By Dr. Marcus Judge

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Pharmacology

Contents

  1. Introduction
  2. Insulin Physiology
  3. Type 1 and Type 2 Diabetes
  4. Insulin Preparations
  5. Insulin Regimens
  6. Adverse Effects of Insulin
  7. Oral and Non-Insulin Antidiabetic Drugs
  8. The NICE Algorithm for Type 2 Diabetes
  9. Hypoglycaemia
  10. Summary
  11. Drug Summary Table
  12. Quiz

Abstract

  • Insulin is a peptide hormone released from pancreatic β-cells in response to a rise in blood glucose. It promotes glucose uptake into liver, muscle and fat, suppresses hepatic glucose output, and stimulates lipid and protein synthesis.
  • Type 1 diabetes is autoimmune destruction of β-cells: always requires insulin. Type 2 diabetes is insulin resistance with relative insulin deficiency: managed initially with lifestyle and oral agents, with insulin added later if needed.
  • Insulin preparations differ only in their rate of absorption: rapid (aspart, lispro), short (Actrapid), intermediate (NPH/Humulin I), and long-acting (glargine, detemir, degludec).
  • Oral antidiabetic drugs include metformin (first line), sulphonylureas, DPP-4 inhibitors ("gliptins"), GLP-1 receptor agonists ("-tides"), SGLT2 inhibitors ("-flozins"), pioglitazone, and the rarely used acarbose.

Core

Introduction

Diabetes affects roughly 1 in 14 adults in the UK and is the most common endocrine disorder a doctor will treat. Insulin pharmacology is the foundation of management for everyone with type 1 diabetes and a substantial fraction of those with type 2. The endocrinology of insulin is covered in Metabolic and Endocrine Regulation; this article focuses on the drugs.

Insulin Physiology

Insulin is a peptide hormone of two chains (A: 21 amino acids; B: 30 amino acids) joined by disulfide bonds. It is synthesised in the β-cells of the pancreatic islets of Langerhans as preproinsulin, processed to proinsulin, and finally cleaved to insulin and a "C-peptide" by-product. Measurement of C-peptide is the standard way to distinguish endogenous insulin (high C-peptide) from injected exogenous insulin (suppressed C-peptide).

Insulin is released in response to a rise in blood glucose. The signalling sequence is worth remembering:

  1. Glucose enters the β-cell via the GLUT2 transporter.
  2. Glucose is metabolised to ATP.
  3. Rising ATP closes ATP-sensitive K+ channels (KATP).
  4. The membrane depolarises.
  5. Voltage-gated Ca2+ channels open, intracellular Ca2+ rises.
  6. Insulin-containing granules fuse with the membrane and release their contents.

The KATP channel is the target of sulphonylureas, which close it directly and trigger insulin release.

Insulin release from the pancreatic β-cell β-cell of pancreatic islet Glucose (plasma) GLUT2 membrane ↑ ATP KATP closed depolarisation VG-Ca2+ opens ↑ Ca2+ Insulin granule exocytosis Insulin (plasma) ▪ Sulphonylureas close KATP directly: trigger insulin release regardless of glucose gliclazide, glimepiride ▪ GLP-1 / DPP-4 inhibitors amplify glucose-driven release via incretin signalling liraglutide, sitagliptin, tirzepatide SimpleMed Original by Dr Marcus Judge

Diagram: Insulin release from the pancreatic β-cell. Glucose → ATP → closure of KATP → depolarisation → calcium influx → insulin exocytosis. Sulphonylureas force the KATP channel closed regardless of glucose; GLP-1 receptor agonists and DPP-4 inhibitors amplify glucose-driven release.

The major effects of insulin are:

  • Stimulates glucose uptake into muscle and adipose tissue via GLUT4 translocation (the liver does not use GLUT4: hepatic glucose uptake uses GLUT2 and is largely concentration-driven).
  • In the liver, insulin promotes glycogen synthesis and inhibits gluconeogenesis and glycogenolysis, suppressing hepatic glucose output.
  • Stimulates lipogenesis and inhibits lipolysis in adipose tissue.
  • Stimulates protein synthesis.

Type 1 and Type 2 Diabetes

  • Type 1 diabetes: autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency. Usually presents in childhood or early adulthood. Insulin is the only treatment, given for life.
  • Type 2 diabetes: the dominant abnormality is insulin resistance, with relative β-cell failure that worsens with disease duration. Most patients are managed initially with lifestyle and oral agents; many will eventually need insulin.

The standard UK diagnostic thresholds (NICE):

  • HbA1c ≥ 48 mmol/mol (6.5%).
  • Fasting glucose ≥ 7.0 mmol/L.
  • Random or 2-hour OGTT glucose ≥ 11.1 mmol/L.

One reading is sufficient if the patient is symptomatic; two are needed if asymptomatic. HbA1c is unreliable in conditions that alter red cell turnover (anaemia, haemoglobinopathies, recent blood transfusion).

Insulin Preparations

Modern insulin preparations differ in their pharmacokinetic profile: the rate of absorption from the subcutaneous tissue and the duration of action; modified by amino-acid substitutions, fatty-acid acylation, formulation tricks (protamine complexing in NPH insulin), and concentration. Strength is standardised at U100 (100 units per mL), with U200 and U500 preparations available for patients on very high doses.

Rapid- and Ultra-Rapid-Acting

Onset within 5-15 minutes; peak at 1-2 hours; duration 3-5 hours. Used for meal-time ("bolus") cover and in continuous subcutaneous infusion pumps.

  • Insulin aspart (NovoRapid).
  • Insulin lispro (Humalog).
  • Insulin glulisine (Apidra).
  • Faster aspart (Fiasp): even quicker onset.

Short-Acting

Onset 30 minutes; peak at 2-3 hours; duration 6-8 hours. Must be taken 15-30 minutes before meals.

  • Soluble (regular) human insulin: Actrapid, Humulin S.

Intermediate-Acting

Onset 1-2 hours; peak at 4-8 hours; duration 12-18 hours. Used as basal cover, often given twice daily.

  • NPH (Isophane) insulin: Humulin I, Insulatard.

Long- and Ultra-Long-Acting

Slow, peakless absorption providing background insulin cover for 24 hours or more. The standard basal insulin in modern UK practice.

  • Insulin glargine (Lantus, Toujeo): ~24 hours.
  • Insulin detemir (Levemir): ~16-20 hours.
  • Insulin degludec (Tresiba): up to 42 hours, very flat profile.

Biphasic / Mixed Insulins

A pre-mixed combination of a rapid- or short-acting insulin with an intermediate insulin (e.g. NovoMix 30 = 30% aspart + 70% protaminated aspart). Usually given twice daily before breakfast and the evening meal.

Insulin Regimens

The two main regimens taught at pre-clinical level:

  • Basal-bolus regimen: long-acting insulin once daily as background plus rapid-acting insulin with each meal, typically four injections per day. Most physiological; the standard for type 1 diabetes.
  • Biphasic (twice-daily) regimen: pre-mixed insulin before breakfast and evening meal. Less flexible but fewer injections; sometimes used in older or less mobile patients.

Specialist alternatives include continuous subcutaneous insulin infusion (CSII) via pump, used in selected type 1 patients, and sensor-augmented pump therapy in which continuous glucose monitoring directs insulin delivery.

Adverse Effects of Insulin

  • Hypoglycaemia: the most important and most common.
  • Weight gain: insulin is anabolic.
  • Lipohypertrophy at injection sites: reduced if injection sites are rotated.
  • Lipoatrophy: immunological reaction at injection site, much rarer with modern human and analogue insulins.
  • Local pain, occasional allergy to additives.
  • Hypokalaemia with high-dose insulin (the basis for using insulin with dextrose to shift potassium intracellularly in hyperkalaemia).

Oral and Non-Insulin Antidiabetic Drugs

Used in type 2 diabetes (and some used in type 1 as adjuncts). The drug classes are best learned by their suffix where possible.

Metformin

Metformin is a biguanide and the first-line drug for type 2 diabetes in NICE guidance. It works by:

  • Reducing hepatic gluconeogenesis (the major effect).
  • Increasing peripheral insulin sensitivity (probably via AMP-activated protein kinase activation).
  • Modestly slowing intestinal glucose absorption.

Metformin does not cause hypoglycaemia when used alone, does not cause weight gain (and may produce modest weight loss), is cheap, and has cardiovascular outcome data. It is the rare drug that ticks every box in pre-clinical diabetes pharmacology.

Side effects:

  • GI symptoms: nausea, diarrhoea, abdominal discomfort. Reduced by starting at low dose, taking with food, or using modified-release preparations.
  • B12 deficiency with prolonged use.
  • Lactic acidosis: rare but serious. Risk increased in renal impairment, sepsis, dehydration and after iodinated contrast.

Renal precautions: dose-reduce if eGFR < 45, stop if eGFR < 30. Withhold around iodinated contrast administration in patients with reduced renal function.

Sulphonylureas

Gliclazide and glimepiride are the most commonly used UK sulphonylureas. They close ATP-sensitive K+ channels in pancreatic β-cells, depolarising the cell and triggering insulin release. They therefore require some functioning β-cell mass to work.

Effective and cheap, but with two important downsides:

  • Hypoglycaemia: risk is real because insulin secretion is unconditional, regardless of current glucose level.
  • Weight gain.

Gliclazide is largely hepatically metabolised, so is preferred in renal impairment.

DPP-4 Inhibitors

The "-gliptin" drugs: sitagliptin, linagliptin, saxagliptin, alogliptin: inhibit dipeptidyl peptidase-4, the enzyme that breaks down endogenous GLP-1 and GIP (the "incretins"). Higher GLP-1 levels stimulate insulin and suppress glucagon in a glucose-dependent manner.

Modest HbA1c reduction. Weight neutral. Low risk of hypoglycaemia. Watch for: occasional pancreatitis (rare), upper respiratory tract infections.

GLP-1 Receptor Agonists

The "-tide" drugs: liraglutide, semaglutide, dulaglutide, exenatide: are subcutaneous (a few are now available orally) GLP-1 receptor agonists. They are resistant to DPP-4 degradation and produce sustained GLP-1 receptor activation, which:

  • Stimulates glucose-dependent insulin secretion.
  • Suppresses glucagon.
  • Slows gastric emptying.
  • Reduces appetite.

The result is meaningful HbA1c reduction and substantial weight loss (5-15% body weight depending on agent and dose). Several agents (semaglutide, liraglutide) also have proven cardiovascular benefit.

Side effects:

  • GI: nausea is very common, especially on initiation; reduces over weeks.
  • Pancreatitis: the MHRA strengthened its warning in 2026 across the GLP-1 receptor agonist and dual GIP/GLP-1 agonist class. Stop the drug if pancreatitis is suspected and do not restart if confirmed.
  • Increased risk of cholelithiasis with rapid weight loss.
  • Injection-site reactions.

Higher-dose preparations (semaglutide 2.4 mg as Wegovy) are now licensed for obesity in the UK. Tirzepatide (Mounjaro) is a related but distinct drug: a dual GIP/GLP-1 receptor agonist, with even greater HbA1c and weight-loss effects than the pure GLP-1 agonists; same MHRA pancreatitis warning applies.

SGLT2 Inhibitors

The "-flozin" drugs: dapagliflozin, empagliflozin, canagliflozin, ertugliflozin: block the sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubule, preventing reabsorption of filtered glucose. Glucose appears in the urine, taking water with it.

The clinical benefits go well beyond HbA1c:

  • Modest weight loss (~3 kg).
  • Modest blood pressure reduction.
  • Reduction in cardiovascular events in patients with established disease.
  • Reduction in hospitalisation for heart failure: the only diabetes drug class licensed for heart failure in patients without diabetes (covered in Hypertension and Heart Failure).
  • Slowing of CKD progression: now used independently of diabetes status.

Side effects:

  • Genitourinary infections (thrush, balanitis, urinary tract infections): the predictable consequence of glycosuria. Around 5% of patients.
  • Diabetic ketoacidosis: classically euglycaemic DKA, where the glucose looks reassuring. Rare but serious; warn patients to stop the drug if acutely unwell.
  • Volume depletion, especially with co-prescribed diuretics.
  • Rare but well-known: Fournier's gangrene (necrotising fasciitis of the perineum).

Pioglitazone

Pioglitazone (a thiazolidinedione, "glitazone") activates PPAR-γ, increasing insulin sensitivity in muscle and adipose tissue. It is now a niche drug because of side effects:

  • Weight gain and fluid retention.
  • Heart failure (worsens existing HF; contraindicated in HF).
  • Increased fracture risk.
  • Bladder cancer signal (relative contraindication in known bladder cancer).

Acarbose

Acarbose inhibits intestinal α-glucosidase, slowing carbohydrate digestion and absorption. Modest HbA1c reduction (~0.5%). Side effects (flatulence, loose stools, diarrhoea) are predictable from the mechanism and limit use; rarely prescribed in UK practice.

The NICE Algorithm for Type 2 Diabetes

NICE guidance updated in 2022 reorganised the algorithm to give SGLT2 inhibitors a more central role:

  1. Lifestyle measures first.
  2. Metformin is offered to all patients without contraindication.
  3. An SGLT2 inhibitor is added at the same time if the patient has, or is at high risk of, cardiovascular disease, established CVD, or chronic heart failure.
  4. If HbA1c remains above target (typically ≥ 58 mmol/mol on metformin alone, or higher individualised targets in older patients), a second-line agent is added: a DPP-4 inhibitor, sulphonylurea, pioglitazone, or an SGLT2 inhibitor if not already used.
  5. If still uncontrolled, add a third oral or injectable drug, or move to a GLP-1 receptor agonist in patients with obesity and high cardiovascular risk.
  6. Eventually, basal insulin if oral and injectable non-insulin therapies fail.

The HbA1c target depends on the regimen and the patient: typically 48 mmol/mol (6.5%) on lifestyle or one drug not associated with hypoglycaemia, 53 mmol/mol (7.0%) on a sulphonylurea or insulin.

Hypoglycaemia

Hypoglycaemia is the commonest acute adverse effect of diabetes treatment. Defined as plasma glucose < 4 mmol/L (or symptomatic, whichever is lower; "four is the floor" is the standard UK teaching mnemonic).

Symptoms divide into:

  • Autonomic (counter-regulatory adrenergic): sweating, tremor, palpitations, hunger.
  • Neuroglycopenic: confusion, slurred speech, drowsiness, seizures, coma.

Treatment depends on whether the patient can swallow safely and reliably:

  • Conscious and cooperative: oral fast-acting carbohydrate (e.g. glucose tablets, fruit juice, sugary drink), followed by a longer-acting carbohydrate to prevent recurrence.
  • Unable to swallow safely: intravenous glucose (10% glucose 100-200 mL) or, if no IV access, intramuscular glucagon 1 mg.
  • Sulphonylurea-induced hypoglycaemia: can be prolonged; admit and observe; consider IV glucose infusion or, in refractory cases, IV octreotide.

The key prescribing point is that beta-blockers, particularly non-selective, can mask the autonomic warning symptoms of hypoglycaemia in diabetic patients.

Summary

  • Insulin is essential in type 1 diabetes; usually delayed in type 2.
  • Insulins differ only in absorption rate: rapid (-aspart, lispro), short (Actrapid), intermediate (NPH), long (glargine, detemir, degludec).
  • The basal-bolus regimen is the most physiological.
  • Insulin's main risks are hypoglycaemia, weight gain, and lipohypertrophy.
  • Non-insulin diabetes drug classes by suffix: biguanide (metformin), sulphonylurea (gliclazide), "-gliptin" (DPP-4), "-tide" (GLP-1 agonist), "-flozin" (SGLT2 inhibitor), "-glitazone" (pioglitazone), and acarbose.
  • Modern UK practice front-loads metformin and SGLT2 inhibitors in patients with cardiovascular or renal risk.
  • Hypoglycaemia ("four is the floor") is the most common acute adverse effect; treat with oral carbohydrate if possible, IV glucose or IM glucagon if not.

Drug Summary Table

Insulins and the principal non-insulin antidiabetic agents.

Class Examples Mechanism Notable points Key side effects
Rapid-acting insulin Aspart (NovoRapid), lispro (Humalog), glulisine Insulin receptor agonist Onset 5-15 min; meal-time bolus Hypoglycaemia, weight gain, lipohypertrophy
Short-acting insulin Soluble (Actrapid, Humulin S) As above 15-30 min before meals As above
Intermediate-acting NPH/isophane (Humulin I, Insulatard) As above Basal cover, often BD As above
Long-acting insulin Glargine (Lantus), detemir (Levemir), degludec (Tresiba) As above; peakless OD basal; degludec t½ up to 42 h As above
Biguanide Metformin ↓ hepatic gluconeogenesis; ↑ insulin sensitivity First-line in T2DM; weight neutral, no hypos; CV benefit GI upset, B12 deficiency, lactic acidosis (rare). Stop if eGFR <30
Sulphonylureas Gliclazide, glimepiride Close KATP in β-cells → ↑ insulin secretion Cheap; effective Hypoglycaemia, weight gain
DPP-4 inhibitors (gliptins) Sitagliptin, linagliptin, saxagliptin ↑ endogenous GLP-1 Weight neutral; low hypo risk URTI, rare pancreatitis
GLP-1 receptor agonists Liraglutide, semaglutide, dulaglutide, exenatide GLP-1 receptor agonism Weight loss, CV benefit; SC injection (some oral) Nausea, pancreatitis (MHRA warning), gallstones
Dual GIP / GLP-1 agonist Tirzepatide (Mounjaro) Dual incretin agonism Largest weight loss; T2DM and obesity As GLP-1 class
SGLT2 inhibitors (-flozins) Dapagliflozin, empagliflozin, canagliflozin Block SGLT2 in proximal tubule → glycosuria Weight loss, BP ↓, HF benefit, CKD benefit Genitourinary infections, euglycaemic DKA, Fournier's gangrene
Thiazolidinediones (glitazones) Pioglitazone PPAR-γ agonism Niche use Weight gain, fluid retention, HF, fractures, ?bladder cancer
α-glucosidase inhibitor Acarbose Slows carbohydrate digestion Rarely used Flatulence, diarrhoea

Reviewed by: Dr. Marcus Judge

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