Insulin - Complete Pharmacology

(Based on Standard Medical Pharmacology - KD Tripathi Framework)

CHEMISTRY & STRUCTURE

CLASSIFICATION OF INSULIN PREPARATIONS

A. By Duration of Action

B. By Source

• Human insulin - biosynthetic (recombinant DNA), e.g., Humulin, Novolin
• Human insulin analogs - modified human insulin, e.g., lispro, aspart, glulisine, glargine, detemir, degludec
• Animal insulins - pork/beef-derived (isophane, neutral, lente) - still available outside USA but largely replaced

C. Rapid-Acting Analog Modifications

• Insulin lispro: B28 lysine, B29 proline residues swapped - reduces self-aggregation, faster absorption
• Insulin aspart: B28 proline replaced by aspartic acid
• Insulin glulisine: B3 asparagine replaced by lysine; B29 lysine replaced by glutamic acid

D. Long-Acting Analog Modifications

• Insulin glargine: A-chain gets extra arginine at A21 + two arginines at B-chain C-terminus - precipitates at physiologic pH after SC injection, slow dissolution
• Insulin detemir: B30 threonine removed + C14 fatty acid chain added - binds albumin, prolonging action
• Insulin degludec: B30 deleted + C16 fatty acid attached via gamma-glutamic acid spacer - forms depot multihexamers at injection site

E. Premixed Preparations

• 70/30: 70% NPH + 30% Regular
• 75/25: 75% NPL (neutral protamine lispro) + 25% lispro
• 50/50 preparations also available

MECHANISM OF ACTION (MoA)

1. Insulin Receptor

• α-subunits: extracellular, contain insulin binding domains
• β-subunits: transmembrane + intracellular, contain tyrosine kinase domains

2. Signal Transduction

1. Insulin binds α-subunits → conformational change
2. Activates intrinsic tyrosine kinase of β-subunits
3. Autophosphorylation of β-subunits on tyrosine residues
4. Phosphorylation of insulin receptor substrates (IRS-1, IRS-2)
5. Activation of PI3-kinase pathway → phosphorylates PIP₂ → PIP₃ → activates PDK1 → activates Akt (PKB)

3. Downstream Effects of Akt Activation

• Translocation of GLUT-4 transporters to plasma membrane (in muscle and fat) → glucose uptake
• Activation of glycogen synthase → glycogen synthesis
• Activation of protein synthesis machinery
• Inhibition of lipolysis (phosphodiesterase activation → reduced cAMP → reduced HSL activity)
• Inhibition of gluconeogenesis and glycogenolysis (suppression of PEPCK, G6Pase via FOXO1 inhibition)

4. Additional Pathway: MAP Kinase

• IRS → Grb2/SOS → Ras → MAP kinase cascade → cell growth and gene expression effects

PHARMACOLOGICAL ACTIONS

1. Carbohydrate Metabolism

• Increases glucose uptake into muscle and adipose tissue (via GLUT-4 translocation)
• Stimulates glycogen synthesis in liver and muscle (activates glycogen synthase)
• Inhibits glycogenolysis (inhibits phosphorylase)
• Inhibits gluconeogenesis in liver
• Net effect: lowers blood glucose

2. Fat Metabolism

• Stimulates lipogenesis (activates fatty acid synthase, promotes conversion of glucose to fat)
• Inhibits lipolysis in adipose tissue (inhibits hormone-sensitive lipase)
• Inhibits ketogenesis (reduces supply of FFA to liver)
• Promotes uptake of triglycerides from blood into fat cells (activates lipoprotein lipase)

3. Protein Metabolism

• Stimulates protein synthesis (promotes amino acid uptake and ribosomal activity)
• Inhibits protein catabolism (decreases proteolysis)
• Net effect: positive nitrogen balance, anabolic effect

4. Potassium

• Stimulates Na⁺-K⁺-ATPase → drives K⁺ into cells → lowers serum potassium
• Clinically used to treat hyperkalemia

5. Growth-Promoting Effects

• Via MAP kinase pathway: stimulates cell growth, mitogenesis
• Promotes growth in children when combined with GH

INDICATIONS

1. Type 1 Diabetes Mellitus (T1DM)

• Mandatory - absolute insulin deficiency requires lifelong replacement
• Basal-bolus regimens used

2. Type 2 Diabetes Mellitus (T2DM)

• When oral hypoglycemics fail or are contraindicated
• Uncontrolled hyperglycemia despite maximum oral therapy
• HbA1c persistently >9-10%

3. Diabetic Ketoacidosis (DKA)

• IV regular insulin is the treatment of choice

4. Hyperglycemic Hyperosmolar State (HHS)

5. Gestational Diabetes

• Insulin is the only safe antidiabetic for pregnancy (metformin is used in some centers but insulin remains first-line)

6. Diabetes with Special Situations

• Serious infections, surgery, trauma, myocardial infarction
• Hepatic/renal failure (where oral agents are contraindicated)
• Corticosteroid-induced hyperglycemia

7. Hyperkalemia

• Insulin (with dextrose) to shift K⁺ into cells acutely

8. Severe Malnutrition / Total Parenteral Nutrition

• To control hyperglycemia from TPN

COMPLICATIONS OF INSULIN THERAPY

1. Hypoglycemia (Most Common and Important)

• Causes: excess dose, missed meal, unusual exercise, drug interactions (beta-blockers mask symptoms)
• Symptoms: sympathetic (sweating, palpitations, tremor, anxiety) → neuroglycopenic (confusion, seizures, coma)
• Blood glucose usually <70 mg/dL
• Treatment: oral glucose if conscious; IV dextrose (25-50 mL of 50% dextrose) or glucagon 1 mg IM/SC if unconscious
• Somogyi effect: rebound hyperglycemia following nocturnal hypoglycemia
• Dawn phenomenon: early morning hyperglycemia due to nocturnal GH and cortisol surges (not insulin-related but affects dosing)

2. Insulin Allergy

• Local reactions: redness, swelling, induration at injection site - usually transient
• Systemic reactions: urticaria, angioedema, anaphylaxis - rare; more common with animal insulins
• Management: desensitization, switching to human insulin or analog

3. Lipodystrophy

• Lipoatrophy: local fat loss at injection sites (immune-mediated, less common with human insulin)
• Lipohypertrophy: local fat accumulation from repeated injection at same site; causes erratic absorption
• Prevention: rotate injection sites

4. Insulin Edema

• Transient edema (ankles, face) when starting insulin therapy, especially after prolonged poor control
• Due to sodium retention (insulin stimulates renal Na⁺ reabsorption)

5. Weight Gain

• Anabolic effect, reduced glycosuria, lipogenesis
• Common with T2DM insulin therapy

6. Insulin Resistance

• Defined as requiring >200 units/day
• (See note below)

7. Immunological Resistance

• Anti-insulin antibodies (mostly IgG) - mainly with animal insulins
• Can cause erratic glucose control

NOTE ON INSULIN REGIMENS

1. Conventional Therapy (Split-Mixed)

• One or two injections/day of premixed insulin (NPH + Regular)
• e.g., 2/3 dose before breakfast, 1/3 before dinner
• Simpler but less physiological; not ideal for tight control
• Used mainly in T2DM

2. Intensive Insulin Therapy (Basal-Bolus)

• Basal insulin: long-acting (glargine, detemir, degludec) once daily - mimics overnight/fasting basal secretion
• Bolus insulin: rapid-acting (lispro, aspart, glulisine) before each meal - mimics postprandial spikes
• Aims for near-normal HbA1c; reduces microvascular complications (proven by DCCT trial)
• Requires frequent SMBG (4-6 times/day)
• Rule of 500: to determine insulin-to-carbohydrate ratio
• Correction factor (insulin sensitivity factor): 1800 ÷ TDD (total daily dose)

3. Continuous Subcutaneous Insulin Infusion (CSII - Insulin Pump)

• Delivers programmed basal rate + patient-activated boluses
• Uses only rapid-acting insulin
• Best for T1DM patients who are motivated and educated
• Closed-loop systems ("artificial pancreas"): CGM-linked CSII, automatically adjusts doses
• Complications: ketoacidosis if interrupted, skin infections, cost

4. Sliding Scale Insulin

• Regular insulin given based on blood glucose readings
• Used mainly in hospitalized patients; not ideal for outpatient management

5. Biphasic / Premixed Regimens

• Two injections of premixed insulin (70/30 or 75/25)
• Before breakfast and before dinner
• Simpler than basal-bolus; used in T2DM

Starting Dose Guidelines

• T1DM: 0.5-1 unit/kg/day (50% basal, 50% bolus)
• T2DM starting insulin: basal insulin 10 units/day (or 0.1-0.2 units/kg/day), titrated up

NOTE ON INSULIN RESISTANCE

Definition

Types / Causes

1. Physiological Insulin Resistance

• Puberty, pregnancy (placental hormones)
• Obesity (most common cause) - reduced receptor number + post-receptor defects
• Counter-regulatory hormone excess: Cushing's, acromegaly, pheochromocytoma, glucagonoma

2. Immunological Insulin Resistance

• Anti-insulin antibodies (mainly IgG class) - particularly with old animal insulins
• Antibodies bind and inactivate insulin, requiring massive doses
• Management: switch to human insulin; high-dose glucocorticoids; plasmapheresis in severe cases

3. Receptor-Level Resistance

• Downregulation of insulin receptors (chronic hyperinsulinemia, obesity)
• Mutations in insulin receptor gene (rare - type A insulin resistance, Rabson-Mendenhall syndrome, leprechaunism)

4. Post-Receptor Resistance (Most Common Mechanism in T2DM)

• Defects in IRS-1/IRS-2 phosphorylation
• Reduced PI3-kinase activity
• Impaired GLUT-4 translocation
• Associated with increased serine phosphorylation of IRS proteins by inflammatory mediators (TNF-α, IL-6, free fatty acids)

5. Drug-Induced Resistance

• Corticosteroids (most common drug cause)
• Thiazides, beta-blockers, atypical antipsychotics

Management of Insulin Resistance

• Treat underlying cause (weight loss in obesity, treat Cushing's)
• Insulin sensitizers: metformin, thiazolidinediones (pioglitazone)
• For immunological resistance: switch to human insulin, add glucocorticoids if needed
• Concentrated insulin (U500 regular) for patients requiring very large doses

MANAGEMENT OF DIABETIC KETOACIDOSIS (DKA)

Pathophysiology (Brief)

• No glucose uptake → hyperglycemia → osmotic diuresis → severe dehydration
• Unrestrained lipolysis → elevated FFA → hepatic ketogenesis (acetoacetate, β-hydroxybutyrate)
• Anion gap metabolic acidosis + Kussmaul breathing (respiratory compensation)
• Electrolyte losses: Na⁺, K⁺, Mg²⁺, PO₄³⁻, Cl⁻

Diagnostic Criteria (ADA)

• Water: 70-120 mL/kg
• Sodium: 8-10 mEq/kg
• Potassium: 5-7 mEq/kg
• Chloride: 6-8 mEq/kg
• Phosphorus: ~3 mEq/kg

Goals of Management

1. Correct dehydration
2. Correct hyperglycemia
3. Correct acidosis and ketosis
4. Replace electrolytes (especially K⁺)
5. Identify and treat precipitating cause

Management Protocol

STEP 1: Immediate Assessment

• Airway: avoid intubation if possible (patients have high respiratory drive); intubate only if comatose/vomiting
• If in hypovolemic shock: rapid IV isotonic crystalloid
• Establish IV access, monitor vitals, urine output

STEP 2: IV Fluid Resuscitation

• Adult: 1-2 L of 0.9% normal saline (NS) in first 1-2 hours
  • If in shock: give as fast as possible until systolic BP >80 mmHg
  • Then switch to 0.45% NS at 250-500 mL/h
• Child: 20 mL/kg bolus in first hour; adjust per degree of dehydration
• When blood glucose falls to 200-250 mg/dL: switch IV fluid to 5% Dextrose in 0.45% NS
• Target: urine output 1-2 mL/kg/h

STEP 3: Insulin Therapy (Regular Insulin IV)

• Do NOT start insulin until K⁺ > 3.5 mEq/L (risk of fatal hypokalemia)
• Loading dose (bolus): 0.1 units/kg IV regular insulin (some protocols omit this)
• Maintenance infusion: 0.1 units/kg/hour IV infusion of regular insulin
• Target: glucose falls by 50-75 mg/dL/hour
• If glucose not falling in first 1-2 hours: double the insulin infusion rate
• When glucose reaches 200-250 mg/dL: reduce insulin to 0.05-0.1 units/kg/h + add dextrose to IV fluids
• Continue insulin infusion until anion gap normalizes and ketoacidosis resolves (NOT just when glucose normalizes)
• Transition to SC insulin: when patient can eat; give first SC dose 1-2 hours before stopping infusion

STEP 4: Potassium Replacement

• K⁺ < 3.5 mEq/L: Give 40 mEq/h KCl IV + hold insulin until K⁺ >3.5 mEq/L
• K⁺ 3.5-5.0 mEq/L: Give 20-40 mEq/h KCl to maintain K⁺ 4-5 mEq/L
• K⁺ > 5.0 mEq/L: No K⁺, monitor every 2 hours
• Recheck K⁺ every 1-2 hours during active treatment
• Note: Despite initially normal/high serum K⁺, total body K⁺ is always depleted. As acidosis corrects and insulin is given, K⁺ shifts back into cells, causing potentially fatal hypokalemia.

STEP 5: Bicarbonate - Controversial

• Generally NOT recommended routinely
• May consider if pH < 6.9: give 100 mmol NaHCO₃ in 400 mL water over 2 hours
• Risks of NaHCO₃: paradoxical CNS acidosis, hypokalemia, delayed ketone clearance, alkalosis
• Recheck pH after 2 hours; repeat if still <6.9

STEP 6: Phosphate Replacement

• Not routinely recommended
• Consider if serum phosphate <1 mg/dL or respiratory/cardiac dysfunction
• Give 20-30 mEq potassium phosphate if replacing

STEP 7: Treat Precipitating Cause

• New-onset T1DM (30% of DKA)
• Infection (most common in known diabetics) - give antibiotics as indicated
• Missed insulin doses - patient education
• Myocardial infarction, stroke, pancreatitis
• Drugs: corticosteroids, SGLT2 inhibitors (euglycemic DKA)

Monitoring During DKA Treatment

• Vital signs every 30-60 minutes
• Blood glucose every hour
• Serum electrolytes (K⁺, Na⁺, HCO₃⁻, Cl⁻) every 2-4 hours
• Blood pH every 2-4 hours
• Urine output hourly
• Amount of insulin administered

Resolution Criteria for DKA

• Blood glucose <200 mg/dL
• Serum bicarbonate ≥15 mEq/L
• Venous pH >7.30
• Anion gap <12 mEq/L
• Patient able to eat

Complications of DKA Management

• Cerebral edema: most dangerous, especially in children; caused by rapid fluid shifts or overly aggressive rehydration
• Hypokalemia: from insulin therapy without adequate K⁺ replacement
• Hypoglycemia: from excessive insulin
• Hyperchloremic metabolic acidosis: from large volumes of normal saline
• Aspiration pneumonia: in comatose patients

• Classification by duration (ultrashort, short, intermediate, long-acting)
• MoA via receptor tyrosine kinase → GLUT-4 translocation
• Pharmacological actions on carbohydrate, fat, protein metabolism
• Indications, complications (hypoglycemia, lipodystrophy, allergy, resistance)
• Insulin regimens (conventional vs intensive)
• Insulin resistance (immunological >200 U/day definition)
• DKA management with IV regular insulin protocol

• Quote Tripathi's exact page numbers or his specific worded definitions
• Reproduce his specific tables (e.g., his "Properties of insulin preparations" table)
• Use his exact section headings or italicized notes