Absence of a sexual dimorphism in postprandial glucose metabolism after administration of a balanced mixed meal in healthy young volunteers

The study investigates whether men and women differ in their ability to regulate glucose homeostasis in the postprandial state, a question relevant to understanding sex disparities in diabetes prevalence and in prediabetic conditions (impaired fasting glucose, impaired glucose tolerance). Prior reports show inconsistent sex differences, likely due to methodological heterogeneity and inadequate control of confounders such as age, body composition, and physical activity. Because these same factors also determine daily energy expenditure, the authors hypothesized that administering a balanced mixed meal normalized to each subject’s daily energy needs would better control confounding and reveal true sex-related differences, if any, in postprandial glucose metabolism. The aim was to compare postprandial glucose, insulin, and C-peptide responses between young men and women under this normalized feeding paradigm.

Prior studies using fixed carbohydrate loads (e.g., standard OGTT) often reported higher 2-hour glucose in women; however, large cohorts (AusDiab, Inter99) showed that this difference disappears after adjusting for height/body size, suggesting methodological artifacts due to fixed dosing irrespective of body mass and muscle mass. Studies with mixed meals normalized to body weight (e.g., 10 kcal/kg) reported higher postprandial glucose, insulin, and C-peptide in women, interpreted as impaired insulin action; yet, differences may reflect normalization to body weight rather than metabolically active mass and differences in physical fitness. Clamp studies indicate lower absolute insulin-mediated glucose uptake in women, but this often disappears after adjustment for fat mass, and when normalized to muscle mass women can have greater insulin sensitivity and glucose disposal. Collectively, these data imply that dosing strategies and body composition strongly influence observed sex differences, motivating an approach that normalizes meal size to daily energy expenditure, inherently accounting for age, body composition, and physical activity.

Design and setting: Experimental study at ICANS, University of Milan (Italy), March–June 2018. Participants: Thirty-six healthy young adults (18 women, 18 men), aged 18–35 years, normal weight, non-smokers, not elite athletes, and free of diseases or medications affecting endocrine function. Exclusions included overweight/obesity, relevant diseases (e.g., Crohn’s disease, malignancy, end-stage renal failure, cirrhosis, heart failure, chronic infection), endocrine diseases (thyroid disorders, diabetes), recent acute illness/injury, oral contraceptive use. To minimize sex hormone effects, women were tested in the follicular phase. Ethics: Approved by University of Milan Ethics Committee (protocol 32/17); informed consent obtained; conducted per Declaration of Helsinki. Pre-study screening: Physician exam; medical history; anthropometry; abdominal ultrasound for SAT and VAT thickness; fasting labs to exclude impaired fasting glucose (glucose ≥100 mg/dl) and insulin resistance (HOMA >2.5); IPAQ for physical activity assessment; documentation of last menstrual period. Pre-test standardization: Standardized dinner the evening prior (carbohydrate-rich options with olive oil, protein, vegetables, bread, fruit; water only). Test day protocol: Subjects arrived fasting at 08:30; IV catheter placed; baseline venous sample collected. Test meal consumed within 15 min; subsequent venous samples at 10, 20, 30, 45, 60, 90, 120, and 180 min for serum glucose and insulin; C-peptide measured at baseline and every 30 min to 180 min. Test meal: Balanced sandwich (white bread, ham, extra virgin olive oil, tomato) providing 40% of individual daily energy expenditure (DEE). DEE computed as resting energy expenditure (Harris & Benedict equation) multiplied by physical activity level using SINU coefficients. Macronutrient composition fixed at approximately 60% carbohydrate, 25% fat, 15% protein; about 9 g fiber per 1000 kcal. Meal energy and grams differed by individual (and by sex on average) but macronutrient percentages were matched. Anthropometry: Weight (Seca 700, 0.1 kg precision), height (stadiometer, 0.1 cm), BMI, waist circumference (midway between lower rib margin and anterior superior iliac spine, 0.5 cm precision), skinfolds (biceps, triceps, subscapular, suprailiac; Holtain calipers; triplicate; means used). Body density by Durnin & Womersley; fat mass by Siri formula. Ultrasonography: Fasting measurements of SAT and VAT 1 cm above the umbilicus (Logiq 3 Pro; 7.5 MHz linear for SAT, 3.5 MHz convex for VAT); standardized probe pressure; end-expiration; triplicate means. Laboratory assays: Serum glucose and insulin at all specified time points; C-peptide at baseline and every 30 min; Roche Diagnostics kits on Cobas Integra 400 Plus and Cobas 411 analyzers. Statistical analysis: Descriptive statistics as mean ± SD; between-sex comparisons by t-test or rank-sum as appropriate. Linear mixed-effects models for repeated measures assessed effects of sex (0 women, 1 men), time, and sex × time interaction on postprandial glucose, insulin, and C-peptide, with participant as random effect. Significance threshold P < 0.05. STATA 12.0 used.

- Participants: 36 healthy young adults (18 men, 18 women), mean age 23.9 ± 2.8 years, BMI 21.9 ± 1.7 kg/m²; men and women similar in age and BMI. Men had higher waist circumference and lower body fat percentage; SAT higher in women, VAT similar. Men had higher daily energy expenditure than women (2718 ± 177 vs 2190 ± 97 kcal; P < 0.001). - Test meal: Mean energy 972 ± 125 kcal (women 866 ± 46; men 1078 ± 78; P < 0.001); macronutrient percentages matched between sexes (≈58% CHO, 16% protein, 26% fat). - Fasting values: Glucose lower in women vs men (83 ± 7 vs 89 ± 5 mg/dl; P = 0.007). Fasting insulin (6.5 ± 2.1 vs 6.6 ± 1.9 U/l; P = 0.897) and C-peptide (1.8 ± 0.6 vs 1.8 ± 0.4 ng/ml; P = 0.486) did not differ. - Mixed models: No significant effects of sex or sex × time interaction on postprandial glucose, insulin, or C-peptide; only time was significant. Example estimates: glucose increased by approximately 31 mg/dl (95% CI 23.81, 38.97) early postprandially and remained above baseline up to 45 min; insulin increased by ~77.1 U/l; C-peptide by ~6.2 ng/ml at their respective peaks. - AUCs and peak metrics: No sex differences in AUC0–180 for glucose (women 10718 ± 7256 vs men 11234 ± 7206; P = 0.569), insulin (12120 ± 7358 vs 12864 ± 7599 U·min/l; P = 0.359), or C-peptide (1299 ± 437 vs 1343 ± 421 ng·min/ml; P = 0.477). Peak concentrations and times did not differ significantly; insulin time-to-peak tended to be later in women (58 ± 41 min) than men (29 ± 20 min), P = 0.068. - Overall: Postprandial glucose, insulin, and C-peptide responses were similar between sexes when the mixed meal was normalized to individual daily energy expenditure.

The findings indicate no sexual dimorphism in postprandial carbohydrate metabolism among healthy young adults when the meal is tailored to each person’s daily energy expenditure. This design inherently accounts for key confounders—age, body composition, and physical activity—that influence both energy needs and glucose metabolism. The results contrast with prior reports of higher postprandial glucose and insulin responses in women under fixed carbohydrate loads or body weight–normalized dosing, which may overburden smaller or lower–muscle-mass individuals (more often women) and thus artifactually inflate their glycemic and insulinemic responses. Evidence from large cohorts (AusDiab, Inter99) supports that body size adjustments negate apparent sex differences in OGTT responses, and physiological studies suggest that differences in insulin action diminish when normalized to relevant compartments (e.g., muscle mass) and fitness. By emulating real-life intake proportional to energy requirements, the present approach yields similar glycemic excursions and hormone responses in men and women, suggesting comparable regulation of postprandial glucose homeostasis under physiologically matched feeding.

In healthy young adults, ingestion of a balanced mixed meal normalized to individual daily energy expenditure elicits similar postprandial glucose, insulin, and C-peptide responses in men and women, despite lower fasting glucose in women. These results do not support a sexual dimorphism in postprandial carbohydrate metabolism under physiologically matched meal conditions. The study underscores the importance of accounting for energy needs and related confounders when assessing sex differences in glucose metabolism. Future research should validate these findings in older adults and other populations, and explore additional physiological contributors (e.g., gastric emptying, gut hormones, insulin/glucagon sensitivities) to postprandial variability.

- Narrow age range of participants limits generalizability to other age groups. - Daily energy expenditure was estimated using predictive equations (Harris & Benedict) rather than measured by indirect calorimetry, although validation studies support reasonable accuracy in normal-weight individuals. - Sex hormone concentrations were not measured; women were tested in the follicular phase to mitigate hormonal variability. - Exclusion of competitive athletes may limit applicability to highly trained individuals. - Potential unmeasured contributors to postprandial responses (gastric emptying rates, gut hormone responses, pancreatic secretory capacity, peripheral and central insulin/glucagon sensitivities, liver size, cardiac output) were not assessed.