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Diabetes mellitus

Types and the immune effector mechanisms of diabetes.

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Diabetes mellitus

  1. 1. Diabetes Mellitus AUW School of Medicine Dr Awadelkarim A.Ibrahim
  2. 2. • Diabetes mellitus (DM) The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs.
  3. 3. • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus • Gestational Diabetes • Other types: LADA (Latent Auto immune diabetes of Adulthood ) MODY (maturity-onset diabetes of youth) Secondary Diabetes Mellitus Types of Diabetes
  4. 4. Type 1 diabetes Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic β-cells.
  5. 5. 5 Regulation of Plasma Glucose Level
  6. 6. Genetic factors Environmental factors Population 9% Monogenic Polygenic Aging Lifestyle Infections Diabetes Type I <10% Type II >90% Eatiology
  7. 7. TYPE 1 DIABETES IS AN AUTOIMMUNE DISEASE -Genetic and familial clustering of diabetes and additional autoimmune disorders -Presence of high-affinity autoantibodies and T cells reactive to islet cell autoantigens -Strong HLA association (DR3/DR4) -Ability to transfer the disease in animal models through adoptive transfer of islet cell-reactive T-cell clones -Recurrence of disease in pancreas transplanted between identical twins
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  9. 9. 1-There is direct virus-induced lysis of β cells following infection 2-Molecular mimicry Partial sequence homology between the a viral Ag & β cells protein that constitutes a target autoantigen in T1D pathology. The ir directed towards the viral Ag lead , by cross reactivity , to the production of cytotoxic T lymphocytes ( Tc) and/or Abs that are able to attack the pancreatic tissue & ,thus, participating in the pathogenesis of T1D 3- Bystander activation or innocent -bystander killing.
  10. 10. 1-Strong HLA association : DR3/DR4 &Strong HLA protection :DR2 DR6 DR7 CTLA-4 gene mutation The cytotoxic T-lymphocyte antigen (CTLA-4) gene encoded on chromosome 2q33 was recognized as T1D susceptibility gene. Inherited changes in the CTLA-4 gene expression can increase T cell self-reactivity and therefore play an important role in autoimmune diseases such as T1D.
  11. 11. PTPN22 (Protein tyrosine phosphatase, non-receptor type 22 ) PTPN22, a gene found on chromosome 1p13 that encodes lymphoid protein tyrosine phosphatase, was found to be associated with susceptibility to T1D. A SNP in the PTPN22 gene potentially contributes to susceptibility to T1D because of increased negative regulation of T cell activation. IL2RA Allelic variation in the interleukin (IL)-2 receptor- gene (IL2RA) region accounts for another genetic risk factor implicated in T1D
  12. 12. Insulin Gene (INS) Class I VNTR 26-63 repeats 21 alleles Predisposing IDDM2 Insulin Gene (INS) Class III VNTR 140-200 repeats 15 alleles IDDM2 Protective The IDDM2 Locus VNTR = Variable Number of Tandem Repeats
  13. 13. The variable number of tandem repeat (VNTR ; also named the insulin gene minisatellite ) is promoter upstream of the insulin gene translation initiation site where the transcription factor Pur1 bind .
  14. 14. Pathogenesis: Diabetes mellitus type 1 is an autoimmune disease. The autoimmune process begins many years before clinical detection and presentation. It is directly against beta cell of the islets of Langerhans. The destruction must be very heavy, more then 90 percent of beta cells must be destroyed for clinical symptoms to develop. The speed of the beta cell destruction is variable. Causes :viruses and other environmental factors in genetically susceptible individuals.
  15. 15. - CD4 T lymphocytes reactive with islet antigens maydestroyb-cells through MQ activation, production of inflammatorycytokines, etc - Cytolytic CD8 T lymphocytes may lyse islet cells and locally produce cytokines (TNF and IL-1) that damage islet cells - The role of B lymphocytes debated: data from the NOD model suggest that B lymphocytes are required as antigen presenting cells early during induction of disease. Possiblyalso later to present antigen and maintain autoreactivity. - At later times, autoantibodies further damage β-cells Immune effector mechanisms of T1D
  16. 16. Viral antigens released from β cells is processed by macrophages and presented to T - helper lymphocytes (CD4+) associated with HLA class II antigens. Activated T lymphocytes then secrete interleukin (IL) - 2 and other cytokines that activate other immune cells. B lymphocytes produce immunoglobulins against the viral antigens, while activated natural killer (NK) cells and cytotoxic (CD8+) lymphocytes cause destruction of β cells that carry the viral antigens. Macrophages, activated by interferon - γ (IFN - γ ), also participate in the destruction of the target cells. NKCF, natural killer cell factor; TNF, tumour necrosis factor.
  17. 17. There are four stages in the development of Type 1 DM: 1-Preclinical period with positive β-cell antibodies 2-Hyperglycemia when 80-90% of the β- cells are destroyed 3-Transient remission (honeymoon phase). 4-Establishment of the disease
  18. 18. “Stages” in Development of Type1Diabetes Age (years) Genetic Predisposition Betacellmass (?Precipitating Event) Overt immunologic abnormalities Normal insulin release Progressive loss insulin release Glucose normal Overt diabetes C-peptide present No C-peptide
  19. 19. Immunological Diagnosis of T1D There are currently four standard autoantibodies whose presence is used to predict the development of T1D: -These are Autoantibodies against 1-Insulin, 2-Glutamic acid decarboxylase (GAD65), 3-A tyrosine phosphatase-like protein (ICA512 also termed IA-2) 4-Zinc T8 transporter (ZnT8) . -Islet-associated protein–2 (IA-2) and IA-2β (also known as phogrin) are unique neuroendocrine-specific protein tyrosine phosphatases (PTPs).
  20. 20. •Type 2 Diabetes Mellitus (Insulin Resistance) •Formerly known as “adult onset” or “ Non insulin dependent Diabetes”. Type 2 diabetes (non-insulin-dependent diabetes mellitus) Insulin concentrations are mostly increased but peripheral tissues are resistant to insulin (insulin resistance). . It results from insulin resistance with a defect in compensatory insulin secretion. (Beta cells are not able increase secretion of insulin to overcome this resistance. ) Insulin may be low, normal or high!
  21. 21. Onset of Disease Gradual onset Person may go many years with undetected hyperglycemia Gradual onset Person may go many years with undetected hyperglycemia . Accounts for >90% of patients with diabetes Usually occurs in people over 40 years old 80-90% of patients are overweight ,(lately in obese adolescents.) About 30% of the Type 2 DM patients are undiagnosed (they do not know that they have the disease) because symptoms are mild.
  22. 22. Etiology and pathophysiology of type 2 diabetes
  23. 23. Activation of the NLRP3 Inflammasome The inflammasome is a large multiprotein complex which plays a key role in innate immunity by participating in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. These related cytokines cause a wide variety of biological effects associated with infection, inflammation and autoimmune processes. They are both produced as inactive precursors, pro-IL-1β and pro- IL-18, and share a common maturation mechanism that requires caspase-1 IL-1β induced within the islet impairs β cell insulin secretion and induces Fas death receptor–dependent, apoptotic β cell. Glucose- induced IL-1β is a key mediator of islet dysfunction and destruction.
  24. 24. Progression Of Beta Cell Failure in Type 2 Diabetes Progressive β-cell defect in type 2 diabetes Impaired glucose tolerance (IGT) ,Postprandial = after eating a meal while preprandial is before a meal
  25. 25. Acanthosis Nigricans Skin Tags Acanthosis nigricans Currently thought to be an effect of insulin-like growth factor 1 (IGF-1). At one point was thought to be a result of skin folds rubbing together
  26. 26. Type 1 vs. Type 2 Type 1 Type 2 Age of onset Childhood, young adult Usually > 40 + some obese children Pathogenesis Autoimmune process Defect in insulin secretion, tissue resistance to insulin, increased HGO Autoantibodies Positive Negative Body cells Responsive to insulin Resistant to insulin Endogenous insulin Little or none Low Normal or high Pancreatic function Beta cells not functional Beta cell normal Severity of symptoms Severe; liable to DKA Mild; few or none, not liable to DKA
  27. 27. Characteristics Type I DM Type II DM % of diabetic pop 5– 10% 90 % Obesity Uncommon Common Family history Generally not strong Strong Acute complication Ketoacidosis Hyperosmolar coma Treatment Insulin, Diet Exercise Diet ,Exercise Oral antidiabetics,Insulin Diabetic ketoacidosis
  28. 28. • Latent Auto immune diabetes of Adulthood (LADA) or type 1.5 diabetes A slowly progressive form of type 1 diabetes mellitus. Patients are often diagnosed as type II diabetes, but have Positive pancreatic islet antibodies, especially to glutamic acid decarboxylase (GAD). Pts. do not immediately require insulin for treatment, are often not overweight, and have little or no resistance to insulin
  29. 29. Presence of autoimmunity to islet protein is the feature of IDDM. However there are some pts over 30 yrs of age present with diabetic symptoms and require insulin therapy within one to two yrs, many of these pts. have autoantibodies to islet protein. They are called as LADA About 10-15% have ICA (Islet cell antibody) and / or Glutamic acid decarboxylase antibody (GADA)
  30. 30. Diabetes Types Key characteristics of type 1, LADA (latent autoimmune diabetes in adults), and type 2. Type 1 LADA Type 2 Typical age of onset Youth or adult Adult Adult Progression to insulin dependence Rapid (days/weeks) Latent (months/years) Slow (years) Presence of autoantibodies* Yes Yes No Insulin dependence At diagnosis Within 6 years Over time, if at all Insulin resistance No Some Yes *Proteins that indicate the body has launched an autoimmune attack on the insulin- producing beta cells in the pancreas.
  31. 31. MODY (maturity onset diabetes of the young) –is a monogenic and autosomal dominant form of diabetes mellitus (single-gene disorder) with onset of the disease often before 25 years of age ( early onset ) strong family history, present as type 2 diabetes . It is due to dysfunction of pancreatic ß cells characterised by non-ketotic diabetes and absence of pancreatic auto- antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus
  32. 32. Gestational diabetes mellitus: ◆ Definition: Carbohydrates intolerance of variable severity Develops during pregnancy .Detected at 24 to 28 weeks of gestation As type II is characterized by insulin resistance, usually is mild, but show risk of later development of diabetes 2 type Associated with high risk for cesarean delivery, perinatal death, and neonatal complication