacetate captured on urine dip and levels increase as DKA resolves –Beta-hydroxy-butyrate main ketone (75%) in DKA, often not measured directly –Acetone “fruity breath” in 5% pt’s
  • 36. CLINICAL PRESENTATION • Evidence of dehydration • Clouding of mental status • Kussmaul's respiration • Fruity breath odor • Lipemia retinalis in some patients • Possible evidence of precipitating factors • Abdominal or CVA tenderness in some patients
  • 37. DIFFERENTIAL DIAGNOSIS • Hyperosmolar nonketotic state • Alcoholic ketoacidosis • Uremic acidosis • Metabolic acidosis secondary to methyl alcohol, ethylene glycol • Salicylate poisoning
  • 38. Feature DKA HNKS Age of patient Usually <40 yr Usually >60 yr Duration of symptoms Usually <2 days Usually >5 days Serum glucose Usually <800 mg/dl Usually >800 mg/dl Serum Na+ Likely normal or low Likely normal or high Serum HCO3 Low Normal Ketone bodies At least 4 + in 1:1 dilution <2 + in 1:1 dilution pH Low Normal Serum osmolality Usually <350 mOsm/kg Usually >350 mOsm/kg Cerebral edema Occasionally clinical symptoms Rarely (never?) clinical Prognosis 3%-10% mortality 10%-20% mortality Subsequent course Insulin therapy required in almost all cases Insulin therapy not required in most cases
  • 39. LABORATORY TESTS • Pco2 <40 mm Hg • 1. Serum HCO⁻₃ <18 mEq/L. 2. Serum K⁺ may be low, normal, or high 3. Serum Na⁺ is usually decreased (hyperglycemia, dehydration, and lipemia) 4. Calculate AG: AG = Na+ - (Cl- + HCO-3)
  • 40. LABORATORY TESTS… • CBC with differential, urinalysis, urine and blood cultures to rule out infectious precipitating factor • Serum Ca⁺, Mg⁺, and P0₄⁻ • BUN and creatinine • Amylase, liver enzymes if abdominal pain
  • 41. OTHER INVESTIGATIONS • ECG • Chest x-ray- may be negative if there is significant dehydration
  • 42. NONPHARMACOLOGIC THERAPY • Monitor mental status, vital signs, and urine output qh until improved, then monitor q2 to 4h • Monitor electrolytes, renal function, and glucose level
  • 43. DKA: Management Goals • Replacement of fluid deficits • Resolution of metabolic ketoacidosis (pH >7.3, AG < 12, BG <12) • Correction of electrolyte abnormalitiesHCO3 >18 • Diagnose and treat coexisting illnesses • Prevent complications
  • 44. FLUID REPLACEMENT • “Focus on shock NOT sugar” – Average deficit is 100ml/kg or 5-7L – Fluid loss 2⁰ to osmotic diuresis • Fluid resuscitation alone will lead to improvements in acidosis and blood sugar – ~80% reduction of BG in 1st 4 hr of therapy is from fluids alone • First step is to attain euvolemia
  • 45. FLUID REPLACEMENT… • If the patient is “shocky”- IV NS 1-2 L/hr • Rough guide: correct ½ deficit in 1st 8-12 hrs and the remainder over 12-16hrs: –IV NS 500 ml/hr X 4hr –IV NS 250 ml/hr X 4hr –Change to D5NS or D10 when BS < 14 mmol/L • If Na is normal or elevated ½ NS
  • 46. DKA: R. Insulin(0.1U/Kg/hr) • Insulin is used to treat acidemia/ketonemia – The effects on blood sugar are secondary – Average time to clearance: 18 hours – No rush to start insulin, no need to give large amounts up front – Find out serum potassium before starting insulin – Titrate insulin drip against the anion gap, serum ketones
  • 47. Serum Potassium Action < 3.3 Hold Insulin Give 40 mmol/L KCL if u/o 3.3-5 Start insulin drip KCL @ 10-40 mmol/L >5 Start insulin drip Hold potassium, re- check K in 2 hr
  • 48. HKNS • A state of extreme hyperglycemia, marked dehydration, serum hyperosmolarity, altered mental status, and absence of ketoacidosis
  • 49. CLINICAL PRESENTATION • Evidence of extreme dehydration • Neurologic defects (reversible hemiplegia, focal seizures) • Evidence of precipitating factors (pneumonia, infected skin ulcer) • Coma (25% of patients), delirium
  • 50. ETIOLOGY • Infections, 20% to 25% • New or previously unrecognized diabetes (30% to 50%) • Reduction or omission of diabetic medication • Stress (MI, CVA) • Drugs: diuretics (dehydration), phenytoin, diazoxide (impaired insulin secretion), glucocorticoids, chemotherapeutic agents, calcium channel blockers, TPN, substance abuse (alcohol, cocaine)
  • 51. DIFFERENTIAL DIAGNOSIS • Diabetic ketoacidosis • Differential diagnosis of coma
  • 52. LABORATORY TESTS • Serum glucose usually >600 mg/dl, serum/urine ketones absent or “small.” • Serum osmolarity usually >320 mOsm/L • Serum Na: may be low, normal, or high • Serum K: may be low, normal, or high (body deficit ~5 to 15 mEq/kg) • Serum HCO₃: usually >15 mEq/L (average is 17 mEq/L)
  • 53. LABORATORY TESTS… • Arterial pH: usually >7.3 • BUN: (60 to 90 mg/dl) • ↓PO₄⁻ (average deficit is 70 to 140 mm) • ↓Ca (average deficit is 50 to 100 mEq) • ↓Mg (average deficit is 50 to 100 mEq) • CBC with differential, urinalysis, blood and urine cultures should be performed to rule out infectious etiology
  • 54. OTHER INVX •Chest x-ray •CT scan of head - suspected CVA
  • 55. MANAGEMENT • Fluid replacement: 1000 to 1500 ml/hr 0.9% NS for the initial 1 to 2 L; then 500 ml/hr • Serum glucose 300 mg/dl 5% DW with 0.45% NS • Replace electrolytes and monitor serum levels frequently (e.g., serum Na and K q2h for 12 hr) • Continuous ECG monitoring and urinary output Qhr • Severe hypoK (<3.3 mEq/L) 40 mEq of K/hr until K is >3.3 mEq/L.
  • 56. MANAGEMENT • Correct glucose by at least 50 to 100 mg/dl/hr • Vigorous IV hydration  by 80 mg/dl/hr; • Regular insulin IV bolus (0.15 U/kg of body weight) • Insulin infusion- 0.1 U/kg/hr till BS ~300 mg/dl; then regular SC insulin (sliding scale) • BS q1-2h in the initial 12 hr