Insulin & Hypoglycaemics — Pharmacology

SYNTHESIS in the pancreatic β-cell (proinsulin → insulin + C-peptide):

• Translated on ribosomes of the rough ER as preproinsulin (110 aa), the signal peptide cleaved to proinsulin (86 aa).
• In secretory granules, proinsulin is cleaved by prohormone convertases (PC1/3, PC2) at two basic-residue sites, releasing C-peptide (31 aa) and the mature insulin (51 aa = A-chain 21 aa + B-chain 30 aa, joined by two interchain disulphide bonds, with one intrachain disulphide on the A-chain).
• Stored as a hexamer (six insulin molecules + two zinc ions) in the granule — the hexamer is the storage form; all subcutaneous preparations must dissociate to monomers before absorption, which is the rate-limiting step that distinguishes rapid from short-acting insulins.
• Clinical correlate: C-peptide is co-secreted 1:1 with endogenous insulin and is measured to distinguish endogenous hyperinsulinaemia (e.g. insulinoma — high C-peptide) from exogenous insulin overdose (suppressed C-peptide). [1]

SECRETION — glucose-stimulated insulin secretion (GSIS):

• Glucose enters the β-cell via GLUT2 (low-affinity, high-capacity transporter that senses blood glucose).
• Glucose is phosphorylated by glucokinase (the rate-limiting glucose sensor), metabolised → ↑ATP:ADP ratio.
• ↑ATP closes the ATP-sensitive K+ channel (K-ATP) — composed of Kir6.2 pore + SUR1 regulatory subunit (the molecular target of sulfonylureas).
• K-ATP closure → β-cell depolarisation → opens voltage-gated Ca2+ channels → Ca2+ influx → insulin granule exocytosis.
• This K-ATP channel is exactly what sulfonylureas close directly (bypassing glucose) and what diazoxide opens (inhibiting insulin release — used for insulinoma and as an adjunct in sulfonylurea overdose). [1]

INSULIN RECEPTOR — a receptor tyrosine kinase:

• The insulin receptor is a heterotetramer (two extracellular α-subunits that bind insulin + two transmembrane β-subunits with intrinsic tyrosine-kinase domains).
• Insulin binding → β-subunit autophosphorylation → phosphorylates insulin receptor substrate (IRS) proteins.
• Two downstream cascades: (a) PI3K-Akt pathway → GLUT4 translocation to muscle/adipose membrane (glucose uptake), glycogen synthase activation (glycogen storage), mTOR (protein synthesis), anti-lipolysis — the metabolic arm; (b) Ras-MAPK pathway → gene transcription, cell growth, mitogenesis (the mechanism by which insulin is a growth factor).
• Clinical correlate: insulin resistance (type 2 diabetes, sepsis, critical illness, steroids) is a post-receptor defect (impaired IRS-1/PI3K signalling); the MAPK arm is relatively preserved, contributing to atherosclerosis. [1]

METABOLIC EFFECTS — net anabolic, storage-promoting:

• Liver: ↓glycogenolysis, ↓gluconeogenesis, ↓ketogenesis, ↑glycogen synthesis.
• Muscle: ↑glucose uptake (GLUT4), ↑glycogen synthesis, ↑protein anabolism (↓proteolysis).
• Adipose: ↑lipogenesis, ↓lipolysis (↓free fatty acids, ↓ketogenesis — the reason insulin is the cornerstone of DKA treatment).
• Electrolytes: drives K+, Mg2+, phosphate INTO cells (the basis of insulin-dextrose for hyperkalaemia, and the reason K+ falls during DKA treatment).

INDICATION: any critically ill patient with sustained glucose >10 mmol/L where the underlying illness (sepsis, steroids, pancreatitis, post-op, post-cardiac arrest) has caused insulin resistance and endogenous insulin cannot keep up. VRII provides smooth, titratable IV soluble insulin (Actrapid 50 U in 50 mL 0.9% saline = 1 U/mL). [1]

CHOOSE THE RIGHT FLUID: run a substrate (glucose-containing) fluid alongside the insulin to prevent hypoglycaemia and ketogenesis — typically 10% glucose at 50-100 mL/h, or glucose-saline; do NOT run insulin without substrate unless treating DKA (where endogenous substrate is the ketones). Add K+ to the substrate bag. [1]

USE A TRUSTED ALGORITHM: local sliding-scale tables prescribe the rate (U/h) by current glucose and rate of change. Most algorithms have three tiers — low-rate (insulin-naïve, low BMI, renal), standard, and high-rate (steroids, infection, high BMI). Start at the standard rate and re-check glucose hourly until stable. [1]

MONITOR AND TITRATE: check glucose hourly until stable (within target for 4 h), then every 2 h. Aim to keep glucose 6-10 mmol/L, avoiding excursions >10 and never below 4. Adjust by one tier if persistently above or below target. [1]

TRANSITION OFF safely: when the patient is eating / the acute insult has resolved and usual diabetes medication is appropriate, give the long-acting background insulin (e.g. glargine) and continue the VRII for at least 2-4 h overlap before stopping the IV insulin, to prevent rebound hyperglycaemia and ketogenesis. Never stop a VRII without background cover.

FLUIDS FIRST (0.9% saline, 1 L stat then over 1 h, then titrated) — restore circulating volume before/at the same time as insulin; the profoundly volume-depleted DKA patient is at risk of cardiovascular collapse. [1]

START FIXED-RATE INSULIN 0.1 U/kg/h based on actual body weight (Actrapid 50 U in 50 mL 0.9% saline). This rate is NOT adjusted for glucose — the target is ketone suppression, which requires continuous tissue insulin levels. [1]

POTASSIUM REPLACEMENT — measure K+ at baseline (often normal/high from acidosis despite total-body deficit):

• If K+ >5.5 — omit K+, recheck in 2 h.
• If K+ 3.5-5.5 — add 40 mmol/L to each substrate bag (the most common scenario).
• If K+ <3.5 — defer insulin, give IV K+ (and cardiology input if <3.0) until K+ ≥3.5, then start insulin. [1]

ADD GLUCOSE SUBSTRATE when blood glucose <14 mmol/L — switch to 10% glucose at 125 mL/h (with K+) alongside the saline, to allow continuation of the full FRII without hypoglycaemia. Do NOT reduce the insulin rate while ketones persist. [1]

MONITOR — blood ketones (β-hydroxybutyrate), glucose, venous pH/bicarbonate and K+ every 1-2 h. Expected fall: glucose 3 mmol/L/h, ketones 0.5 mmol/L/h, bicarbonate ↑3 mmol/L/h. [1]

STOP CRITERIA — ketones <0.6 mmol/L, bicarbonate ≥15, pH ≥7.3. Then convert to subcutaneous regimen: ensure long-acting background insulin given and a meal then stop the FRII 30-60 min later. [1]

COMPLICATIONS — hypoglycaemia, hypokalaemia, cerebral oedema (mainly in children/young adults — avoid overly rapid correction; some units add phosphate only if <0.5), ARDS.

MECHANISM: insulin activates the Na+/H+ exchanger → ↑intracellular Na+ → drives the Na+/K+-ATPase → shifts K+ out of serum INTO cells. Onset within 15 min, peak effect at 30-60 min, duration 4-6 h (the effect is transient — K+ will leak back out — so a definitive removal strategy, i.e. potassium-binding resin or dialysis, is needed if hyperkalaemia is ongoing). [1]

REGIMEN: traditionally 10 units Actrapid + 25 g dextrose IV (25 mL of 50% or 125 mL of 20%); some units use 5 U + 25 g in dialysis-dependent renal patients to reduce hypoglycaemia. Give over 15-30 min. [1]

HYPOGLYCAEMIA is the commonest complication (up to 20-75%), occurring 1-6 h later — especially in renal failure, anuric patients, and those without diabetes. Monitor glucose every 30-60 min for 4-6 h; consider a prophylactic 10% glucose infusion or smaller insulin dose in high-risk patients. [1]

PRACTICAL: albuterol (salbutamol nebulised) has an additive K-lowering effect; combine for synergy. Insulin-dextrose does NOT remove K+ from the body — it only redistributes it. For total-body K+ removal use patiromer/sodium zirconium/potassium-binding resins or dialysis.

PHYSIOLOGY: after oral glucose, gut L- and K-cells release the incretin hormones GLP-1 and GIP, which amplify glucose-stimulated insulin secretion (the 'incretin effect' — oral glucose evokes more insulin than IV glucose). Native GLP-1/GIP are rapidly degraded (1-2 min) by the enzyme dipeptidyl peptidase-4 (DPP-4). [1]

MECHANISM of gliptins: sitagliptin, linagliptin, vildagliptin, saxagliptin competitively inhibit DPP-4, prolonging the half-life of endogenous incretins → enhanced glucose-dependent insulin secretion. Because the effect is glucose-dependent (only amplifies insulin release when glucose is high), hypoglycaemia is uncommon and the drugs are weight-neutral. [1]

SAFETY: the TECOS trial (2015) established that sitagliptin is cardiovascularly neutral in T2DM with established CV disease — no increase in CV events, heart failure or pancreatitis. (Saxagliptin and alogliptin showed a signal for heart-failure hospitalisation in their CVOTs, so are used with caution in HF.) [1]

ADVERSE EFFECTS: pancreatitis (rare but reported — stop and avoid if history), arthralgia, bullous pemphigoid, upper-respiratory symptoms. Dose-reduce in renal impairment (sitagliptin, saxagliptin); linagliptin is hepatically cleared and needs no renal dose adjustment. [1]

ICU CONTEXT: generally held in acute critical illness; low glycaemic volatility makes them attractive when restarting post-ICU.[9]

RECOGNISE — glucose <4.0 mmol/L (severe <2.8 or any level with impaired consciousness). Symptoms: autonomic (sweating, tremor, palpitations, hunger) and neuroglycopaenic (confusion, seizures, coma). In ICU, neuroglycopaenic signs may be the only clue in sedated patients. [1]

STOP any insulin infusion / oral hypoglycaemic and send a laboratory glucose to confirm. [1]

GIVE IV DEXTROSE — 50% 25-50 mL via large vein, or 10% 100-250 mL via central line (safer). Recheck glucose in 10-15 min and repeat until >6 mmol/L. [1]

IF NO IV ACCESS — glucagon 1 mg IM/SC (note: ineffective in alcohol or starved states). [1]

IDENTIFY AND REMOVE THE CAUSE — review all insulin/sulfonylurea; check renal function; consider sepsis/adrenal insufficiency/hepatic failure. If sulfonylurea is the cause → octreotide 50-100 mcg SC q6-8h + continuous dextrose infusion + 24-48 h observation. [1]

PREVENT RECURRENCE — once glucose stable >6, start a background glucose substrate infusion if on IV insulin; reduce the insulin dose; reassess the glycaemic-control target (was it too tight?). [1]

DOCUMENT and review — every severe hypoglycaemic event is a critical incident; tight control (NICE-SUGAR lesson) is dangerous.