L4-Diabetes Mulitas.pptx

Diabetes Mulitas (DM) DM Definitions: DM is defined as “group of metabolic disorders characterized by persistent hyperglycemia”. It has specific criteria to be diagnosed. Prediabetes (impaired glucose tolerance) is defined as “a status of elevated blood glucose level that is still does NOT rea...

Diabetes Mulitas (DM) DM Definitions: DM is defined as “group of metabolic disorders characterized by persistent hyperglycemia”. It has specific criteria to be diagnosed. Prediabetes (impaired glucose tolerance) is defined as “a status of elevated blood glucose level that is still does NOT reach the criteria of DM”. It has specific criteria to be diagnosed. The classical symptoms of DM are: polyuria, polydipsia, and polyphagia. Criteria To Dx. DM Classification of DM And Their Pathophysiology Type-1 DM: It is “an autoimmune process against endogenous pancreatic β-cells”. Represent 5-10% of the cases in general. It is the commonest type of DM in children and people younger than 20 years. Those patients have absolute insulin insufficiency and they will depend on exogenous insulin. Type-1 DM: Although the onset is abrupt, the autoimmune process is chronic and started years ago but it will NOT be manifested until 90% of β-cells are destroyed. This type is characterized by failure of self-tolerance in Tcells against β-cells → Autoactivation of T-cells → Activation of B-cells → Formation of auto-Ab against β-cells (which can be detected in the blood of 80% of the cases) → Destruction of β-cells. Examining the pancreas in the early process shows islets of β-cells necrosis and lymphocytic infiltrates (insulitis). Type-1 DM: Why failure of self-tolerance in Tcells against β-cells happen? Genetic Factors Environmental Factors Type-1 DM: For the genetic factor, there are many genes involved in the process. The strongest association is with MHC (HLADR) genes that are present in 95%. The genes are contributing but NOT causing the disease by themselves. The genetic factor in this type is NOT as strongest as in type-2, which is cleared by observing monozygotic twins. Type-1 DM: For the environmental factor: Infections: like viral infection (Mumps, Rubella, Coxsacki-B) that may have similar Ag to β-cells. Human microbiome: dysbiosis (changes in normal flora composition) esp. the intestine may lead to type-1 DM through unknown mechanism. Type-2 DM: The commonest type of DM. It is a multifactorial disease showing combination of: Genetic Factors Environmental Factors Inflammatory Factors (Mutliple diabetogenic genes and 90% Monozygous twins) All of these factors leads to TWO significant defects:  Insulin resistance by peripheral tissues.  Inadequate insulin production due to β-cells dysfunction. Insulin Resistance: It defined as “failure of targeted tissues to respond normally to insulin”. This leads to: Failure to inhibit gluconeogenesis in the liver. So gluconeogenesis will continue and produce more glucose. ↓ glucose uptake & glycogenesis in the muscles. So the glucose will stay in the blood. Failure to inhibit lipase in adipose tissue. So lipase will continue to work, leading to excessive circulation of FFA. Insulin Resistance: One of the major factors that’s contributing in the development of insulin resistance is OBESITY. Obesity leads to abnormality in intracellular insulin signaling cascade esp. central (visceral) obesity. This happen because of many ways include: Excessive FFA in obesity: discussed later. Adipokines (adipose cytokines): discussed later. Inflammation: FFA induce inflammation → release of some cytokines that cause insulin resistance & β-cells dysfunction. Excess FFA: Excess FFA participate in the pathogenesis of type-2 DM by: FFA induce inflammation. Intracellular triglyceride & other metabolic products of FFA inhibit the intracellular signaling cascade of the insulin.  Therefor, there is proportional relationship between fasting plasma FFA and insulin resistance. Adipokines: The adipose tissue can release some hormones in response to human metabolic status. These hormones called “Adipokines”. Some of these adipokines promotes hyperglycemia, whereas others inhibit it as leptin & adiponectin. Leptin & adiponectin increase insulin sensitivity. Unfortunately, their levels decrease in obesity. β-cells Dysfunction: In the early stage of DM, there will be β-cells hypertrophy & hyperplasia as a compensatory response for hyperglycemic status. In late stage, β-cells become unable to adapt, leading to relatively insulin deficiency. This happen due to: β-cells lipotoxisity: by FFA. Glucotoxisity: by the chronic hyperglycemia. Decrease incretin levels. Amyloid deposition in β-cells (90% of the cases). Differences Between Type-1 and Type-2 DM: Monogenic DM: This type of DM occur as a result of mutation/deletion of SINGLE gene. There are multiple genes in which mutation/deletion of one of them can lead to DM. These genes are involved in β-cells function, insulin receptor formation, insulin function, or insulin intracellular signaling cascade. These genes are in both nucleus & mitochondrial DNA. Gestational DM: A type of DM that is arising during pregnancy. Occur in 5% of pregnant women. Pregnancy by itself is a diabetogenic status due to the hormones. Although it is usually resolved after delivery, those patients still have increase risk for DM. Gestational DM: Hyperglycemia can lead to stillbirth & some congenital anomalies; therefore, blood glucose level must be controlled. The most important anomaly is “macrosomia” which occur due to increase release of insulin-like growth factors in the fetus as a compensatory response to maternal hyperglycemic status. Complications of DM Complications of DM: Complications of DM Acute Diabetic Ketoacidosis (for type-1) NonKetoacidosis Diabetic coma (for type-2) Chronic Neuropathy, Retinopathy, Nephropathy, Vasculopathy, Others Diabetic Ketoacidosis: Arising in type-1 DM where there is absolute insulin deficiency (insulin inhibit ketogenesis). Always associated with stress. Usually blood glucose level exceed 500 mg/dl. In this scenario, there will be activation of ketogenic pathway to form “Keton Bodies (KB)” by the liver as a source of energy to the organs. Diabetic Ketoacidosis: In type-1 DM, the initial 2 years after the Dx (Honeymoon period) required minimal dose of insulin because still there are some remaining β-cells. Later, the amount is increased esp. during stressful situations. Diabetic Ketoacidosis: NO Insulin + ↑ Energy Demand ↑ Lipolysis ↑ FFA Converted to KB by the Liver KB are acid. Since the rate of KB formation exceeds the rate of their utilization & excretion in the urine (due to dehydration), number of KB in the blood will increase, leading to “metabolic acidosis”. Presented with nausea, vomiting, dehydration, respiratory difficulties, & a highly characteristic smell. Non-Ketoacidosis Coma: Diabetic Arising in type-2 DM where most of the cases discovered incidentally during in asymptomatic patients. In decompensated hyperosmolar non-ketotic DM, there will be severe dehydration because most of the patients are disable (by stroke) or have very stressful situation with inadequate water intake. NO KB. Chronic of DM: Complications Occur due to damage to all kinds of B.V.: Micro-vascular diseases: affecting renal, retinal, & PNS. Macro-vascular diseases: accelerate atherosclerosis & its complications (MI, stroke, ischemia). The duration from the Dx to the appearance of chronic complications, their severity, and particular organ involved is extremely variable. Tight control of blood glucose level in diabetic patients is important to delay those complications. Chronic of DM: Complications Why chronic complications occur in Due to multifactorialDM? pathophysiology in which glucotoxicity is the key player. 3 major changes are involved in this process: Formation of Advanced Glycation Endproducts (AGE) Activation of Protein Kinase C Disturbance of Polyol Pathways Formation of AGE: A non-enzymatic reaction between proteins leads to the formation of AGE. the glucose & AGE is bind to a specific receptor called RAGE. This receptor is located in inflammatory cells, endothelial cells, & vascular smooth muscle cells. Formation of AGE: Once AGE binds to RAGE, intracellular signals are generated and causing: Release of cytokins & growth factors which cause excess deposition of BM & proliferation of capillaries. Generation of ROS (Reactive oxygen species). ↑ Procoagulant activation. Synthesis of ECM. AGE is also cross-linked with extracellular proteins, leading to protein entrapment as LDL in the wall of B.V. Activation Kinase C: of Protein This intracellular enzyme is activated by Ca+2. It is important in many intracellular events like: ↑ Production of proangiogenic molecules like VEGF. ↑ Deposition of ECM & BM materials. Disturbance Pathway: of Polyol In non-insulin-dependent tissues, glucose is metabolized by enzyme that use NADPH. NADPH is essential for regeneration (endogenous anti-oxidant molecule). ↑ Consumption of NADPH ↓ NADPH NO Glutathione Regeneration of ↑ ROS glutathion ↑ Tissue Damage This scenario happen esp. in the nerves (glucose neurotoxicity). Morphology of DM Morphology of DM: All these changes are related to the causes or compilations of DM. Pancreatic Changes in DM Morphology of DM: ↑ Size & Numbers of Islets Occur in the early phase of type-2 and in the infants of diabetic mothers as a compensatory mechanism ↓ Size & Numbers of Islets Occur in type-1 and in the late phase of type-2. The islets become small to the point that they become very difficult to be recognized. Lymphocytic Infiltration into The Islets [Insulitis] Mainly in type-1 and most of the cells are T-cells. Amyloid Deposition Mainly in type-2. The amyloid will be in & around the capillaries and between the cells of islets. Later, it may obliterate the islets. Insulitis shows lymphocytic inflammation around the islets Amyloid deposition Morphology of DM: Diabetic macrovascular diseases occur due to accelerated atherosclerosis process which morphologically indistinguishable from non-diabetic cases. Hyaline atherosclerosis shows amorphous hyaline pinkish material deposition in the wall of the arteries, causing narrowing to the lumen. It is NOT specific morphological changes. These changes can cause ischemia as MI, CVA, & lower extremities ischemia. Renal hyaline arteriolosclerosis shows markedly thickened tortuous arteriole [PAS] Morphology of DM: The key feature of diabetic microangiopathy is diffuse thickening of BM due to marked concentric deposition of type-IV collagen (in epithelial, capillaries, & nerves). The change is indistinguishable from aging process. Despite this thickening, the capillaries are leaky, leading to extravasation of plasma proteins. Microangiopathy is the main cause of retinopathy, nephropathy, & to some degree neuropathy. Renal tubules shows BM [PAS] Morphology of DM: Thickened BM [NOT specific] Diabetic Nephropathy Glomerular Diffuse Mesangial Sclerosis [NOT specific] ↑ Mesangial Matrix → Scar → Ischemia Nodular Glomerulosclerosis [Pathognomonic] Ball-like laminated matrix at the periphery of the glomeruli Vascular [NOT specific] Atherosclerosis Infectious [NOT specific] Pyelonephritis esp. necrotizing papillitis Nodular glomerulosclerosis Diabetic Ophthalmic Complications Morphology of DM: NonProliferative Causing hemorrhage, edema, microanyorism (saccular due to loss of pericytes), & thickening of retinal capillaries BM. It can be soft (microinfarct) or hard exudate. Proliferative (The most serious) Due to ischemia → infarction → production of VEGF → neovascularization + fibrosis → retinal detachment & blindness (esp. if it is involving the macula) Retinopathy Cataract Glaucoma Diabetic Neuropathy Morphology of DM: CNS As cranial nerve paresis Sensory [the most] PNS Motor Autonomic Nerves System Bowel movement, bladder control, sexual activities All of these occur due to microangiopathy & Thank you!