diabetes mellitus.pptx

Diabetes mellitus

1. MODERATOR: Dr. RAMYA BS PRESENTER : Dr. CHITRA R PATHOLOGY AND PATHOGENESIS OF DIABETES MELLITUS

2. A 12 yr old child came with complaints of severe weight loss with polyuria after puberty A neonate develops hyperglycemia at 1 st wk of life and resolved spontanseously after 12 wks A 25 yr old male showed mild stable hyperglycemia and responds well to oral agents. A diabetic women become pregnant????? ALL ARE DM IS IT SAME OR DIFFERENT

3. OVERVIEW Definition Epidemiology Diagnosis Classification Regulation of glucose hemostasis DM 1 pathogenesis DM 2 Pathogenesis Other specific type of diabetes Gestational diabetes Complication of DM

4. Definition Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action or most commonly both.

5. Epidemiology The World Health Organization estimates that as many as 346 million people suffer from diabetes worldwide , with India and China being the largest contributors to the world’s diabetic load.

6. Diagnosis

7. Diagnosis-WHO AND ADA CRITERIA IMPAIRED GLUCOSE TOLERENCE 1.A fasting plasma glucose ≥ 126 mg/ dL 2. A random plasma glucose ≥ 200 mg/ dL ( with hyperglycemic signs) 3. 2-hour plasma glucose ≥ 200 mg/ dL during an oral glucose tolerance test (OGTT) with a loading dose of75 gm, and 4.A glycated hemoglobin (HbA1C) level ≥ 6.5% DIABETES MILLETUS 1. A fasting plasma glucose between 100 and 125 mg/ dL (“ impaired fasting glucose”), 2. 2-hour plasma glucose between 140 and 199 mg/Dl following a 75-gm glucose OGTT, and/or 3. A glycated hemoglobin (HbA1C) level between 5.7%and 6.4%

8. CLASSIFICATION Type 1 diabetes is an autoimmune disease characterized by pancreatic β cell destruction and an absolute deficiency of insulin. Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells (“ relative insulin deficiency ”). OTHER SPECIFIC TYPE OF DIABETES. GESTATIONAL DIABETES.

9. REGULATION OF GLUCOSE HEMOSTASIS Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium, but neural input , metabolic signals, and other hormones (e.g., glucagon) result in integrated control of glucose supply and utilization.

10. NORMAL PANCREAS

11. REGULATION OF GLUCOSE HEMOSTASIS INSULIN BIOSYNTHESIS: Insulin is produced in the beta cells of the pancreatic islets.

12. REGULATION OF GLUCOSE HEMOSTASIS INSULIN SECRETION : Glucose is the key regulator of insulin secretion by the pancreatic beta cell. Glucose stimulation of insulin secretion begins with its transport into the beta cell by a facilitative glucose transporter.

13. REGULATION OF GLUCOSE HEMOSTASIS INSULIN SECRETION :

14. REGULATION OF GLUCOSE HEMOSTASIS INSULIN SECRETION : Oral intake of food leads to secretion of multiple hormones that play a role in glucose homeostasis and satiety. Of these, the most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding is the incretins . Two incretins have been identified : 1 . glucose-dependent insulinotropic polypeptide (GIP) - “K cells” in the proximal small bowel 2. glucagon-like peptide-1 (GLP-1 )- L cells in the distal ileum and colon.

15. REGULATION OF GLUCOSE HEMOSTASIS INSULIN SECRETION: Once released, circulating GIP and GLP-1 are degraded in circulation by a class of enzymes known as dipeptidyl peptidase (DPPs), especially DPP-4. GLP-1 receptor agonists and DPP-4 inhibitors

16. REGULATION OF GLUCOSE HEMOSTASIS INSULIN ACTION:

17. REGULATION OF GLUCOSE HEMOSTASIS INSULIN ACTION ON THE TARGET CELL:

18. PATHOGENEISIS OF TYPE -1 DM Type 1 DM is the result of interactions of genetic, environmental and immunologic factors that ultimately lead to the destruction of the pancreatic beta cells and insulin deficiency. Can develop at any age, develops most commonly before 20 years of age. Incidence of type 1 DM is increasing at the rate of 3–4% per year for uncertain reasons.

19. PATHOGENEISIS OF TYPE -1 DM Genetic Susceptibility: Susceptibility to type 1 DM involves multiple genes. Of these, the most important locus is the HLA gene cluster on chromosome 6p21, which according to some estimates contributes as much as 50% of the genetic susceptibility to type 1 diabetes. This region contains genes that encode the class II major histocompatibility complex (MHC) molecules which present antigen to helper T cells and thus are involved in initiating the immune response

20. PATHOGENEISIS OF TYPE -1 DM Genetic Susceptibility: Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplotype . Haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are most strongly associated with type 1 DM. In addition to MHC class II associations, genome association studies have identified at least 20 different genetic loci that contribute susceptibility to type 1 DM (polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin 2 receptor, CTLA4, and PTPN22) The haplotype DQA1*0102,DQB1*0602

21. PATHOGENEISIS OF TYPE -1 DM Insulin Gene Locus, IDDM2: It is estimated that this locus accounts for approximately 10% of the familial risk of T1DM. This highly polymorphic region consists of anywhere from 30 to several hundred repeats of a 14-15 bp unit sequence (ACAGGGGTCTGGGG). A shorter number of repeats is associated with increased risk of T1DM. PTPN22 (Lymphoid Tyrosine Phosphatase ): A single-nucleotide polymorphism in the PTPN22 gene on chromosome 1p13 that encodes lymphoid tyrosine phosphatase correlates strongly with the incidence of T1DM

22. PATHOGENEISIS OF TYPE -1 DM Cytotoxic T Lymphocyte Antigen 4: The cytotoxic T lymphocyte antigen 4 (CTLA-4) gene is located on chromosome 2q33 and is associated with T1DM and other autoimmune disease. This gene is a negative regulator of T-cell activation. Interleukin-2 Receptor: Single-nucleotide polymorphisms in or near the gene for the IL-2 receptor have been found to have an association with T1DM risk.

23. PATHOGENEISIS OF TYPE -1 DM Interleukin-1 Receptor: IL-1 receptor activation and chemokines involved in monocyte /macrophage and neutrophil chemotaxis have been also identified as critical steps in nitric oxide–induced islet necrosis and subsequent apoptosis. Interferon-Induced Helicase : Significant association exists with T1DM as well as Graves disease and multiple sclerosis. CYP27B1: Cytochrome P450, subfamily 27, polypeptide 1 gene encodes vitamin D 1 α- hydroxylase .

24. PATHOGENEISIS OF TYPE -1 DM Environmental Factors: 1.Viral infections: Have been suggested as triggers for development of the disease. Some studies suggest that viruses might share epitopes with islet antigens and the immune response to the virus results in cross-reactivity and destruction of islet tissues, a phenomenon known as molecular mimicry.

25. PATHOGENEISIS OF TYPE -1 DM Environmental Factors: 2.Congenital Rubella Syndrome: Prenatal infection with rubella is associated with β-cell autoimmunity in up to 70%, with development of T1DM in up to 40% of infected children. The time lag between infection and development of diabetes may be as high as 20 yr. Interestingly, there appears to be no increase in risk of diabetes when rubella infection develops after birth or when live-virus rubella immunization is used.

26. PATHOGENEISIS OF TYPE -1 DM Environmental Factors: 3.Enteroviruses 4. Mumps Virus 5. The Hygiene Hypothesis: Possible Protective Role of Infections 6. Diet 7. Psychologic Stress

27. PATHOGENEISIS OF TYPE -1 DM Thus, the natural history of T1DM involves some or all of the following stages: 1. Initiation of autoimmunity 2.Preclinical autoimmunity with progressive loss of β-cell function 3. Onset of clinical disease 4. Transient remission 5. Established disease 6. Development of complications

28. NATURAL HISTORY OF DM-1

29. PATHOGENEISIS OF TYPE -1 DM Mechanisms of β Cell Destruction: The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells specific for islet antigens. The initial activation of these cells is thought to occur in the peripancreatic lymph nodes, perhaps in response to antigens that are released from damaged islets. Multiple T-cell populations have been implicated in this damage, including TH1 cells and CD8+ CTLs. The islet autoantigens that are the targets of immune attack may include insulin, the β cell enzyme glutamic acid decarboxylase (GAD), and islet cell autoantigen 512 (ICA512).

30. PATHOGENEISIS OF TYPE -1 DM

31. TYPE -2 DM Type 2 diabetes is a complex disease that involves an interplay of genetic and environmental factors and a proinflammatory state. Most studies support the view that insulin resistance precedes an insulin secretory defect but that diabetes develops only when insulin secretion becomes inadequate.

32. PATHOGENEISIS OF TYPE -2 DM Genetic factors Environmental factors

33. PATHOGENEISIS OF TYPE -2 DM Genetic factors : Type 2 DM has a strong genetic component. The disease is polygenic and multifactorial , because in addition to genetic susceptibility, environmental factors . The genes that predispose to type 2 DM are incompletely identified. Most prominent is a variant of the transcription factor 7–like 2 gene.

34. PATHOGENEISIS OF TYPE -2 DM Genetic factors : Genetic polymorphisms associated with type 2 DM have also been found in the genes encoding the peroxisome proliferator – activated receptor γ, inward rectifying potassium channel, zinc transporter, IRS, and calpain 10. The mechanisms by which these genetic loci increase the susceptibility to type 2 DM are not clear, but most are predicted to alter islet function or development or insulin secretion .

35. PATHOGENEISIS OF TYPE -2 DM Environmental factors: The most important environmental risk factor for type 2 diabetes is obesity, particularly central or visceral obesity. Obesity contributes to the cardinal metabolic abnormalities of diabetes and to insulin resistance early in disease.

36. PATHOGENEISIS OF TYPE -2 DM Metabolic Defects in Diabetes: The two cardinal metabolic defects that characterize type 2 diabetes are: Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin( insulin resistance) Inadequate insulin secretion in the face of insulin resistance and hyperglycemia ( β- cell dysfunction)

37. PATHOGENEISIS OF TYPE -2 DM Insulin Resistance: Insulin resistance is the failure of target tissues to respond normally to insulin. Insulin resistance results in : 1. Failure to inhibit endogenous glucose production ( gluconeogenesis ) in the liver, which contributes to high fasting blood glucose levels. 2. Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal, which contributes to high post- prandial blood glucose level. 3. Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs), which in turn, amplify the state of insulin resistance.

38. PATHOGENEISIS OF TYPE -2 DM The precise molecular mechanism leading to insulin resistance in type 2 DM has not been elucidated. Reduced tyrosine phosphorylation of the insulin receptor and IRS proteins is observed in peripheral tissues, which compromises insulin signaling and reduces the level of the glucose transporter GLUT-4 on the cell surface . In fact, one of the mechanisms by which exercise can improve insulin sensitivity is through increased translocation of GLUT-4 to the surface of skeletal

39. PATHOGENEISIS OF TYPE -2 DM Obesity and Insulin Resistance: The risk for diabetes increases as the body mass index increases. Obesity can adversely impact insulin sensitivity in numerous ways -Free fatty acids. - Adipokines . -Inflammation.

40. PATHOGENEISIS OF TYPE -2 DM Free fatty acids: Excess FFAs overwhelm the intracellular fatty acid oxidation pathways leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG). These “toxic” intermediates can attenuate signaling through the insulin receptor pathway. Attenuated insulin signaling allows phosphoenolpyruvate carboxykinase to “ramp up” gluconeogenesis

41. PATHOGENEISIS OF TYPE -2 DM Adipokines : A variety of proteins secreted into the systemic circulation by adipose tissue have been identified and these are collectively termed adipokines . Some of these promote hyperglycemia, and other adipokines (such as leptin and adiponectin ) decrease blood glucose, in part by increasing insulin sensitivity in peripheral tissues. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance.

42. PATHOGENEISIS OF TYPE -2 DM Inflammation: Proinflammatory cytokines that are secreted in response to excess nutrients such as free fatty acid (FFAs) and glucose results in both insulin resistance and β-cell dysfunction. Excess FFAs within macrophages and β cells can activate the inflammasome , a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin IL-1β. IL-1 and other cytokines are released into the circulation and act on the major sites of insulin action to promote insulin resistance

43. PATHOGENEISIS OF TYPE -2 DM

44. PATHOGENEISIS OF TYPE -2 DM β- Cell Dysfunction: Several mechanisms have been implicated in promoting β-cell dysfunction in type 2 diabetes, including: Excess free fatty acids that compromise β cell function and attenuate insulin release (“ lipotoxicity ”). The impact of chronic hyperglycemia (“ glucotoxicity ”). An abnormal “ incretin effect,” leading to reduced secretion of GIP and GLP-1, hormones that promote insulin release. Amyloid deposition within islets.

45. GENETIC DEFECTS OF Β-CELL FUNCTION A. MODY (maturity-onset diabetes of the young) syndromes 1. MODY 1 chromosome 20, HNF4α 2. MODY 2 chromosome 7, glucokinase 3. MODY 3 chromosome 12, HNF1α, TCF-1 4. MODY 4 chromosome 13, IPF-1 5. MODY 5 chromosome 17, HNF1β, TCF-2 6. MODY 6 chromosome 2q32, neuro-D1/ β2 B. Mitochondrial DNA mutations (includes 1 form of Wolfram syndrome, Pearson syndrome, Kearns-Sayre, diabetes mellitus,deafness ) C. Wolfram syndrome—DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness): WFS1-Wolframin—chromosome 4p 1. Wolfram locus 2—chromosome 4q22-24 2. Wolfram mitochondrial D. Thiamine responsive megaloblastic anemia and diabetes

46. MATURITY-ONSET DIABETES OF YOUNG This subtype of DM consists of a group of heterogeneous clinical entities that are characterized by onset before 25 yr, autosomal dominant inheritance and a primary defect in insulin secretion. Strict criteria for the diagnosis of MODY include diabetes in at least 3 generations with autosomal dominant transmission and diagnosis before age 25 yr in at least 1 affected subject.

47. MATURITY-ONSET DIABETES OF YOUTH

48. MITOCHONDRIAL DNA MUTATIONS Point mutations in mitochondrial DNA are sometimes associated with maternally inherited DM and deafness. The most common mitochondrial DNA mutation in these cases is the point mutation m.3243A>G in the transfer RNA leucine gene. Diabetes in most of these cases presents insidiously but approximately 20% of patients have an acute presentation resembling T1DM. The mean age of diagnosis of diabetes is 37 yr

49. WOLFRAM SYNDROME Wolfram syndrome 1 is characterized by diabetes insipidus , DM, optic atrophy, and deafness—thus the acronym DIDMOAD. Wolfram syndrome 2 has early-onset optic atrophy , DM, deafness, and a shortened life span but no diabetes insipidus ;

50. DIABETES MELLITUS OF THE NEWBORN Transient Neonatal Diabetes Mellitus: The syndrome of transient DM in the newborn infant has its onset in the 1st wk of life and persists several weeks to months before spontaneous resolution. Median duration is 12 wk. It occurs most often in infants who are small for gestational age and is characterized by hyperglycemia and pronounced glycosuria , resulting in severe dehydration. About 70% of cases are due to a bnormalities of an imprinted locus on chromosome 6q24. Most of the remaining cases are caused by mutations in KATP channels

51. DIABETES MELLITUS OF THE NEWBORN Permanent Neonatal Diabetes Mellitus: Permanent DM in the newborn period is caused in approximately 50% of the cases by mutations in the KCNJ11 (potassium inwardly-rectifying channel J, member 11) and ABCC8 (adenosine triphosphate–bindingcassette , subfamily C, member 8) genes. The most severely affected patients have the syndrome of developmental delay, epilepsy and neonatal diabetes(DEND syndrome).

52. DIABETES MELLITUS OF THE NEW BORN IPEX Syndrome: IPEX means immunodysregulation,polyendocrinopathy , and enteropathy,X -linked. In most patients with IPEX, mutations in the FOXP3 ( Forkhead box P3) gene, a specific marker of natural and adaptive regulatory T cells, leads to severe immune dysregulation and rampant autoimmunity. Autoimmune diabetes develops in >90% of cases,usually within the 1st few wk of life.

53. GENETIC DEFECTS OF INSULIN ACTION Various genetic mutations in the insulin receptor can impair the action of insulin at the insulin receptor or impair postreceptor signaling leading to insulin resistance. Type A insulin resistance. Donohue Syndrome. Rabson -Mendenhall Syndrome. Lipoatrophic Diabetes. Stiff-Person Syndrome. Systemic Lupus Erythematosus

54. GESTATIONAL DIABETES Definition: Women who were previously euglycemic develop impaired glucose tolerance and diabetes for the first time during pregnancy is called gestational diabetes . Mechanism: Pregnancy is a “ diabetogenic ” state in which the prevailing hormonal milieu favors a state of insulin resistance .

55. GESTATIONAL DIABETES NICE CRITERIA FOR DIAGNOSIS OF GDM Fasting blood glucose level >126 mg/dl A blood glucose >140 mg/dl measured 2 hour after 75 gram of oral glucose tolerenec test

56. The Classic Triad of Diabetes The onset of type 1 diabetes is usually marked by the triad of polyuria , polydipsia , polyphagia , and, when severe diabetic ketoacidosis all resulting from metabolic derangements.

57. COMPLICATIONS Acute complications: 1.Diabetic ketoacidosis . 2. Hyperosmolar hyperosmotic syndrome. 3. Hypoglycemia. Chronic complications: 1. Diabetic macrovascular disease. 2. Diabetic microvascular disease .

58. ACUTE METABOLIC COMPLICATIONS OF DIABETES 1.Diabetic ketoacidosis : Severe acute metabolic complication of type 1 diabetes. The most common precipitating factor is a failure to take insulin, although other stressors such as intercurrent infections, illness, trauma and certain drugs might also lead to this complication.

59. ACUTE METABOLIC COMPLICATIONS OF DIABETES The hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. Infections, illness, trauma Release of the catecholamine epinephrine The insulin deficiency coupled with glucagon excess causes hyperglycemia.

60. ACUTE METABOLIC COMPLICATIONS OF DIABETES The second major effect of insulin deficiency is activation of the ketogenic machinery.

61. ACUTE METABOLIC COMPLICATIONS OF DIABETES The clinical manifestations of diabetic ketoacidosis include fatigue, nausea and vomiting, severe abdominal pain, a characteristic fruity odor, and deep, labored breathing(also known as Kussmaul breathing).

62. ACUTE METABOLIC COMPLICATIONS OF DIABETES 2.HYPEROSMOLAR HYPEROSMOTIC SYNDROME: Type 2 diabetics may develop a condition known as hyperosmolar hyperosmotic syndrome (HHS) due to severe dehydration resulting from sustained osmotic diuresis . Furthermore, the absence of ketoacidosis and its symptoms (nausea, vomiting, Kussmaul breathing) delays the seeking of medical attention. The hyperglycemia is usually more severe than in diabetic ketoacidosis , in the range of 600 to1200 mg/Dl.

63. ACUTE METABOLIC COMPLICATIONS OF DIABETES 3.HYPOGLYCEMIA: The most common acute metabolic complication. Usually as a result of having missed a meal, excessive physical exertion, an excess insulin administration, or during the phase of dose finding for antidiabetic agents. The signs and symptoms of hypoglycemia include dizziness,confusion , sweating, palpitations, and tachycardia; if hypoglycemia persists, loss of consciousness may occur.

64. CHRONIC METABOLIC COMPLICATIONS OF DIABETES

65. CHRONIC METABOLIC COMPLICATIONS OF DIABETES At least four distinct mechanisms have been implicated in the deleterious effects of persistent hyperglycemia on peripheral tissues Formation of Advanced Glycation End Products. Activation of Protein Kinase C. Oxidative Stress and Disturbances in Polyol Pathways. Hexosamine Pathways and Generation of Fructose-6-Phosphate.

66. CHRONIC METABOLIC COMPLICATIONS OF DIABETES 1.Formation of Advanced Glycation End Products: Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between intracellular glucose derived dicarbonyl precursors with the amino groups of both intracellular and extracellular proteins. AGEs bind to a specific receptor (RAGE) that is expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle.

67. CHRONIC METABOLIC COMPLICATIONS OF DIABETES 1.Formation of Advanced Glycation End Products: The detrimental effects of the AGE-RAGE signaling axis within the vascular compartment include: Release of cytokines and growth factors. Generation of reactive oxygen species (ROS) in endothelial cells. Increased procoagulant activity on endothelial cells and macrophages. Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix.

68. CHRONIC METABOLIC COMPLICATIONS OF DIABETES In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins. Crosslinking of collagen type I molecules in large vessels decreases their elasticity, which may predispose these vessels to shear stress and endothelial injury. AGE-induced cross-linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid. AGE-modified matrix components also trap nonglycated plasma or interstitial proteins(accelerating atherogenesis , diabetic microangiopathy ).

69. CHRONIC METABOLIC COMPLICATIONS OF DIABETES 2. Activation of Protein Kinase C: Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic intermediates, and hence causes excessive PKC activation. The downstream effects of PKC activation are numerous, including production of VEGF, TGF-β, and the procoagulant protein plasminogen activator inhibitor-1 (PAI-1) by the vascular endothelium.

70. CHRONIC METABOLIC COMPLICATIONS OF DIABETES 3 . Oxidative Stress and Disturbances in Polyol Pathways: Even in some tissues that do not require insulin for glucose transport (e.g., nerves, lenses, kidneys, blood vessels), persistent hyperglycemia in the extracellular milieu leads to an increase in intracellular glucose. This excess glucose is metabolized by the enzyme aldose reductase to sorbitol , a polyol , and eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor.

71. CHRONIC METABOLIC COMPLICATIONS OF DIABETES 4 . Hexosamine Pathways and Generation of Fructose-6-Phosphate: Finally it is postulated that hyperglycemia induced flux through the hexosamine pathway increases intracellular levels of fructose-6-phosphate, which is a substrate for glycosylation of proteins, leading to generation of excess proteoglycans . These glycosylation changes are accompanied by abnormal expression of TGFβ or PAI-1 which further exacerbate the end-organ damage.

72. MORPHOLOGY OF DIABETES

73. MORPHOLOGY PANCREAS: TYPE 1 DM: Reduction in the number and size of islets Leukocytic infiltrates in the islets TYPE 2 DM: Subtle reduction in islet cell mass, demonstrated only by special morphometric studies. Amyloid deposition within islets in type 2 diabetes An increase in the number and size of islets is especially characteristic of nondiabetic newborns of diabetic mothers INSULITIS AMYLOID DEPOSITION

74. MORPHOLOGY Diabetic Macrovascular Disease: The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. Myocardial infarction caused by atherosclerosis of the coronary arteries is the most common cause of death in diabetics. Gangrene of the lower extremities, as a result of advanced vascular disease is about 100 times more common in diabetics than in the general population.

75. MORPHOLOGY Diabetic Microangiopathy : One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy.

76. MORPHOLOGY Diabetic Nephropathy: The kidneys are prime targets of diabetes. Three lesions are encountered: Glomerular lesions . Renal vascular lesions . Pyelonephritis

77. Diabetic Nephropathy 1. Glomerular lesions : The most important glomerular lesions Capillary basement membrane thickening Diffuse mesangial sclerosis Nodular glomerulosclerosis .

78. Diabetic Nephropathy Capillary Basement Membrane Thickening: Widespread thickening of the glomerular capillary basement membrane(GBM) occurs in virtually all cases of diabetic nephropathy and is part and parcel of the diabetic microangiopathy .

79. Diabetic Nephropathy Diffuse Mesangial Sclerosis: This lesion consists of diffuse increase in mesangial matrix. The mesangial increase is typically associated with the overall thickening of the GBM. The matrix depositions are PAS-positive. The progressive expansion of the mesangium has been shown to correlate well with measures of deteriorating renal function such as increasing proteinuria .

80. Diabetic Nephropathy Nodular Glomerulosclerosis : This is also known as intercapillary glomerulosclerosis or Kimmelstiel -Wilson disease. The glomerular lesions take the form of ovoid or spherical, often laminated nodules of matrix situated in the periphery of the glomerulus . The nodules are PAS-positive.

81. Diabetic Nephropathy They lie within the mesangial core of the glomerular lobules and can be surrounded by patent peripheral capillary loops As the disease advances, the individual nodules enlarge and may eventually compress and engulf capillaries, obliterating the glomerular tuft. These nodular lesions are frequently accompanied by prominent accumulations of hyaline material in capillary loops (“ fibrin caps”) or adherent to Bowman capsules (“capsular drops”).

82. Diabetic Nephropathy As a consequence of the glomerular and arteriolar lesions, the kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes overall contraction in size

83. Diabetic Nephropathy Hyaline arteriolosclerosis: The vascular lesion associated with hypertension is both more prevalent and more severe in diabetics than in nondiabetics . It takes the form of an amorphous hyaline thickening of the wall of the arterioles which causes narrowing of the lumen.

84. Diabetic Nephropathy Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules. One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics .

85. OPHTHALMOLOGIC COMPLICATIONS OF DIABETES MELLITUS DIABETIC RETINOPATHY: It refers to changes seen in patients with diabetes mellitus. DM is the leading cause of blindness between the ages of 20 and 74 Risk factors: Duration of diabetes mellitus Poor metabolic control Hereditary Pregnancy Hypertension Other risk factors( smoking,obesity,anemia,hyperlipidemia )

86. DIABETIC RETINOPATHY

87. DIABETIC RETINOPATHY Classification: Non-proliferative diabetic retinopathy Proliferative diabetic retinopathy Diabetic maculopathy Advanced diabetic eye disease

88. DIABETIC RETINOPATHY 1.NON-PROLIFERATIVE DIABETIC RETINOPATHY : includes a spectrum of changes resulting from structural and functional abnormalities of retinal vessels (i.e., confined beneath the internal limiting membrane of the retina). - Microanerysms -Retinal hemorrhage - Oedema -Hard exudates -Cotton-wool spots -Venous abnormalities - Intraretinal microvascular abnormalities -Dark –blot hemorrhages.

89. DIABETIC RETINOPATHY

90. DIABETIC RETINOPATHY 2.PROLIFERATIVE DIABETIC RETINOPATHY: is defined by the appearance of new vessels sprouting on the surface of either the optic nerve head or the surface of the retina. The term “retinal neovascularization ” is only applied when the newly formed vessels breach the internal limiting membrane of the retina. The neovascularisation leads to retinal detachment and neovascular glaucoma.

91. DIABETIC RETINOPATHY

92. DIABETIC NEUROPATHY Diabetes is the most common cause of peripheral neuropathy. The most common is an ascending distal symmetric sensorimotor polyneuropathy . PATHOGENESIS: Excess glucose within cells is reduced to sorbitol , a process that depletes NADPH and increases intracellular osmolality . These and other metabolic disturbances may predispose peripheral nerves to injury by reactive oxygen species.

93. DIABETIC NEUROPATHY MORPHOLOGY Nerve biopsies show reduced numbers of axons. Variable degrees of ongoing axonal damage, marked by degenerating myelin sheaths. Endoneurial arterioles show thickening, hyalinization and intense periodic acid–Schiff positivity.

94. OTHER COMPLICATIONS OF DIABETES GASTROINTESTINAL/GENITOURINARY DYSFUNCTION: The most prominent GI symptoms are delayed gastric emptying ( gastroparesis ) and altered small- and large-bowel motility (constipation or diarrhea). Parasympathetic dysfunction secondary to chronic hyperglycemia is important in the development of gastroparesis , hyperglycemia itself also impairs gastric emptying.

95. OTHER COMPLICATIONS OF DIABETES GASTROINTESTINAL/GENITOURINARY DYSFUNCTION: Diabetic autonomic neuropathy may lead to genitourinary dysfunction including cystopathy and female sexual dysfunction Symptoms of diabetic cystopathy begin with an inability to sense a full bladder and a failure to void completely. Erectile dysfunction and retrograde ejaculation are very common in DM and may be one of the earliest signs of diabetic neuropathy.

96. OTHER COMPLICATIONS OF DIABETES INFECTIONS: Individuals with DM have a greater frequency and severity of infection. The reasons for this include incompletely defined abnormalities in cell-mediated immunity and phagocyte function associated with hyperglycemia, as well as diminished vascularization . S everal rare infections are seen almost exclusively in the diabetic population. Examples of this category include rhinocerebral mucormycosis , emphysematous infections of the gallbladder and urinary tract, and “malignant” or invasive otitis externa

97. OTHER COMPLICATIONS OF DIABETES DERMATOLOGIC MANIFESTATIONS: xerosis and pruritus pigmented pretibial papules, or “diabetic skin spots,” Bullosa diabeticorum Necrobiosis lipoidica diabeticorum Acanthosis nigricans granuloma annulare sclerederma

98. References Robbins and cotran pathological basis of disease 9 th edition. Nelson textbook of pediatrics , 20 th edition. Harrison’s prinicples of internal medicine ,19 th edition. Textbook of biochemistry for medical students,7 th edition.