In a healthy pregnant woman without pre‑existing diabetes, is there an increased insulin secretory response to glucose during normal pregnancy?

Insulin Response to Glucose During Normal Pregnancy

Yes, there is a marked increase in insulin secretory response to glucose during normal pregnancy, beginning in early pregnancy and continuing through late gestation, which compensates for the progressive insulin resistance that develops to maintain normal glucose levels. 1

Physiological Insulin Response Changes Across Pregnancy

Early Pregnancy (First Trimester through ~16 weeks)

• Insulin secretory response increases substantially in early pregnancy (12-14 weeks gestation), with first-phase insulin response rising from approximately 465 to 720 pmol/L—a ~55% increase—even before significant insulin resistance develops. 2
• This augmentation occurs independent of changes in insulin sensitivity, indicating a primary enhancement of β-cell function rather than a compensatory response to resistance. 2
• Insulin sensitivity actually increases slightly in early pregnancy (by ~20%), yet insulin secretion still rises markedly, demonstrating that the β-cell response is proactive rather than reactive. 2
• The early-pregnancy insulin response appears to be mediated by circulating hormones, particularly leptin, which is positively associated with insulin secretory response independent of adiposity. 2

Mid-to-Late Pregnancy (16 weeks through term)

• Insulin resistance increases exponentially beginning around 16 weeks gestation, driven primarily by placental growth hormone and tumor necrosis factor-α, which create post-receptor defects in skeletal muscle insulin signaling. 1, 3
• Insulin secretory response continues to increase through late pregnancy, with first-phase and second-phase insulin responses rising approximately threefold compared to non-pregnant women by the third trimester. 4
• Total daily insulin requirements typically increase by ~5% per week through week 36, often resulting in a doubling or tripling of insulin needs in women with pre-existing diabetes. 1, 3
• In women with normal pancreatic function, this enhanced insulin production is sufficient to meet the challenge of physiological insulin resistance and maintain normal glucose levels. 1

Quantitative Changes in Insulin Dynamics

Insulin Sensitivity

• Insulin sensitivity in normal pregnant women during the third trimester is reduced to approximately one-third that of non-pregnant women of similar age and weight. 4
• This marked insulin resistance is a universal physiological adaptation to ensure adequate glucose delivery to the fetus and placenta. 1, 3

Compensatory β-Cell Response

• The reciprocal enhancement of insulin secretion precisely matches the degree of insulin resistance in healthy pregnancy, maintaining glucose homeostasis. 4
• First-phase insulin response increases threefold, and second-phase response shows similar augmentation compared to the non-pregnant state. 4
• In mouse models, β-cell mass increases 2-3-fold during pregnancy through proliferation of existing β-cells, differentiation of progenitor cells, and enhanced glucose-stimulated insulin release. 5

Clinical Implications and Contrast with Gestational Diabetes

Normal Pregnancy vs. GDM

• Women with gestational diabetes mellitus (GDM) have insulin sensitivity similar to normal pregnant women, indicating that their insulin resistance is appropriate for late pregnancy. 4
• The critical difference is that GDM is characterized by impaired pancreatic β-cell function rather than exaggerated insulin resistance—the insulin secretory response fails to increase sufficiently to compensate for normal pregnancy-related insulin resistance. 4
• In GDM, first-phase insulin response is significantly reduced (p < 0.001) compared to normal pregnant women, and second-phase response is also lower (p < 0.09). 4

Dual Insulin Resistance in GDM

• Women who develop GDM have two forms of insulin resistance: (1) the universal physiological pregnancy-induced resistance beginning at ~16 weeks, and (2) chronic pre-existing insulin resistance present before conception. 3, 6
• This combined resistance state makes women with GDM substantially more insulin-resistant than normoglycemic pregnant women in late pregnancy. 3, 6

Postpartum Resolution

• Pregnancy-specific insulin resistance resolves rapidly after placental delivery, with insulin signaling typically returning to normal within one year in women with normal glucose tolerance. 3, 6
• Insulin requirements fall precipitously immediately postpartum, necessitating dose reductions to 50-80% of pre-pregnancy levels to prevent severe hypoglycemia. 3, 7

Common Pitfalls

• Do not confuse the increased insulin secretory response with insulin resistance—both occur simultaneously in normal pregnancy, with enhanced secretion compensating for reduced sensitivity. 4, 2
• The early-pregnancy increase in insulin secretion precedes the development of insulin resistance, indicating it is not merely a compensatory mechanism but a primary metabolic adaptation. 2
• Failure to recognize that GDM represents β-cell dysfunction rather than excessive insulin resistance can lead to inappropriate management strategies. 4