Chapter 38: Agents to Control Blood Glucose Levels

Pancreas Function and Hormonal Control of Blood Glucose

• The Pancreas and Islets of Langerhans     * The pancreas produces hormones within specific cell clusters known as the islets of Langerhans.     * Insulin:         * Produced by beta cells of the islets of Langerhans.         * Released in response to increasing blood glucose levels (the prandial state).         * Released during and after meals, which causes blood glucose levels to fall.         * Stimulates glycogen synthesis (storage of glucose).         * Stimulates the conversion of lipids into fats to be stored in adipose tissue.         * Stimulates the synthesis of proteins from amino acids.     * Glucagon:         * Released from alpha cells into the islets of Langerhans.         * Released in response to low blood glucose levels (the fasting state).         * Released between meals, which causes blood glucose levels to rise.         * Causes the immediate breakdown of glycogen stored in the liver to raise blood glucose levels.

Understanding Insulin and Diabetes Mellitus

• Mechanism of Insulin Action     * Insulin acts as a "key" that unlocks cells, enabling glucose to enter and provide fuel and energy.     * It is released into circulation when glucose levels around the beta cells rise.     * It reacts with specific insulin receptor sites to stimulate the transport of glucose into cells for energy use.     * It stimulates the liver to uptake, store, and use glucose.     * It circulates and affects general metabolism, causing blood glucose levels to fall.

• Diabetes Mellitus (DM) Pathophysiology     * Characterized by complex disturbances in carbohydrate, protein, and fat metabolism.     * Type 1 Diabetes Mellitus:         * The "key" to unlock the cell is entirely missing (absolute deficiency of insulin).         * Usually has a rapid onset and is commonly seen in younger patients.         * Without insulin, glucose cannot travel from the blood into individual cells.     * Type 2 Diabetes Mellitus:         * The "key" does not work correctly and only unlocks the cell sometimes (insulin resistance and relative deficiency).         * Usually occurs in mature adults with a slow and progressive onset.     * Consequences of Loss of Glucose Control:         1. Cells run out of fuel and function abnormally.         2. Extracellular (blood) glucose levels rise to unhealthy levels.

• Clinical Signs and Symptoms of Diabetes     * Hyperglycemia: Fasting blood sugar level greater than $126\,mg/dL$.     * Glycosuria: Sugar spilled into the urine.     * Polyuria: Increased urination.     * Polyphagia: Increased hunger.     * Polydipsia: Increased thirst.     * Lipolysis: Fat breakdown.     * Ketosis: Metabolism shifts to using fat for energy.     * Acidosis: Occurs when the liver cannot remove all waste products of fat metabolism.

• Long-term Complications     * Macrovascular: Atherosclerosis, leading to heart attacks and strokes related to atherosclerotic plaques.     * Microvascular:         * Retinopathy: Loss of vision due to the narrowing and closing of tiny eye vessels.         * Nephropathy: Renal dysfunction related to changes in the glomerular basement membrane.     * Neurovascular:         * Neuropathy: Motor, sensory, and autonomic nerve changes, particularly in the feet and legs.

Hyperglycemic Conditions: DKA and HHS

• Diabetic Ketoacidosis (DKA)     * Associated with Type 1 DM.     * Clinical signs: Fruity-smelling breath (ketones), altered mental status.     * Lab values: Hyperglycemia with blood glucose less than $600\,mg/dL$; high ketones in urine ($4+$).     * Treatment: Treated with an insulin drip. Only regular insulin can be administered intravenously.

• Hyperosmolar Hyperglycemic Syndrome (HHS)     * Associated with Type 2 DM.     * Lab values: Blood glucose levels of $600^{+}\,mg/dL$; urine ketones less than $2+$.     * Treatment: Treated with insulin, fluids, and electrolytes.

Insulin Therapy and Preparations

• Mechanism of Action     * Functions as a substitute for endogenous hormone.     * Promotes cellular uptake of glucose and decreases extracellular levels.     * Converts glucose to glycogen for storage.     * Moves potassium ($K^{+}$) into the cell along with glucose.     * Indicated for glycemic control in both Type 1 and Type 2 DM to prevent complications.

• Contraindications and Adverse Effects     * Contraindications: Hypoglycemia; known allergic reactions (rare with human recombinant DNA vs. porcine/bovine sources).     * Adverse Effects:         * Hypoglycemia.         * Weight gain.         * Hypokalemia.         * Lipodystrophy/Lipoatrophy: Loss or distortion of subcutaneous fat appearing as skin depressions. Can cause irregular absorption. Avoided by rotating injection sites.

• Pharmacokinetic Comparison of Insulin Types     * Rapid-acting: Lispro:         * Onset: $15\,min$.         * Peak: $1-2\,hr$.         * Duration: $3-5\,hr$.         * Half-life: $80\,min$.     * Short-acting: Regular:         * SubQ Route: Onset $30-60\,min$, Peak $2.5\,hr$, Duration $6-10\,hr$, Half-life $1.5\,hr$.         * IV Route: Onset Immediate, Peak Unknown, Duration $2-6\,hr$, Half-life $0.5-1\,hr$.     * Intermediate-acting: NPH:         * Onset: $1-2\,hr$.         * Peak: $4-8\,hr$.         * Duration: $10-18\,hr$.     * Long-acting: Glargine:         * Onset: $1-2\,hr$.         * Peak: None.         * Duration: $24\,hr$.

• Insulin Estimation Rules     * Rapid: Onset $15\,min$, Peak $1\,hr$, Duration $4\,hrs$.     * Short: Onset $30\,min$, Peak $2\,hrs$, Duration $8\,hrs$.     * Intermediate: Onset $1\,hr$, Peak $8\,hrs$, Duration $18\,hrs$.     * Long: Onset $1\,hr$, Peak None, Duration $1\,day$.

• Drug Interactions     * Additive effects: Oral hypoglycemics (Sulfonylureas and Meglitinides).     * Masking effects: Beta-blockers (BB) mask hypoglycemic symptoms and can augment effects.     * Counteractive effects: Thiazide diuretics and corticosteroids increase blood sugar, decreasing insulin's efficacy.

Oral and Injectable Hypoglycemic Medications (Type 2 DM)

• Biguanides: Metformin (Glucophage)     * Mechanism: Decreases hepatic glucose production (gluconeogenesis); increases glucose uptake by skeletal muscle.     * Special Note: Has no effect on insulin secretion, leading to a low incidence of hypoglycemia.     * Indications: Type 2 DM, PCOS, prevention of Type 2 DM.     * Contraindications: Renal disease/dysfunction (renally excreted), alcoholism, metabolic acidosis, hepatic disease.     * Adverse Effects: GI distress (bloating, nausea, diarrhea, weight loss), metallic taste (dysgeusia), reduced $B_{12}$ and folic acid absorption (anemia), and rare but lethal Lactic Acidosis.     * Interaction: Must hold Metformin $48\,hours$ before and after IV contrast dye procedures to avoid lactic acidosis.

• Sulfonylureas: Glipizide, Glyburide, Glimepiride     * Mechanism: Stimulates release of insulin from the pancreas.     * Contraindications: Advanced age, ethanol use. Potential cross-allergy with sulfonamide antibiotics.     * Adverse Effects: Hypoglycemia, weight gain, nausea, heartburn, skin rash.     * Interactions: Disulfiram-like reaction with alcohol ($ETOH$); Beta-blockers inhibit early signs of hypoglycemia.

• Meglitinides (-glinides): Repaglinide, Nateglinide     * Mechanism: Rapid and short-lived stimulation of insulin release; must be given just before meals.     * Duration: Shorter duration of action than Sulfonylureas.

• Thiazolidinediones (-glitazones): Pioglitazone (Actos), Rosiglitazone     * Mechanism: Increases insulin sensitivity and glucose uptake in muscle; decreases hepatic gluconeogenesis.     * Adverse Effects: Fluid retention, peripheral edema, weight gain, decreased bone density (fracture risk), hepatotoxicity (monitor ALT), linked to bladder cancer.     * Black Box/Warnings: Contraindicated in Heart Failure (HF). Rosiglitazone is linked to increased cardiovascular events and elevated LDL.     * Interactions: Increased toxicity risk with CYP3A4 inhibitors (ketoconazole, erythromycin).

• Alpha-glucosidase Inhibitors: Acarbose, Miglitol     * Mechanism: Inhibits enzyme alpha-glucosidase, delaying carbohydrate absorption.     * Administration: Must be taken orally $3\,times$ daily with the first bite of each meal.     * Adverse Effects: Flatulence, diarrhea, abdominal distention.     * Interactions: Reduces bioavailability of digoxin and propranolol.

• The Incretin Effect and Related Drugs     * The Incretin Effect: Hormones (GLP-1 and GIP) secreted during food intake increase insulin, lower glucagon, and slow gastric emptying. These are metabolized by the Dipeptidyl peptidase-IV (DPP-IV) enzyme.     * DPP-IV Inhibitors (-gliptins): Sitagliptin (Januvia):         * Mechanism: Inhibits DPP-IV to prolong incretin activity; stimulates insulin and suppresses glucagon.         * Details: Weight neutral; low hypoglycemia risk unless used with insulin or SU. Can increase digoxin levels.     * GLP-1 Receptor Agonists (-glutides/-atides): Liraglutide (Victoza), Dulaglutide (Trulicity), Exenatide:         * Mechanism: Mimics GLP-1 activities; slows gastric emptying and increases satiety.         * Indications: Type 2 DM; off-label for obesity.         * Black Box Warning: Potential development of thyroid C-cell tumors. Contraindicated in history of pancreatitis.

• SGLT2 Inhibitors (-gliflozins): Canagliflozin (Invokana), Dapagliflozin, Empagliflozin     * Mechanism: Inhibits SGLT2 pumps in the kidney, decreasing renal glucose reabsorption and increasing excretion.     * Adverse Effects: Genital yeast infections, UTIs, polyuria, hypotension, hypovolemia.     * FDA Warnings: Ketoacidosis, acute kidney injury (AKI), necrotizing fasciitis of the perineum (Fournier's Gangrene).     * Black Box Warning: Increased risk for leg and foot amputations.

Glucose Elevating Agent: Glucagon

• Prototype: Glucagon     * Mechanism: Hormone that increases plasma glucose levels; opposite effects of insulin.     * Indication: Treatment of hypoglycemia from insulin overdose in unconscious patients without IV access.     * Adverse Effects: Nausea and vomiting; cardiovascular effects (increased heart rate and contractility).     * Nursing Priority: In an unconscious patient, ensure they are rolled onto their side prior to administration due to induced vomiting risk.

Nursing Considerations and Patient Safety

• Pre-administration Assessment     * Obtain a thorough history, vital signs, and HbA1C status.     * Always check blood glucose levels before giving medications.     * Assess for the ability to consume food. If NPO for a procedure, consult the provider to clarify orders.

• Drug Administration Specifics     * Rapid-acting insulin: Do not administer until food is readily available.     * NPH insulin: Do not shake the vial; roll it between hands to mix.     * Alpha-glucosidase inhibitors: Give with the first bite of the meal.     * Metformin: Take with meals to reduce GI effects.     * Glinides: Take just before a meal.

• Monitoring and Education     * Hypoglycemia Signs (TIRED):         * T: Tachycardia/Tremor         * I: Irritability         * R: Restlessness         * E: Excessive hunger         * D: Diaphoresis         * Mnemonic: "Cold and clammy: need some candy."     * Hyperglycemia Signs:         * Mnemonic: "Hot and dry: sugar high."     * Patient Education: Focus on the disease process, diet/exercise recommendations, self-administration techniques, and recognition of complications.