Chapter 38 Agents to Control Blood Glucose Levels Study Guide

Pancreatic Function and Glucose Regulation

The Pancreas as a Dual-Function Gland * Endocrine Gland: The pancreas functions in an endocrine capacity within the islets of Langerhans. It produces several key hormones directly into the bloodstream: * Insulin: Produced by beta cells to lower blood glucose. * Glucagon: Produced by alpha cells to raise blood glucose. * Somatostatin: Produced by delta cells. * Exocrine Gland: The pancreas releases sodium bicarbonate and various digestive enzymes directly into the common bile duct. These substances are then released into the small intestine to assist in neutralizing stomach acid and breaking down nutrients.
Insulin Physiology * Production Source: Synthesized and secreted by the beta cells of the islets of Langerhans. * Trigger for Release: Insulin is released into circulation when glucose levels surrounding the beta cells rise (typically postprandial). * Mechanism of Action: * Reacts with specific insulin receptor sites on cell membranes. * Stimulates the transport of glucose into cells to be utilized for energy production. * Stimulates the liver to uptake, store, and utilize glucose. * Metabolic Impact: As insulin circulates, it affects overall metabolism and causes blood glucose levels to fall.
Glucagon Physiology * Production Source: Released from alpha cells in the islets of Langerhans. * Trigger for Release: Secreted in response to low blood glucose levels. * Mechanism of Action: * Causes immediate mobilization of glycogen (stored glucose) from the liver. * Stimulates the liver to convert proteins into glucose (gluconeogenesis). * Metabolic Impact: Results in an immediate rise in blood glucose levels.
Additional Regulatory Factors * Adipocytes: Secretion of adiponectin increases insulin sensitivity, decreases liver glucose release, and protects blood vessels from inflammation. * Endocannabinoid Receptors: Part of a signaling system that keeps the body in a state of energy gain to prepare for stressful situations. * Sympathetic Nervous System (SNS): Decreases insulin release, increases the release of stored glucose, and increases the breakdown of fat. * Corticosteroids: Decrease insulin sensitivity, increase glucose release, and decrease protein building. * Growth Hormone (GH): Decreases insulin sensitivity, increases free fatty acids (FFAs), and increases protein building.

Disorders of Blood Glucose Control

Physiological Terminology * Hyperglycemia: An increase in blood sugar levels. * Glycosuria: The presence of sugar (glucose) spilling into the urine. * Polyuria: Increased frequency and volume of urination. * Polyphagia: Increased hunger/appetite. * Polydipsia: Increased thirst. * Lipolysis: The breakdown of fat. * Ketosis: A metabolic shift where the body uses fat for energy instead of glucose. * Acidosis: Occurs when the liver cannot remove all waste products, leading to an acidic state in the blood.
Diabetes Mellitus (DM) * Characterization: A complex disturbance in carbohydrate, protein, and fat metabolism. * Clinical Diagnostic Signs: * Hyperglycemia defined as a fasting blood sugar level greater than $126\,mg/dL$ . * Presence of Glycosuria. * Long-term Complications: Resulting vascular damage can lead to: * Atherosclerosis. * Retinopathy (vision loss). * Neuropathies (nerve damage). * Nephropathy (kidney damage). * Infections and foot ulcers.
Classification of Diabetes * Type 1 Diabetes: Caused by the autoimmune destruction of the pancreatic beta cells; these patients require exogenous insulin replacement. * Type 2 Diabetes: Characterized by a progressive loss of beta-cell insulin release and decreased insulin sensitivity in peripheral cells (insulin resistance). * Other Causes: Hyperglycemia due to secondary causes, such as medication-induced diabetes. * Gestational Diabetes: Generally diagnosed during the second or third trimester of pregnancy.
Hyperglycemia Clinical Presentation * General Signs: Fatigue, lethargy, irritation, glycosuria, polyphagia, and polydipsia. * Immune/Healing Effects: Frequent infections and poor wound healing. * Dangerous Complications (Impending Crisis): * Fruity breath (acetone smell). * Dehydration. * Slow, deep respirations. * Loss of orientation and potential coma.
Hypoglycemia * Definition: Blood glucose levels of $70\,mg/dL$ or lower. * Initial Response: Parasympathetic stimulation, leading to increased GI activity to aid digestion and absorption. * Secondary Response: SNS "fight-or-flight" reaction, involving the breakdown of fat and glycogen to release glucose. The pancreas also releases glucagon and somatostatin.

Antidiabetic Agents Across the Lifespan

Children * Challenges: Balancing diet, activity, growth, and stressors. Fast metabolism and lack of body reserves make children susceptible to rapid shifts into severe hyper- or hypoglycemia. * Dosing: Insulin doses, especially in infants, may be extremely small. High-alert practice includes having a second person check calculations and doses. Dilution may be necessary for visibility in a syringe. * Adolescence: Social pressure and fluctuating metabolism make management difficult; a team approach is recommended. * Oral Agents: Metformin is the only oral antidiabetic drug approved for children (ages $10$ years and older).
Adults * Education: Focus on warning signs and the impact of exercise, stress, and diet. * Management: Frequent monitoring for changes in drug response as the disease progresses. * Caution: Warn against herbal/Alternative therapies and OTC products that may alter glucose levels. * Pregnancy/Lactation: Insulin is the preferred treatment due to high stress and metabolic demands. Close consultation between the obstetrician and endocrinologist is required, especially during labor.
Older Adults * Complications: Poor vision or lack of coordination affects injection preparation. Taste changes or absorption issues lead to glucose fluctuations. * Systemic Review: Kidney and liver function must be evaluated before starting noninsulin meds due to high incidence of renal/hepatic impairment. * Comorbidities: Increased risk of end-organ damage (heart disease, vision loss, infections). Screen carefully for drug-drug interactions.

Insulin Therapy

Actions and Indications * Actions: Replaces endogenous insulin; promotes fuel storage; facilitates transport of metabolites (ions) across membranes; stimulates glycogen, fat, and protein synthesis. * Indications: Treatment of Type 1 DM; Type 2 DM in adults non-responsive to other interventions; DKA; hyperkalemia; and insulin resistance.
Insulin Preparations (Pharmacokinetics) * Regular (Humulin R, Novolin R): Onset $30-60\,min$ ; Peak $2-4\,h$ ; Duration $6-12\,h$ . * lispro (Humalog): Onset $< 15\,min$ ; Peak $30-90\,min$ ; Duration $2-5\,h$ . * aspart (NovoLog): Onset $10-20\,min$ ; Peak $1-3\,h$ ; Duration $3-5\,h$ . * glulisine (Apidra): Onset $2-5\,min$ ; Peak $30-90\,min$ ; Duration $2\,h$ . * NPH (Novolin N): Onset $1-1.5\,h$ ; Peak $4-12\,h$ ; Duration $24\,h$ . * glargine (Lantus, Toujeo): Onset $60-70\,min$ ; Peak None; Duration $24\,h$ . * detemir (Levemir): Onset $1-2\,h$ ; Peak $3-6\,h$ ; Duration $5.7-23.3\,h$ . * Inhaled (Afrezza): Onset $12-15\,min$ ; Peak $60\,min$ ; Duration $2.5-3\,h$ .
Contraindications and Safety * Inhaled Insulin: Contraindicated in patients with asthma, COPD, or lung cancer (current or history). * Adverse Effects: Hypoglycemia, local injection site reactions, and hypokalemia (decreased blood potassium). * Interactions: Beta-blockers (can mask hypoglycemia symptoms); thiazide diuretics and glucocorticoids (increase glucose levels).

Oral Antidiabetic Agents

Sulfonylureas (Example: Glyburide) * Mechanism: Stimulate beta cells to release insulin; may improve insulin binding and increase receptor count. * Requirements: Effective only if functioning beta cells are present. * Generations: Second-generation drugs (e.g., Glyburide) are preferred as they interact with fewer protein-bound drugs and have a longer duration of action ( $24\,h$ ). * Adverse Effects: Hypoglycemia, GI distress, allergic skin reactions.
Alpha-Glucosidase Inhibitors (Example: Acarbose) * Mechanism: Inhibit the enzyme that breaks down glucose for absorption in the GI tract; delays glucose absorption. * Indications: Combination therapy to lower HbA1c. * Adverse Effects: Significant GI effects (bloating, diarrhea), anemia. * Specific Contraindication: Acarbose is contraindicated in cirrhosis.
Biguanides (Example: Metformin) * Importance: First-line standard of care for Type 2 DM. * Mechanism: Decreases hepatic glucose production; increases peripheral glucose uptake; improves insulin sensitivity. * Pharmacokinetics: Duration $10-16\,h$ ; half-life $6.2-17\,h$ . * Safety Warning: Boxed Warning for Lactic Acidosis. * Contraindications: Severe renal impairment, metabolic acidosis. * Interactions: Alcohol; iodine-containing contrast media (requires temporary discontinuation).
DPP-4 Inhibitors (Example: Sitagliptin) * Mechanism: Slows the inactivation of incretin hormones, leading to increased insulin release and lower glucagon secretion. * Adverse Effects: Rare but serious risks of pancreatitis, heart failure, and severe arthralgia.
Meglitinides (Example: Repaglinide) * Mechanism: Stimulate beta cells to release insulin (similar to sulfonylureas). * Interaction: Gemfibrozil must not be administered with repaglinide.
SGLT-2 Inhibitors (Example: Canagliflozin) * Mechanism: Block the cotransporter system in the kidney so glucose is lost in the urine rather than reabsorbed. * Benefits: Reduces risk of CV events and end-stage kidney disease. * Adverse Effects: Dehydration, hypotension, UTIs, genital fungal infections, DKA. Specifically for Canagliflozin: lower limb amputation risk and bone fractures.
Thiazolidinediones (Example: Pioglitazone) * Mechanism: Decrease insulin resistance in peripheral cells and the liver. * Contraindications: Moderate to severe heart failure. * Adverse Effects: Rapid weight gain, edema, increased total cholesterol, and rare hepatic injury.

Non-Insulin Injectable Agents

Human Amylin (Example: Pramlintide) * Mechanism: Slows gastric emptying; suppresses liver glucagon; modulates appetite (satiety). * Administration: Subcutaneous injection before each major meal. * Caution: Insulin dosing should be decreased when starting to prevent severe hypoglycemia.
GLP-1 Agonists (Example: Liraglutide) * Mechanism: Increase insulin release; decrease glucagon release; slow GI emptying; stimulate satiety center. * Safety Warning: Boxed warnings for thyroid C-cell tumors (animal studies) for Liraglutide and Semaglutide. * Adverse Effects: Pancreatitis, GI effects.

Glucose-Elevating Agents

Glucagon (Prototype) * Indications: Counteracts severe hypoglycemia reactions. * Mechanism: Accelerates breakdown of liver glycogen to glucose. * Pharmacokinetics (IV): Onset $1\,min$ ; Peak $15\,min$ ; Duration $9-20\,min$ . * Adverse Effects: Hypotension, hypertension, GI upset, respiratory distress.
Diazoxide * Mechanism: Increases blood glucose by decreasing insulin release. * Contraindications: Allergies to sulfonamides or thiazides. * Drug Interactions: Thiazide diuretics.

Questions & Discussion

Question: Which is a clinical manifestation of hyperglycemia? * Answer: Frequent infections. * Rationale: Elevated blood sugar levels impair immune response and healing; other signs include fatigue, lethargy, glycosuria, polyphagia, and polydipsia.
Question: True or False: Second-generation sulfonylureas interact with more protein-bound drugs than first-generation drugs. * Answer: False. * Rationale: A key advantage of second-generation sulfonylureas is that they interact with fewer protein-bound drugs and have a longer duration of action.
Question: Which of the following is a primary action of glucose-elevating agents? * Answer: Accelerate the breakdown of glycogen. * Rationale: These agents raise blood glucose by accelerating glycogenolysis in the liver and decreasing insulin release.