Antidiabetic drugs

How the β cell releases insulin

• Glucose enters the β cell through GLUT2, is phosphorylated by glucokinase and metabolised, raising the ATP:ADP ratio. ATP closes K-ATP channels, the membrane depolarises, voltage-gated Ca2+ channels open and calcium triggers insulin exocytosis.
• Insulin release is increased by glucose, amino acids, incretins (GLP-1, GIP), glucagon and vagal (M3) stimulation; it is inhibited by somatostatin, α2 adrenergic stimulation (adrenaline), and diazoxide (opens K-ATP).
• Insulin moves glucose into muscle and fat through GLUT4, the insulin-dependent transporter; brain, liver and red cells use insulin-independent transporters.
• Lack of insulin unleashes glycogenolysis, gluconeogenesis, lipolysis and hepatic ketogenesis.
• Proinsulin is cleaved into insulin and C-peptide in equal amounts; injected insulin contains no C-peptide.

Insulins

• Why analogues act faster: soluble human insulin forms hexamers in the vial and subcutaneous tissue, which must dissociate into monomers before absorption (hence injection 30 minutes before meals). Aspart and lispro have amino acid changes that stop hexamer formation, so they absorb as monomers within minutes; injecting them long before a meal risks hypoglycaemia.
• Adverse effects: hypoglycaemia, weight gain, lipohypertrophy (rotate sites), hypokalaemia with IV insulin.
• Somogyi effect (night hypoglycaemia then rebound morning hyperglycaemia) versus dawn phenomenon (early-morning GH and cortisol): check 3 am glucose.
• DKA: IV fluids first, fixed-rate IV insulin 0.1 unit/kg/h, potassium replacement, continue basal insulin, add dextrose when glucose falls below 14 mmol/L (250 mg/dL).

Metformin

• A biguanide that reduces hepatic gluconeogenesis (through AMPK and inhibition of mitochondrial glycerophosphate dehydrogenase and complex I) and improves peripheral insulin sensitivity. No hypoglycaemia on its own; weight-neutral; first line; used in gestational diabetes and polycystic ovary syndrome.
• Lactic acidosis: lactate is normally cleared by the liver through gluconeogenesis (the Cori cycle). Metformin blocks hepatic use of lactate for glucose. It is renally excreted, so in AKI it accumulates and lactate builds up: high anion gap acidosis with normal glucose and low ketones, as in an elderly woman who kept taking metformin through days of vomiting and diarrhoea. Withhold in dehydration, sepsis, hypoxia, before surgery and around iodinated contrast when eGFR is low; avoid if eGFR below 30.
• Vitamin B12 deficiency with long-term use (impaired calcium-dependent ileal absorption). Check B12 when a metformin user develops numb feet despite good control.
• GI upset is common; start low and use modified-release.

Other agents for type 2 diabetes

• Glibenclamide in CKD: long-acting, with active metabolites cleared by the kidney; it keeps the K-ATP channel closed and insulin flowing, so hypoglycaemia lasts more than 24 hours and recurs after correction. Gliclazide (hepatic) is safer; observe overnight after any sulphonylurea hypoglycaemia (octreotide for overdose).
• Pioglitazone takes 6–12 weeks for full effect because it works by changing gene transcription and adipocyte differentiation.
• SGLT2 inhibitors lower glucose and insulin, favouring lipolysis and ketogenesis, so ketoacidosis can occur with near-normal glucose; stop during acute illness and before surgery. Glycosuria feeds genital Candida. They reduce cardiovascular death, heart failure admissions and CKD progression.

Exam trap Lactic acidosis on metformin is rare with normal kidneys; the usual trigger is AKI, hypoxia or sepsis.

Choosing therapy in type 2 diabetes

• Lifestyle and metformin first.
• Heart failure or CKD: add an SGLT2 inhibitor; atherosclerotic disease or obesity: add a GLP-1 agonist, regardless of HbA1c.
• Otherwise DPP-4 inhibitor, sulphonylurea, pioglitazone or SGLT2 inhibitor by patient factors; insulin when needed.
• HbA1c targets about 48 mmol/mol (6.5%), or 53 (7.0%) on drugs that cause hypoglycaemia; individualise in the elderly.
• Pregnancy: insulin and metformin only.

Steroids and β-blockers in diabetes

• Prednisolone given in the morning peaks in effect in the afternoon and evening: fasting glucose is normal but afternoon glucose is high. Check pre-lunch and pre-dinner glucose; morning gliclazide or NPH insulin matches the profile.
• Propranolol in an insulin user masks adrenergic warning symptoms (tremor, palpitations, anxiety; sweating is cholinergic and remains) and delays recovery by blocking glycogenolysis. Cardioselective agents are safer.

Hypoglycaemia

• Below 4 mmol/L (72 mg/dL): adrenergic symptoms, then neuroglycopenia (confusion, seizures, coma).
• Conscious: 15–20 g fast-acting glucose, recheck in 15 minutes. Unconscious: IV glucose or IM glucagon.
• Glucagon works by mobilising liver glycogen, so it fails when glycogen is depleted: alcohol binges with starvation, prolonged fasting, and it is unreliable in sulphonylurea overdose and adrenal insufficiency. Give IV glucose (and thiamine in alcohol misuse).

Remember C-peptide separates the body's own insulin from insulin given by injection.

Perioperative diabetes

Put first on the list; withhold SGLT2 inhibitors the day before and day of surgery, sulphonylureas on the day, and metformin if a long fast, contrast or low eGFR; reduce basal insulin by about 20%; use a variable-rate IV insulin infusion if more than one meal will be missed; check glucose hourly.

How FCPS asks about this

• Long-term metformin and numb feet: check vitamin B12.
• Metformin lactic acidosis mechanism: blocks hepatic use of lactate for gluconeogenesis; accumulates in AKI.
• Sitagliptin: DPP-4 inhibition prolongs incretin action.
• SGLT2 inhibitor adverse effects: genital thrush and euglycaemic ketoacidosis.
• Glibenclamide hypoglycaemia over 24 hours in CKD: closes K-ATP channels and accumulates.
• Glucagon fails in a starving drinker: liver glycogen is depleted.
• Aspart acts faster than soluble insulin: does not form hexamers, so absorbs as monomers.