Diabetes Mellitus PDF

Diabetes Mellitus SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AN...

Diabetes Mellitus SCOTT HANES, PHARMD ASSOCIATE PROFESSOR COLLEGE OF PHARMACY AT ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE Learning Objectives 1. Define diabetes according to blood glucose concentrations and hemoglobin A1c 2. Describe the role of insulin (and insulin deficiency) and glucagon on protein, fat and carbohydrate regulation 3. Identify and explain how counter-regulatory hormones influence glucose concentrations 4. Differentiate the pathophysiology of type I and type II diabetes mellitus, diabetic ketoacidosis, and hyperglycemic hyperosmolar syndrome 5. Based of patient characteristics, determine if a patient is likely to have type I or type II diabetes, diabetic ketoacidosis, and/or hyperglycemic hyperosmolar syndrome 6. Define polydipsia, polyuria, and polyphagia 7. Identify macrovascular from microvascular diabetes outcomes and describe their pathophysiology 8. Explain abnormal laboratory, diagnostic tests, physical exam findings, and clinical signs/ symptoms using knowledge of physiology and pathophysiology 9. Explain how pathophysiologic derangement in an organ system can affect other organ systems Pancreas Physiology Overview Pancreatic hormonal function Exocrine (acini) Pancreatic enzymes Endocrine (Isle of Langerhans) Beta cells – insulin, amylin Alpha cells – glucagon Delta cells - somatostatin  25% of glucose cellular uptake is insulin dependent (adipose, muscle, liver) Insulin: 75% tissue uptake non-insulin Inhibits gluconeogenesis dependent (including brain) Stimulated glycogen storage Facilitates glucose cellular uptake Pancreatic Endocrine Hormone Function Substrate Insulin Glucagon Glucose ↑glucose uptake into adipose/skeletal tissue ↑glycogen synthesis ↑Glycogenolysis ↓gluconeogenesis ↑Gluconeogenesis Fat ↓lipase (adipose) ↑Fatty acid transport to adipose Activates lipase releasing Fatty acids ↑Fatty acid/triglyceride liver synthesis Protein ↑ Amino acid transport/protein synthesis ↑amino acid transport to liver/gluconeogenesis ↓ Protein catabolism Role Promote glucose utilization for energy Maintain glucose between meals, exercise Energy storage via fat/protein Stimulated by hypoglycemia  Counter-Regulatory Hormones Non-pancreatic hormones that counteract the actions of insulin Epinephrine ○ Released from adrenal medulla during stress ○ +glycogenolysis from liver ○ Inhibits insulin release ○ Inhibits glucose skeletal tissue uptake ○ Lipolytic releasing fatty acids from adipose tissue Growth Hormone ○ Increases protein synthesis ○ Lipolytic releasing fatty acids from adipose tissue ○ Inhibited by insulin Cortisol ○ Increase gluconeogenesis Diagnosis and Laboratory Glucose ○ Blood  Fasting blood glucose (> 8 hours of fasting)  Random blood glucose (no relation to meals)  Blood glucose in response to Oral Glucose Tolerance Test (75 g of oral glucose)  Hemoglobin A1C – glycosylated hemoglobin; correlates to glucose control over life span of RBC ○ Urine  Blood glucose > 180mg/dl exceed renal absorptive capacity  spills into urine  Not commonly used C-Peptide Diagnostic Thresholds for Diabetes Paramter Diagnostic Threshold Fasting blood glucose (FBG) ≥126 mg/dl 2h Post-OGTT ≥200 mg/dl Random* ≥200 mg/dl *In patient displaying signs/symptoms of DM HgA1c ≥6.5% Know these values! ADA guidelines 2020; Diabetes Care 2020:43: suppl 1  Correlation between Blood Glucose and HgAIC HgA1C (%) Mean Blood Glucose (mg/dL) 6 126 7 154 8 183 9 212 10 240 11 269 12 298 Types of Diabetes Mellitus Type I Type II (90-95%) Gestational ○ Related to pregnancy Miscellaneous ○ Chronic pancreatitis ○ Excess steroids  Cushing syndrome (excess steroid production)  Chronic glucocorticoid administration ○ Various genetic syndromes (including Down syndrome) Type I Diabetes Mellitus Former terms ○ Juvenile diabetes mellitus ○ Insulin-dependent diabetes mellitus Key pathophysiologic characteristics ○ Autoimmune destruction of pancreatic beta cells (type 1A) Islet cell autoantibodies stimulate immune destruction Glucose dysregulation when > 60% of beta cells destroyed  ∅ insulin production (absolute insulin deficiency)  Amylin secretion   glucagon secretion and  satiety  Type II Diabetes Mellitus Formerly ○ Adult-onset diabetes mellitus ○ Non-insulin dependent diabetes mellitus Key pathophysiologic characteristics 1. Altered insulin secretion (relative insulin deficiency)  Beta dysfunction and loss of 5-7% per year  ↓ incretin effect (in GI tract); normally stimulates 50% of insulin secretion Glucagon-like Peptide (GLP-1)  ↓ insulin release and  glucagon Type II Diabetes Mellitus 2. Insulin receptor resistance  Obesity ○ Majority of type II diabetics have obesity ○ Central obesity greater risk vs peripheral obesity ↑ waist circumference, waist/hip ratio  Free fatty acids ○ Chronic increase causes beta cell dysfunction ○ Inhibit cellular glucose uptake and glycogen storage ○ Impairs liver insulin sensitivity triggering gluconeogenesis ○ May be key mediator of obesity related insulin resistance Type II Diabetes Mellitus 3. Increased glucose availability A. ↓ Gluc0se cellular uptake B.  hepatic glucose production Glycogenolysis Gluconeogenesis C.  Na/Glucose transporters in renal tubule Glucose reabsorption Threshold for glucose elimination From 180 to 220 mg/dl D.  GLP-1 and amylin  glucagon secretion  satiety á á  Gestational Diabetes Mellitus 7% of pregnancies Secondary to  counter-regulatory hormones Important to prevent complications ○ Maternal ○ Fetus/neonate  Macrosomia (large body size) Clinical Presentation Patient Characteristics Type I Type II Common age of onset < 20 years >30 years (but variable) Onset character Abrupt; symptomatic Gradual onset; may be First presentation may be diabetic asymptomatic ketoacidosis (DKA) Body habitus Normal or weight loss Overweight, central obesity Family history 60% [Insulin] Low Normal to high Clinical Presentation 3 Ps Polyuria – excessive urination Polydipsia – excessive thirst Polyphagia – excessive hunger ○ Secondary to caloric loss from glucosuria ○ Less common in type II  Polyuria H2O Blood Vessel (hyperglycemia) Interstitial Cell Glucose exceed max H2O Reabsorption glucosuria Polydipsia Excessive fluid loss Stimulation of thirst center via osmolarity and low blood volume Clinical Presentation Other signs/symptoms Weight loss (type I) ○ Fluid losses ○ Absolute insulin deficiency  utilize fat and protein stores for gluconeogenesis ○ Glucosuria  caloric loss Fatigue ○ Low blood volume ○ Low energy utilization Blurred vision ○ Hyperosmolar ocular fluids Infections ○ Urinary ○ Dermatologic  Diabetes Complications Acute ○ Diabetic Ketoacidosis (DKA) ○ Hyperglycemic Hyperosmolar Syndrome (HHS) ○ Hypoglycemia Chronic ○ Macrovascular  CV events, stroke, peripheral vascular disease ○ Microvascular  Nephropathy  Neuropathies  Retinopathy  Gastrointestinal dysmotility Chronic Complications Macrovascular Increased risk for: ○ Ischemic heart disease ○ Myocardial infarction ○ Stroke ○ Peripheral arterial disease Largely related to atherosclerosis ○ Dyslipidemia  Hypertriglyceridemia common due to lipolysis  FFA   VLDL  VLDL clearance  LPL (lipoprotein lipase) activity  LDL and  HDL ○  adipose tissue is poorly vascularized  ischemia  chronic inflammation (and procoagulant) Hypertension ○  Nitric oxide and  Endothelin-1  vasoconstriction ○ Secondary to nephropathy  Na/H20 retention  Microvascular Complications Involves ○  protein deposition in vessel walls ○ Endothelial cell dysfunction and loss ○ Occlusion Common Microvascular Complications Nephropathy ○ Glomerularsclerosis (See CKD lecture)  proteinuria  Microalbuminuria Retinopathy ○ Most frequent cause of blindness  Increased retinal vascular permeability  Microaneurysm formation  Neovascularization ○ Macular edema ○ Hemorrhage ○ Retinal detachment Microvascular Complications Neuropathies ○ Arterial wall thickening supplying nerves  Nerve damage possibly from ischemia ○ Decreased clearance of free radical (damages nerves)  Via NADPH consumption and decreased glutathione production ○ Schwann cell demyelination  Slows neuronal conduction Types ○ Somatic  ↓perception of pain, vibration/touch, temperature  Lower >> upper extremities  Commonly occurs in bilaterally; stocking-glove pattern  If affects somatosensory nerves  painful neuropathy Microvascular Complications Neuropathies (cont) ○ Autonomic  Impact PNS and SNS  Associated with dysregulation of ○ Vasomotor responses  orthostatic hypotension, erectile dysfunction ○ Cardiac response orthostatic hypotension, blunted HR response ○ Bladder  incontinence  Gastroparesis ○ Slow/delayed emptying of stomach Nausea, post-prandial vomiting, bloating, early satiety, epigastric discomfort  Microvascular Complications Diabetic foot ulcer ○ Atherosclerosis + ○ Neuropathy + ○  Immune response (neutrophil chemotaxis and macrophage phagocytosis) + ○ Impaired healing https://sa1s3optim.patientpop.com/assets/images/provider/photos/2433217.png Diabetic Ketoacidosis Previously fatal until recombinant insulin produced ○ Now ~ 1% fatality Associated with absolute insulin deficiency ○ New diagnosis of type I  Less common in type II (subform associated with transient beta cell dysfunction) ○ Insulin not administered  No planned meal  Sick – not eating Stress response ○ Infection ○ Medical event (MI, trauma, pancreatitis, stroke, etc) Medications (corticosteroids, sympathomimetic drugs (illicit and Rx) Hyper- Acidosis glycemia DKA Ketones  Diabetic Ketoacidosis Hyperglycemia (blood glucose > 250mg/dl) ○ Lack of insulin  Stimulates glucagon release ○ Release of counter regulatory hormones  Cortisol, epinephrine, growth factor ○ Can present as euglycemia when associated with poor oral intake, recent insulin administration, sodium-glucose cotransporter 2 inhibitors Ketosis (+serum and urine ketones) ○ Lack of insulin allows lipolysis   Beta-hydroxybutryric acid  acetoacetone Anion Gap metabolic acidosis (pH < 7.3, HCO3 < 18) ○ Ketones ○ Lactic acid DKA: Clinical Presentation Onset – rapid; within 24 hours typically Fluid loss ○ Osmotic diuresis  6L loss on average ○ Hypotension  Compensatory tachycardia ○ Dehydration  Dry mucous membrane, poor skin turgor Electrolyte abnormalities (Na, K, Mg, PO3, Cl, Ca) ○ secondary to osmotic diuresis and ketone salt formation ○ Na  Dilutional hyponatremia ○ Recall: actual Na = measured Na + (1.6 for every 100 mg/dl of glucose > 100mg/dl)  DKA:Clinical Presentation Electrolyte abnormalities ○ K  Serum concentration commonly normal or high ○ H+/K + cellular exchange ○ Lack of insulin  Body stores of K nonetheless are low ○ K loss via Osmotic diuresis + ketone salt GI loss (emesis) RAAS (aldosterone) DKA: Clinical Presentation Gastrointestinal ○ Nausea,vomiting common ○ Abdominal pain Fruity breath ○ Due to ketone; often confused with alcohol intoxication Pulmonary ○ Kussmaul respirations (deep labored breaths) –compensation for metabolic acidosis Neurologic ○ Alertcoma  Related to severity of acidosis and hyperosmolarity Weakness, fatigue Prothrombotic state ○ Low blood volume ○ Pro-inflammatory mediator release  procoagulant Hyperglycemic Hyperosmolar Syndrome More common in type II DM since typically have sufficient insulin to suppress lipolysis ○ Therefore no ketogenesis or subsequent acidosis Onset typically more gradual over days Characterized by ○ Hyperglycemia (> 600 mg/dl) ○ Hyperosmolarity ○ Both more profound compared to DKA due to prolonged ○ More severe neurologic effects due to hyperosmolarity HOMEWORK – how will clinical presentation differ from DKA?  Hypoglycemia Generally defined as blood glucose < 60 mg/dl with symptoms Most common causes ○ Insulin/secretagogues dose error (too much)/inappropriate prescription ○ Insulin/secretagogues given but failure to eat ○ Exercise ○ Excessive alcohol consumption (suppresses hepatic gluconeogenesis) Clinical Presentation ○ Cerebral function  Headache, cognitive dysfunction, stupor (“drunk”), coma, seizures ○ Activation of ANS  SNS – anxiety, tachycardia, sweating, vasoconstriction (cool, clammy skin) Treatment Type I DM Insulin DKA & HHS IV fluids (saline based) K replacement Insulin