Insulin, Glucagon, and Diabetes Mellitus Lecture Outline PDF

Insulin, Glucagon, and Diabetes Mellitus Lecture Outline I. Insulin and Its Metabolic Effects II. Glucagon and Its Function III. Summary of Blood Glucose Regulation IV. Diabetes Mellitus V. Anesthetic Concerns 1 Insulin, Glucagon, and Diabetes Mellitus Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 1...

Insulin, Glucagon, and Diabetes Mellitus Lecture Outline I. Insulin and Its Metabolic Effects II. Glucagon and Its Function III. Summary of Blood Glucose Regulation IV. Diabetes Mellitus V. Anesthetic Concerns 1 Insulin, Glucagon, and Diabetes Mellitus Objectives 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. List the three major cell types of the pancreas, their hormones, and basic function of those hormones with emphasis on their regulation of plasma glucose Identify the relationship of the arrangement of the islet cells and intercellular communication Understand insulin and its metabolic effects on carbohydrates, fats, and lipids Describe insulin synthesis and combination with the insulin receptor Identify metabolic effects of insulin including its effects at its three target tissues and on ECF K+ Explain diabetic ketoacidosis Explain factitious hyponatremia Describe how glucose stimulates insulin secretion and list factors that affect secretion Identify the function and regulation of glucagon- including the effects of glucagon during starvation Summarize the integrated control of blood glucose Identify the risks associated with hypoglycemia and hyperglycemia Understand the pathophysiology of both Type I and Type II diabetes mellitus and insulin resistance Identify anesthetic concerns of diabetic autonomic neuropathy Explain how diabetes is diagnosed Identify anesthetic concerns related to hyperglycemia and hypoglycemia 2 References Assigned reading from your text: Hall Chapter 79 3 I. Insulin and Its Metabolic Effects 4 Endocrine Pancreas ❑ Pancreas Exocrine digestive function Digestive enzymes Bicarbonate solution Endocrine function Insulin Glucagon ❑ Insulin and glucagon Most important hormones controlling blood glucose Altered secretion or activity of these hormones produces diabetes mellitus 5 Pancreatic Hormones ❑ Pancreas composed of two major types of tissue Acini secrete digestive juices into duodenum Islets of Langerhans secrete hormones into blood from: – Three major cell types and their hormones: Alpha – glucagon – – Beta – insulin & amylin – – – Hypoglycemic hormone Secreted in response to glucose, amino acids, gut hormones, and glucagon Amylin inhibits glucagon secretion Delta – somatostatin – – – – – Hyperglycemic hormone Counter-regulatory hormone to insulin Inhibits the synthesis and secretion of most peptide hormones » Somatostatin inhibits insulin, glucagon, GH release » Inhibits gallbladder contraction and gastric motility Same somatostatin or GHIH (SS-14) produced by the hypothalamus- Inhibits growth hormone release » Higher potency than brain SS-14 Octreotide-an analog with a longer half-life -used to treat ectopic peptide hormone production by tumors Stimulated by same stimuli for insulin secretion And one minor cell type F cells/ PP cell – pancreatic polypeptide – – Inhibits gastrointestinal motility and pancreatic exocrine secretion May be involved with satiety and weight control 6 Intercellular Communication ❑ Proximity and arrangement promotes direct control of secretion by hormones: – Examples include: Insulin inhibits glucagon secretion Somatostatin inhibits both insulin and glucagon Glucagon stimulates somatostatin and insulin secretion – Blood flows through islets from the center toward periphery Insulin secreted at core Big Picture Medical Physiology FIGURE 8-30 Endocrine cells in a pancreatic islet of Langerhans Ganong FIGURE 18–1 Schematic diagram indicating paracrine/endocrine regulation of islet cell hormones. Inhibition is indicated by a blunt line, stimulation by an arrow. 7 Insulin And Its Metabolic Effects ❑ Insulin action: – Associated with blood glucose Hypoglycemic hormone – Crucial for regulation of glucose, lipid, and protein metabolism – Is an anabolic hormone associated with energy abundance Stores excess energy – Carbohydrates stored as glycogen in liver and muscle – Carbohydrates that cannot be stored as glycogen are converted into fats in adipose 8 Insulin Chemistry and Synthesis ❑β cells secrete insulin, proinsulin, and C (connecting) peptide Insulin synthesis – – – Preproinsulin is formed in beta cells Cleaved to proinsulin in ER Most proinsulin cleaved in Golgi to insulin Insulin is secreted along with C peptide – Insulin: Is a small protein – Two amino acid chains linked by disulfide bonds » A and B chain Circulates in unbound form, 6 min half-life – Cleared in 10-15 mins Is degraded by insulinase- mainly in the liver – C peptide: Activates Na+K+ ATPase and NOS In serum, C peptide is: – Elevated in endogenous hyperinsulinemia – Absent if hyperinsulinemia results from exogenous insulin 9 Insulin receptor ❑ Insulin must bind with its enzyme-linked receptor to: Activate some enzymes And inactivate others ❑ Insulin receptor is 4 subunits 2 alpha subunits are enzyme-linked to 2 beta subunits ❑ Insulin→ dimer of alpha subunits Activates beta subunits of the receptor Activated beta then acts as an enzyme Tyrosine kinase- autophosphorylates beta subunits ❑ 3 target tissues: Muscle Adipose Liver 10 Main Effects of Insulin Stimulation ❑ Main effects include: Immediate changes include: – Membranes (80%) markedly increase uptake of glucose Especially muscle and adipose Exception- neurons do not require insulin for glucose transport Uses glucose transporters - GLUT- that translocate intracellular vesicles to PM Post insulin: – Vesicles separate from the PM and return to the interior of the cell (3-5 mins) Changes over next 10-15 minutes – Cell membrane permeability increases for AA, K+, phosphate ions Changes over hours to days – Slower enzymatic effects→ very slow changes in gene expression – Insulin remodels cellular enzymatic machinery 11 Metabolic Effects of Insulin ❑ Insulin directs fuel metabolism toward the use of carbohydrate to prevent sustained increases in blood glucose postprandially – Post carbohydrate ingestion, glucose causes a rapid secretion of insulin – The maintenance of a normal blood glucose is important for normal CNS function ❑ Causes rapid uptake, storage, and use of glucose by liver, skeletal muscle, and adipose – Main effects of insulin on metabolism (also on next slide) - Insulin increases: – Rate of glucose transport into target cells – Rate of glucose utilization and ATP generation – Conversion of glucose to glycogen – Amino acid absorption and protein synthesis – TG synthesis in adipose ❑ Insulin causes K+ to enter cells- increases the activity of the Na+-K+- ATPase pump – Increases cellular uptake of K+ - normally in response to a meal Most meals contain enough K+ to cause a dangerous increase in K+ – Insulin infusion can quickly reduce plasma K+ in patients with hyperkalemia – Hypokalemia often develops when patients with diabetic acidosis are treated with insulin 12 Insulin Promotes Glucose Utilization and Substrate Storage ❑ Insulin reduces plasma substrates (glucose, amino acids, fatty acids, and ketoacids) in the: Liver- Insulin regulates enzymes that: – Increase glycogenesis and inhibit gluconeogenesis – Increase conversion of glucose to triglycerides – Stimulates hepatic protein synthesis and inhibits protein breakdown Skeletal muscle- Insulin increases glucose uptake (15x) by stimulating GLUT 4 – Increases glycogenesis in muscle Without insulin, muscle is poorly permeable to glucose Also directs increased use of glucose as fuel – Insulin promotes protein synthesis Inhibits protein catabolism Increases translation of mRNA into new proteins Depresses the rate of gluconeogensis – Exercising muscle directly stimulates GLUT4 without insulin Less insulin required during exercise Adipose- Insulin increases glucose uptake by stimulating GLUT 4 – Reduces use of TG as fuel & Increases glucose storage as TG within adipocytes – Inhibits hormone sensitive lipase (HSL) 13 Insulin Deficiency Promotes Ketoacidosis ❑ Insulin deficiency causes: – Lipolysis and release of free fatty acids – Ketoacidosis Large amounts acetoacetic acid formed in the liver cells – Insulin deficiency promotes acetoacetic acid production and ketone body formation – Ketone bodies= B-hydroxybutyric acid and acetone – Ketosis- large amounts of ketones present – Ketosis progresses from acidosis to coma to death if untreated 14 Diabetic Ketoacidosis ❑ Accumulation of ketone bodies (weak acids) → Anion gap metabolic acidosis Etiology – More common with Type I DM – Infection often the initial presenting etiology – Insufficient insulin causes ketoacidosis, hyperosmolarity, and dehydration Clinical manifestations – Tachypnea (respiratory compensation)- Kussmaul respiration – Acetone breath- “fruit” smell – Abdominal pain, n/v – Altered mental status Treatment: – Volume resuscitation NS→ D5W Rapid correction can produce cerebral edema – Correct hyperglycemia – Correct total body potassium depletion – Goal is to decrease glucose by 75-100 mg/dl/h or 10%/hr 15 Hyperglycemic Hyperosmolar State ❑ Insufficient insulin produces hyperglycemia with hyperosmolarity Etiology – – – Clinical manifestations – – – – More common with Type II DM Insufficient insulin (resistance or low production) causes hyperosmolarity Enough insulin present to prevent ketone formation Greater increases in glucose and osmolarity than DKA Significant hyperglycemia (> 600 mg/dL) produces high osmolarity (>330 mOsm/L) Hyperosmolality induces dehydration of neurons Hyperglycemia-induced diuresis produces: Dehydration May produce mild metabolic acidosis without an anion gap Treatment – – – Volume resuscitation NS→ D5W Rapid correction can produce cerebral edema Insulin Goal is to decrease glucose by 75-100 mg/dl/h or 10%/hr Correct electrolytes ❑ Severe hyperglycemia→ factitious hyponatremia – – Each 100 mg/dl  in plasma glucose lowers plasma sodium concentration by 1.6 mEq/L 16 Glucose Stimulation of Insulin Secretion ❑ Primary regulator of insulin secretion is blood glucose concentration – Increased blood glucose stimulates insulin secretion Feedback between blood glucose and insulin secretion ❑ Glucose stimulates insulin secretion Glucose taken up by pancreatic β cells via GLUT2 – Oxidized to produce ATP ATP-sensitive K+ channels are inhibited by increased ATP – Cell membrane depolarized Depolarization activates voltage-gated Ca+ channels – Ca+ influx causes Ca+-induced Ca+ release – Exocytosis of insulin ❑ Sulfonylureas inhibit ATP-sensitive channels – Stimulate insulin release (not synthesis) 17 Control Of Insulin Secretion ❑ Hormones that increase insulin release: – Glucagon, Growth hormone, Cortisol Prolonged secretion of any of these can lead to exhaustion of islet β cells – Acetylcholine and parasympathetic stimulation – Catecholamines via β-adrenergic stimulation (secondary effect) Causes glycogenolysis in the liver – Increased lipolysis for fatty acid utilization ❑ Hormones that decrease insulin release: – Catecholamines inhibit insulin secretion via ⍺2-adrenergic receptors (primary effect) Prevents hypoglycemia during exercise Allows glucose to be available for uptake by skeletal muscle – Somatostatin 18 II. Glucagon 19 Glucagon Opposes the Effects of Insulin- Increases BG ❑ Glucagon increases the hepatic production of glucose and ketones Main target organ is the liver ❑ Glucose production is via glycogenolysis and gluconeogenesis Increased breakdown of glycogen to glucose (liver and skeletal muscle) Increased breakdown of fat to fatty acids in adipose Increased synthesis and release of glucose in liver ❑ Stimulated by: Hypoglycemia Protein-rich meal Maintains glucose by balancing the effects of insulin ❑ Inhibited by hyperglycemia 20 Effects of High Concentrations of Glucagon ❑ In high concentrations- such as during periods of starvation- glucagon: Stimulates lipolysis and proteolysis to supply substrate – Increased fatty acids synthesize ketones – Ketones provide an alternative energy source for many tissues including brain Enhances inotropy Enhances bile secretion and inhibits gastric acid Decreases gut motility – Given during endoscopic procedures (colonoscopy) 21 III. Summary of Blood Glucose Regulation 22 Blood Glucose (BG) Regulation- Summary ❑ Narrow control usually 80-90 mg/dL fasting in early morning 115 mg/dL upper limit normal before “prediabetic” 120-130 mg/dL first hour after a meal Return to baseline by ~ 2 hours postprandial ❑ Summary Liver functions as an important BG buffer system A sink for excess glucose and a source for needed glucose Insulin and glucagon feedback to maintain a normal BG concentration Severe hypoglycemia directly effects hypothalamus to stimulate the SNS Adrenal epinephrine promotes glycogenolysis Prolonged hypoglycemia over several hours and days minimizes glucose utilization Growth hormone and cortisol are secreted Decrease rate of glucose utilization Increase fat utilization over glucose 23 Integrated Control of Blood Glucose ❑ Blood glucose is determined by a balance between glucose input and output from the circulation Rapid response to hypoglycemia: – Glucagon and catecholamines Sustained counter response to hypoglycemia: – Cortisol and growth hormone Big Picture Medical Physiology FIGURE 8-34 Integrated control of blood glucose concentration 24 Importance of Blood Glucose Regulation ❑ Avoidance of hypoglycemia important since some organs only use glucose: – – – ❑ Brain Retina Germinal epithelium of the gonads Most glucose formed during the interdigestive period is used for brain metabolism – Some brain cells can use ketones if glucose unavailable after a period of time ❑ Effects of hyperglycemia include: – – – – – Glucose exerts large amount osmotic pressure in the ECF→ cellular dehydration Glucosuria begins when BG exceeds 200 mg/dL Polyuria- Osmotic diuresis from glucosuria depletes body of fluid and electrolytes Polydipsia- increased stimulation of thirst center by dehydration and osmolarity Long-term hyperglycemia damages blood vessels and nerves increasing risk of: MI CVA ESRD Blindness Ischemia and gangrene of limbs 25 IV. Diabetes Mellitus 26 Diabetes Mellitus ❑ Type I diabetes (insulin-dependent diabetes) is due to destruction of pancreatic β cells – – Loss of insulin Diabetic ketoacidosis (DKA) may occur if untreated ❑ Type II diabetes (non-insulin dependent diabetes) is strongly linked to obesity – – – Hyperinsulinemia occurs in response to insulin resistance in target cells Later in disease- pancreatic beta cell exhaustion decreases insulin production Hyperosmolar hyperglycemic nonketotic coma (HHNK is also HHS) may occur if untreated ❑ Metabolism is altered in both types of diabetes – – – Prevents efficient uptake and utilization of glucose by cells Except the brain Blood glucose concentration increases while cell utilization of glucose falls Catabolism occurs due to utilization of fats (lipolysis) and proteins (proteolysis) ❑ Classic symptoms of diabetes – – – Polydipsia Polyuria Catabolism and unintentional weight loss 27 Type I (Insulin-dependent) Diabetes Mellitus ❑Type I DM - lack of plasma insulin production by beta cells Etiology- predisposition to autoimmune destruction of beta cells Usual presentation: Juvenile onset (~ 14 yo) Hyperglycemia- 300-1200 mg/dL Ketones (fats used for energy) Proteolysis- depletion of body’s proteins irrespective of diet Treatment- Insulin ❑Chronic hyperglycemia causes tissue injury and widespread organ damage Peripheral neuropathy and autonomic nervous system dysfunction Impaired CV reflexes, bladder control, decreased sensation in extremities Impaired blood supply due to structural changes of vessels of many tissues Affects proteins of endothelial and vascular smooth muscle cells Derangement of autoregulation of blood flow Increased risk of CV events Development of hypertension and atherosclerosis – these amplify damage Microvascular disease – neuropathy, retinopathy, nephropathy Macrovascular disease – CAD, PVD, cerebrovascular disease Increased utilization of fats leads to metabolic acidosis (DKA) Increased circulating cholesterol leads to arteriosclerosis 28 Type II (Non-insulin dependent) Diabetes Mellitus ❑ Type II DM - Hyperinsulinemia occurs in response to insulin resistance Etiology- A gradual process that begins with weight gain/obesity Subjects may have fewer insulin receptors More likely due to impaired insulin signaling related to weight gain Usual presentation: Historically adult onset Excess weight gain Insulin resistance and metabolic syndrome Plasma insulin elevated ❑ Treatments Early treatment: Lifestyle modification- exercise, diet Increasing insulin sensitivity- thiazoledinediones Suppressing liver glucose production- metformin Enhancing insulin secretion- sulfonylureas, incretin drugs (adjunct) Additional treatments: SGLT2 inhibitors prevent glucose and water reabsorption from the proximal tubule Metabolic surgeries- gastric bypass and vertical sleeve gastrectomy Later treatment: Insulin 29 Insulin Resistance ❑ Insulin resistance is part of a complex collection of disorders- “metabolic syndrome” Hyperinsulinemia is compensatory response by pancreatic beta cells for insulin resistance – – Metabolic syndrome - common features: – – – – – Truncal obesity Insulin resistance- elevated plasma insulin Fasting hyperglycemia Dyslipidemia- high triglycerides and low HDLs Hypertension Consequences; – – Diminished sensitivity of tissues to effects of insulin Impaired carbohydrate usage raises blood glucose and stimulates increased insulin secretion CV disease- includes atherosclerosis and organ damage Type II Diabetes Other factors that cause insulin resistance and Type II DM – – – Polycystic ovary disease Excess glucocorticoids Excess growth hormone 30 Diabetic Autonomic Neuropathy ❑ 50% Diabetic patients with hypertension have Reflex dysfunction of the ANS – – – – Limits ability to compensate for intravascular volume changes – – – – Tachycardia Increased peripheral resistance Postinduction hypotension Sudden cardiac death Contributes to diabetic gastroparesis (can be asymptomatic) – Old age DM >10 years CAD Beta-adrenergic blockade Gastric ultrasound for data Clinical signs of diabetic autonomic neuropathy – – – – – – – – – Hypertension Painless MI Orthostatic hypotension Lack of heart rate variability Reduced heart rate response to atropine/bb Resting tachycardia Early satiety Neurogenic bladder Lack of sweating 31 Physiology Of Diagnosis of DM ❑ Diagnosed by: Detectable urinary glucose Fasting blood glucose Reproducible fasting plasma glucose >126 mg/dL Glycated hemoglobin represents exposure of RBC to BG for life of cell – > 6.5% indicates diabetes Fasting insulin Absent in Type I DM Elevated in Type II DM Glucose tolerance Impaired glucose tolerance is due to the reduced entry of glucose into cells Decreased peripheral utilization Glucose Tolerance Test Given 1g of oral glucose/kg body weight Negative if BG < only rises to 140 mg/dL and returns to baseline 2 hours post Blood glucose monitored to verify response to glucose load and return to baseline 32 V. Anesthetic Concerns 33 Prayer Sign ❑ Airway and glycosylation of the joints- may indicate reduced ROM of AO joint Glycosylated proteins produce stiff joints Produces difficult intubations in ~ 30% type 1 DM patient Temperomandibular join and cervical spine AO joint mobility decreased – Prayer sign assesses for possible difficult intubation Inability to approximate palms and fingers 34 Anesthetic Concerns ❑ Preoperative concerns – Schedule early in day due to hypoglycemic therapy- adjust hypoglycemic agents – Check glucose perioperatively- know their baseline – Assess prayer sign for an indication of possible difficult airway ❑ Intraoperative concerns – Autonomic neuropathy may impair response and include gastroparesis – Lactate in LR can be converted to glucose- worsen hyperglycemia – Hyperglycemia worsens neurologic outcomes after ischemia – Osmotic diuresis places patients at risk for hypovolemia – Check glucose if abnormalities arise or patient slow to awaken ❑ Intraoperative hypoglycemia and insulin shock may be masked by: – General anesthesia – Diabetic autonomic neuropathy – Beta-blockers→ blunt the SNS response 35 5.5 1. A 34 year-old man has Type I DM and administers his routine insulin injection. Which of the following would be expected one hour after his insulin treatment compared to one hour prior to his treatment? A. Higher glucose, higher fatty acids, higher ketones B. Higher glucose, lower fatty acids, higher ketones C. Higher glucose, lower fatty acids, lower ketones D. Lower glucose, higher fatty acids, higher ketones E. Lower glucose, lower fatty acids, higher ketones F. Lower glucose, lower fatty acids, lower ketones 2. Which of the following are incorrectly paired: A. B cells: insulin B. D cells: somatostatin C. A cells: glucagon D. F cells: gastrin E. Pancreatic exocrine cells: chymotrypsinogen 3. A rat is injected with an experimental drug that destroys all of its pancreatic B cells. Which of the following would be least likely 14 days post injection? A. A rise in plasma H+ concentration B. A rise in plasma glucagon concentration C. A fall in plasma glucose concentration D. A fall in plasma amino acid concentration E. A rise in plasma osmolality 4. Insulin increases the entry of glucose into: A. All tissues B. Renal tubular cells C. The mucosa of the small intestine D. Most neurons in the cerebral cortex E. Skeletal muscle 5. A meal rich in proteins containing the amino acids that stimulate insulin secretion but low in carbohydrates does not cause hypoglycemia because: A. The meal causes a compensatory increase in T4 secretion B. Cortisol in the circulation prevents glucose from entering muscle C. Glucagon secretion is also stimulated by the meal D. The amino acids in the meal are promptly converted to glucose E. Insulin does not bind to insulin receptors if the plasma concentration of amino acids is elevated 36