Pathophysiology of Diabetes Mellitus Lecture Notes PDF

Pathophysiolog y of Diabetes Mellitus Luigi Brunetti PharmD, PhD 1 Objectives Describe the functions of insulin Understand the difference between the pathogenesis of type I versus type II diabetes mellitus List common complications of diabetes and the mechanis...

Pathophysiolog y of Diabetes Mellitus Luigi Brunetti PharmD, PhD 1 Objectives Describe the functions of insulin Understand the difference between the pathogenesis of type I versus type II diabetes mellitus List common complications of diabetes and the mechanisms of injury Discovery of Pancreatic Diabetes Oskar Minkowski (1858-1931) and Joseph von Mering (1849-1908) von Mering J, Minkowski O. Diabetes mellitus nach Pankreas extirpation. Arch f exper Path u Pharmakol. 1889;26:371. Diabetes History Ikle JM, Gloyn AL. J Endocrinol. 2021 Jul 22;250(3):R23-R35. Pancreas: Islet of Langerhans Insulin: Structure and Release Glucose is oxidized generating ATP via mitochondrial Insulin is synthesized (INS gene) in the β-cells of oxidative phosphorylation the islets of Langerhans ATP inhibits the KATP channel leading to membrane Insulin and C-peptide molecules are connected depolarization and the opening of calcium channels at two sites by dipeptide links Calcium triggers the fusion of insulin-containing secretory Half-life of about 5 minutes vesicles with the plasma membrane and the release of insulin to the circulation. What are the functions of insulin? Transport glucose and amino acids Glycogen formation in liver and skeletal muscle Glucose transformation to triglycerides Nucleic acid synthesis Protein synthesis Decreases degradation of glycogen, lipid, and protein Major anabolic hormone Insulin and Glucose Uptake Dependent on insulin (70% of Not dependent on insulin body mass) Lens Striated muscle (including heart) Brain Adipose tissue Kidney Liver Blood vessels Fibroblasts Definition of Diabetes Diabetes is a group of metabolic disorders characterized by hyperglycemia Hyperglycemia in diabetes is due to defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic abnormalities of diabetes often cause damage in multiple organ systems Kidneys, eyes, nerves, and blood vessels Current State of Diabetes in the United States 34 million 37.3 million people in the United States have diabetes 23% of them don’t know they have it. 88 million 96 million US adults have prediabetes > 80% of them don’t know they have it. 7th leading cause of death in the United States Type 2 diabetes accounts for approximately 90% to 95% Adults diagnosed with diabetes has more than doubled in the past 20 years Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2022. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2022. Diagnosis of Diabetes Blood glucose is normally 70 to 120 mg/dL Diagnostic criteria for diabetes Fasting plasma glucose ≥126 mg/dL Random plasma glucose ≥200 mg/dL Two-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test with a loading dose of 75 gm Glycated hemoglobin (HbA1c) level ≥6.5% ***All tests, except the random blood glucose test in a patient with classic hyperglycemic signs, must be repeated and confirmed on a separate day Prediabetes versus Diabetes Prediabetes Diabetes HbA1c 5.7 – 6.4% ≥ 6.5% FPG 100 – 125 mg/dL ≥ 126 mg/dL OGTT 140 – 199 mg/dL ≥ 200 mg/dL RPG ≥ 200 mg/dL Normal Insulin Function Normal glucose homeostasis is regulated by Glucose production in the liver Glucose uptake and utilization by peripheral tissues Insulin and glucagon action (counter regulatory hormone) Response to Oral Glucose Load The Ominous Octet Tahrani AA et al. The Lancet 2011; 378:182-07. Types of Diabetes Type I (insulin dependent) Type 1A (autoimmune) Type 1B (no autoimmunity) Type II (non-insulin dependent) Monogenic forms LADA (latent autoimmune diabetes in adults) MODY (Maturity-onset diabetes of the young) Syndrome related Drug Induced Steroids Gestational diabetes (5% of pregnancies) Insult related (cancer, pancreatitis) Type I versus Type II Diabetes Mellitus Typical Presentation T1DM versus T2DM T1DM T2DM Abrupt onset Slow onset Lack of insulin Onset in adulthood Onset in youth No islet cell antibodies Islet cell antibodies Insulin resistance Recent weight loss DKA prone Not insulin dependent Dependent on exogenous insulin Familial patterns Genetic determinants Obesity Autoimmune/viral etiology Metabolic syndrome Summary of Symptoms and Presentation in Patients with Diabetes Type 1 Diabetes Mellitus Pathogenesis Absolute insulin deficiency Result of pancreatic beta cell destruction Prone to diabetic ketoacidosis Lose about 90% of all β cells Can be autoimmune or idiopathic About 10% of all diabetes cases  Glycogen and protein breakdown causing keto- acidosis Accumulation of acetyl CoA, beta- hydroxybutyric acid and acetone Diabetic ketoacidosis. Nat Rev Dis Primers 6, 41 (2020).  Type of Diabetes in Youth by Race/Ethnicity and Etiology SEARCH for Diabetes in Youth Study (N=2291) 100% 6.2 15.9 11.1 Distribution of etiologic categories 28.3 80% 40.1 40.8 10.1 19.8 6.6 by race/ethnicity 67.8 19.5 60% 9.4 Non-autoimmune + IR 21.3 10.8 Non-autoimmune + IS 18 Autoimmune + IR 40% 15.1 Autoimmune + IS 62.9 3.2 54.5 20% 43.7 12.9 32.5 33.3 16.1 0% NHW Hispanic AA API AI Total AA, African American; AI, American Indian; API, Asian/Pacific Islander; IR, insulin resistant; IS, insulin sensitive; NHW, non-Hispanic white. Dabelea D, et al. Diabetes Care. 2011;34:1628-1633. Type 1 Diabetes Pathophysiology Inflammation -cell destruction FasL IFN-g – Usually leading to TNF-a absolute insulin deficiency T cell Immune mediated Autoimmune Reaction Macrophage Idiopathic Class II TNF-a Class I MHC MHC IL-1 -cell NO CD8+ T cell Dendritic cell -cell Destruction CD8, cluster of differentiation 8; FasL, Fas ligand; IFN-, interferon ; IL-1, interleukin 1; MHC, major histocompatibility complex; NO, nitric oxide; TNF-, tumor necrosis factor . Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497. Pathophysiologic Features of Type 1 Diabetes Chronic autoimmune disorder Occurs in genetically susceptible individuals May be precipitated by environmental factors Autoimmune response against Altered pancreatic -cell antigens Molecules in -cells that resemble a viral protein Antibodies Approximately 85% of patients: circulating islet cell antibodies Majority: detectable anti-insulin antibodies Most islet cell antibodies directed against GAD within pancreatic -cells GAD, glutamic acid decarboxylase. Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39:481-497.  Trends in T1D Immunophenotype at Diagnosis Prevalence of IA-2A and ZnT8A has increased significantly, mirrored by raised levels of IA-2A, ZnT8A, and IA-2β autoantibodies (IA-2βA) IAA and GADA prevalence and levels have not changed Increases in IA-2A, ZnT8A, and IA-2βA at diagnosis during a period of rising incidence suggest that the process leading to type 1 diabetes is now characterized by a more intense humoral autoimmune response Autoantibodies to insulin, IAA; GAD, GADA; islet antigen-2, IA-2A; T1D, type 1 diabetes; zinc transporter 8, ZnT8A. Long AE, et al. Diabetes. 2012;61:683-686. Autoimmune Basis for Type 1 Diabetes Immune Environmental dysregulation triggers and regulators IAA GADA, ICA512A, ICA Interactions -Cell mass between genes imparting Loss of first-phase insulin response (IVGTT) Variable insulinitis susceptibility and -cell sensitivity to resistance Glucose intolerance injury Prediabetes Overt T1D C-peptide undetec- Time table Atkinson MA. Diabetes. 2005;54:1253-1263. Adapted from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221-229. How Type 1 Diabetes Might Arise van Belle TL, et al. Physiol Rev. 2011;91:79-118. Type II Diabetes Mellitus Pathogenesis Involves a complex interaction between genetic and environmental factors Two major defects Decreased ability of peripheral tissues to respond to insulin (insulin resistance) β -cell dysfunction that is manifested as inadequate insulin secretion in the presence of insulin resistance and hyperglycemia Summary of Characteristics in Type II Diabetes Lack of insulin availability or effectiveness Inadequate production Premature destruction Released out of phase Decreased insulin receptors Insulin resistance Not ketosis-prone (but can occur) Hyperglycemic hyperosmolar syndrome (HHS) Link with obesity Dysregulation of adipokines Chronic inflammation Insulin Resistance versus β-Cell Dysfunction Insulin Resistance β-Cell Dysfunction Failure to inhibit endogenous glucose production Polymorphisms in genes that control insulin secretion (gluconeogenesis) in the liver are associated with an increased lifetime risk for T2D Abnormally low glucose uptake and glycogen synthesis Excess free fatty acids compromise β-cell function and in skeletal muscle following a meal attenuate insulin release (lipotoxicity) Failure to inhibit hormone-sensitive lipase in adipose Chronic hyperglycemia (glucotoxicity) tissue, leading to excess circulating free fatty acids (FFAs) Abnormal incretin effect, leading to reduced secretion of hormones that promote insulin release Amyloid replacement of islets, present in more than 90% of diabetic islets  Tissue-specific regulation of metabolism Tissue Specific Regulation of James, D.E., Stöckli, J. & Birnbaum, M.J. The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol 22, 751–771 (2021). https://doi.org/10.1038/s41580-021-00390-6 Tissue-specific regulation of metabolism Dose–response characteristics of insulin action  Obesity and the Diabetes Link Wen, X., Zhang, B., Wu, B. et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Sig Transduct Target Ther 7, 298 (2022). https://doi.org/10.1038/s41392-022-01149-x  2004 High Middle Low Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Low Middle High Diagnosed Diabetes (%): Low (13.9); Obesity (%): Low (36.0)  2010 High Middle Low Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Low Middle High Diagnosed Diabetes (%): Low (13.9); Obesity (%): Low (36.0)  2016 High Middle Low Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Low Middle High Diagnosed Diabetes (%): Low (13.9); Obesity (%): Low (36.0) Metabolic Derangements in Diabetes Insulin and Glucose Metabolism Major Metabolic Effects of Insulin Stimulates glucose uptake into muscle and adipose cells Inhibits hepatic glucose production Consequences of Insulin Deficiency Hyperglycemia  osmotic diuresis and dehydration 39 Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency Insulin effects: inhibits breakdown of triglycerides (lipolysis) in adipose tissue Consequences of insulin deficiency: elevated FFA levels Insulin effects: inhibits ketogenesis Consequences of insulin deficiency: ketoacidosis, production of ketone bodies Insulin effects in muscle: stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription Consequences of insulin deficiency: muscle wasting 40 Chronic Metabolic Impairments Formation of advanced glycation end-products (AGEs) Non-enzymatic reaction between glucose derived cellular elements and amino groups on proteins Proliferation of smooth muscle and matrix, increased ROS, release of cytokines and growth factors Disturbance of polyol pathways in non-insulin dependent tissues Osmotic effects, increases extracellular matrix Activation of protein C Increased ROS, osmotic injury, pro-angiogenic molecules, activation of multiple pathways Non-enzymatic glycosylation of hemoglobin In the presence of high glucose hemoglobin is irreversibly glycated at one or both N-terminal valines of the beta chains HbA1c is a reliable indicator except when the average RBC lifespan is significantly