YR1 Lecture 1H - Pathophysiology of Type 1 Diabetes Mellitus PDF

Type 1 diabetes. Jane Estrella, MD, MMed (InIm), FRACP Learning Objectives Explain the pathogenesis (development and sequence of events leading to disease) and aetiology (cause) of Type 1 Diabetes Mellitus Apply knowledge of the metabolic actions of insulin to discuss the acute metabolic consequence...

Type 1 diabetes. Jane Estrella, MD, MMed (InIm), FRACP Learning Objectives Explain the pathogenesis (development and sequence of events leading to disease) and aetiology (cause) of Type 1 Diabetes Mellitus Apply knowledge of the metabolic actions of insulin to discuss the acute metabolic consequences of insulin deficiency Discuss available management options for patients with Type 1 Diabetes Mellitus, their goals and factors affecting better outcomes Exciting times to be an Endocrinologist/Diabetologist!! Reference: William’s Textbook of Endocrinology; 13th Edition Text in red: represents new knowledge, contrary to previous schools of thought Learning Objectives There is a growing appreciation that type 1 (and other forms of diabetes), represents a heterogenous disorder with a common phenotype at presentation/diagnosis Implication: We are slowly steering away from binary classification of diabetes eg type 1 or type 2 All presentations of diabetes before 6 months is genetic in origin until proven otherwise Multiple disorders and syndromes have been identified that include diabetes as part of their presentation, and have been classified as part of Type 1 diabetes due to early age of presentation Life (with diabetes)is short, disgusting and painful. Arataeus (1 BCE) Diabetes Mellitus Diabetes- siphon; Mellitus- sweet “The pissing evil” Diagnosis: biochemical Fasting glucose: >/= 7 mmol/L 2 hour glucose: >/= 11.1 mmol/L Symptoms of diabetes and a glucose level above 11.1 mmol/L Polonsky KS. N Engl J Med 2012;367:1332-1340. Photo courtesy of Prof Mark Mclean Accessed from: http://philschatz.com/anatomy-book/contents/m46685.html Circulating glucose Gluconeogenesis from amino acids Glycogenolysis, gluconeogenesis Lipolysis, Ketogenesis Muscle proteolysis Muscle proteolysis decreases Lipolysis, Ketogenesis Ketogenesis is an expected physiological response to fasting, and ketones are used as an alternative fuel source in prolonged fasts. Fun fact: the heart preferentially runs on free fatty acids and ketones. 0-2 hrs 2-4 hrs 4-8 hrs >8 hrs >12 hrs >3 days Slide courtesy of Prof Mark McLean What insulin does Accessed from: https://www.youtube.com/watch?v=YA91m_--WAg Insulin secreted in two phases in response to caloric consumption Genetic defects identified in most, if not all pathways of insulin synthesis, processing and signalling Insulin actions not restricted to glucose control Anabolic- affects multiple pathways regulating cellular growth and differentiation Aetiology: Immune-mediated beta cell destruction Quick Review: Innate immune system non-specific Neutrophils, macrophages, complement Adaptive Immune system Specific response to immune trigger (antigen) T- cells: Cytotoxic cell destruction (CD8), others B-Cells- Antibody production Homeostasis depends on a balanced immune response ie tolerance (the ability to distinguish self from non-self antigens), and the ability to recognize non-self antigens and mount an effective immune response. THIS IS AN ONGOING PROCESS IN THE BODY THAT TAKES PLACE THROUGHOUT THE LIFESPAN OF AN INDIVIDUAL (Cradle to grave). Aetiology: Immune-mediated beta cell destruction Ability to recognize self and non-self starts in-utero, but for the first six months of life, an infant is dependent on transplacental passage of maternal IgG antibodies Reason why all presentations of diabetes before 6 months is genetic in origin until proven otherwise Cytotoxic T-cell mediated destruction of beta cells (and some parts of the exocrine pancreas) Antibodies to pancreas detectable and often precludes diabetes onset Surrogate marker of disease process/autoimmunity. These antibodies are not responsible for beta cell destruction GAD, IA2, ZnT8, ICA Historically, Type 1 diabetes presumed to be triggered by viral infection (Enterovirus, congenital rubella) HLA I locus susceptibility (codes for T cell receptors) Increased risk in monozygotic twins>dizogotic twins/siblings>first degree relative Must have three islets containing more than 15 CD45+ cells in a pancreas William’s Textbook of Endocrinology, 13th Ed Clinical presentation Young child, presents with infectious symptoms (cough/GI issues) and weight loss with polyuria, polydipsia and/or polyphagia Acutely unwell with ketoacidosis Insidious symptoms in older individuals End result of chronic hyperglycemia Beta cell mass varies among individuals Think of Type 1 diabetes as a chronic, relapsing-remitting disease process Need for insulin is absolute Photos of MODY patients courtesy of Prof Adnrew Hattersley Other photos accessed from: https://ghr.nlm.nih.gov/condition/kearns-sayresyndrome http://www.starwishesforchildren.org/2012/05/gene -decorated-a-cake-with-the-cake-boss/ http://www.jpedsurg.org/article/S0022- Management Goals: maintain normoglycemia as much as possible Avoid hypoglycaemia as much as possible Prevent complications Normal quality of life See-saw courtesy of Prof Simmons DCCT and EDIC: The Diabetes Control and Complications Trial and Follow-up Study How do we deal with thisSeverely insulin deficient diabetes (largely Type 1)? Insulin Pump Therapy Hypo’s BG Flexible, patient controlled basal bolus regimen -OZDAFNE Tailored Fixed Basal Bolus regimen Diagnosis Education SBGM Insulin Slide courtesy pf Prof D Simmons Carbs (and Fat, Protein, etc..) Not all carbohydrates are made equal!! Rapidity of absorption depends on complexity of structure 1 CHO=4 cal Protein Fat Basic structure: amino acids Glucogenic amino acids- turned into alpha ketoacids then glucose Glucogenic AND ketogenic amino acids: Ile, Phe, Tyr, Thr, Trp Purely ketogenic: Leu and Lys 1 CHON=4 cal Energy dense Fat: 9 cal Cornerstone of Therapy: Carbohydrate counting Estimate amount of carbohydrate in the meal 1 slice of bread- 15 gm CHO CHO ratio amount of insulin needed to cover carbohydrate Correction Amount of insulin needed to decrease blood glucose level to target range Lifestyle Sick days Sport Recreational drugs Alcohol Driving Treatment options for Type 1 diabetes Insulin Basal-bolus (long-acting with rapid acting insulin) Continuous subcutaneous insulin “artificial pancreas” Pramlintide Amylin analogue; promotes satiety Islet cell transplantation Compliance versus Adherence Transitional Clinics- multidisciplinary team input Mental Health Limited evidence Immunosuppression Immunologic vaccination Targeting mechanisms in Beta cell death What does not work inhaled insulin Oral insulin- maybe? Want to learn more about diabetes and management in a clinical setting? Join us for the Campbelltown Hospital Safety Snapshot this May!!! We promise Epicurean pleasures- friends, food and lots of thinking and learning!! Or join us at the Integrated Care Clinics and learn not only about diabetes presentation and management, but meet your future allied health colleagues and collaborate early on exciting projects!