Lecture 10: Glucose Regulation and Diabetes

Lecture 10: Glucose Regulation and Diabetes Endocrine Basics · Endocrine organs synthesize & secrete "hormones" ↳ endocrine hormones: released into bloodstream ↳ paracrine hormones: act on other cells than where they are synthesized ↳ these hormones have a long half life and are often highly PPB · Secretion is triggered by: ↳ concentrations of substances (eg. glucose) ↳ neural stimulation (eg. SNS, epinephrine) ↳ endocrine sequences (from one endocrine gland to another) · regulated by a negative feedback mechanism · function tests are either done on the hormone itself, or how it behaves · dysfunctions: hyposecretion or hypersecretion ↳ assessed by BW or S&S of excess or deficit of that hormone Sugars · glucose is the molecule all sugars are broken down into · glucose and dextrose are typically synonymous terms ↳ we only measure glucose because dextrose is eventually converted to glucose through metabolism · Fructose: Fruit sugars · Maltose: beer and fermented sugars all are metabolized into glucose · Lactose: milk sugars · 0-calorie sweeteners like Splenda or aspartame either travel unchanged or have an extremely low calorie amount, however, they can get distorted in baking Energy Sources · There are 2 primary energy sources used by the body: glucose and fatty acids 1) Glucose · glucose is readily distributed, as it does not need to be metabolized · it is the preffered energy source of the body · the most needy system for glucose is the brain, as it requires a constant supply of glucose and cannot store it for later · extra glucose is stored as glycogen (in the liver and muscles), & triglycerides (in adipose tissue) ↳ When blood glucose falls, glucagon breaks down glycogen via glycogenolysis 2) Fatty Acids · fatty acids are distributed via lymph into circulation · CNS & RBC cannot use fatty acids (only glucose) · extra fatty acids are stored as triglycerides (3 fatty acids + glycerol) · fatty acids are NOT converted into glucose · When fatty acids are metabolized in the liver they release ketone metabolites as a byproduct ↳ ketones are always present in small amounts, but when large amounts of fatty acids are utilized for * energy, ketone levels rise, the body can't utilize them, and they cause metabolic acidosis - - The Pancreas · The pancreas has both exocrine and endocrine functions, but we are only focusing on endocrine · Islets of Langerhans cells are responsible for the secretion of glucagon and insulin into the blood ↳ alpha cells: secrete glucagon ↳ beta cells: secrete insulin · Insulin is secreted in response to high glucose levels in the blood, which then causes glucose to leave the blood and enter tissue cells. Lowered blood glucose levels provide a negative feedback to stop secreting insulin · Insulin affects the metabolism of carbs, lipids, and proteins in the body. It opens the glucose transporters to allow glucose to be used by the cells, and also promotes storage formation ↳ without insulin, glucose cannot be stored and is then secreted · Glucagon is an antagonist to insulin, and is secreted when blood glucose is low, causing stored glucose to be utilized by the body (triglyceride & glycogen breakdown, amino acid conversion into glucose) · somatostatin functions as part of this negative feedback to inhibit insulin and glucagon as needed * - Review: Beta Cells · insulin synthesis: stimulant is high serum glucose · glucose enters pancreatic beta cell via glucose transporter -> metabolized via glucokinase into ATP -> closes K channels -> depolarization -> insulin secretion · insulin from pancreas enters hepatic circulation -> 50% lost to 1st pass metabolism -> metabolites are renally excreted (CO2 & H2O) · insulin action: binds to cellular membrane receptor (tyrosine Kinase) -> activates Kinase enzyme within cell -> stimulates glucose transporter channels to open to glucose ↳ tyrosine kinase is a transmembrane receptor type · Insulin inhibition: Somatostatin (D cell produced) Beta Cell Destruction · Beta cells are destroyed in Type 1 Diabetes causing dysfunction of glucose, fat, and protein metabolism ↳ immediate effect: disabled transport of glucose into cells · Pathophysiology sequelae ↳ increased glucose in plasma ↳ high solute concentration and cellular dehydration ↳ metabolic shift to use fat for energy (break down triglycerides & glycerol) ↳ hepatic metabolism of fatty acids -> Ketone bodies -> metabolic acidosis · Therefore: hyperglycemia, polydipsia, polyuria, glycosuria, Ketonuria, changes in LOC, acetone breath, metabolic acidosis (Diabetic Ketoacidosis, DKA), coma, death Consequences of Reduced Glucose Uptake · energy substitution leads to altered cellular function ↳ Proteolysis: protein breakdown - weight loss and muscle wasting ↳ Lipolysis: fatty acid breakdown - fatty acid oxidation -> ketones & Ketonuria · altered cellular functions (eg. insulin resistance) · injury: endothelial dysfunction, decreased angiogenesis, increased oxidative stress (= inflammatory consequences) ↳ organ injury: retinopathy, neuropathy, nephropathy, CV Diabetes Mellitus · Insulin Dependent Diabetes Mellitus (IDDM) due to total destruction of beta cells ↳ insulin resistance or insulin deficiency · Type 1A: genetic predisposition + triggering event causing immune reaction to beta cell antigens ↳ autoimmune disease · Type 1B: idiopathic (familial), rare · Dx: fasting glucose >7 mmol/L (normal < 6), usually diagnosed in toddlers/teens · Tx: insulin ↳ if w/o tx, diabetic ketoacidosis -> death Diabetes & Atherosclerosis (Video) · many metabolic factors related to diabetes promotes formation of atherosclerotic plaque eg.) dyslipidemia, hypertension, increased fatty acids, hyperglycemia · hyperglycemia increases oxidative stress, and the increase of free radicals increases lipid and lipoprotein peroxidation, leading to foam cell formation on arterial walls · insulin resistance causes endothelial dysfunction through loss of NO which is a precursor to atherosclerosis · diabetes is a prothrombotic state which increases atherosclerotic plaque formation (risk of CAD) Insulin TX · insulin is always measured in units (IU or U) · basal level = 5-15 IU/mmol · peak rise = 60-90 IU/mmol · Clinically normal glucose level = 4-8 mmol · goal of tx: mimic normal glucose patterns (mimic basal and bolus) and minimize risk of hypoglycemia · Administration is SC (unless critically ill, then use IV) ↳ must be SC not IM as IM can affect onset and duration ↳ most commonly in abdomen and buttocks · 7 rights, dose double checked Note: Insulin is by injection because the GI tract destroys insulin 4 Basic Preparation Categories: 1) Rapid Acting 2) Long Acting 3) Short Acting ("regular") 4) Intermediate Acting 1) Rapid Acting Insulin · onset: 10-15 min · peak: 1-2 hr · duration: 3-5 hr · ideal for: meal time bolus (eat right away!) · drugs: Humalog (Lispro), Novorapid (Aspart), Apidra (Glulisine) ↳ Fiasp (Aspart) - onset 4 min - Rapid Acting Insulin in Pumps · meal time boluses per carb intake · glucose level pre-meal and 1-2 hr post · basal insulin requirements ↳ slow infusion of rapid acting insulin over 24 hours ↳ careful monitoring ↳ endocrinology appts 2) Long Acting Insulin · onset: 90 min · Plateaus for: up to 24 hrs (Sometimes 12) · ideal for: background, admin 1-2x daily, never IV · drugs: Levemir (Detemir), Lantus (Glargine) ↳ Tresiba (Degludec) -> ultra long acting (> 30hrs) - 3) Short Acting Insulin ("regular") · onset: 30 min · peak: 2-3 hr · duration: 6.5 hrs (dose dependent) · ideal for: meals (30-45 min pre/post meal), BUT issues with hypoglycemia & balancing dose with intake ↳ used IV for Ketoacidosis or new diagnosis of diabetes · drugs: Novolin ge Toronto, Humulin R ↳ Entuzity (KwikPen) -> 5x more concentrated for daily requirements - 4) Intermediate Acting Insulin · onset: 1-3 hr · peak: 5-8 hrs · duration: up to 18 hrs (dose dependent) · ideal for: background replacement, admin 1-2x daily, if pt on steroids, monitor for night hypoglycemia, never IV · drugs: Humulin N, Novolin ge NPH - Insulin Therapy & Insulin Dosing · Estimated daily insulin requirement = 0.55(U) x pt wt (kg) ↳ does not factor in BMR, activity/stress, food -> its a starting point ↳ 40% is background requirement (basal) ↳ 60% is meal time (boluses) · info required for actual dosages: ↳ blood glucose (BG) ↳ Carbohydrate content per meal ↳ goal: normal BG of 4-8 “BBIT ” · B = basal (long acting insulin) in am · B = bolus (short rapid acting insulin) for meals · I = insulin correction (short/rapid acting) if necessary based on BG · T = titrate doses to achieve 4-8 mmol/L Accurate Bolus Dosing · Carbohydrate intake: ↳ Carb counting (45-60 g/meal) - carb total - fibre = total count * * - 15g of carb = 1 unit rapid acting insulin (on average) - 1 unit = 2.5 BG levels ↳ regular meals & snacks (eg. bedtime snack) * Insulin Bolus · rapid or short acting insulin 3x per day · check BG before and after meal ↳ goal: 4-8mmol/L = normal · Insulin correction & titrate ↳ may need more or less insulin based on pre and post levels Most Common Signs of Hypo/Hyperglycemia · Hypoglycemia ↳ loss of focus ↳ nervousness ↳ shakiness ↳ rapid onset of symptoms · Hyperglycemia ↳ thirst ↳ fatigue (b/c body doesn't utilize the glucose) ↳ longer onset of symptoms Blood Glucose Checks 1) Pre each meal 2) Post meals (if new dx) 3) at bedtime · 4 checks per day is minimum requirement · 8 checks for newly diagnosed pts Ketones · high ketones may be present due to insufficient insulin-glucose transport -> fatty acid breakdown into ketones for energy · urine Ketones: use ketone strip · if ketones rise -> DKA May infuse potassium because in DKA potassium shifts out of cells and when treated with insulin can lead to hypokalemia * * Illness & Exercise · illness can increase blood sugar levels due to the release of stress hormones, as well as through common illness symptomology ↳ Stress hormones are present in illness such as catecholamines/adrenergics (specifically NE, E, and cortisol). These hormones increase the lysis of stores (glucogenolysis) which increases BG ↳ illness also requires more energy to heal which can increase basal metabolic rate to use up glucose stores, also N&V, low appetite · Exercise decreases BG levels by using up energy from stores/cells - - Pathology of Insulin Imbalance 1) Hypoglycemia · causes: diet change (low carbs), activity (higher than anticipated), insulin (too much) · S&S: weakness, tachycardia, tremors, nausea, thirst/hunger, diaphoresis, headache · Tx: glucose ↳ conscious: glucose gel/tablet (PO), 15g x4, apple juice ↳ unconscious: D5OW (IV), Glucagon (IM)-> glucagon releases energy from stores but is slower acting 2) Hyperglycemia · high plasma glucose (high osmolality) · potassium imbalance ↳ Short term causes hyperkalemia, long term causes hypokalemia b/c Na/K pump requires ATP (from glucose) to work, since glucose isn't being made into ATP, pump doesn't work and potassium leaves cells and is renally excreted · low cellular function (b/c no energy for cells) · ketone accumulation -> DKA-tissue injury · S&S: high BG, high urine ketones, glucose in urine, acetone breath, high lactate (metabolic acidosis), changes in LOC, Polydipsia, polyuria N&V, Kussmaul resps Short acting insulin like Humulin R · Tx: 1st IV fluids, then insulin, then KCI for pottasium (close monitoring GI q1h) ↳ neutralize metabolic acidosis with sodium bicarbonate (rarely used - doesn't fix root of issue) - - Managing Blood Glucose · Blood glucose monitoring · food intake monitoring · exercise · control stress levels · Tests: Glycohemoglobin (A1c hemoglobin) ↳ measures how much sugar is bound to hemoglobin over 2-3 months