Short summary

Gestational diabetes mellitus (GDM) is highly associated with developing type 2 diabetes (T2D) in the years after giving birth. Women with previous GDM (pGDM) show impaired insulin action and secretion, but it remains to be established how these metabolic mechanisms are associated with molecular abnormalities in adipose and skeletal muscle tissue and to what extent high-intensity interval training (HIIT) can have beneficial effect, compared to women without pGDM.

Rationale

Gestational diabetes mellitus (GDM), is defined as diabetes diagnosed for the first time during pregnancy and affects ~6% of pregnancies in Denmark. GDM significantly increases the risk of type 2 diabetes (T2D), chronic kidney disease, and cardiovascular disease in affected women. Although blood glucose levels typically normalize after delivery, women with prior GDM (pGDM) exhibit persistent insulin resistance and β-cell dysfunction. These metabolic disturbances may be linked to altered body composition, low-grade inflammation, and reduced cardiorespiratory fitness (VO₂max), yet their exact molecular basis remains poorly understood. Early evidence points to possible defects in insulin signaling, lipid accumulation, and mitochondrial function in skeletal muscle and adipose tissue, similar to patterns seen in obesity and T2D. The distinct genetic background of GDM further suggests that unknown molecular mechanisms may contribute to the increased cardiometabolic risk in women with pGDM, independent of subsequent T2D . Physical activity improves insulin sensitivity, β-cell function, VO₂max, and body composition and is effective in reducing T2D risk. High-intensity interval training (HIIT) may provide greater benefits than endurance training but has not been adequately studied in women with pGDM. At the molecular level, exercise enhances insulin signaling, mitochondrial function, and triggers beneficial changes in the transcriptome and proteome of muscle and adipose tissue. However, most existing studies have been conducted in men, leaving a major knowledge gap in women-particularly in those with pGDM. Aims & Hypotheses: 1. Women with pGDM have reduced insulin sensitivity, β-cell function and VO2max as well as increased systemic low-grade inflammation and an altered body composition compared with women without pGDM, and that these metabolic abnormalities are explained by unique molecular abnormalities in skeletal muscle and adipose tissue. 2. Eight weeks of HIIT combining rowing and cycling markedly improve insulin sensitivity, β-cell function, VO2max, body composition and systemic low-grade inflammation in women with pGDM and these improvements are explained by beneficial cellular and molecular changes in skeletal muscle and adipose tissue. 3. The beneficial effects of the HIIT intervention on these clinical, metabolic, and molecular outcomes are intact in women with pGDM compared to women without pGDM, and the cellular and molecular responses to HIIT are significantly associated with the clinically and metabolically healthy effects of this intervention.

Description of the cohort

We will recruit 20 women with pGDM, who have not developed T2D, and 20 healthy, glucose tolerant women without pGDM. The groups will be matched on age, BMI and time since last pregnancy.

Data and biological material

The study collects the following data types: - Clinical and physiological data: Age, weight, height, blood pressure, ECG, VO₂max, and body composition (DXA). - Biochemical data: Blood samples, OGTT, and IVGTT. - Molecular data: Muscle and adipose tissue biopsies (for analyses of insulin signaling, mitochondrial function, gene/protein expression, and electron microscopy). - Metabolic data: Insulin sensitivity, β-cell function, energy expenditure, and substrate oxidation (via Botnia clamp and indirect calorimetry).

Collaborating researchers and departments

Department of Sports Science and Clinical Biomechanics, University of Southern Denmark

• Niels Ørtenblad, Professor

Department of Biochemistry and Molecular Biology, University of Southern Denmark

• Søren Fisker, Associate Professor
• Nils Færgeman, Professor

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen

• Atul Shahaji Deshmukh, Associate Professor