Pathogenesis DM

Diabetes Millitus

1. Pancreas Pathology Lecture-29 Dr. Imtiaz A hmad Q ureshi 2019-20

2. Learning Outcomes Identify the morphological changes in different tissues and organs due to long standing diabetes mellitus Describe pathogenesis of diabetes mellitus and its complications Describe autoimmune insulitis and amyloidosis of pancreas due to DM Describe macro and microvascular disease due to DM Identify diabetic nephropathy, retinopathy and neuropathy

3. Pathogenesis of Type -1 DM Autoimmune factors: Failure of self tolerance in T cells specific for beta cell antigens. Autoantibodies react against β-cell antigens and cause β-cell damage by release of IFN-γ from CD8+T cells and production of TNF and IL-1 from activated macrophages. Autoantibodies, detected in the blood of 70-80% of cases Genetic susceptibility P rincipal genetic susceptibility locus resides in the (HLA-D) region in chromosome 6, several non-HLA genes also confer susceptibility, resulting in excessive T cell activation and cell damage Environmental factors Viral infections, (mumps, rubella, and coxsackie B) as some of viral antigens, antigenically similar to β cell antigens leading to islets damage

4. Pathogenesis of Type 2 DM A complex multifactorial disease which involves interactions of genetics, environmental risk factors and inflammation with no autoimmune basis Genetic factors; M ore than a dozen “ diabetogenic ” genes identified (both parents diabetic; 50% risk to the child) Environmental factors; Sedentary life style, dietary habits and obesity Insulin resistance; Decreased ability of peripheral tissues to respond to insulin Beta cell dysfunction; Manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia

5. Type 2 DM: Insulin Resistance Insulin resistance is influenced by; Genetic defects of Insulin r eceptor Genetic defects of Insulin s ignaling p athway (inactivating mutations) O besity

6. Type 2 DM: Genetic Factors

7. Obesity and Insulin Resistance Role of free fatty acids (FFAs ); In obese, increased intracellular TG’s in muscle and liver and products of FFAs metabolism are potent inhibitors of insulin signaling pathways Role of Adipokines Released by adipose tissue into systemic circulation (like; leptin, adiponectin, and resistin ), changes in their levels associated with insulin resistance as for example; Adiponectin levels reduced in states of obesity causing insulin resistance where as its normal levels contributes to insulin sensitivity in peripheral tissues where as; Resistin levels increased in obesity which contributes to insulin resistance Inflammation Pro-inflammatory cytokines secreted in response to FFAs results in both insulin resistance and beta cell dysfunction

8. β-Cell Dysfunction Qualitative; when secretary defect progresses to involve all phases of insulin secretion Quantitative; a decrease in β-cell mass, islet degeneration with deposition of islet amyloid protein (amylin) ,a characteristic finding in individuals with Type 2 DM. Pathogenesis: In peripheral insulin resistance, insulin secretion is initially higher for each level of glucose in order to compensate for peripheral resistance and results in β-cell hyperplasia (as seen in the pre-diabetic state) later; followed by decrease in β-cell mass that progress to diabetes due to adverse effects of high circulating FFAs (" lipotoxicity ") or chronic hyperglycemia (" glucotoxicity “)

9. Etiologic Classification of Diabetes Mellitus Type 1 Diabetes β- cell destruction - absolute insulin deficiency Type 2 Diabetes Insulin resistance with relative insulin deficiency Genetic Defects of β- Cell Function Maturity onset diabetes of the young (MODY) caused by mutations in MODY1 to MODY6 Mitochondrial DNA mutations Genetic Defects in Insulin Processing or Insulin Action Defects in proinsulin conversion, Insulin gene mutations, Insulin receptor mutations Exocrine Pancreatic Defects Chronic pancreatitis, Pancreatectomy, Neoplasia, Cystic fibrosis, Hemochromatosis Endocrinopathies Growth hormone excess, Cushing syndrome, Hyperthyroidism, Pheochromocytoma , Glucagonoma Infections Mumps, CMV and Coxsackievirus B Drugs Glucocorticoids , Thyroid hormone and β- adrenergic agonists Genetic Syndromes Associated with Diabetes Down syndrome, Kleinfelter syndrome and Turner syndrome Gestational Diabetes Mellitus

10. Late Complications of Type I and II DM

11. Pathogenesis of Complications of DM The long-term complications of DM are similar in both types of DM and involve three underlying mechanisms 1- Non-enzymatic glycosylation 2- Activation of protein kinase C 3- Intracellular hyperglycemia- disturbances in polyol pathways

12. 1- Non-enzymatic glycosylation In this process glucose chemically attaches to free amino groups of proteins without the aid of enzymes and is directly related to blood glucose level Glycosylated hemoglobin; its levels in the blood provides an index of the average blood glucose levels over the 120-day life span of erythrocytes Advanced glycosylation end products (AGEs); formed as a result of non-enzymatic reaction between intracellular glucose precursors and amino groups of proteins

13. ADVANCED GLYCOSYLATION END PRODUCTS (AGEs) AGEs bind to a specific receptor (RAGE), which is expressed on inflammatory cells (macrophages & T cells ), endothelial cells and on vascular smooth muscle E arly glycosylation products of collagen and other long lived proteins in the interstitial tissues and blood vessel walls undergo chemical rearrangements to form irreversible AGEs which may trap non-glycosylated plasma and interstitial proteins In large vessels, trapping LDL, for example, retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima, thus accelerating atherogenesis In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the glycated basement membrane, resulting in basement membrane thickening characteristic of diabetic glomerulopathy

14. AGEs E ffects of the AGE-RAGE signaling axis within the vascular compartment includes; Release of pro-inflammatory cytokines and growth factors from intimal macrophages Generation of reactive oxygen species in endothelial cells Increased procoagulant activity on endothelial cells and macrophages Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix

15. 2- Activation of protein kinase C Activation of intracellular protein kinase C (PKC) by calcium ions and the second messenger diacylglycerol (DAG) is an important signal transduction pathway in many cellular systems Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause activation of PKC, which induces production of; Pro- angiogenic molecules; like, VEGF, involved in neovascularization seen in diabetic retinopathy Pro- fibrogenic molecules; like, TGF β, leads to increased deposition of extracellular matrix and basement membrane material

16. 3- Intracellular hyperglycemia- disturbances in polyol pathways Tissues that, do not require insulin for glucose transport (e.g., nerves, lens, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by enzyme aldose reductase to sorbitol (a polyol) and to fructose Accumulated sorbitol and fructose causes cell injury via increased intracellular osmolarity and water influx, by an increase in cellular susceptibility to oxidative stress because intracellular antioxidant reserves are diminished in the course of sorbitol metabolism

17. Morphology of Pancreas in DM Type 1 DM: Reduced number and size of islets, and Leukocyte infiltration of the islets, principally mononuclear cells, an early feature, but inflammation is often absent by the time the disease is clinically evident Type 2 DM: Amyloid replacement of islets, amyloid deposition occurs around capillaries and between cells and in advanced stages the islets may progress to fibrosis Note: non-diabetic newborns of diabetic mothers, fetal islets undergo hyperplasia in response to maternal hyperglycemia

18. Diabetic Arterial Vasculopathy Macrovascular Disease ; accelerated atherosclerosis of aorta, coronary and renal arteries ; results in MI and or gangrene of lower extremities Hyaline arteriolosclerosis; thickening of arteriolar walls, narrowing of lumen (as in hypertensive ) more prevalent and severe Microangiopathy ; diffuse thickening of vascular and nonvascular basement membranes , by hyaline material, most evident in capillaries of skin , skeletal muscle, retina, renal glomeruli , and renal medulla and in nonvascular structures like, renal tubules, Bowman capsule, peripheral nerves , and placenta * Despite increase in thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins.

19. Diabetic Nephropathy Three types of renal lesions identified: Glomerular lesions Renal vascular lesions Pyelonephritis and necrotizing papillitis

20. Diabetic - Glomerular Lesions Basement membrane thickening; of glomeruli & renal tubules Diffuse mesangial sclerosis; increase in mesangial matrix along with mesangial cell proliferation (as in old age & hypertension) associated basement membrane thickening when marked, present as nephrotic syndrome Nodular glomerulosclerosis ; Ball-like deposits of a laminated (PAS-positive) matrix in the periphery of glomerulus usually contain trapped mesangial cells called Kimmelstiel -Wilson lesion, pathognomonic of diabetes a nd is a major contributor to morbidity and mortality

21. Diabetic Renal Vascular lesions and Pyelonephritis Renal vascular lesions Renal atherosclerosis and hyaline arteriolosclerosis affects both afferent and efferent arterioles as compare to only afferent in hypertensive Pyelonephritis and necrotizing papillitis Begins as acute or chronic interstitial inflammation, then spreads to involve tubules, more common in diabetes One special pattern of acute pyelonephritis is necrotizing papillitis (or papillary necrosis), much more prevalent in diabetics than in non-diabetics Severe renal hyaline arteriolosclerosis; note markedly thickened, (PAS Positive) tortuous afferent arteriole

22. Diabetic Retinopathy Nonproliferative retinopathy Intraretinal or preretinal hemorrhages Retinal exudates ; either “soft” ( microinfarcts ) or “hard”(deposits of plasma proteins and lipids) Microaneurysms ; and venous dilations Microangiopathy ; thickening of the retinal capillaries Edema; excessive capillary permeability due to focal weakening of capillary wall by loss of capillary pericytes Edema and retinal exudates that are "soft" microinfarcts or "hard" yellowish waxy exudates

23. Retinopathy Proliferative retinopathy Neovascularization and fibrosis leads to blindness, if it involves the macula Vitreous hemorrhages can result from rupture of newly formed capillaries Retinal detachment; organization of the hemorrhage can pull the retina off its substratum (retinal detachment) Neovascularisation near optic disk when bleed, produces vitreal hemorrhages obscuring vision Advanced stage with retinal hemorrhages, exudates, neovascularization, and retinal detachment

24. Diabetic Neuropathy Both CNS and PNS are affected The most frequent pattern of involvement is that of; a peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function, particularly the latter Others; autonomic neuropathy, which produces disturbances in bowel and bladder function and sometimes sexual disorders

25. References Robbins Basic Pathology 10 th edition by Kumar Abbas Aster www.webpathology.com