COMPARING INSULIN AND ORAL HYPOGLYCEMIC DRUGS

Pharmacology of Insulin

Insulin is a peptide hormone secreted by the beta cells of the pancreas in response to elevated blood glucose levels. It plays a critical role in glucose homeostasis by facilitating cellular uptake of glucose, particularly in muscle and adipose tissues, and by suppressing hepatic glucose production. The pharmacology of insulin encompasses its structure, mechanism of action, pharmacokinetics, and clinical applications.

(a) Mechanism of Action

Insulin binds to specific insulin receptors on the surface of target cells. These receptors are transmembrane proteins with intrinsic tyrosine kinase activity. Upon binding:

1. The receptor undergoes autophosphorylation.
2. This activates intracellular signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein kinase (MAPK) pathway.
3. These pathways mediate various effects:
   • Increased translocation of GLUT4 transporters to the cell membrane in muscle and adipose tissue, enhancing glucose uptake.
   • Stimulation of glycogen synthesis via activation of glycogen synthase.
   • Inhibition of gluconeogenesis and glycogenolysis in the liver.
   • Promotion of lipogenesis and inhibition of lipolysis.

(b) Types and Pharmacokinetics

Insulin preparations are classified based on their onset, peak, and duration of action:

1. Rapid-acting insulins (e.g., insulin lispro, aspart, glulisine): Onset within 15 minutes; peak at 1–2 hours; duration 3–5 hours.
2. Short-acting insulin (e.g., regular insulin): Onset within 30 minutes; peak at 2–4 hours; duration 6–8 hours.
3. Intermediate-acting insulin (e.g., NPH insulin): Onset within 1–2 hours; peak at 4–12 hours; duration up to 18 hours.
4. Long-acting insulins (e.g., glargine, detemir): Provide basal insulin levels with no pronounced peak; duration up to 24 hours.
5. Ultra-long-acting insulins (e.g., degludec): Duration exceeds 42 hours.

The pharmacokinetics depend on factors such as solubility, formulation additives (e.g., zinc or protamine), and injection site.

(c) Clinical Uses

1. Type 1 Diabetes Mellitus: Insulin is essential for survival due to absolute deficiency caused by autoimmune destruction of beta cells.
2. Type 2 Diabetes Mellitus: Used when oral hypoglycemic agents fail to achieve glycemic control or during periods requiring tight control (e.g., surgery or pregnancy).
3. Gestational Diabetes Mellitus: Preferred treatment when lifestyle modifications are insufficient.
4. Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS): Regular insulin is used intravenously for rapid correction.

(d) Administration

Insulin is typically administered subcutaneously using syringes, pens, or pumps. Intravenous administration is reserved for emergencies like DKA or HHS.

(e) Adverse Reactions

1. Hypoglycemia: The most common adverse effect due to excessive dosing or missed meals.
2. Weight Gain: Associated with anabolic effects on fat storage.
3. Lipodystrophy: Atrophy or hypertrophy at injection sites due to repeated use without rotation.
4. Allergic Reactions: Rare but may occur due to preservatives or additives in formulations.

Pharmacology of Oral Hypoglycemic Drugs

Oral hypoglycemic drugs are used primarily for managing type 2 diabetes mellitus (T2DM). They work through various mechanisms aimed at improving insulin sensitivity, increasing insulin secretion, reducing hepatic glucose production, or delaying carbohydrate absorption.

(a) Classes and Mechanisms

1. Sulfonylureas

These drugs stimulate pancreatic beta cells to secrete more insulin by closing ATP-sensitive potassium channels on cell membranes:

• Examples: Glipizide, Glyburide, Glimepiride.
• Side Effects: Hypoglycemia (especially with long-acting agents), weight gain.

2. Biguanides

Metformin is the only drug in this class:

• Mechanism: Reduces hepatic gluconeogenesis and increases peripheral glucose uptake without stimulating insulin secretion.
• Advantages: Weight neutrality or modest weight loss; reduced risk of hypoglycemia.
• Side Effects: Gastrointestinal discomfort; rare but serious lactic acidosis risk.

3. Thiazolidinediones

These drugs act as peroxisome proliferator-activated receptor-gamma (PPARγ) agonists:

• Examples: Pioglitazone, Rosiglitazone.
• Mechanism: Improve peripheral tissue sensitivity to insulin by altering gene expression related to glucose metabolism.
• Side Effects: Weight gain, fluid retention leading to edema/heart failure exacerbation.

4. Alpha-glucosidase Inhibitors

Examples include Acarbose and Miglitol:

• Mechanism: Delay carbohydrate digestion in the gut by inhibiting alpha-glucosidase enzymes.
• Side Effects: Flatulence and diarrhea due to undigested carbohydrates reaching the colon.

5. Meglitinides

Repaglinide and Nateglinide are short-acting agents that stimulate rapid bursts of insulin secretion:

• Mechanism: Similar to sulfonylureas but shorter acting.
• Side Effects: Hypoglycemia if meals are skipped.

6. DPP-IV Inhibitors (“Gliptins”)

Examples include Sitagliptin and Saxagliptin:

• Mechanism: Prolong incretin activity by inhibiting dipeptidyl peptidase-IV enzyme degradation.
• Advantages: Low risk of hypoglycemia; weight-neutral profile.

7. SGLT2 Inhibitors (“Flozins”)

Examples include Empagliflozin and Dapagliflozin:

• Mechanism: Block sodium-glucose co-transporter 2 in renal tubules to promote urinary glucose excretion.
• Benefits: Modest weight loss; cardiovascular benefits observed in some studies.
• Risks: Genitourinary infections due to glucosuria; dehydration-related side effects like hypotension.

(b) Clinical Uses

Oral hypoglycemics are indicated for T2DM patients who cannot achieve glycemic targets through diet/exercise alone:

1. Metformin is first-line therapy unless contraindicated (e.g., renal impairment).
2. Sulfonylureas may be added if metformin alone fails but carry a higher risk for hypoglycemia.
3. SGLT2 inhibitors or GLP-1 receptor agonists may be preferred for patients with cardiovascular disease or obesity concerns.

Combination therapy using agents from different classes can improve efficacy while minimizing side effects.

(c) Administration

Most oral hypoglycemics are taken once daily with meals except alpha-glucosidase inhibitors which must be taken at meal onset for efficacy.

(d) Adverse Reactions

Adverse reactions vary depending on drug class but commonly include:

1. Hypoglycemia – Most frequent with sulfonylureas/meglitinides when meals are skipped or overdosed.
2. Gastrointestinal Symptoms – Common with metformin/alpha-glucosidase inhibitors.
3. Weight Changes – Weight gain with sulfonylureas/thiazolidinediones versus weight loss/neutrality with metformin/SGLT2 inhibitors.