Diabetes Mellitus FS 2024 - Part I PDF

DIABETES DR. J. SAVORY  Université d’Ottawa | University of Ottawa DISCLOSURE You may only access and use this PowerPoint presentation for personal educational use. It is against the law to post this presentation online or distribute i...

DIABETES DR. J. SAVORY  Université d’Ottawa | University of Ottawa DISCLOSURE You may only access and use this PowerPoint presentation for personal educational use. It is against the law to post this presentation online or distribute it without the permission of the author. uottawa.ca  Pre-lecture Review (Self learning) You’ll need a good understanding of metabolism and pancreatic function to tackle diabetes. You may want to take some time to review either: the relevant chapters in the you Anatomy and Physiology text ▪ Chapter 16 - Pancreatic function ▪ Chapter 24 - Metabolism Slides with this symbol will be discussed VERY briefly during the lecture because the information on these slides would have been covered in your ANP courses and it will be assumed that you have taken the time to review the information on your own if you need a refresher.  OBJECTIVES 1. Review: briefly summarize the metabolic processes that take place during absorptive and post absorptive states and their hormonal regulation 2. Describe the cellular composition of the islets of Langerhans; identify the cells responsible for the synthesis of insulin and glucagon 3. Glycemic control 3.1. Summarize the regulation of the synthesis of insulin and glucagon; give examples of physiological conditions that can increase or decrease the secretion of each hormone. 3.2. Identify the target tissues of insulin and glucagon. 3.3. Summarize the mechanisms of insulin and glucagon action and describe the metabolic effects of insulin and glucagon on carbohydrate, lipid and protein metabolism. 3.4. Identify and briefly describe the neural mechanisms and hormones that can support the effects of glucagon. 3.5. Define: glucose sparing  OBJECTIVES CONTINUED 4.1. Define: 'diabetes mellitus’ 4.2. Describe screening for diabetes mellitus using the fasting plasma glucose test, oral glucose tolerance test, the concentration of glycosylated hemoglobin and the presence of antibodies. 4.2.1. Distinguishing between the primary and secondary diabetes mellitus 4.2.2. Distinguish between type 1 and type 2 diabetes mellitus with respect to the causes, risk factors, pathogenesis, and main characteristics. 4.2.3. Define gestational diabetes mellitus and explain its causes and the consequences for the mother and her fetus. 4.3. List and describe the three classic signs of diabetes mellitus. 4.4. Define and identify the signs and symptoms of hyperglycemia and hypoglycemia and their treatment; explain physiological causes of the Somogyi effect and the Dawn phenomenon. 4.5. Compare and contrast the three acute complications of diabetes mellitus: (1) diabetic ketoacidosis, (2) hyperosmolar coma, and (3) reactions to insulin, according to the causes, clinical signs, metabolic changes, and treatment. 4.6. Describe the chronic effects of diabetes mellitus on the vascular, renal, visual, and nervous systems. 4.7. Summarize the treatment of diabetes mellitus type 1 and type 2 and discuss lifestyle modification and pharmacological strategies for treatment of type 2. Chapter 41  METABOLISM All the chemical reactions that occur within the cells of the body ▪ includes reactions involving the degradation, synthesis, and transformation of proteins, carbohydrates, and fats Energy requirements met by carbohydrate (CHO), fats and proteins >> Glucose (body’s fuel) Amount is tightly regulated ▪ Too much- hyperglycemia ▪ Too little- hypoglycemia GLUCOSE HOMEOSTASIS  THE PANCREAS The hormonal control of blood glucose resides largely with the endocrine pancreas ▪ Retroperitoneal gland with both exocrine (80%) and endocrine functions ▪ Head and neck opens into the C-shaped part of the duodenum ◼ The exocrine part composed of the acini  secrete digestive juices into duodenum via special ducts ◼ The endocrine part composed of the islets of Langerhans (~2 million)  secrete insulin, glucagon and other hormones directly to blood https://jigsaw.vitalsource.com/books/9780323088541/content/image/9780323088541_0515.jpg  ISLETS OF LANGERHANS ▪ Beta (b) cells ( 60%) produce proinsulin. ▪ Stored in granules, where it is cleaved into insulin and C-peptide that are secreted together ▪ Alpha (a) cells (25%) produce & secrete glucagon into the blood. ▪ Delta (d) cells (10%) produce somatostatin (inhibits insulin and glucagon) Physiological anatomy of an islet ▪ F cells produce pancreatic of Langerhans in the pancreas polypeptide (PP) Guyton & Hall, 2016 Insulin and glucagon are most important in regulating fuel metabolism  STRUCTURE OF INSULIN ◼ Insulin is a polypeptide hormone, produced and stored in the body as an inactive hexamer ◼ Monomeric form: composed of two chains A (21 aa) and B (30 aa) linked by disulfide bridges ◼ BOTH chains are derived from proinsulin, a prohormone. ◼ Active insulin and the inactive C- peptide are packaged into secretory granules and released simultaneously from the b cells ◼ Insulin from human, cows and pig are very similar  FIG. 41.1 PROCESSES OF GLUCOSE-STIMULATED EXOCYTOSIS OF INSULIN FROM ΒETA CELLS OF THE PANCREAS Amylin Inhibits gastric emptying Suppress glucagon release  GLUCOSE AND INSULIN RELEASE Under normal circumstances insulin secretion occurs in 2 phases: 1st Phase (rapidly releasable pool) The post prandial  in blood glucose & the incretin hormones (GIP & GLP) produce the first phase within 3-5 min of  blood glucose, [insulin] in plasma  almost 10x Release of preformed insulin 2nd Phase (extended) at ~ 15 min; insulin secretion rises a second time and reaches a new plateau in 2-3 hours ↑ synthesis and release of new insulin from b- cells ▪ In type 2 diabetes, even though lots of insulin is produced, the first phase is lost  this has a major effect on insulin action ▪ With time – second phase also decreases  FACTORS THAT REGULATE INSULIN SECRETION GIP GLP-1 Note: GIP: glucose-dependent insulinotropic polypeptide GLP-1: glucagon-like peptide 1 Incretins are inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV)  FACTORS THAT REGULATE INSULIN SECRETION Counter-regulatory hormones Growth Hormone  Stress hormones: Glucocorticoids (Cortisol)  (↑ production of glucose in the liver, stimulate glucagon release, & decrease glucose use) ▪ E/NE: ↑ production of FFAs & inhibit peripheral glucose uptake ▪ All these events lead to stress hyperglycemia ▪ Can also occur with psychological stress Exercise ▪ Initially insulin levels ; glucagon & catecholamine levels , increasing production of FFAs & stimulating glycogenolysis →→ glucose from liver meets energy demands ▪ Muscle contractions increase insulin sensitivity, maintaining normal blood glucose levels in the presence of lower insulin levels  INSULIN ACTIONS LIVER Anabolic hormone Primary role in maintaining normal Promotes cellular uptake of blood glucose levels glucose, fatty acids, & amino Principal site for metabolic acid; enhances their interconversions e.g. gluconeogenesis conversion into glycogen, triglycerides, & proteins, ADIPOSE TISSUE respectively Primary energy storage site Lowers blood concentration of Important in regulating fatty acid levels these small organic molecules in the blood Secretion is increased during MUSCLE absorptive state Primary site of amino acid storage Major energy user BRAIN ▪ Normally can only use glucose as an energy source ▪ Does not store glycogen / mandatory blood glucose levels must be maintained  GLUCAGON SECRETION & ACTIONS ▪ Major stimulus for glucagon Liver release is  in blood [glucose]. increased hepatic glucose ▪ Amino acids stimulate production & release → an glucagon release (high protein, increase in blood glucose levels low carbohydrate meal). Adipose ▪ Activation of the sympathetic NS antagonizes the actions of insulin ▪ Stress: epinephrine acts on b- with regard to fat metabolism by adrenergic receptors on alpha promoting lipolysis & inhibiting cells, increasing glucagon TG synthesis release ( availability of glucose for energy) Protein inhibits hepatic protein synthesis ▪ Other counter regulatory and promotes degradation of hormones (GH, cortisol) hepatic protein INSULIN ACTION: SIGNAL TRANSDUCTION Glucose Glycogen Protein Lipid Growth & gene Transport Synthesis Synthesis Synthesis Expression  INSULIN REGULATION OF GLUCOSE TRANSPORT ▪ Diffusion of glucose into cells is controlled by glucose transporters (GLUT 1- 4) specific to each tissue ▪ GLUT 1-3 are insulin independent Tissue Transporter Blood Brain Barrier GLUT 1 Neurons GLUT 3 predominantly Liver GLUT 2 Pancreatic b cells GLUT 1 & 3, small amounts of GLUT 2 Muscle & Adipose GLUT 4 tissue ▪ GLUT 4: normally located in the cell’s cytoplasm preformed and packaged into vesicles.  INSULIN RECEPTOR INTERNALIZATION ▪ Insulin binds to its receptor & insulin- receptor complex enters cell via endocytosis ▪ Receptors are recycled to the cell surface ▪ Insulin is largely degraded in lysosomes What would be the effect of having a super high concentration of insulin? ENERGY METABOLISM IN THE FED AND FASTING STATES FIG. 41.4 Energy metabolism in FIG. 41.5 Energy metabolism in the the fed (absorptive) state. fasting (post-absorptive) state. [Glucose] [Glucose] G, Glucose FFA, Free fatty acid(s)  DIABETES MELLITUS (DM) Glucose intolerance disorder ▪ is a chronic condition characterized by elevated blood glucose levels (hyperglycemia). A group of multisystem metabolic diseases resulting from ▪ defects in insulin production ▪ impaired insulin action ▪ both of the above ▪ disturbances of CHO, FAT and PRO metabolism ▪ variety of organic changes resulting primarily from blood vessel pathology ▪ Leading cause of heart disease, stroke, adult blindness, and non-traumatic lower limb amputations 22  TYPES OF DIABETES MELLITUS DIABETES MELLITUS (DM) Pre- Other types of DM Primary DM Gestational DM Diabetes (Secondary DM) Pancreatic Type 1 DM Type 2 DM Diseases Endocrinopathies Drug Induced Type 1A Type 1B Cushing’s Glucose (idiopathic) Acromegaly (autoimmune) Syndrome Hypersecretion Polygenic Monogenic LADA (80-90% of cases) (very rare) Latent Autoimmune Diabetes in Adults (2-12%; typically diagnosed after age 35 ) TYPE 1 DIABETES MELLITUS (T1 DM) https://www.ndss.com.au/wp-content/uploads/images/type1-diabetes.png  TYPE 1 DIABETES MELLITUS (T1 DM) Usually diagnosed between 5 and 20 years of age Characterized by destruction of the β cells of the pancreas Etiology may be immune-mediated or idiopathic (without autoimmune markers or HLA association)  Results in absolute insulin deficiency  Overproduction of glucagon stimulates glycogenolysis and gluconeogenesis  Glucose levels rise leading to the clinical phenotype of T1 DM [Glucose] FIG. 41.7 Pathophysiology of energy metabolism in type 1 diabetes mellitus. FFA, Free fatty acid(s); G, glucose; KA, ketoacid(s).  PATHOPHYSIOLOGY OF TYPE 1A IMMUNE MEDIATED DM McCance and Huether's Pathophysiology: The Biologic Basis for Disease in Adults and Children  TYPE 1A: IMMUNE MEDIATED DM GENETIC PREDISPOSITION ENVIRONMENTAL FACTORS INHERITED SUSCEPTIBILITY DIABETOGENIC VIRUSES Strongest linkage Infection of beta-cells (e.g. polymorphism of human leucocyte cytomegalovirus - CMV) antigen (HLA) genes in the MHC (provides Systemic infection with cross-reacting ~50% of the susceptibility that leads to immune response type 1 DM) – mumps, chickenpox, coxsackie B, 95% Type 1 diabetics carry HLA-(DR3 – measles, rubella DQ2) / (DR4-DQ8) other weaker links found (~60) DIETARY FACTORS (early weaning in infants)? SEROLOGICAL Cow milk proteins in formula (TRIGR- compare protein to hydrolysate – no Type 1 diabetes associated with the difference) https://www.trigr.org/ following autoantibodies Decreased vitamin D (decreased Insulin Auto Antibodies (IAA) exposure to the sun) Glutamic acid decarboxylase (GADA) zinc transporter 8 (ZnT8A) Insulinoma-associated autoantigen 2 MICROBIOTA (IA2A) Alterations to gut bacterial population and production of metabolites may impact autoimmunity 27  MODEL OF STAGES OF TYPE 1 DM J Clin Invest. 2021;131(8):e142242. https://doi.org/10.1172/JCI142242. Date of Download: 8/25/2024 Copyright © 2024 American Diabetes Association. All rights reserved.  DIAGNOSIS OF DIABETES Normoglycemic IFG§ IOGT§ DM TEST (mM) (mM) (mM) (mM) FPG < 5.6 5.6 – 6.9 7.0 Symptoms of hyperglycemia and a casual plasma glucose ≥11.1 mM. The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. 2 h-OGTT < 7.8 7.8 - 11.0 > 11.1 HbA1C 4% - 5.6% 5.7% - 6.4% > 6.5% Clinical diagnosis rely on two main features presence of islet-directed autoantibodies insulin deficiency and the need for insulin therapy FPG is defined as no caloric intake for 8 hours OGTT with 2-hour measurement of venous plasma or serum glucose after a 75-g oral glucose load IFG – impaired fasting glucose IGT- impaired glucose tolerance HbA1C –hemoglobin A1C § these are considered pre-diabetic states Type 1 diabetes mellitus: much progress, many opportunities J Clin Invest DOI: 10.1172/JCI142242  HONEYMOON PERIOD Short period after diagnosis during which the ability of the failing b cells become hyper-productive and compensate for failing insulin response. During this time Symptoms of diabetes disappear Insulin injections are reduced or not needed 31  TYPE 2 DIABETES MELLITUS ▪ Most common form of DM (90 – 95%) ▪ Non-Caucasian and elderly disproportionately affected Possible causes of b cell failure ▪ Insulin resistance and β cell dysfunction lead to a relative lack of insulin Suspect decreased number of insulin receptors or abnormal translocation of glucose transporters As disease progresses, insulin production may be impaired ▪ increased plasma insulin concentration (hyperinsulinemia) – a compensatory response to insulin resistance b cell dysfunction / dedifferentiation rather than b-cell death and decrease in b-cell mass Information about type 2 DM in Canada https://www.diabetes.ca/DiabetesCanadaWebsite/media/Managing-My-Diabetes/Tools%20and%20Resources/type-2-diabetes-the-basics.pdf?ext=.pdf RISK FACTORS FOR TYPE 2 DIABETES ▪ Age: being 40 years of or older ▪ Family history: having a close relative (parent/ sibling) with type 2 DM ▪ Being a member of a high-risk population, such as those of African, Arab, Asian, Hispanic, Indigenous or South Asian descent, ▪ Hypertension: high blood pressure or cholesterol ▪ Obesity: being overweight, especially around your abdomen. ▪ Level of physical activity ▪ Stress (hypothalamic-pituitary- adrenal axis:  cortisol/catecholamines) ▪ Socio-economic factors: low education / unemployment ▪ Having obstructive sleep apnea ▪ Low socioeconomic status ▪ Having a history of prediabetes (IGT or IFGT) / a history of gestational diabetes ▪ Having a history of giving birth to a baby that weighed over 4 kg (9 lb) at birth ▪ Having some evidence of the complications of diabetes, such as eye, nerve or kidney problems ▪ Having heart disease ▪ Having a history of using glucocorticoid medication  METABOLIC SYNDROME AND TYPE 2 DM Also known as insulin resistance syndrome is a cluster of conditions that occur together, increasing your risk of type 2 diabetes (as well as cardiovascular disease and stroke) ▪ central obesity, ▪ Dyslipidemia (↑ TG, ↓ HDL) ▪ Hypertension, ▪ elevated fasting blood glucose level (impaired glucose tolerance) https://relatyv.com/wp-content/uploads/2023/05/metabolic-syndrome-illustration.webp PATHOPHYSIOLOGY OF TYPE 2 M McCance and Huether's Pathophysiology: The Biologic Basis for Disease in Adults and Children  [Glucose] Insulin Resistance ↑FFA FIG. 41.8 Pathophysiology of energy metabolism in type 2 diabetes mellitus. G, Glucose.