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DM- LONG TERM COMPLICATIONS, HYPOGLYCEMIA

DM- LONG TERM COMPLICATIONS, HYPOGLYCEMIA. MOHAMMAD ISHAQ ARASTU, M.D. ishaqarastu@gmail.com. WE EXPRESS OUR SINCERE GRATITUDE FOR THE USE OF SOME LECTURE MATERIAL PROVIDED BY DRS. DANIEL RUBIN AND ELIAS SIRAJ AT TUSM. Disclosure There are no conflicts of interest to disclose.

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DM- LONG TERM COMPLICATIONS, HYPOGLYCEMIA

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  1. DM- LONG TERM COMPLICATIONS, HYPOGLYCEMIA MOHAMMAD ISHAQ ARASTU, M.D. ishaqarastu@gmail.com WE EXPRESS OUR SINCERE GRATITUDE FOR THE USE OF SOME LECTURE MATERIAL PROVIDED BY DRS. DANIEL RUBIN AND ELIAS SIRAJ AT TUSM.

  2. Disclosure There are no conflicts of interest to disclose.

  3. DM-LONG TERM COMPLICATION, HYPOGLYCEMIA LEARNING OBJECTIVES • THE STUDENT WILL BE ABLE TO: Understand and explain the relationship between the duration and the intensity of hyperglycemia and the evolution of macro- and micro-vascular diseases Describe how calorie excess, decreased physical activity, obesity, hypertension, and hyperglycemia lead to an “inflammatory reaction” to excessive body fat Recognize and explain the long term complications of DM with the proper algorhythms of Dx and Rx Explain the normal physiology of euglycemia and the pathophysiology of hypoglycemia

  4. DM-LONG TERM COMPLICATION, HYPOGLYCEMIA HYPERGLYCEMIA: MEDICAL COMPLICATIONS • Small vessels (microvascular): • Retinopathy, nephropathy, neuropathy • (peripheral mononeuritis & dysautonomia) • Large vessels (macrovascular): • Cardiovascular disorders • Cataracts • (“snowflake” and “senile” types) • Infections • (monilia, mucormycosis, malig otitis externa, osteomyelitis) • Connective tissue disorders • (calcific bursitis, Dupyetren contractures, carpal tunnel syndrome) • Diabetes in pregnancy (impact on the “maternal-fetal unit”)

  5. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Pancreas Insulitis-Type 1/amyloid 2 HBP ERECTILE DYSFUNCTION POSTURAL HYPOTENSION

  6. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA

  7. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA NATURAL HISTORY OF TYPE 2 DIABETES Impaired glucose tolerance Undiagnosed diabetes Known diabetes Insulin resistance Insulin secretion Postprandial glucose Fasting glucose Microvascular complications Macrovascular complications 7

  8. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA DIABETIC COMPLICATIONS: CONSEQUENCES • #1cause new blindness in adults • #1cause kidney failure • 40% of diabetics affected by nephropathy • 50% of nontraumatic amputations, USA • Life span: 7-10 years shorter because of complications • >60% of diabetics affected by neuropathy

  9. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Risk of microvascular complications increase with HbA1C Type 1 Type 2 Prevalence of retinopathy increases with type 2 DM

  10. Systolic Blood Pressure PredictsRisk in Type 2 Diabetes DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Incidence per 1000 person-years (%) 50 Microvascular end points 40 30 20 10 0 110 120 130 140 150 160 170 Updated mean systolic blood pressure (mm Hg) 10

  11. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA HYPERGLYCEMIA: TISSUE DAMAGE • Effects of hyperglycemia • Glycation of proteins (eg, hemoglobin, collagen) • Accumulation of sorbitol and fructose (eg, in nerves, lens) • Activation of protein kinase C (eg, on vascular cells) • Tissue changes • Altered protein function and turnover, cytokine activation • Osmotic and oxidative stress • Reduced nerve conduction velocity • Increased glomerular filtration rate and renal blood flow

  12. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Pathophysiologic Features of Microvascular Complications • Abnormal endothelial cell function • ↓ NO in efferent capillaries  ↑ intracapillary pressure  vascular permeability of retina, glomerulae, vasa nervorum • Microvessel occlusion  loss of function • Leakage of plasma proteins and microvascular hypertension stimulates production of growth factors and extracellular matrix • Microvascular cell death

  13. 1. Direct tissue damage 2. Chronic hyperglycemia   reactive oxygen species  oxidative stress 3.Activation of multiple pathways Polyol pathway Hexosamine pathway Protein kinase C pathway Advanced glycation end-product pathway (AGE) DM-LONG TERM COMPLICATION, HYPERGLYCEMIA HYPERGLYCEMIA-INDUCED TISSUE DAMAGE MECHANISMS * * Fully listed in archive slides at the end of this lecture

  14. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Consequences of Hyperglycemia-induced Activation of Protein Kinase C (PKC) Hyperglycemia Diacylglycerol (DAG) PKC • Vascular permeability • Angiogenesis • Vascular occlusion, vasoconstriction • Inflammation • Oxidative stress

  15. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Advanced Glycation End-Products • Promote activation of PKC • ↑ vascular permeability, ↑ VEGF  macular edema, retinal neovascularization, glomerular hyperfiltration, microalbuminuria • Cross-link collagen  basement membrane thickening • Binding to RAGE is proinflammatory • Activate procoagulants • Inhibit healing response (neovascularization) to hypoxia

  16. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Diabetic Retinopathy (DR)Pathophysiology • Gradually progressive alterations in retinal microvasculature  retinal nonperfusion  increased vascular permeability  macular edema  pathologic intraocular proliferation of retinal vessels (neovascularization) • Macular edema and proliferative DR  blindness

  17. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA

  18. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA

  19. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA RETINOPATHY: IMPROVEMENT & DIABETIC CARE

  20. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Diabetic Retinopathy (DR) Management • No known direct means of DR prevention • Decreased risk of onset and progression with control of blood glucose and blood pressure • Vision loss from DR can be prevented • Annual dilated ophthalmic exam • Panretinal laser photocoagulation for PDR • Increases O2 delivery to untreated retina • Focal laser photocoagulation for macular edema • Intravitreal injections of anti-VEGF under study

  21. Diabetic Nephropathy DM-LONG TERM COMPLICATION, HYPERGLYCEMIA • HTN + proteinuria + renal impairment DISEASE

  22. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Natural History of Diabetic Nephropathy Hyperfiltration ↑ GFR and capillary glomerular pressure Renal hypertrophy Silent Stage GFR decreases back to normal Basement membrane thickening and mesangial expansion Microalbuminuria Urine albumin excretion 30-300 mg/24 hr Spot urine albumin:creatinine ratio 30-300 mcg/mg GLOMERULOPATHY Mesangial expans GBM thickening KW lesions TUBULOPATHY Hyperplasia TBM thickening • Macroalbuminuria “overt nephropathy” • Urine albumin excretion > 300 mg/24 hr • Spot albumin:creatinine > 300 mcg/mg • Uremia “end-stage renal disease” • Requires dialysis or renal transplant

  23. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Management of Diabetic Nephropathy • Blood pressure control <130/80 • Decreases risk of onset and progression • ACE inhibitors and Angiotensin receptor blockers confer additional benefit for nephropathy progression • Blood glucose control, A1c <7% • Decreases risk of onset and progression • No specific benefit to any individual therapy

  24. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Diabetic Neuropathies Different types of neuropathy A useful chart of the

  25. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Distal Symmetric Polyneuropathy • Most common form of Diabetic Neuropathy • Onset insidious • Sensory, motor, small and/or large fibers • Large fiber  weakness, wasting, ↓vibration sense, proprioception, reflexes • Small fiber  Autonomic, pain, ↓thermal sense but normal strength and reflexes • Glove-and-stocking distribution of sensory loss

  26. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Diagnosis of Diabetic Neuropathy • History • Physical • Achilles and patellar reflexes • 128 Hz tuning fork • Monofilament testing • Proprioception • Testing in select cases • Nerve conduction velocity, electromyogram, quantitative autonomic function tests, labs to rule out other causes of neuropathy

  27. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Management of Diabetic Neuropathy • Glucose control, A1c <7% • Reduces risk of onset and progression • May decrease neuropathic symptoms • Pain control

  28. Blood pressure Glucose DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Summary of Intervention Studies Effect of Treatment of Risk Microvascular events Target

  29. Metabolic injury to large vessels DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Biology ofMacro-vascular Complications Heart Brain Extremities • Coronary artery disease* • – Coronary syndrome • – MI • – CHF • *#1 cause of death • Cerebrovascular disease • – TIA • – CVA • – Cognitive impairment • Peripheral vascular disease • – Ulceration • – Gangrene • – Amputation 29

  30. 2x 4–5x 0–3 4–7 8–11 12–15 16–19 20–23 DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Diabetes Is a Cardiovascular Disease (CVD) Risk Factor Mortality rate per 1000 Men Women 60 60 Diabetes No diabetes 50 50 40 40 30 30 20 20 10 10 0 0 0–3 4–7 8–11 12–15 16–19 20–23 Years of follow-up Type 2 Diabetes and Prior Myocardial Infarction Predict Mortality Equally Review archived slide on MI/DM predictive rates of MI 30

  31. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Impaired glucose tolerance (IGT) and postprandial (post-meal) hyperglycemia are CVD risk factors A1c predicts risk, no apparent threshold

  32. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Postprandial Decreases in Antioxidant Defenses Associated With Hyperglycemia After low-carbohydrate meal (47 g) After high-carbohydrate meal (80 g) MDA/CHOL + TRIG 600 Lipid oxidation Antioxidant capacity TRAP 0.3 * 550 0.2 500 450 0.1 400 * *P<0.001 0 350 0 60 120 0 60 120 Time MDA/CHOL+TRIG=malondialdehyde/cholesterol + triglycerides TRAP=total radical-trapping antioxidant parameter (mol/L) 32

  33. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Adverse Effects on Balance Between Thrombosis and Fibrinolysis Subjects With Diabetes • Predisposition to thrombosis • Increased platelet aggregation • Elevated concentrations of procoagulants • Decreased activity of antithrombotic factors • Predisposition to attenuation of fibrinolysis • Decreased t-PA activity • Increased PAI-1 • Decreased concentrations of a2-antiplasmin

  34. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Systolic Blood Pressure PredictsRisk in Type 2 Diabetes Incidence per 1000 person-years (%) 50 MI Microvascular end points 40 30 20 10 0 110 120 130 140 150 160 170 Updated mean systolic blood pressure (mm Hg) 34

  35. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA LDL and HDL Cholesterol Predict CAD in Type 2 Diabetes HDL LDL Estimated hazard ratios 3 1 0.4 35 40 45 50 110 135 155 175 LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) 35

  36. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA TG and HDL Cholesterol PredictCV Mortality in Type 2 Diabetes High triglycerides Low HDL 4 4 Adjusted odds ratios 3 3 2 2 1 1 HDL cholesterol <35 mg/dL Triglycerides >200 mg/dL All subjects All subjects 36

  37. DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Summary of Epidemiologic Studies • Microvascular complications are predicted by • Duration of diabetes • A1C • Blood pressure • Macrovascular complications are predicted by • Duration of diabetes • A1C • Blood pressure • Lipids

  38. Blood pressure Lipids --- Glucose DM-LONG TERM COMPLICATION, HYPERGLYCEMIA Summary of Intervention Studies Effect of Treatment of Risk Microvascular events Macrovascular events Target * * *No decreased risk in long-standing type 2 DM

  39. Hypoglycemia FIRST AND FOREMOST…. THE AIM OF DIABETIC TREATMENT IS CORRECTING FASTING HYPERGLYCEMIA THE LIMITING FACTOR IN TREATMENT IN THEN TREATMENT OF DM IS HYPOGLYCEMIA

  40. HYPOGLYCEMIA Postabsorptive (Fasting) State GLUCAGON INSULINCELLS MUSCLE FAT 4 g/hr LIVERGLUCOSE 10 g/hr~ 80 mg/dL BRAIN 6 g/hr PANCREAS ab BLOOD Normoglycemia

  41. HYPOGLYCEMIA InsulinOverdose INSULIN+ MUSCLE FAT - 24 g/hr LIVERGLUCOSE 1 g/hr~ 20 mg/dL BRAIN 6 g/hr GLUCAGON Hypoglycemia

  42. HYPOGLYCEMIA DRIVING PRINCIPLE IN DIABETIC TREATMENT FIRST AND FOREMOST…. THE AIM OF DIABETIC TREATMENT IS CORRECTING FASTING HYPERGLYCEMIA AND THE LIMITING FACTOR IN THESE EFFORTS IS HYPOGLYCEMIA

  43. Glucagon Epinephrine Cortisol Growth hormone Stimulate hepatic glucose production (glycogenolysis + gluconeogenesis) Inhibit peripheral glucose uptake HYPOGLYCEMIA COUNTER-REGULATORY HORMONES(0PP0SERS OF INSULIN ACTION)

  44. HYPOGLYCEMIA SYMPTOMS OF HYPOGLYCEMIA

  45. NORMAL RECOVERY DUE TO INSULIN-INDUCED HYPOGLYCEMIA REQUIRES APPROPRIATE RELEASE OF GLUCAGON OR EPINEPHRINE

  46. HYPOGLYCEMIA Defective Counterregulation in Type 1 Diabetes • Impaired counterregulatory response within 5 years of diagnosis • Thresholds influenced by the degree of glycemic control • Antecedent hypoglycemia impairs counterregulatory responses to subsequent hypoglycemia (hypoglycemia begets hypoglycemia) • Chronic hypoglycemia  unawareness In the management of Type 1 DM glucagon-emergency kit (1 mg) should be provided to the patient and ID medalert bracelet/necklace should be worn!!

  47. HYPOGLYCEMIA EVALUATION OF HYPOGLYCEMIA Obtain blood and urine tests during hypoglycemia May need 72-hr fast or mixed meal test IS THE PATIENT A DIABETIC OR NOT ???!!!!

  48. HYPOGLYCEMIA DIFFERENTIAL DIAGNOSIS ILLNESS/MEDICATION APPARENTLY ILL LIVER,KIDNEY DISEASE HEART FAILURE SEPSIS CORTISOL DEFICIENCY ETOH

  49. HYPOGLYCEMIA DIFFERENTIAL DIAGNOSIS APPARENTLY WELL POSTPRANDIAL (REACTIVE) HYPOGLYCEMIA APPARENTLY ILL ENDOG. HYPERINSULINISM INSULINOMA FUNCTL. NESIDIOBLASTOSIS Abs TO INSULIN/I-RECPTOR INS SECRETAGOGUE ACCIDENTAL/SURRETITIOUS • Descriptor of timing, not a diagnosis per se • Postprandial syndrome debunked • No correlation between glucose and symptoms • Symptoms often occur with placebo • No corresponding increase in cortisol or epi • Often psychiatric disorders • Can’t document Whipple’s Triad RARE CAUSES ARE THE SAME AS FASTING HYPOGLYCEMIA WHICH ARE CAUSED BY: ACKEE FRUIT, HEREDEITARY FRUCTOSE INTOLERANCE

  50. HYPOGLYCEMIA INSULINOMA • Insulin-producing tumor • Usually pancreatic, not metastatic • Dysregulated insulin production • Causes intermittent (fasting) hypoglycemia • Rare: 4 cases/million/yr • Peak incidence 40-50 years old • Diagnosed by unsuppressible insulin levels

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