Insulin Preparations & Analogues

Insulin is the cornerstone of type 1 diabetes management and a key tool in type 2 diabetes, gestational diabetes and inpatient hyperglycaemia. For NEET PG, the high-yield core is the onset–peak–duration profile of each preparation, the design of a basal-bolus regimen, and the classic distinction between the Somogyi effect and the dawn phenomenon.

Physiology recap — why preparations matter

Endogenous insulin secretion has two components that any therapeutic regimen tries to mimic:

• Basal secretion — a low, continuous output (~0.5–1 unit/hour) that restrains hepatic glucose production between meals and overnight.
• Prandial (bolus) secretion — sharp spikes after meals to dispose of an absorbed glucose load.

Insulin is a 51-amino-acid peptide of two chains (A: 21 aa, B: 30 aa) joined by two disulphide bonds, secreted as proinsulin and cleaved into insulin + C-peptide (equimolar). C-peptide measurement distinguishes endogenous secretion (type 2, retained) from exogenous/absent (type 1, low). Insulin acts on a tyrosine-kinase receptor, driving GLUT-4 translocation in muscle and adipose tissue.

High-yield: C-peptide is low/absent in type 1 DM and normal/high in early type 2 DM. Exogenous insulin contains no C-peptide — useful to detect factitious hypoglycaemia (insulin high, C-peptide low) versus an insulinoma (both high).

Classification of insulin preparations

Preparations are grouped by their pharmacokinetic profile. Modern analogues are engineered by amino-acid substitution to alter the rate of hexamer dissociation in subcutaneous tissue — faster dissociation = faster onset; slower/precipitating = longer, flatter action.

Category	Agents	Onset	Peak	Duration	Role
Rapid-acting analogue	Lispro, Aspart, Glulisine	5–15 min	1 h	3–5 h	Prandial (bolus)
Short-acting (regular)	Regular soluble insulin	30–60 min	2–4 h	6–8 h	Prandial; only IV-usable form
Intermediate-acting	NPH (isophane)	1–2 h	4–10 h	10–18 h	Basal (twice daily)
Long-acting analogue	Glargine, Detemir	1–2 h	minimal/flat	~24 h (detemir 12–20 h)	Basal (once daily)
Ultra-long-acting	Degludec	1 h	flat	>42 h	Basal, very stable

High-yield: Regular insulin is the ONLY preparation that can be given intravenously (and the only one used in DKA infusions). Analogues and NPH are subcutaneous only.

Rapid-acting analogues — the engineering trick

• Lispro — B-chain Lys-Pro reversed (proline28 ↔ lysine29).
• Aspart — proline28 replaced by aspartic acid.
• Glulisine — asparagine3→lysine, lysine29→glutamic acid.

These substitutions reduce self-association into hexamers, so the insulin stays as monomers/dimers and is absorbed rapidly. Practically, they are injected immediately before (or even just after) a meal, better matching the post-prandial glucose spike and reducing late post-prandial hypoglycaemia compared with regular insulin (which must be given ~30 min before eating).

Long-acting analogues

• Glargine — isoelectric point shifted to ~7.4 by adding two arginines and substituting glycine for asparagine (A21). It is soluble in the acidic vial (pH 4) but precipitates as microcrystals at neutral subcutaneous pH, dissolving slowly → flat, peakless 24-hour profile. Never mix glargine with other insulins (the acidic pH disrupts them) and never give IV.
• Detemir — a myristic fatty-acid chain attached to lysine B29 binds reversibly to albumin, prolonging and smoothing action; often needs twice-daily dosing.
• Degludec — forms soluble multi-hexamer chains in the subcutis that release monomers slowly; half-life ~25 h, duration >42 h, very low variability and reduced nocturnal hypoglycaemia.

High-yield: Glargine precipitates at physiological pH → cannot be mixed and gives a peakless basal profile. It is the most frequently tested basal analogue mechanism.

Premixed and inhaled forms

• Premixed (biphasic): e.g. 70/30 (70% NPH + 30% regular), or analogue mixes (70% protamine-aspart/30% aspart; 75/25 lispro). Convenient (two injections/day) but lock the basal:bolus ratio and increase hypoglycaemia risk — not for type 1 fine control.
• Inhaled insulin (Technosphere/Afrezza): ultra-rapid prandial; contraindicated in asthma and COPD (bronchospasm) and requires baseline spirometry.

Designing the regimen

The physiological gold standard for type 1 DM is the basal-bolus regimen (multiple daily injections, MDI) or a continuous subcutaneous insulin infusion (CSII) pump.

Stepwise basal-bolus design →

1. Estimate total daily dose (TDD) ≈ 0.5–0.6 units/kg/day (lower, ~0.3–0.4, during the post-diagnosis "honeymoon"; higher in puberty/illness).
2. Split: ~50% basal (long-acting glargine/detemir/degludec once daily) + ~50% bolus divided across the three main meals.
3. Add correction doses using an insulin sensitivity factor (rapid analogue): drop in mg/dL per unit ≈ 1800 ÷ TDD (the "1800 rule"; 1500 rule for regular insulin).
4. Estimate prandial dose by carbohydrate counting: grams of carb covered per unit ≈ 500 ÷ TDD (the "500 rule").
5. Titrate against fasting (basal) and post-prandial (bolus) readings.

High-yield: In the basal-bolus model, basal ≈ 50% of TDD, the remaining 50% split as prandial boluses. Pumps deliver only rapid-acting analogue (no separate basal insulin needed — the basal rate is programmed).

Insulin in type 2 DM and special situations

• Start basal insulin in type 2 DM when oral/GLP-1 therapy fails to reach HbA1c target; typical start 10 units or 0.1–0.2 units/kg at bedtime, titrated to fasting glucose.
• Pregnancy/GDM: insulin is preferred when diet fails. NPH, regular, lispro, aspart and detemir have the best safety data; glargine is generally considered acceptable but detemir is the analogue with formal approval-level data.
• DKA/HHS: IV regular insulin infusion (~0.1 unit/kg/h), only after potassium is checked (give K⁺ if <3.3 mmol/L before insulin).

DKA: the potassium pitfall

Insulin drives potassium intracellularly (along with glucose). In DKA total-body potassium is depleted even when serum K⁺ looks normal/high.

DKA insulin–potassium rule → check K⁺ first:

• K⁺ < 3.3 mmol/L → hold insulin, replace potassium first (insulin will worsen lethal hypokalaemia).
• K⁺ 3.3–5.2 → give insulin and add potassium to fluids.
• K⁺ > 5.2 → insulin + fluids, recheck K⁺, no potassium yet.

High-yield: Insulin is used clinically to treat hyperkalaemia (insulin + dextrose drives K⁺ into cells within minutes). The flip side is iatrogenic hypokalaemia — always monitor potassium.

Adverse effects

Adverse effect	Mechanism / notes
Hypoglycaemia	Commonest; most dangerous; ↑ risk with regular & NPH peaks, missed meals, exercise, alcohol, renal failure
Weight gain	Anabolic effect; contrast with metformin/GLP-1
Lipohypertrophy	Repeated injection at same site → erratic absorption; rotate sites
Lipoatrophy	Immune-mediated fat loss (rare with modern human insulin)
Hypokalaemia	Intracellular K⁺ shift
Allergy / injection-site reaction	Rare with recombinant human insulin
Insulin oedema	Transient sodium/fluid retention on starting therapy
Weight-neutral myth	Glargine/detemir cause slightly less weight gain than NPH

Hypoglycaemia — recognition and management

Symptoms split into autonomic (early, adrenergic: sweating, tremor, palpitations, hunger, anxiety) and neuroglycopenic (later: confusion, slurred speech, seizures, coma). Beta-blockers and long-standing diabetes blunt the autonomic warning → hypoglycaemia unawareness.

Management flow →

• Conscious, can swallow: 15–20 g fast carbohydrate (glucose tablets/juice) → recheck in 15 min → repeat if still low → then a complex-carb snack ("rule of 15").
• Unconscious / no IV access: glucagon 1 mg IM/SC (ineffective if glycogen-depleted — alcoholics, prolonged fasting).
• Unconscious + IV access: IV dextrose — 25 g (e.g. 50 mL of 50% / 100–150 mL of 25%) bolus, then infusion.

High-yield: Sulfonylurea-induced hypoglycaemia is prolonged and may recur — admit, give continuous dextrose, and consider octreotide (suppresses residual insulin secretion). Pure insulin overdose does not respond to octreotide.

Drug interactions

• Beta-blockers (esp. non-selective) — mask adrenergic warning signs, may prolong hypoglycaemia; sweating is preserved (cholinergic).
• Drugs that worsen control / raise glucose: glucocorticoids, thiazides, atypical antipsychotics (olanzapine), protease inhibitors, octreotide (variable).
• Drugs that potentiate hypoglycaemia: alcohol (inhibits gluconeogenesis), sulfonylureas, ACE inhibitors, salicylates.

Storage and administration pearls

• Unopened insulin: refrigerate 2–8 °C; do not freeze (denatures). In-use vials/pens are stable ~28 days at room temperature.
• NPH is cloudy — roll gently to resuspend; clear solutions (regular, glargine, lispro, aspart) should never be cloudy.
• When mixing regular + NPH, draw clear (regular) before cloudy (NPH) — "clear before cloudy / RN rule" to avoid contaminating the regular vial with protamine.
• Inject subcutaneously (abdomen fastest, then arm > thigh > buttock); IM/IV only for regular insulin in emergencies.

High-yield: Mnemonic for mixing order — "Clear before Cloudy" (draw Regular first, then NPH). Cloudy NPH appearance = protamine-bound (isophane) insulin.

Somogyi effect vs dawn phenomenon vs waning insulin

A favourite NEET PG discriminator: the patient with morning (fasting) hyperglycaemia. Distinguish by checking the glucose at ~3 a.m.

Feature	Somogyi effect	Dawn phenomenon	Waning insulin
Mechanism	Nocturnal hypoglycaemia → rebound counter-regulatory surge (GH, cortisol, glucagon, adrenaline)	Early-morning surge of GH/cortisol raising glucose	Basal insulin runs out overnight
~3 a.m. glucose	LOW	Normal/high	Falling
Morning glucose	High	High	High
Correct action	Decrease evening insulin / add bedtime snack	Increase or shift basal insulin later	Increase/redistribute basal

High-yield: 3 a.m. glucose LOW = Somogyi (decrease evening dose); 3 a.m. normal/high = dawn phenomenon (increase/adjust basal). Giving more insulin in Somogyi worsens it — this is the trap.

Key differentials & related concepts

• Insulinoma vs factitious hypoglycaemia: insulinoma → high insulin + high C-peptide + high proinsulin; exogenous insulin → high insulin + low C-peptide; sulfonylurea abuse → high insulin + high C-peptide but sulfonylurea screen positive.
• Honeymoon period in new type 1 DM: transient residual beta-cell function lowers insulin requirement (may drop to <0.3 u/kg/day) — do not stop insulin entirely.
• Insulin resistance syndromes (type A receptor defects, acanthosis nigricans) may need very high doses (U-500 concentrated regular insulin).

Recently asked / exam angle

• Onset–peak–duration matching: a single-best-answer table question asking which insulin has the fastest onset (rapid analogue — lispro/aspart/glulisine) or no peak (glargine/degludec). Memorise the table.
• Glargine mechanism: "Which insulin precipitates at physiological pH and cannot be mixed?" → glargine.
• IV insulin: "Which preparation is used in DKA / can be given IV?" → regular (soluble) insulin.
• 3 a.m. glucose scenario: classic Somogyi vs dawn phenomenon two-liner — answer pivots on the 3 a.m. value.
• C-peptide interpretation: factitious hypoglycaemia (low C-peptide) vs insulinoma (high C-peptide).
• Hypoglycaemia management: conscious → oral glucose; unconscious without access → IM glucagon; with access → IV dextrose.
• Potassium before insulin in DKA when K⁺ < 3.3.
• Beta-blockers mask hypoglycaemia but sweating is preserved — a recurring fine point.
• Lispro structure: reversal of proline-lysine at B28–29.
• Pregnancy: NPH, regular, aspart, lispro, detemir preferred.

Rapid revision

1. Rapid analogues = lispro, aspart, glulisine: onset 5–15 min, peak ~1 h, given at the meal.
2. Regular insulin is the only IV-compatible insulin and the one used in DKA.
3. NPH = isophane (protamine), cloudy, intermediate-acting basal, peaks 4–10 h.
4. Glargine precipitates at neutral pH → flat 24-h profile; never mix, never IV.
5. Degludec is ultra-long-acting (>42 h), lowest variability, least nocturnal hypoglycaemia.
6. Basal-bolus TDD ≈ 0.5–0.6 u/kg/day, split 50% basal : 50% bolus.
7. 500 rule = carb grams/unit; 1800 rule = mg/dL drop per unit (1500 for regular).
8. Insulin pumps use rapid-acting analogue only.
9. Somogyi → low 3 a.m. glucose → reduce evening insulin; dawn phenomenon → normal/high 3 a.m. → increase basal.
10. Hypoglycaemia: conscious → oral glucose ("rule of 15"); unconscious → glucagon IM or IV dextrose.
11. Insulin drives K⁺ into cells — treats hyperkalaemia, but check K⁺ < 3.3 before giving in DKA.
12. C-peptide low with high insulin = exogenous (factitious); C-peptide high = insulinoma/sulfonylurea; mixing order = clear before cloudy.