Type I Diabetes Mellitus | Pathophysiology | PDF

Type I Diabetes Mellitus Robbins and Cotran’s Pathologic Basis of Disease Chapter 25 BMS 150 Week 12  Diabetes - Intro 1 million islets of Langerhans – mainly interested in the beta cells ▪ key players are the targets of insulin action, and t...

Type I Diabetes Mellitus Robbins and Cotran’s Pathologic Basis of Disease Chapter 25 BMS 150 Week 12  Diabetes - Intro 1 million islets of Langerhans – mainly interested in the beta cells ▪ key players are the targets of insulin action, and their sensitivity to the hormone Multiple disorders, with the common theme of hyperglycemia ▪ diabetes = “urinates excessively”, mellitus = “sweet” Diabetes – laboratory definition Diabetes = hyperglycemia ▪ Results from defects in insulin secretion, insulin action, or (usually) both Diagnosis (basic): 1.random blood glucose (RBG) concentration > 11.1 mmol, with classical signs and symptoms (only has to be observed once) 2.FBG concentration > 7.0 mmol on more than one occasion 3.Abnormal oral glucose tolerance test (OGTT): > 11.1 mmol 1 hour after ingestion on more than one occasion 4.Hemoglobin A1c > 6.5% Fasting glucose should be < 5.6 mmol – it’s tightly regulated Diabetes - classification Type 1 diabetes - ~ 5 – 10% ▪ autoimmune disease ! pancreatic beta cell destruction, usually onset is in childhood but sometimes in early adulthood ▪ Discussed next class Type 2 diabetes - ~ 90 – 95% ▪ combination of peripheral resistance to insulin action and an inadequate secretory response by beta cells Monogenic and secondary causes – quite uncommon ▪ single-gene disorders or secondary to infection or pancreatic destruction by other means (tumours, inflammation, ischemia) FYI – Diabetes is not one disease Insulin Actions (Review) Regulation of Blood Glucose Levels When blood glucose levels rise, such as after a meal, insulin is released into the bloodstream. Insulin promotes the uptake of glucose by various tissues, including skeletal muscle, liver, and adipose tissue, where it can be used for energy or stored for future use. Promotion of Glycogen Synthesis In the liver and muscles, insulin stimulates the conversion of excess glucose into glycogen, a storage form of glucose This helps to regulate blood glucose levels by storing glucose when levels are high and releasing it when levels are low, maintaining a steady supply of glucose for energy. Inhibition of Gluconeogenesis Insulin inhibits the process of gluconeogenesis, which is the production of glucose from non-carbohydrate sources, such as amino acids and glycerol By suppressing gluconeogenesis, insulin helps to prevent excess glucose production and further contributes to the regulation of blood glucose levels. Cellular Growth and Differentiation Insulin plays a role in cellular growth, proliferation, and differentiation in various tissues, including the liver, muscles, and adipose tissue It helps to regulate cell growth and tissue remodelling processes. Insulin Actions Stimulation of Protein Synthesis Protein synthesis and inhibiting protein breakdown It enhances the uptake of amino acids by cells and stimulates protein synthesis in tissues such as skeletal muscle Regulation of Lipid Metabolism Promotes the storage of fatty acids in adipose tissue by stimulating lipogenesis, the synthesis of fatty acids and triglycerides It also inhibits lipolysis, the breakdown of triglycerides into free fatty acids and glycerol By promoting lipid storage and inhibiting lipid breakdown, insulin helps to regulate lipid levels in the bloodstream. Modulation of Appetite and Satiety Insulin can also act in the brain to regulate appetite and satiety It interacts with neural circuits involved in hunger and feeding behaviour, helping to signal when the body has consumed enough food and promoting feelings of satiety. Insulin physiology - review Diabetes – pancreatic pathology Type I: Reduction in the number and size of islets and leukocytic infiltrates in the islets (T- cells, mostly) ▪ inflammation and reduction in the size of islets ▪ More later – the immune system kills the pancreatic beta cells Type II: Reduction in islet cell mass as well as amyloid deposition around beta cells ▪ no inflammatory infiltrate ▪ insulin resistance is the primary trigger Type 1 Diabetes: Pathogenesis Healthy Type 1 Diabetes Type 2 Diabetes: Pathogenesis Healthy Type 2 Diabetes Insulin Resistance Type 1 Diabetes – Catch-Up Diabetes Mellitus Type 1 is a chronic metabolic disorder characterized by the pancreas not producing enough insulin. In this condition, glucose needs insulin to help it enter the cells to be used for energy. Since cells cannot use glucose, the blood glucose levels become extremely high. Typically occurs in adolescents and young adults. Type 1 Diabetes ▪ Usually diagnosed in those < 20 years can develop at any age ▪ Autoimmune destruction of beta cells Absolute deficit in insulin, insulin resistance is not found ▪ Twin concordance rate ~ 30% to 50% Genes implicated – major histocompatibility genes, other genes that are important in teaching the immune system to “tolerate” self-tissues Pathogenesis – T1DM Genetic etiologic factors: ▪ HLA DR3 or DR4 – the histocompatibility genes Account for 50% of genetic risk ▪ People with one copy of both DR3 and DR4 show greatly increased risk DQ8 also presents increased risk Polymorphisms are within antigen-presenting portion ▪ CTLA-4 and PTPN-22 – the “tolerance” genes CTLA-4 is a major “downregulator” of antigen presentation by APCs, interacts with CD-28 (Treg) PTPN-22 is important in the development of central Tregs in the thymus Pathogenesis – T1DM Environmental theories - Viral infections: Associations with mumps, rubella, coxsackie B, or cytomegalovirus ▪ Three different mechanisms proposed: “Bystander” damage - viral infections induce islet injury and inflammation, leading to release of β-cell antigens and activation of autoreactive T cells Viruses produce proteins that mimic β-cell antigens, and immune response to viral protein cross-reacts with self-tissue Viral infections early in life persist in pancreas, and re-infection with a related virus (“precipitating virus”) that shares antigenic characteristics leads to immune response against infected islet cells ▪ All these mechanisms need further confirmation before they can be definitively identified as causing the disease Pathogenesis – T1DM Gradual loss of β-cell mass likely due to destruction of β -cells by cytotoxic T-cells ▪ Disease manifestations appear after 90% of β cells destroyed ▪ T-cells seem to be the main problem: Self-reactive T-cells not destroyed in thymus Defects in regulatory T-cell function (the tolerance cells) Antigens likely attacked: insulin, glutamic acid decarboxylase, others (islet cell autoantigen 512) Autoantibodies may cause damage or just be a sign of immune dysregulation Pathogenesis – T1DM Viruses?  Development of T1 DM Honeymooning: remaining β- cells become hyper-productive and compensate for failing insulin response Disease manifestations appear after 90% of β cells destroyed 18 Honeymooning and Islet cell loss As you kill β cells - remaining cells become hyperproductive ▪ When glucose goes up, remaining cells make insulin and glucose goes down again ▪ Some more die off and remaining ones become even more hyperactive Honeymooning is ability of remaining β-cells to become hyper-productive and compensate for failing insulin response ▪ once the “honeymooning” cells fail, deterioration is rapid  Type I DM – Clinical Features Progresses quickly once significant loss of beta-cell mass occurs Typical initial presentation – acute, known as diabetic ketoacidosis: ▪ Subacute history of polyphagia, polydipsia, polyuria Why do these occur? ▪ Patients are often emaciated and quite dehydrated ▪ As patients lose the ability to use serum glucose to generate ATP and adipose tissue releases increasing amounts of fatty acids, liver generates ketones ketones are acidic, resulting in a drop in blood pH as blood pH drops, steady deterioration in level of consciousness ▪ For unclear reasons, patients who experience DKA often experience fairly severe generalized abdominal pain Figure 24-33 Sequence of metabolic derangements underlying the clinical manifestations of diabetes. An absolute insulin deficiency leads to a catabolic state, culminating in ketoacidosis and severe volume depletion. These cause sufficient central nervous system compromise to lead to coma and eventual death if left untreated. Volume depletion in DKA Elevated blood glucose ! an osmotic diuresis in the kidney ▪ Excess sugar in the urine ! drawing water from the blood into the urine ! loss of high volumes of water and dehydration ▪ The increased osmolarity of the blood contributes to the increased sensation of thirst As more and more fluid is lost and the sodium- potassium pump activity is reduced, K+ loss occurs ▪ Insulin stimulates activity of Na+/K+ ATPase ▪ More K+ outside the cells ! more K+ lost in the urine Complications of long- term hyperglycemia Remember: DM is associated with - Small vessels disease - Large vessels disease Hyperglycemia – who cares? Persistent hyperglycemia leads to: ▪ Advanced glycation end products (AGEs) – metabolic products of glucose non-enzymatically linked to amino groups of intra-and extracellular proteins ▪ AGE binds to R-AGE on macrophages, T-cells, smooth muscle cells and endothelial cells Hyperglycemia – who cares? Advanced glycation end products cont… ▪ Leads to: Release of pro-inflammatory cytokines and growth factors from intimal macrophages Generation of ROS in endothelial cells Increased procoagulant activity on endothelial cells Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix ▪ AGEs cause cross-linking of matrix proteins and render them resistant to proteolysis Hyperglycemia – who cares? In the end, AGEs seem to contribute to: ▪ Decreased large artery elasticity ▪ Narrowing of smaller arteries ▪ Deposition of atherosclerotic plaques (trapping of LDL in AGE-linked matrix, smooth muscle proliferation) ▪ Increased susceptibility to coagulation Activation of protein kinase C pathway by hyperglycemia contributes to deposition of excess matrix, secretion of pro-inflammatory cytokines, and increased susceptibility to coagulation Diabetes – small vessel disease Hyaline arteriolosclerosis ▪ Vascular lesion associated with HTN more prevalent and more severe in diabetics than in nondiabetics ▪ Amorphous, hyaline thickening of wall of arterioles - causes narrowing of lumen Diabetic Microangiopathy ▪ Diffuse thickening of basement membranes ▪ Prominent in capillaries of skin, skeletal muscle, retina, renal glomeruli, and renal medulla ▪ Diabetic capillaries more leaky than normal to plasma proteins - underlies development of diabetic nephropathy, retinopathy, and some forms of neuropathy Diabetes - Neuropathy Loss of small and large axons, myelinated and unmyelinated ▪ Loss of pain sensation quite early - somewhat unique among peripheral neuropathies ▪ Can also lose vibration, proprioception, fine touch, much like many of the other peripheral neuropathies ▪ Autonomic neuropathy can feature postural hypotension, incomplete emptying of bladder resulting in recurrent infections, and sexual dysfuction