Gestational Diabetes

Mechanism

Mechanism of Action

Therapy for gestational diabetes seeks to counteract the state of physiological insulin resistance induced by placental hormones during the second and third trimester of pregnancy.

Physiology of Gestational Insulin Resistance

From week 20 to 24 of gestation, the placenta begins to progressively synthesize hormones with a powerful counterregulatory action of insulin, notably human placental lactogen (hPL), gestational free cortisol, progesterone and placental growth hormone. These hormones inhibit the signaling of intracellular glucose transporters GLUT4 in maternal muscle and adipose tissue, causing a physiological transient postprandial hyperglycemia aimed at nourishing the fetus. If the reserve of maternal beta cells is insufficient to secrete the compensatory amount of insulin, Gestational Diabetes manifests.

Therapeutic Options of Choice

Human Insulins (Treatment of Choice)

NPH insulin (intermediate action) and rapid-acting insulins (Aspart, Lispro):

• Insulin is a high molecular weight protein that does not cross the placental barrier in a proven way, eliminating any risk of direct toxicity to the fetus.
• Restores intracellular glucose metabolism and blocks maternal hepatic gluconeogenesis in a predictable manner.
• Aspart or Lispro are ideal for controlling postprandial peaks, imitating the physiological pattern.

Metformin (Clinical Debate and Oral Biguanide)

Inhibitor of hepatic mitochondrial glucose production:

• Crosses the placental barrier freely (cord/maternal ratio close to 1.0).
• It does not present teratogenic effects directly or immediately according to large-scale trials.
• Improves the mother's peripheral insulin sensitivity.
• It is associated with a theoretical residual risk of alteration of energy metabolism and long-term fetal metabolic programming.

Pharmacokinetics

Pharmacokinetics

• NPH Insulin (Subcutaneous): Onset of action 1-2 hours after injection, reaching its peak of maximum activity at 4-8 hours. Its effective depot half-life lasts 12 to 18 hours, typically requiring two daily subcutaneous doses.
• Insulin Lispro / Aspart (Subcutaneous): Ultra-rapid onset of action in 10 to 15 minutes, with a peak of action one hour after injection and a short duration of effect of 3 to 4 hours. It is injected immediately before or after eating food.
• Metformin (Oral): Incomplete absorption (50-60% bioavailability). It does not bind to plasma proteins. It is not metabolized, being purified unchanged by active renal secretion and filtration. Plasma elimination half-life of 6 hours.

Indicators and dose

Indications

• Treatment of choice for gestational diabetes in adult women who fail to achieve optimal glycemic control (strict criteria: fasting basal glycemia 95 mg/dL or 1 hour postprandial 140 mg/dL / 2 hours 120 mg/dL) after an interval of 1 to 2 weeks of dietary intervention and regulated physical exercise.
• Treatment of the pregnant woman's previous type 1 or type 2 diabetes mellitus.

Dosing and Precision Adjustment

Initial calculation of the Insulin dose (NPH + Rapid combined):

• The total daily dose of insulin is calculated based on the weight of the pregnant woman and progresses throughout gestational age due to the increase in placental insulin resistance:

The total calculated dose is typically divided into 2/3 of the dose given in the morning before breakfast (with a 2:1 ratio of NPH versus rapid insulin) and 1/3 given in the evening before dinner (fractionated equally between NPH and rapid, or delaying NPH at bedtime to avoid nocturnal hypoglycemia in the early morning).

Pregnancy and Breastfeeding

Insulin is the standard treatment of choice validated by the ADA and ACOG, free of placental passage and fetal risk. Compatible with breastfeeding (insulin is a normal component of milk that is inactivated orally in the infant's digestive tract).

Security

Adverse Effects (ADR)

• Insulins: Maternal hypoglycemia (ADR more common and risky if severe; requires strict dose control before sleeping to avoid nocturnal hypoglycemia), maternal weight gain and local reactions of subcutaneous lipodystrophy.
• Metformin: Transient diarrhea, nausea, colicky epigastric pain, metallic taste and marginal risk of lactic acidosis in the presence of severe renal failure.