Insulin, metabolic pathways and steroidogenesis in pregnancy

Overview

The TOS lists three biochemistry MCQs here: insulin's role in metabolism, metabolic pathways, and steroidogenesis. In pregnancy these come together: the mother changes her metabolism to keep a steady supply of fuel to the fetus, the placenta makes large amounts of steroid hormones, and when the mother's insulin cannot keep up, gestational diabetes results.

Insulin and glucagon: the basics

• Insulin: from pancreatic beta cells, released when blood glucose rises. It is an anabolic (storage) hormone.
• Glucagon: from alpha cells, released when glucose falls. It mobilises fuel.
• The insulin receptor is a tyrosine kinase; it phosphorylates insulin receptor substrates, which switch on the downstream effects.

Actions compared

Glucose transporters

Fed and fasting states

How pregnancy changes metabolism

Early pregnancy

• The mother lays down stores (protein, calcium, iron and some fat) ahead of the large fetal needs of the last trimester.
• Hypoglycaemia is more common and more dangerous in diabetic women in pregnancy, especially with poor hypoglycaemia awareness.

Second half of pregnancy

• Placental hormones rise in step with placental size, especially human placental lactogen (hPL); cortisol, progesterone and prolactin also contribute.
• hPL (growth-hormone-like, made from about 5 weeks):
  • lowers maternal insulin sensitivity and glucose use by maternal tissues;
  • promotes lipolysis, so the mother burns more fatty acids and spares glucose.
• Result: insulin resistance increases markedly, maternal glucose after meals is higher and lasts longer, and the pancreas must make much more insulin.
• Between meals, fatty acids and ketones rise faster than before pregnancy.
• Basal metabolic rate rises about 15% in the latter half.

Getting fuel to the fetus

• Glucose is the fetus's main fuel. In late pregnancy the fetus can use about as much glucose as the mother's whole body.
• The fetus makes its own insulin; fetal insulin, IGFs and thyroxine drive fetal growth, especially fat and glycogen laying-down in the third trimester.

Gestational diabetes (GDM)

Definition and frequency

• Glucose intolerance first recognised in pregnancy; it complicates about 10-15% of pregnancies depending on criteria.
• It happens when the pancreas cannot raise insulin output enough to overcome the insulin resistance of late pregnancy.

Risk factors (screen these women)

• Previous GDM
• Previous baby 4.5 kg or more
• BMI 30 or more
• First-degree relative with diabetes
• Ethnic groups with high rates of type 2 diabetes (South Asian, black Caribbean, Middle Eastern)

Testing

• 75 g OGTT at 24-28 weeks if risk factors are present.
• Previous GDM: early test at 16-18 weeks, repeated at 24-28 weeks if normal.

Management (outline)

• Diet and exercise; capillary glucose targets: fasting below 5.3 mmol/L, 1 hour after meals below 7.8 mmol/L.
• Metformin and/or insulin if targets are not met.
• Growth scans for macrosomia and polyhydramnios; plan timing of delivery.
• In labour keep glucose 4-7 mmol/L to reduce neonatal hypoglycaemia.
• After birth: stop treatment; check fasting glucose or HbA1c 6-13 weeks postpartum; lifelong raised risk of type 2 diabetes.

(Pre-existing diabetes is covered in the chapter on diabetes in pregnancy.)

Pedersen hypothesis: why babies of diabetic mothers are big

1. Maternal hyperglycaemia → more glucose crosses the placenta.
2. The fetal pancreas responds with fetal hyperinsulinaemia.
3. Insulin is a fetal growth hormone: more fat and glycogen → macrosomia (especially shoulders and abdomen).
4. At birth the maternal glucose supply stops but fetal insulin stays high → neonatal hypoglycaemia.

Other consequences: shoulder dystocia, birth trauma, polyhydramnios, late stillbirth, delayed lung maturity (surfactant production is delayed in maternal diabetes).

Steroidogenesis in pregnancy

The pathway (recap)

• All steroids come from cholesterol.
• Rate-limiting step: cholesterol → pregnenolone by the side-chain cleavage enzyme (desmolase, P450scc), with StAR moving cholesterol into mitochondria.
• Pregnenolone → progesterone (3-beta-HSD) → corticosteroids, or → androgens (17-alpha-hydroxylase) → oestrogens (aromatase).
• Enzyme defects and congenital adrenal hyperplasia are covered in the chapter on disorders of sex development.

The placenta as an endocrine organ

• The fetal adrenal is very large, mainly a fetal zone that makes DHEA.
• So oestriol reflects the fetus, adrenal and placenta together (the fetoplacental unit): very low in anencephaly (poor fetal adrenal stimulation) and in fetal death.

Pakistani practice note

South Asian origin is itself a listed risk factor for GDM, so most Pakistani women qualify for an OGTT under risk-based screening. Screening policies differ between units; follow the current national or hospital protocol.

Quick revision

• Insulin: store (glycogen, fat, protein); blocks gluconeogenesis and lipolysis.
• GLUT4 (muscle, fat) is insulin-dependent; liver uses GLUT2.
• Glucagon: glycogenolysis, gluconeogenesis, lipolysis, ketogenesis.
• Pregnancy: insulin resistance in the second half, mainly hPL.
• Glucose crosses by facilitated diffusion; ketones diffuse easily.
• GDM (NICE): fasting 5.6 or 2-hour 7.8 mmol/L on 75 g OGTT at 24-28 weeks.
• Pedersen: maternal glucose → fetal insulin → macrosomia → neonatal hypoglycaemia.
• Placenta: progesterone from maternal cholesterol; oestriol from fetal adrenal DHEA.

Written by The House Job from standard references (Obstetrics by Ten Teachers; Guyton and Hall Textbook of Medical Physiology).

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