Diabetes drugs in pregnancy
Insulin, metformin and sulphonylureas in pregnancy
Diabetes drugs in pregnancy for FCPS Part 1: why insulin needs rise and fall, insulin types, metformin and sulphonylureas. Covers placental transfer, causes of hypoglycaemia, C-peptide, DKA treatment and drug interactions.
Why insulin needs change in pregnancy
- First trimester: insulin sensitivity is normal or increased and nausea reduces intake, so hypoglycaemia is common in type 1 diabetes.
- Second and third trimesters: human placental lactogen, placental growth hormone, cortisol, progesterone and prolactin cause insulin resistance. Requirements may double or treble.
- After delivery of the placenta resistance disappears within hours, so insulin must be cut at once. Breastfeeding lowers needs further.
- Fetal effect: glucose crosses the placenta but maternal insulin does not. Fetal hyperglycaemia drives fetal hyperinsulinism: macrosomia, delayed lung maturity, neonatal hypoglycaemia.
- Beta-agonists and antenatal corticosteroids raise glucose and can precipitate ketoacidosis.
Insulin secretion and action
- Release: glucose enters beta cells (GLUT2), is phosphorylated by glucokinase, ATP rises, ATP-sensitive K+ channels close, the cell depolarises, calcium enters and granules fuse. Stimulated by rising blood glucose, amino acids, GLP-1 and vagal input; inhibited by adrenaline (alpha-2), somatostatin and fasting.
- Proinsulin is cleaved into insulin and C-peptide, secreted in equal amounts. C-peptide distinguishes endogenous from exogenous insulin, because pharmaceutical insulin contains none.
- The insulin receptor is a receptor tyrosine kinase: autophosphorylation, then IRS, PI3-kinase and Akt, moving GLUT4 to the membrane in muscle and fat (the insulin-dependent transporter). It also drives potassium and phosphate into cells.
- Lack of insulin removes the brake on glycogen phosphorylase (glycogenolysis), hormone-sensitive lipase (lipolysis) and hepatic ketogenesis.
- Insulin does not cross the placenta or enter milk in active form.
Insulin types
| Type | Examples | How action is shaped | Onset and duration |
|---|---|---|---|
| Rapid analogue | Aspart, lispro | Do not form stable hexamers, absorbed as monomers | 10–15 minutes; 3–5 hours |
| Short | Soluble (regular) human | Hexamers dissociate slowly; the insulin given IV | 30 minutes; 6–8 hours |
| Intermediate | Isophane (NPH) | Cloudy protamine–zinc crystals dissolve slowly | Peaks 4–8 hours; 12–18 hours |
| Long | Glargine | Clear acidic solution that forms microprecipitates at neutral tissue pH, dissolving slowly | About 24 hours, flat |
| Long | Detemir | Fatty acid chain binds albumin | Up to 24 hours |
- Glargine shows that clear does not always mean short-acting; it must not be mixed with other insulins.
- Absorption rises with exercise, heat or massage. Injecting rapid insulin into the thigh and then walking briskly speeds absorption from the exercising muscle; contracting muscle also moves GLUT4 to the membrane without insulin, so hypoglycaemia comes early. The abdomen is preferred before exercise.
- Insulin is cleared partly by the kidney (filtered and degraded in the proximal tubule). As nephropathy advances, clearance falls and hypoglycaemia recurs on usual doses; falling insulin needs can be the first clue to worsening renal function.
- Diabetic coma (DKA): IV soluble (regular) insulin as a fixed-rate infusion of 0.1 unit/kg/hour, continued with 10% dextrose after glucose falls, because insulin is needed to switch off ketogenesis.
Metformin
- A biguanide that mainly reduces hepatic gluconeogenesis (AMPK activation) and improves peripheral insulin sensitivity. It does not release insulin, so alone it is antihyperglycaemic, not hypoglycaemic, and weight neutral.
- In gestational diabetes it lowers maternal glucose by these actions, with less maternal weight gain and less neonatal hypoglycaemia than insulin; many women still need added insulin.
- It crosses the placenta, giving fetal levels close to maternal, without fetal hypoglycaemia.
- Lactic acidosis: it blocks hepatic use of lactate and is excreted unchanged by the kidney; withheld in AKI, shock, sepsis, severe PPH, hypoxia and with iodinated contrast in poor renal function.
- Long-term use reduces ileal absorption of vitamin B12. Compatible with breastfeeding.
Sulphonylureas (glibenclamide, gliclazide)
- Close ATP-sensitive K+ channels on beta cells, so insulin is released regardless of glucose: hypoglycaemia and weight gain.
- Glibenclamide is linked to more neonatal hypoglycaemia and macrosomia than insulin or metformin.
- Interactions: fluconazole and co-trimoxazole inhibit CYP2C9, prolonging hypoglycaemia; beta-blockers mask warning symptoms.
- Overdose: octreotide blocks insulin secretion. Quinine also closes K-ATP channels (hypoglycaemia in malaria).
Working out the cause of hypoglycaemia
| Insulin | C-peptide | Cause |
|---|---|---|
| High | Low | Injected insulin (factitious, or given by someone else) |
| High | High | Sulphonylurea ingestion or insulinoma; measure a sulphonylurea screen |
| Low | Low | Non-insulin causes: hypopituitarism, adrenal failure, liver failure, alcohol |
- A non-diabetic woman with high insulin and high C-peptide whose scan shows no insulinoma, living with a relative on tablets for type 2 diabetes, has most likely taken a sulphonylurea. Insulin injection would give a low C-peptide.
- Insulinoma is the commonest functioning pancreatic endocrine tumour.
Newer agents
- SGLT2 inhibitors cause glycosuria and euglycaemic DKA; stopped before conception.
- GLP-1 agonists (semaglutide, half-life about a week) are stopped 2 months before conception.
Hypoglycaemia awareness
- Tremor and palpitations are beta-adrenergic and blunted by beta-blockers; sweating is sympathetic cholinergic and preserved.
- Recurrent hypoglycaemia causes hypoglycaemia unawareness, common with tight control in early pregnancy.
Insulin and inulin: do not confuse
- Inulin is a plant polysaccharide that is filtered and neither reabsorbed nor secreted, so its clearance equals GFR. A substance with a clearance greater than inulin (such as para-aminohippurate) must also be secreted.
- Inulin stays in the extracellular fluid, so ECF volume = amount given divided by plasma concentration: 100 mg reaching 1 mg/100 mL gives 10 L.
Remember Insulin needs rise from the second trimester, peak near term and fall abruptly when the placenta is delivered.
Exam trap Metformin crosses the placenta; insulin does not.
Exam trap High insulin with high C-peptide is endogenous (sulphonylurea or insulinoma); injected insulin suppresses C-peptide.
How FCPS asks about this
- Distinguishing endogenous from exogenous insulin: C-peptide level.
- Insulin used in diabetic coma: IV soluble (regular) insulin.
- Why glargine lasts 24 hours: microprecipitates at tissue pH.
- Recurrent hypoglycaemia as nephropathy worsens: reduced renal clearance of insulin.
- Metabolic effect of metformin in GDM: reduced hepatic gluconeogenesis and improved insulin sensitivity, without insulin release.
- Insulin release is inhibited by: adrenaline (alpha-2) and somatostatin.
- Insulin needs after delivery of the placenta: fall abruptly as placental hormones disappear.
Test yourself on this topic
5 of the 37 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A woman on glibenclamide for type 2 diabetes is prescribed a 7-day course of oral fluconazole for recurrent vaginal candidiasis after delivery. On day 3 she is found confused with glucose 2.1 mmol/L (38 mg/dL). How did fluconazole cause this?
Answer: It inhibited hepatic CYP2C9 metabolism of glibenclamide
Glibenclamide is metabolised in the liver mainly by cytochrome P450 enzymes, including CYP2C9 and CYP3A4. Fluconazole is a potent CYP2C9 inhibitor and also inhibits CYP3A4, so glibenclamide levels rise and prolonged hypoglycaemia follows. Sulphonylurea hypoglycaemia is prolonged and may need extended glucose infusion. Other drugs that raise sulphonylurea effect include co-trimoxazole and some NSAIDs.
Glibenclamide interactions
- Metabolised by CYP2C9, 3A4
- Fluconazole inhibits them
- Levels rise: prolonged hypo
- Also co-trimoxazole, some NSAIDs
Remember Azole plus sulphonylurea: watch for hypos.
Exam trap Topical or vaginal azoles have far less effect than oral fluconazole.
Why the other options are wrong
- It displaced glibenclamide from renal transporters Not the main mechanism.
- It directly stimulated β-cell insulin secretion Fluconazole does not act on β cells.
- It reduced hepatic glycogen stores Not a recognised effect of fluconazole.
- It increased gut absorption of glibenclamide Absorption is not the issue.
Insulin given to a woman with gestational diabetes binds to the α subunits of its receptor on muscle cells. What is the next step that starts the intracellular signal?
Answer: β-subunit tyrosine kinase autophosphorylation
The insulin receptor is a receptor tyrosine kinase made of two extracellular α and two transmembrane β subunits. Insulin binding to the α subunits activates the tyrosine kinase in the β subunits, which phosphorylate each other and then insulin receptor substrate (IRS) proteins. IRS activates PI3-kinase and Akt, leading to GLUT4 translocation to the membrane, glycogen synthesis and other effects. Adenylyl cyclase is used by glucagon and adrenaline.
Insulin signalling
- Receptor tyrosine kinase
- β subunits autophosphorylate
- IRS, PI3-kinase, Akt
- GLUT4 moves to the membrane
Remember Insulin's receptor is its own kinase.
Exam trap Glucagon uses a G-protein receptor and cAMP; insulin does not.
Why the other options are wrong
- Activation of adenylyl cyclase through Gs This is the glucagon and β-adrenergic pathway.
- Opening of a ligand-gated ion channel Insulin does not act on an ion channel receptor.
- Translocation to a nuclear hormone receptor Steroid and thyroid hormones use nuclear receptors.
- Activation of membrane guanylyl cyclase This is the ANP and nitric oxide pathway.
A woman with gestational diabetes at 30 weeks is treated with metformin. Cord blood at delivery shows a metformin concentration similar to her own plasma level. Which property explains this?
Answer: It crosses the placenta freely
Metformin is a small, unbound molecule that crosses the placenta readily, using organic cation transporters, so fetal levels approach maternal levels. This contrasts with insulin, a large protein that does not cross. Metformin does not cause fetal hypoglycaemia because it does not stimulate insulin secretion, but because the baby is exposed, women are counselled and insulin is added if control is not achieved. Metformin is not protein-bound and is not produced by the placenta.
Metformin and the placenta
- Small, unbound molecule
- Crosses the placenta freely
- Fetal level ≈ maternal level
- No fetal hypoglycaemia: no insulin release
Remember Insulin stays with the mother; metformin reaches the baby.
Exam trap Crossing the placenta is not the same as being harmful; metformin is widely used in GDM.
Why the other options are wrong
- It is actively secreted by the fetal kidney Fetal renal secretion would lower, not equalise, fetal levels.
- It is bound to fetal albumin Metformin is not significantly protein-bound.
- It is made by placental metabolism The placenta does not make metformin.
- It is concentrated in amniotic fluid by the fetus Not the reason for equal cord levels.
A pregnant woman being treated for diabetic ketoacidosis with an insulin infusion becomes weak, with shallow breathing, on day 2. Potassium is normal after replacement, but serum phosphate is 0.25 mmol/L (0.8 mg/dL). What caused the fall in phosphate?
Answer: Insulin drove phosphate into cells
In ketoacidosis total body phosphate is depleted by osmotic diuresis, but plasma levels may be normal at presentation. Insulin stimulates glucose uptake and glycolysis, and phosphate moves into cells to form phosphorylated intermediates and ATP, so plasma phosphate falls steeply. Severe hypophosphataemia impairs ATP production and 2,3-BPG, causing muscle and respiratory weakness. The same shift underlies the refeeding syndrome.
Insulin and phosphate
- DKA: total phosphate depleted
- Insulin drives phosphate into cells
- Used for ATP and glycolysis
- Weakness, respiratory failure
Remember Insulin moves potassium and phosphate into cells.
Exam trap The same mechanism causes refeeding syndrome in malnourished patients.
Why the other options are wrong
- Insulin increased renal phosphate excretion The fall is from a shift into cells.
- Insulin increased PTH secretion Insulin does not stimulate PTH.
- Insulin blocked gut phosphate absorption Not the mechanism.
- Insulin caused phosphate to bind albumin Phosphate is not significantly albumin-bound.
A woman with type 1 diabetes planning pregnancy is changed to insulin detemir as her basal insulin. How is the action of detemir prolonged?
Answer: A fatty acid chain lets it bind albumin
In insulin detemir, the B30 amino acid is removed and a 14-carbon fatty acid (myristic acid) is attached to lysine B29. The fatty acid makes the molecule bind reversibly to albumin in the subcutaneous tissue and plasma, and it also forms hexamers that associate more strongly. Only the free fraction is active, so action is slow and prolonged. Protamine is used in NPH and pH-dependent precipitation in glargine.
Detemir
- Myristic acid on B29
- Reversible albumin binding
- Only free fraction active
- Smooth basal insulin
Remember Detemir hides on albumin and leaks out slowly.
Exam trap Albumin binding is also why detemir doses are higher in units than human insulin.
Why the other options are wrong
- Protamine slows its absorption This is NPH.
- It precipitates at tissue pH This is glargine.
- Zinc crystals form at the injection site Zinc stabilises hexamers in many insulins but is not detemir's main mechanism.
- It is resistant to insulinase in the liver Not its mechanism.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Drugs in obstetrics and gynaecology, Insulin and oral hypoglycaemics in pregnancy
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