Impact of Dietary Fat and Menstrual Cycle Phases in Type 1 Diabetes (DIABETEXX/3)

Instituto de Investigacion Sanitaria La Fe

Status: Not yet enrolling

Conditions: Postprandial Glucose; Type 1 Diabetes Mellitus; Sex Characteristics; Menstrual Cycle; Glycemic Variability; Dietary Fat

Treatments: Other: Low Fat Mixed Meal; Other: High Fat Mixed Meal

Study type: Interventional

Funder types: Other

Identifiers

NCT07278063

2025-0897-1

Details and patient eligibility

About

This clinical trial aims to evaluate how variations in dietary fat content and hormonal status influence postprandial glycemic response in individuals with type 1 diabetes (T1D), with a special focus on women. The main objective is to clarify the impact of both factors individually and their interaction, which could inform more personalized strategies for insulin adjustment, optimizing glycemic control, and improving patient outcomes.

The main objective is to investigate the effects of low-fat versus high-fat meals, sex, menstrual cycle phases, and their interaction on postprandial glycemic control in adults with T1D treated with advanced hybrid closed-loop (AHCL) insulin delivery systems.

Specifically, the study will:

• Compare postprandial glycemic responses after standardized low and high-fat meals in men and women with T1D.
• Assess the differences in postprandial glycemic responses between early follicular and late luteal phases in women, using standardized meals with low and high fat content.
• Identify sex-related differences in glycemic response after equivalent meals.

This research addresses the unmet clinical need for precise, tailored postprandial insulin dosing recommendations, especially among women whose insulin sensitivity fluctuates with menstrual phases. The results may contribute to sex-specific predictive models in AHCL systems, reducing acute complications and improving overall quality of life.

This is a randomized controlled crossover trial in which each participant serves as her/his own control. Fifty adults will be enrolled: 25 women and 25 men. Women will undergo four mixed-meal tests in random order:

• low-fat given during the early follicular phase,
• high-fat given during the early follicular phase,
• low-fat given during the late luteal phase,
• high-fat given during the late luteal phase. The menstrual phase will be confirmed with home-based hormonal monitoring devices that function with urine sample and use a single-use test wand (MIRA system).

Men will complete two mixed-meal tests (low-fat and high-fat), in randomized order.

All meals will be standardized for carbohydrate content and matched in other macronutrients, except for fat (with a 30-40g difference), administered after an 8-hour fast. The day of the mixed meal test, AHCL systems will be switched from automatic to manual mode just before eating to standardize the prandial insulin dose and to avoid differences in insulin infusion rates in the postprandial state due to algorithm compensations. Continuous glucose monitoring (CGM) and hourly capillary glucose testing will measure the postprandial response. Additional fasting blood samples will assess metabolic, hormonal, and lipid markers. Optional gastric emptying studies may be performed to exclude confounding gastroparesis in selected patients.

Participants will be recruited from the endocrinology outpatient unit of La Fe Polytechnic University Hospital . The projected recruitment period is from December 2025 to July 2027, with mixed-meal tests and data collection occurring between January 2026 and December 2027. Women are expected to complete the protocol in 6 weeks (4 tests), while men will require about 2 weeks (2 tests).

At baseline, participants will undergo blood tests to rule out endocrine disorders and confirm sex hormone status. Women participating in the study will use the MIRA home device to monitor their hormonal levels, allowing them to accurately determine and record the phases of their menstrual cycle as part of the study protocol. During meal tests, CGM (Freestyle Libre 3) will be used uniformly among subjects.

The study dependent variables will be the following:

• Postprandial glucose area under the curve - AUC_PG_5h
• Mean glucose level - MG
• Continuous glucose monitoring metrics - TIR, TAR, TBR
• Postprandial glucose standard deviation - SD
• Postprandial glucose coefficient of variation - CV
• Mean amplitude of glycemic excursions - MAGE
• Mean of daily differences (MODD)

Independent variables are

• Type of food: Meals with either low or high fat content.
• Sex and Hormonal status: men; women during the early follicular phase; women during the late luteal phase.

If successful, this study will inform the development of more sophisticated, individualized insulin dosing algorithms and AHCL system improvements, especially for women with T1D. Results may lead to more effective management strategies, reduced GV, lower incidence of complications, and increased quality of life. Insights may directly support the personalization of diabetes care and improve gender equity in treatment standards.

Full description

Each female participant will initiate the protocol with the first mixed meal test during the luteal phase, using the MIRA home device to monitor their hormonal levels. This approach is intended to guarantee accurate assessment of menstruation, and assures the realization of the second mixed meal test in the subsequent follicular phase without interruption in all enrolled subjects..

The meaning of starting in the luteal phase is to avoid potential delays or absence of the menstrual cycle that could occur if randomization began in the follicular phase, which could render the planned sequence infeasible.

Randomization will be performed regarding the type of mixed meal administered: either high-fat or low-fat. Block randomization will be employed: 50% of participants commence with the low-fat meal, while the remaining 50% begin with the high-fat meal. This method is used to maintain balance between groups and to reduce allocation bias throughout the study.

The sample size calculation for this study was based on prior research evaluating postprandial glucose responses and the impact of menstrual cycle phases. Differences in glucose and glucose area under the curve (AUC) from mixed meals with varying fat content, as well as between menstrual phases, informed expected effect sizes. Assuming an intra-subject standard deviation of 25 mg/dl, a correlation of 0.5 between repeated measures, and an expected interaction effect of 20 mg/dl, a total of 50 participants (25 women and 25 men) is needed to achieve 80% statistical power with an alpha of 0.05. This ensures adequate power to detect meaningful differences in the postprandial glucose response measured by AUC according to meal fat content and menstrual cycle phase.

The study keeps the advanced hybrid closed-loop (AHCL) system active during the baseline period to maintain usual insulin delivery and ensure similar glucose concentrations just before the meal test and also during the previous hours. At the time of the mixed meal test, the system is switched to open-loop mode to standardize insulin dosing across all participants. This will prevent the pump from making automated insulin corrections to glucose excursions during the test, which would compensate, at least partially, the possible differences induced by the factors object of the investigation. The HCL systems will be maintained in the open-loop (manual) configuration from time 0 (prandial bolus administration) to the end of the study 5h after. The prandial insulin dose will be based on the usual individual insulin to carbohydrate ratio, while basal insulin will be infused at the planned safety mode rates (those rates programmed by the physician at which the systems infuse when it shift from the automatic to the manual mode). Importantly, both parameters (insulin to carbohydrate ratio and manual basal rates) will be optimized for each patient before the commencement of the meal tests and kept constant during the study participation.

This approach will help ensure similar preprandial glycemia between subjects, avoids confounding factors introduced by adaptive insulin delivery and will allow accurate assessment of the effects of meal composition and hormonal status on postprandial glucose response. Maintaining insulin dosing standardization is essential to isolate the variables under study without interference from the AHCL system's automatic glucose adjustments.

Enrollment: 50 estimated patients

Sex: All

Ages: 18 to 45 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients with a confirmed diagnosis of type 1 diabetes mellitus for more than 2 years, in treatment with AHCL (Advanced Hybrid Closed Loop) system treatment for at least 6 months.
• Both sexes.
• Metabolic control with HbA1c <8%.
• BMI between 18.5 and 29.99 (normal weight to overweight).
• For women: regular menstrual cycles (21-35 days in length with variation between cycles of <4 days) and no use of hormonal contraceptive treatment.

Exclusion criteria

• Diagnosis of diabetic gastroparesis.
• Presence of hypogonadism, anovulation, hyperandrogenism, hyperprolactinemia, pregnancy, or decompensated chronic diseases.
• Use of oral medications that alter glucose metabolism.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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50 participants in 3 patient groups

Female1

Other group

Description:

Female patients in early follicular phase

Treatment:

Other: High Fat Mixed Meal

Other: Low Fat Mixed Meal

Female2

Other group

Description:

Female patients in late luteal phase

Treatment:

Other: High Fat Mixed Meal

Other: Low Fat Mixed Meal

Male

Other group

Description:

Male patients

Treatment:

Other: High Fat Mixed Meal

Other: Low Fat Mixed Meal