Lecture 6 - Diabetes - Tagged 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 mechanisms of injury Discovery of Pan...

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 • Insulin is synthesized (INS gene) in the β-cells of the islets of Langerhans • Insulin and C-peptide molecules are connected at two sites by dipeptide links • Half-life of about 5 minutes • Glucose is oxidized generating ATP via mitochondrial oxidative phosphorylation • ATP inhibits the KATP channel leading to membrane depolarization and the opening of calcium channels • Calcium triggers the fusion of insulin-containing secretory 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 body mass) • • • • Striated muscle (including heart) Adipose tissue Liver Fibroblasts • Not dependent on insulin • • • • Lens Brain Kidney Blood vessels 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 HbA1c FPG OGTT RPG Prediabetes 5.7 – 6.4% 100 – 125 mg/dL 140 – 199 mg/dL Diabetes ≥ 6.5% ≥ 126 mg/dL ≥ 200 mg/dL ≥ 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 • Abrupt onset • Lack of insulin • Onset in youth • Islet cell antibodies • Recent weight loss • DKA prone • Dependent on exogenous insulin • Genetic determinants • Autoimmune/viral etiology T2DM • Slow onset • Onset in adulthood • No islet cell antibodies • Insulin resistance • Not insulin dependent • Familial patterns • Obesity • 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 ketoacidosis • Accumulation of acetyl CoA, betahydroxybutyric 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) Distribution of etiologic categories by race/ethnicity 100% 6.2 11.1 80% 19.8 60% 28.3 15.9 40.1 40.8 6.6 21.3 40% 67.8 9.4 10.8 18 15.1 62.9 43.7 20% 10.1 32.5 33.3 3.2 12.9 19.5 Non-autoimmune + IR Non-autoimmune + IS Autoimmune + IR Autoimmune + IS 54.5 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 – Usually leading to absolute insulin deficiency TNF-a IFN-g T cell • Immune mediated • Idiopathic Autoimmune Reaction Macrophage Class II MHC Class I MHC TNF-a IL-1 -cell NO Dendritic cell 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. -cell Destruction CD8+ T cell 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 dysregulation Environmental triggers and regulators IAA -Cell mass GADA, ICA512A, ICA Interactions between genes imparting susceptibility and resistance Variable insulinitis -cell sensitivity to injury Loss of first-phase insulin response (IVGTT) Glucose intolerance Overt T1D Prediabetes Time C-peptide undetectable 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 (gluconeogenesis) in the liver Abnormally low glucose uptake and glycogen synthesis in skeletal muscle following a meal Failure to inhibit hormone-sensitive lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs) Polymorphisms in genes that control insulin secretion are associated with an increased lifetime risk for T2D Excess free fatty acids compromise β-cell function and attenuate insulin release (lipotoxicity) Chronic hyperglycemia (glucotoxicity) 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 Low Middle High 2004 Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Diagnosed Diabetes (%): Low (<9.0), Mid (9.0–13.9), High (>13.9); Obesity (%): Low (<29.1), Mid (29.1–36.0), High (>36.0) Low Middle High Low Middle High 2010 Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Diagnosed Diabetes (%): Low (<9.0), Mid (9.0–13.9), High (>13.9); Obesity (%): Low (<29.1), Mid (29.1–36.0), High (>36.0) Low Middle High Low Middle High 2016 Estimates are percentages at the county-level; natural breaks were used to create categories using 2016 data Diagnosed Diabetes (%): Low (<9.0), Mid (9.0–13.9), High (>13.9); Obesity (%): Low (<29.1), Mid (29.1–36.0), High (>36.0) Low Middle High 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 <120 days • Low HbA1c results because 50% of glycation occurs in 90-120 days • Blood loss, hemolysis, hemoglobinopathies and red cell disorders, and myelodysplastic disease may result in falsely low HbA1c Gupta S, Jain U, Chauhan N (2017) Laboratory Diagnosis of HbA1c: A Review. J Nanomed Res 5(4): 00120. Common complications in diabetes mellitus • Macrovascular • Coronary artery disease • Peripheral arterial disease • Stroke • Microvascular • Diabetic nephropathy • Neuropathy • Retinopathy The Natural History of T2DM Macrovascular complications Microvascular complications Kendall DM et al. Am J Med. 2009;122:S37-S50. Chronic hyperglycemia and complications What causes micro and macroangiopathy ? Diabetic Glycosylations • Hemoglobin A1c, non-enzymatic binding of glucose to aminoacids of RBC Hemoglobulin, measure of hyperglycemia • Glycosylation can affect albumin, collagen, other proteins: proteins of capillary basement membrane resulting in thickening, leaks and closure: microangiopathy → macroangiopathy Mechanism related to hyperglycemia: damaging basement membrane of capillaries common to all types of DM: type 1 and 2 and GDM What else causes large blood vessel injury and accelerated atherosclerosis ? Diabetic Dyslipidemia (type 2) • abnormal fat carrying lipoproteins: LDL, IDL) • Paradigm shift in therapeutic emphasis (late 1990s) • glucocentric + lipocentric Impaired or deficient insulin effect increase fatty acids in the blood secondary to 1. Lipolysis: release of fatty acids from adipose tissue. 2. Failure to clear fatty acids following meals ↑LIPOLYSIS ↑FFA ↑ Hepatic Lipogenesis More fat to liver More fat and cholesterol-rich proteins into blood Cholesterol is a major factor in diabetic atherogenesis ↑ TG rich LP output Cholesterol rich proteins How often are complications encountered in diabetes Bertoni AG et al. Diabetes Care 2002;25(3):471-75. Macrovascular Complications Are Common • Individuals with diabetes are at a 2-to-6 times higher risk versus the general population • Major cardiovascular risks further increase the risk • Smoking • Hypertension • Dyslipidemia • The development of cardiovascular disease in an individual with diabetes is associated with a reduced life expectancy Microvascular Complications: Retinopathy • Leading cause of blindness • Prevalence increases with age • Other eye complications • Adults with diabetes are 2-5 times more likely than those without diabetes to develop cataract • Diabetes nearly doubles the risk of glaucoma https://nei.nih.gov/health/diabetic/retinopathy Microvascular Complications: Nephropathy • May be present in up to 30% of patients with Diabetes • Prevalence is greater in the African American population • Stages I through V disease with stage V representing end stage renal disease (ESRD) Microvascular complications: Neuropathy • May be autonomic or sensorimotor Sensorimotor • Wide spectrum of patient presentation • May have pain to numbness to painless • Usually feet are affected (hands, too) • Complications include • Ulcers • Edema • Arthropathy Microvascular complications: Neuropathy Autonomic • Wide spectrum of patient presentation • • • • Gastroparesis Erectile dysfunction Neuropathic bladder Diabetic diarrhea Hypoglycemia • Blood glucose less than 70 mg/dL with symptoms or less than 60 mg/dL without symptoms • Can occur secondary to diabetes treatment • Counter-regulatory hormones are stimulated • Uncoordinated administration of insulin or oral hypoglycemic agents • Elderly and children are more prone and more at risk for negative events • Treat with glucose Typical presentation of hypoglycemia Catecholamine release • Sweating • Shaking • Tremor • Hunger • Palpitations • Weak • Tachycardia CNS dysfunction • Confusion • Irritability • Headaches • Abnormal behavior • Diplopia • Convulsion • Coma Nocturnal hypoglycemia • Morning headaches • Night sweats • Nightmares • Difficulty awakening • Loud respirations Suggested Readings • Textbook • Ikle JM, Gloyn AL. 100 YEARS OF INSULIN: A brief history of diabetes genetics: insights for pancreatic beta-cell development and function. J Endocrinol. 2021 Jul 22;250(3):R23-R35. doi: 10.1530/JOE-21-0067. PMID: 34196608; PMCID: PMC9037733. • Li, M., Chi, X., Wang, Y. et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Sig Transduct Target Ther 7, 216 (2022). https://doi.org/10.1038/s41392-022-01073-0