1 Diabetes Mellitus Pathophysiology.docx

Diabetes Mellitus Pathophysiology Session learning objectives Describe the epidemiology, pathophysiology and clinical presentation of diabetes mellitus Describe the concept of glucose homeostasis List patient risk factors for diabetes mellitus Diabetes Mellitus Metabolic disorder characterized by “h...

Diabetes Mellitus Pathophysiology Session learning objectives Describe the epidemiology, pathophysiology and clinical presentation of diabetes mellitus Describe the concept of glucose homeostasis List patient risk factors for diabetes mellitus Diabetes Mellitus Metabolic disorder characterized by “hyperglycemia” due to impaired insulin regulation and/or insulin resistance Eight leading cause of death in the United States in 2021 Leading cause of new cases of blindness among adults in the United States in 2021 Associated with high healthcare cost ~ $413 billion in 2022 Excess medical costs per person associated with diabetes is $12,022 In 2021: 38.4 million people have diabetes (11.6% of the U.S. adult population) 8.7 million undiagnosed cases 97.6 million adults have prediabetes (38% of the U.S. adult population) Prevalence of diagnosed diabetes by race/ethnicity in US adults from 2019 to 2021 American Indian or Alaska Native population (16%) Black (12.5%) Native Hawaiian or Pacific Islander (11.7%) Hispanic (10.3%) Asian (9.2%) White (8.5%) Diabetes Pathophysiology Diabetes mellitus is caused by persistent hyperglycemia due to deficiencies in insulin production and utilization (resistance) This results in abnormal carbohydrate and fat metabolism There have been several models to describe causative factors Glucose homeostasis Glucose is a simple carbohydrate Serves as a primary energy source for cellular function Plasma glucose is maintained at 70 to 100mg/dL and is obtained from: Oral intake (e.g. meals or drinks) Gluconeogenesis Glycogenolysis Glycogenesis Approximately 85% of glucose production is derived from the liver, and the 15% is produced by the kidney in the fasting state Glucose is stored as glycogen in the liver and skeletal muscles Gluconeogenesis Production of glucose from “non-carbohydrate” sources by the liver Occurs after glycogen stores are depleted Adipose tissue provides precursors (glycerol and free fatty acids for the process) Glycogenolysis Breakdown of glycogen Primary source of glucose during shorter fasts (8 to 12 hours) Activated by glucagon Glycogenesis Conversion of excess glucose to glycogen for storage in the liver Activated by insulin KEY REGULATORS OF GLUCOSE HOMEOSTASIS Insulin Glucagon Amylin/incretin Pancreas Liver Skeletal muscle Adipose tissue Kidney Stomach/intestines Homeostasis regulator – Insulin Stimulates cellular uptake of glucose (skeletal muscle, liver and adipose tissue) and depresses the use of fat as an energy source. Promotes protein synthesis. Secretion is promoted by incretin hormones glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). Primary stimulus is oral ingestion of glucose. When insulin is secreted into the portal vein, a portion is cleaved C-peptide can be used as a non-functional marker for insulin production Primarily eliminated by the liver (50% through first pass elimination) Half life of about 5 minutes (in healthy patients) Kidney and muscle tissue are also sites of degradation Glucose and Insulin Homeostasis Homeostasis regulator – Amylin Co secreted with insulin by the beta cells in the pancreas in response to caloric intake Suppresses inappropriate glucagon secretion, slows gastric emptying and satiety (centrally mediated) Patients with diabetes (type 1 and type 2) are deficient in amylin secretion with Homeostasis regulator – Glucagon Produced by the alpha cells in the pancreas and promotes hyperglycemia Stimulates cellular release of glucose (glycogenolysis) and increases the use of fat as an energy source. Promotes gluconeogenesis from the liver and glycogenolysis. Release of insulin suppresses glucagon secretion Half life of 5 minutes. Rapidly metabolized by the liver and kidney KEY REGULATORS OF HYPERGLYCEMIA “Egregious Eleven” Classification Prediabetes Persistent hyperglycemia Type 1 diabetes Autoimmune beta cell destruction Absolute insulin deficiency Includes latent autoimmune diabetes of adulthood (LADA) Type 2 diabetes Progressive loss of beta cells Relative insulin deficiency Insulin resistance Metabolic syndrome Gestational diabetes Diagnosed in the second or third trimester of pregnancy No overt diabetes diagnosis prior to pregnancy Diabetes due to other causes: Neonatal diabetes Maturity-onset diabetes of the young (MODY) Diseases of the exocrine pancreas (i.e. cystic fibrosis and pancreatitis) Drug or chemical induced diabetes (steroids or HIV/AIDS treatment) Prediabetes Hyperglycemia not consistent with diabetes diagnosis Patients are at an increased risk for diabetes and cardiovascular disease It is associated with: Obesity (abdominal or visceral obesity) Dyslipidemia Hypertension Type 1 diabetes Previously termed “insulin-dependent diabetes” or “juvenile-onset diabetes” Accounts for approximately 10% of diabetes diagnosis Often occurs in childhood and adolescence but can occur at any age Features useful for differentiating type 1 diabetes: Younger age of diagnosis (<35 years old) Lower BMI < 25 kg/m2 Unintentional weight loss Ketoacidosis and glucose > 360mg/dL at presentation (diabetic ketoacidosis or DKA) Caused by autoimmune mediated cellular destruction of pancreatic beta cells Precipitated by infection, stress or other environmental risk factors Presence of autoantibodies - Islet cell, GAD, insulin and tyrosine phosphatases Some cases are idiopathic and not due to autoimmune process (rare) Results in absolute insulin deficiency Strong genetic linkage - HLA alleles (DQA and DQ8) Patients are a higher risk of complications like diabetic ketoacidosis (DKA) and other autoimmune diseases like hashimoto thyroiditis, graves disease, addison disease and celiac disease Decline of Beta-Cell Function Type 2 diabetes Previously termed “noninsulin-dependent diabetes” or “adult-onset diabetes” Often occurs in adulthood but can occur at any age Accounts for approximately 90% of diabetes diagnosis Strong link to obesity (increased insulin resistance) At a higher risk of complications like hyperosmolar hyperglycemia syndrome (HHS), microvascular and macrovascular disease Stages of Insulin Resistance Gestational diabetes Glucose intolerance and resistance that occurs during pregnancy (second or third trimester) without prior diagnosis of diabetes Occurs in 9% of pregnancies in the United States Increased risk for the mother and neonate: Increased risk of miscarriage, stillbirth, or preterm delivery Macrosomia (large for gestational age infant, >8 lbs) Increased risk for cesarean section delivery or vaginal delivery with infant injury Preeclampsia/eclampsia Neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia, or respiratory distress syndrome Increased risk of offspring developing T2DM, obesity, or metabolic syndrome Risk factors Type 1 diabetes Genetics and family history Environmental factors Autoantibodies Geography Prediabetes/Type 2 diabetes Genetics and family history Race (Hispanic, Native American, Black, Asian) Age Weight (overweight or obese) Inactivity Gestational diabetes Polycystic ovary syndrome Acanthosis nigricans Hypertension Dyslipidemia Medications Gestational diabetes Family history Age Weight (overweight or obese) Race (Hispanic, Native american, Black, Asian) Delivery of a baby > 9lbs Medications associated with hyperglycemia Glucocorticoids Nicotinic acid or niacin Thyroid hormone Beta-adrenergic agonists Thiazide diuretics Phenytoin Protease inhibitors Atypical antipsychotics Pathophysiology review Clinical presentation Signs and symptoms Polyuria Polydipsia Polyphagia Weight loss (T1DM) Blurred vision Lethargy Nocturia Slow healing sores Frequent infections Patient presentation Complications of Diabetes MICROvascular (damage to small vessels) MACROvascular (damage to large vessels) Hyperglycemic crisis Hyperglycemic crisis Diabetic ketoacidosis Caused by reduced insulin levels in patients with absolute insulin deficiency (T1DM and advanced T2DM) Leads to reduced glucose utilization and increased lipolysis and gluconeogenesis Ketogenesis occurs due to excess lipolysis causing the blood to become acidic Patients present with metabolic acidosis, uncontrolled hyperglycemia, altered mental status and increased ketones Hyperosmolar hyperglycemic state Caused by reduced insulin levels in patients with relative insulin deficiency (T2DM) Ketosis is absent or minimal Patients present with dehydration, altered mental status osmotic diuresis and hyperosmolarity Summary T1DM is caused by ABSOLUTE insulin deficiency secondary to autoimmune destruction of beta-cells in the pancreas (antibodies are present) T2DM is caused by RELATIVE insulin deficiency with the presence of increased insulin resistance Types of symptoms (except weight loss) and complications are the same for both T1DM and T2DM GDM is diabetes diagnosed in the 2nd or 3rd trimester of pregnancy that was not existing or diagnosed prior to the pregnancy The three common symptoms of hyperglycemia are polydipsia, polyphagia and polyuria (also known as the 3 Ps)