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Acute and chronic complications of DM

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Acute and chronic complications of DM

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Acute and chronic complications of DM

  1. 1. Moderator: Dr. DINESH PURI Presenter: Dr. KAPIL DEV
  2. 2. OBJECTIVES 1. To understand the pathophysiology of acute complications of DM due to:  Diabetic Ketoacidosis  Hyperosmolar state 2. To understand the pathophysiology of chronic complications of DM due to hyperglycemia (micro vascular and macro vascular complications) 3. To gain an understanding of the mechanisms that lead to glucose induced vascular damage.
  3. 3. INTRODUCTION  Diabetes mellitus -Group of metabolic disorders that share a common feature of HYPERGLYCEMIA  Prevalence of diabetes in India- 50.8 million(2010)  Expected to rise to 87 million in 2030
  4. 4. Diabetes  Type 1 DM: absolute deficiency of insulin cause by beta cell destruction  Type 2 DM: combination of peripheral resistance to insulin action and inadequate secretory response  Results from defects in Insulin secretion, action or most commonly both
  5. 5. Pathogenesis of Type 1 DM  Lack of insulin is caused by an immunologically mediated destruction of the beta cells  Genetic susceptibility: multiple loci are associated, most commonly MHC class II  The autoimmune insult is chronic by the time the patients first presents, 80-90% b cell destruction has already occurred
  6. 6. Pathogenesis of Type 2 DM  Environmental factors play a large role (lifestyle, dietary habits etc.)  2 Metabolic defects  Decreased ability of peripheral tissues to respond to insulin  b-cell dysfunction that is manifested as impaired insulin secretion
  7. 7. COMPLICATIONS OF DIABETES Acute complications • Diabetic ketoacidosis • HHS Chronic complications • Microcvascular/ Macrovascular • Microvascular Nephro/Retino/Neuropathy • Macrovascular CAD, PVD, CVD Others
  8. 8. Hyperglycemia  Overall net reduction in effective circulation insulin with a net increase in counter regulatory hormones (epinephrine, cortisol, glucagon)  Hyperglycemia is due to:  Impaired peripheral utilization in tissue (post prandial)  Increased gluconeogenesis (fasting state)  Insulin deficiency is more prominent in DKA over HHS • HHS ketoacidosis is not seen • Glucose levels are much higher in HHS than in DKA
  9. 9. Diabetic nephropathy Diabetic nephropathy is characterized clinically as a triad of hypertension, proteinuria, and, ultimately, renal impairment
  10. 10. Retinopathy • Retinopathy has the highest correlation with severity and duration of diabetes • Hyperglycemia is the primary cause of diabetic retinopathy but the specific pathophysiologic mechanisms are not well understood.  Death of microvascular contractile cells (pericytes) and the loss of intracellular contacts which leads to microaneurysms and leakage.   Growth factors have been implicated in the development of the next phase - proliferative retinopathy.  Vascular Endothelium Growth Factor (VGEF)
  11. 11. Classification of Diabetic Retinopathy • Pre proliferative • increased vascular permeability • venous dilation • Microaneurysms • intraretinal hemorrhage • Fluid leakage • Retinal ischemia. • Proliferative • Neovascularization • Vitreous hemorrhage • Fibrous proliferation (scarring).
  12. 12. Diabetic Neuropathy  Sensorimotor neuropathy (acute/chronic)  Ulceration (painless), Charcot arthropathy, Callosities.  Autonomic neuropathy  Mononeuropathy cranial nerve palsies (mc- IV,VI,VII) Spontaneous Entrapment External pressure palsies Proximal motor neuropathy
  13. 13. MECHANISMS  Hyperglycemia and susceptibility  Endothelial cells and mesangial cells MECHANISMS  *Increased flux through Polyol pathway  *Intracellular synthesis of AGEprecursors  *Activation of PKC pathway  *Increased hexosamine pathway activity
  14. 14. POLYOL PATHWAY Nature 414:813–820, 2001.
  15. 15. Aldose reductase pathway • Certain cells are unable to regulate glucose uptake in hyperglycemic states (ex. Endothelial cells) • In a hyperglycemic state glucose is metabolized intracellularly by an enzyme aldose reductase into sorbitol and eventually into fructose • Intracellular NADPH is used as a cofactor in the pathway but is also used to regenerate glutathione • Glutathione is an antioxidant which prevent which decreases cellular susceptibility to oxidative stress
  16. 16. INCREASED AGE PRECURSORS  Non enzymatic reaction btwn sugars & amine residues  From reactive carbonyl grp like 3 deoxyglucosone, glyoxal, methylglyoxal MECHANISM:  Modification of intracellular proteins (regulation of gene transcription)  Modify extracellular matrix protein (changes signaling between the matrix and cell and causes cellular dysfunction)  Modify circulating proteins (albumin. Bind to AGE receptors and activate , causing production of inflammatory cytokines & growth factors, in turn causes vascular pathology)
  17. 17. AGE PRECURSORS
  18. 18. AGE GENERATION - CONTD  RECEPTORS:  RAGE  AGE receptor:AGE-R1, AGE-R2, and AGE-R3/galactin-3  ezrin, radixin, and moesin (ERM) family RAGE: Ig superfamily of receptors.  Activation of secondary messenger PK- C.  Target for rage signalling is NF-B transcription of intercellular adhesion molecule-1, E- selectin, endothelin 1, tissue factor, VEGF, cytokines
  19. 19. Advanced glycation products in vascular pathology.
  20. 20. Advanced glycation products in nephropathy
  21. 21. Advanced glycation products are metabolized to small peptides
  22. 22. ACTIVATION OF PK-C
  23. 23. ACTIVATION OF PK-C  Hyperglycemia ↑ synthesis of a DAG  A cofactor for protein kinase-C α, β, δ  Effects gene expression – ↓eNOS ↑endothelin ↑TGF β ↑PAI- 1 George King, showing that inhibition of PKC prevented early changes in the diabetic retina and kidney
  24. 24. INCREASED FLUX THROUGH HEXOSAMINE PATHWAY
  25. 25. INCREASED FLUX THROUGH HEXOSAMINE PATHWAY  GFAT (glutamine:fructose-6 phosphate amidotransferase)  Fructose-6 phosphate to glucosamine-6 phosphate and finally to UDP N-acetyl glucosamine.  N-acetyl glucosamine gets attached to serine and threonine residues of transcription factors  changes in gene expression  phosphorylation, and overmodification by this glucosamine often results in pathologic changes in gene expression  increased modification of Sp1  ↑TGFβ 1, PAI 1
  26. 26. SUPEROXIDE PRODUCTION BY ETC
  27. 27. SUPEROXIDE PRODUCTION BY ETC  In diabetic cells – more glucose oxidized in the TCA cycle  more NADH and FADH2  voltage gradient across mitochondrial membrane increases  Electron transfer inside complex III is blocked  coenzyme Q donates electrons to molecular oxygen, generating superoxide  Mn SOD degrades O2⁰- to H2O2 subsequently H2O and O2
  28. 28. SUPEROXIDE PRODUCTION BY ETC  Hyperglycemia ↑ production of ROS  If mitochondria ETC is removed, the effect of hyperglycemia on ROS production is lost  UCP effect mitochondrial electron transport chain is the source of the hyperglycemia-induced superoxide
  29. 29. SUPEROXIDE ACTIVATES 4 MECHANISMS Nature 414:813–820, 2001
  30. 30. UNIFIED PATHWAY  Hyperglycemia in cells, decrease activity of enzyme GAPDH  Intermediates upstream to GAPDH -↑  ↑ glyceraldehyde-3-phosphate *activates AGE pathway *activates the PKC pathway
  31. 31. UNIFIED PATHWAY  ↑ F6P increases flux through hexosamine pathwayUDP-GlcNAc  Inhibition of GAPDH increases intracellular levels glucose  ↑ flux through the polyol pathway  Hyperglycemia induced superoxide inhibits GAPDH activity by modifying the enzyme with poly ADP-ribose
  32. 32. PARP ACTIVATION
  33. 33. PARP ACTIVATION  PARP : nucleus, inactive  increased ROS in the mitochondria, induce DNA strand breaks  activating PARP  PARP splits the NAD into : nicotinic acid and ADP-ribose  PARP makes polymers of ADP-ribose accumulate on GAPDH and other nuclear proteins leads to reduced activity
  34. 34. MACROVASCULAR COMPLICATIONS
  35. 35. MACROVASCULAR COMPLICATIONS  Hyperglycemia is not the major determinant of macrovascular disease(UKPDS)  Insulin resistance ↑ FFA flux from adipocytes into arterial endothelial cells ↑ FFA oxidation  generate NADH and FADH2overproduction of ROS  Activates AGEs, PKC, the hexosamine pathway and NFB pathway
  36. 36. REFERENCES  Williams Textbook of Endocrinology 12th Edition  Brownlee M: Banting Lecture 2004,The Pathobiology of Diabetic complications.Diabetes 54:1615-27  Gohs, Copper M E, The Role of Advanced Glycation End Products in Progression and Complications of Diabetes. J Clin Endocrinol Metab, 93(4):1143–1152  Yamagashi S, Matsui T, Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxidative Medicine and Cellular Longevity 3:2, 101-108
  37. 37. Diagnostic criteria for diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS)

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