Anti-Diabetes Drug Mechanisms and Classifications

Anti-Diabetes Drugs

  • Presenter: Dr. Bipin

  • References: Lipponcort, Tripathi, and Internet

Diabetes Mellitus Overview

  • Definition: Diabetes mellitus (DM) is a metabolic disorder characterized by:

    1. Hyperglycemia:

      • Fasting plasma glucose ≥ 126 mg/dl

      • 2 hours after 75 g oral glucose ≥ 200 mg/dl

    2. Additional Features:

      • Glycosuria (glucose in urine)

      • Hyperlipidemia (elevated lipids in the blood)

      • Negative nitrogen balance (improper balance between nitrogen intake and output)

      • Sometimes ketonemia (presence of ketones in the blood)

  • Pathological Changes:

    • Thickening of capillary basement membrane.

    • Increased vessel wall matrix and cellular proliferation leading to:

      • Vascular complications such as lumen narrowing

      • Early atherosclerosis

      • Sclerosis of glomerular capillaries

      • Retinopathy (damage to retina)

      • Neuropathy (nerve damage)

      • Peripheral vascular insufficiency

Blood Glucose Level Chart

  • Over 3 Months:

    Category

    HbA1c (%)

    Fasting Mg/DL

    Fasting mmo/L

    After Meal Mg/DL

    After Meal mmo/L

    2-3 hrs after meal Mg/DL

    2-3 hrs after meal mmo/L


    Normal

    4-5.6%

    80-100

    4.4-5.5

    170-200

    9.4-11.1

    120-140

    6.7-7.8


    Elevated

    5.7-6.4%

    101-125

    5.6-6.9

    190-230

    10.6-12.8

    140-160

    7.8-8.9


    High

    > 6.5%

    > 126

    > 7.0

    220-300

    12.2-16.7

    > 200

    > 11.1

    • Units:

    • (US) mg/dL: milligrams per deciliter

    • (UK) mmo/L: millimoles per liter

Types of Diabetes Mellitus

  • 1. Type I Diabetes Mellitus (IDDM)/Juvenile Onset:

    • Characterized by:

      • Destruction of β cells in the pancreatic islets

      • Majority of cases are autoimmune (Type 1A) where antibodies against β cells are detectable; some are idiopathic (Type 1B) with no antibodies found

      • Low or very low circulating insulin levels

      • Higher propensity for ketosis

      • Less common with low genetic predisposition

  • 2. Type II Diabetes Mellitus (NIDDM)/Maturity Onset:

    • Generally involves:

      • No loss or only moderate reduction in β cell mass

      • Insulin levels may be low, normal or even high

      • No demonstrable anti-β-cell antibodies

      • High genetic predisposition

      • Generally late onset (past middle age)

    • More than 90% of diabetes cases are Type 2 DM

Approaches to Drug Therapy in Type II DM

  • Goals include:

    1. Improving insulin availability

    2. Overcoming insulin resistance

  • Medication Classes:

    • Exogenous insulin

    • Sulfonylureas

    • Meglitinide/Phenylalanine analogues

    • Biguanides (Metformin)

    • Thiazolidinediones (Pioglitazone)

    • Alpha-glucosidase inhibitors

    • Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)

    • GLP-1 receptor agonists

  • Limitations/Challenges:

    • Multiple daily injections (insulins)

    • Hypoglycemic episodes

    • Weight gain

    • Concerns about premature atherosclerosis due to hyperinsulinemia

    • Inability to achieve normoglycemia by themselves in many patients, especially in moderate-to-severe cases

Insulin Overview

  • Discovery:

    • Discovered in 1921 by Banting and Best; demonstrated its hypoglycemic action

    • First obtained in pure crystalline form in 1926; structure worked out in 1956 by Sanger

  • Structure:

    • A two-chain polypeptide consisting of 51 amino acids with molecular weight ~6000.

      • A-chain: 21 amino acids

      • B-chain: 30 amino acids

  • Differences: Between human, pork, and beef insulins exist

Regulation of Insulin Secretion

  • **Secretion Rate:

    • Basal condition:** ~1U insulin is secreted per hour by the human pancreas.

    • After meals, a much larger quantity is secreted.

  • Regulatory Mechanisms:

    • Chemical Mechanisms:

      • Pancreatic β cells have a glucose sensing mechanism based on glucose entry (via glucose transporter GLUT1) and phosphorylation by glucokinase.

      • Activation of glucosensor leads to increased ATP, which inhibits ATP-sensitive K+ channels (K+ATP) and partially depolarizes β cells.

      • Increases intracellular Ca²+ availability leading to insulin exocytosis.

      • Other nutrients (amino acids, fatty acids, ketone bodies) also elicit insulin release, but glucose is the principal regulator.

      • Glucose induces a quick initial output of insulin within 2 minutes (first phase) followed by a sustained second-phase release.

Hormonal Regulation

  • Hormonal Influences:

    • Hormones such as growth hormone, corticosteroids, and thyroxine modify insulin release in response to glucose.

    • Intra-islet paracrine interactions are significant.

    • Different islet cell types (α cells, β cells, and δ cells) interact to provide precise control of insulin release.

Neural Regulation

  • The islets are richly supplied by sympathetic and vagal nerves.

    • Adrenergic α2 receptor activation: Decreases insulin release by inhibiting β cell adenylyl cyclase.

    • Adrenergic β2 stimulation: Increases insulin release by stimulating β cell adenylyl cyclase.

    • Cholinergic Activation: Insulin secretion via IP3/DAG pathway increasing intracellular Ca²+ in β cells.

Actions of Insulin

  • Overall Effects:

    • Insulin is a major anabolic hormone that promotes the synthesis of glycogen, lipids, and protein and facilitates glucose transport across cell membranes.

  • Detailed Actions:

    1. Facilitates glucose transport across cell membrane:

      • Skeletal muscle and adipose tissue are sensitive to insulin.

      • Glucose entry in certain cells is largely independent of insulin (e.g., liver, brain).

      • Muscular activity stimulates glucose entry into muscle.

      • Glucose transporter glycoproteins (GLUT4) are regulated by insulin for translocation.

      • Long-term, insulin upregulates GLUT4 synthesis.

    2. Intracellular utilization:

      • Glucose is phosphorylated to glucose-6-phosphate, enhanced by insulin's action on glucokinase.

      • Stimulates glycogen synthesis and inhibits glycogenolysis in liver and muscle.

    3. Inhibits gluconeogenesis:

      • Reduces glucose production from proteins and fats in the liver.

      • In insulin deficiency, proteins are routed to form glucose, worsening hyperglycemia.

    4. Inhibits lipolysis:

      • Reduces fatty acid and glycerol breakdown, favoring triglyceride synthesis.

      • Excess lipid breakdown in diabetes leads to ketone body production.

    5. Enhances transcription of lipoprotein lipase:

      • Acceleration of the clearance of VLDL and chylomicrons.

    6. Facilitates amino acid uptake:

      • Promotes protein synthesis and inhibits protein breakdown.

      • Insulin deficiency leads to protein breakdown and negative nitrogen balance.

Summary of Insulin Effects on Body Systems

  • Liver:

    • Increases glucose uptake and glycogen synthesis

    • Inhibits glycogenolysis and gluconeogenesis

  • Muscle:

    • Increases glucose uptake

    • Inhibits protein breakdown

  • Adipose Tissue:

    • Increases glucose uptake and triglyceride storage

    • Inhibits lipolysis

Diabetic State Actions

  • In the diabetic state, catabolism outweighs anabolism. Rapid actions of insulin generally occur within seconds/minutes, while others involving DNA-mediated synthesis take hours (intermediate actions). Long-term effects of insulin involve cell differentiation and multiplication.

Fate of Insulin

  • Insulin is distributed extracellularly; it is peptide in nature and is degraded in the gastrointestinal system if given orally.

  • Insulin metabolism occurs primarily in the liver, with a t1/2 of 5-9 minutes. Nearly half of the insulin in the portal vein is inactivated in the liver.

Types of Insulin Preparations

  • Rapid-Acting Insulin:

    • Examples: Insulin lispro, Insulin aspart, Insulin glulisine.

    • Onset: 0.2-0.4 hours, Duration: 3-5 hours.

  • Short-Acting Insulin:

    • Example: Regular insulin.

    • Onset: 0.5-1 hour, Duration: 6-8 hours.

  • Intermediate-Acting Insulin:

    • Example: NPH insulin.

    • Onset: 1-2 hours, Duration: 12-20 hours.

  • Long-Acting Insulin:

    • Examples: Insulin glargine, Insulin detemir.

    • Onset: 1-4 hours, Duration: ~24 hours.

  • Ultra-Long Acting:

    • Insulin degludec (lasts over 42 hours).

  • Pre-Mixed Insulin:

    • Humulin M3, NovoMix 30, etc.

    • Onset: Biphasic 30-60 min, Duration: Up to 24 hours.

Mechanism of Action of Insulin

  1. Receptor Binding: Insulin binds to a specific tyrosine kinase receptor on target cells, which leads to:

    • Autophosphorylation of the β-subunits of the receptor.

  2. Signal Transduction: Phosphorylation cascade that translocates GLUT-4 vesicles to the cell membrane, facilitating glucose uptake.

  3. Metabolic Effects:

    • In liver: Stimulates glycogenesis, inhibits gluconeogenesis and glycogenolysis

    • In adipose: Stimulates lipogenesis and inhibits lipolysis

    • In muscle: Enhances amino acid uptake and protein synthesis

    • Electrolyte Effect: Drives potassium (K+) into cells via Na+/K+-ATPase pump.

Primary Indications for Insulin Use

  1. Type 1 Diabetes Mellitus (T1DM): Essential and life-saving therapy.

  2. Type 2 Diabetes Mellitus (T2DM): Used when glycemic targets are not met with lifestyle changes and other agents.

  3. Gestational Diabetes Mellitus: Used when medical nutritional therapy fails.

Stressful Conditions Requiring Insulin

  • Diabetic Ketoacidosis (DKA) and Hyperosmolar Hyperglycemic State (HHS): Cornerstone of management, typically with IV regular insulin.

  • Acute Hyperkalemia: Administer insulin to shift potassium intracellularly.

  • Diabetes Secondary to Other Conditions: E.g., pancreatitis, pancreatectomy, cystic fibrosis.

  • Stress-Induced Hyperglycemia: In hospitalized patients, e.g., during critical illness.

Dosing and Administration

  • General Principles: Insulin dosing is personalized based on glycemic targets, age, weight, renal function, diet, and activity. Frequent monitoring is crucial for titration.

  • Dosing for Type 1 Diabetes: 0.4 - 1.0 units/kg/day; typical regimen is basal-bolus.

  • Dosing for Type 2 Diabetes: Starting doses often lower; common starting point for basal insulin is 10 units/day or 0.1-0.2 units/kg.

Switching and Titration of Insulin

  • Adjust doses based on fasting and postprandial glucose.

  • A common rule: increase dosage by 2 units or 10-15% twice weekly until targets are met.

Adverse Effects of Insulin

  1. Hypoglycemia: Most common and dangerous effect.

  2. Weight Gain: Due to anabolic effects of insulin.

  3. Injection Site Reactions: Lipohypertrophy, lipoatrophy, and allergic reactions.

  4. Systemic Allergy: Rare but can result in anaphylaxis.

  5. Insulin Resistance: High doses may be needed due to various factors; transient edema and blurred vision can occur.

Contraindications and Precautions

  1. Absolute Contraindication: Hypoglycemia.

  2. Relative Precaution: Hypersensitivity to insulin or its excipients.

  3. Conditions Requiring Dose Adjustment: Various conditions can alter insulin needs.

Drug Interactions

  • Drugs that Decrease Insulin Requirements: Oral antidiabetics, ACE inhibitors, Alcohol, etc.

  • Drugs that Increase Insulin Requirements: Corticosteroids, Thiazide diuretics, etc.

  • Drugs that Mask Hypoglycemia Symptoms: Non-selective beta-blockers.

Overview of Major Classes of Antidiabetic Drugs

## Biguanides (Metformin)

  • Mechanism: Activates AMP-kinase, reduces hepatic gluconeogenesis and increases peripheral insulin sensitivity.

  • Indications: First-line for T2DM, prediabetes, gestational diabetes, PCOS.

  • Side Effects: GI symptoms, B12 deficiency, lactic acidosis risk.

    Sulfonylureas

  • Mechanism: Acts on pancreatic beta cells to stimulate insulin release.

  • Indications: T2DM when Metformin is not effective.

  • Important: Can cause hypoglycemia and weight gain.

    Meglitinides (Glinides)

  • Mechanism: Similar to sulfonylureas with a rapid onset and short duration.

  • Indications: Post-prandial hyperglycemia management.

    Thiazolidinediones (TZDs)

  • Mechanism: Agonists of PPAR-γ increasing insulin sensitivity.

  • Indications: T2DM often in combination therapy.

  • Caution: Risk of heart failure.

    DPP-4 Inhibitors (Gliptins)

  • Mechanism: Inhibit DPP-4 to prolong action of incretin hormones.

  • Indications: Add-on for T2DM patients.

    SGLT2 Inhibitors (Gliflozins)

  • Mechanism: Inhibit SGLT2 in kidneys, causing glucosuria.

  • Indications: T2DM, heart failure, chronic kidney disease.

    Alpha-Glucosidase Inhibitors

  • Mechanism: Inhibit enzymes that digest carbohydrates, reducing post-prandial glucose spikes.

    Oral GLP-1 Receptor Agonists

  • Mechanism: Modulate glucose-dependent insulin secretion and slow gastric emptying.

Conclusion

  • Primary Drug of Choice: Always start with Metformin unless contraindicated.

  • Considerations in Therapy: Always remember individual patient needs and emerging clinical guidelines to effectively manage diabetes.