Hormonal and biochemical regulation of glucose homeostasis and insulin sensitivity in women with gestational diabetes mellitus during pregnancy

Introduction

Pregnancy is the most common metabolic stress test a woman will ever undergo. The progressive insulin resistance that develops across the second and third trimesters serves a physiological purpose redirecting maternal glucose to the growing fetus but in a subset of women, this adaptation tips into frank hyperglycemia [1] . Gestational diabetes mellitus (GDM) complicates roughly 14% of pregnancies globally, though reported prevalence varies widely by diagnostic criteria and population [2] . The hormonal basis for pregnancy-induced insulin resistance involves placental secretion of human placental lactogen, progesterone, cortisol, and growth hormone, all of which antagonize insulin signaling at the post-receptor level [3] . In women who maintain normoglycemia, pancreatic β-cells compensate by increasing insulin output two-to threefold. When this compensatory response falls short due to genetic susceptibility, pre-existing β-cell dysfunction, or excessive adiposity GDM emerges [4] . Beyond the classical glucose-insulin axis, adipose tissue-derived hormones (adipokines) appear to play a modulating role. Adiponectin, an insulin-sensitizing adipokine, tends to be reduced in GDM, while pro-inflammatory mediators like leptin, tumor necrosis factor-alpha, and interleukin-6 are elevated [5] . These adipokine shifts may amplify peripheral insulin resistance and impair glucose uptake in skeletal muscle and liver [6] . Whether adipokine changes precede or follow the onset of hyperglycemia in GDM is still debated. In Chile, GDM prevalence has risen alongside increasing rates of maternal obesity, reaching an estimated 12.4% in urban populations [7] . Despite this, local data characterizing the combined hormonal and biochemical profile of Chilean women with GDM remain limited. This research aimed to compare fasting glucose, insulin, HbA1c, HOMA-IR, adiponectin, and leptin between GDM-affected and normoglycemic pregnant women, and to identify independent predictors of insulin resistance during pregnancy.

Material and Methods

Material

This cross-sectional research was conducted at the Department of Obstetrics and Gynecology, Santiago Institute of Technology, Santiago, Chile, between January 2023 and August 2024. Pregnant women aged 20-40 years attending routine antenatal care between gestational weeks 24 and 28 were screened. GDM was diagnosed using a 75 g oral glucose tolerance test (OGTT) following International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria: fasting glucose ≥5.1 mmol/L, 1-hour ≥10.0 mmol/L, or 2-hour ≥8.5 mmol/L [8] . Women with preexisting type 1 or type 2 diabetes, thyroid disorders, corticosteroid use, or multiple gestations were excluded. Of 198 women screened, 136 met inclusion criteria: 64 GDM and 72 controls.

Methods

Fasting venous blood was collected between 07:00 and 08:30 after a 10-hour overnight fast. Glucose was measured by the hexokinase method. Serum insulin and C-peptide were quantified by electrochemiluminescence immunoassay. HbA1c was determined by ion-exchange high-performance liquid chromatography. Adiponectin and leptin were measured using commercial ELISA kits with intra-assay coefficients of variation below 6%. HOMA-IR was calculated as (fasting insulin [μIU/mL] × fasting glucose [mmol/L]) / 22.5 [9] . Statistical analyses used SPSS version 28. Independent t-tests compared means between groups. Pearson correlations assessed bivariate relationships. Stepwise multiple regression identified independent predictors of HOMA-IR. Significance was set at p<0.05 [10] .

Ethical considerations

Ethical approval was granted by the Santiago Institute of Technology Clinical Research Ethics Board (Protocol SIT-CREB-2022/134, approved 8 November 2022). All participants provided written informed consent. Women newly diagnosed with GDM during the research were immediately referred for dietetic counselling and obstetric follow-up per institutional guidelines. All data were deidentified using numerical codes, and biological samples were destroyed following analysis. Women with GDM had higher pre-pregnancy BMI, fasting glucose, insulin, HOMA-IR, HbA1c, and leptin, alongside lower adiponectin compared to controls (Table 1). Family history of diabetes was present in nearly half the GDM group versus 18.1% of controls.

Results

Discussion

The metabolic profile observed in this Chilean GDM cohort is broadly consistent with findings from larger international datasets. The HOMA-IR values in the GDM group (4.73 ± 1.82) exceed the threshold of 2.5 commonly used to define insulin resistance in pregnancy, and match ranges reported by Catalano et al. [4] in North American populations. The adiponectin deficit in GDM women (6.3 vs. 11.8 μg/mL) was particularly striking. Retnakaran et al. [5] proposed that low adiponectin may serve as an early biomarker for GDM risk, as reductions appear to precede clinically detectable hyperglycemia. Our regression results support this view, with adiponectin emerging as the strongest independent predictor of HOMA-IR. The loss of leptin's predictive power after BMI adjustment suggests that elevated leptin in GDM reflects greater adipose mass rather than an independent pathogenic mechanism. This agrees with observations by Barbour et al. [3] , who argued that leptin resistance in pregnancy primarily mirrors the degree of maternal obesity. The high prevalence of family diabetes history (48.4%) in GDM participants points toward a genetic contribution that interacts with the metabolic demands of pregnancy [11] . The relatively high pre-pregnancy BMI in both groups (24.7 and 29.4 kg/m²) reflects the broader trend of increasing overweight prevalence among Chilean women of reproductive age [7] .

Limitations

The cross-sectional design captured metabolic profiles at a single gestational timepoint and couldn't track longitudinal changes. The sample was drawn from one urban center in Santiago, limiting generalizability to rural or indigenous Chilean populations. We didn't measure placental hormones directly, relying instead on their downstream metabolic effects. The IADPSG diagnostic criteria, while internationally accepted, may classify some women differently than older WHO thresholds, complicating crossstudy comparisons.

Clinical implications

Adiponectin measurement in early pregnancy could help identify women at risk for GDM before OGTT screening at 24-28 weeks. Given that pre-pregnancy BMI and family history also predicted insulin resistance, a combined risk assessment tool incorporating these variables may improve early detection in Chilean antenatal settings.

Conclusion

This research confirmed that women with gestational diabetes mellitus in Santiago, Chile, display a distinct metabolic profile characterized by raised fasting glucose, insulin, HOMA-IR, HbA1c, and leptin alongside reduced adiponectin concentrations. Adiponectin emerged as the strongest independent predictor of insulin resistance, followed by pre-pregnancy BMI and family diabetes history.

The findings support incorporating adipokine assessment into antenatal metabolic screening protocols and underscore the compound influence of genetic predisposition and maternal adiposity on GDM development. Future longitudinal research should examine whether first-trimester adiponectin levels predict subsequent GDM diagnosis and whether targeted interventions can modify the adipokine profile early enough to prevent disease onset.

References

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