Longitudinal Multi-Omic Profiles to Reveal Mechanisms of Obesity-Mediated Insulin Resistance

Обзор

This 12-week controlled diet and weight intervention study seeks to define the molecular pathways that link excess body weight to the development of insulin resistance (IR). Blood, adipose and stool are sampled at three timepoints; baseline, peak weight (4 weeks) and post weight loss to monitor changes in cellular processes. Additionally, direct insulin sensitivity testing, and radiological measurement of visceral fat and intrahepatic fat content is measured at three timepoints to correlate clinical indices with cellular changes.

Подробное описание

Obesity has become an epidemic worldwide. Metabolic/cardiovascular complications of obesity are likely related to the fact that obese individuals tend to be insulin resistant (IR). While insulin- mediated glucose uptake (IMGU) correlates with adipose tissue mass, not all obese individuals are IR, and metabolic and cardiovascular profiles of those who are IR vs insulin sensitive (IS) differ significantly. Why one individual who reaches a BMI of 30 kg/m2 will develop IR and another with similar BMI and activity level remains IS is unclear. Furthermore, while insulin sensitivity improves with weight loss, this response varies as well. Given that fat mass per se does not fully explain the obesity contribution to IMGU, itis likely that differential adipocyte function plays a role. With this study, our purpose is to employ an integrated omics strategy to identify analyte/pathway signatures in blood and adipose tissue that characterize IR versus IS states and expand our biological knowledge of the mechanisms underlying IR.

Вмешательства

• Поведенческое Dietary Intervention Mediterranean Low Carbohydrate Diet
  Assigned participants will receive instruction by a registered dietitian on a diet that is high in unsaturated fats and low in carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.
• Поведенческое Dietary Intervention Standard Low Carbohydrate Diet
  Assigned participants will receive instruction by a registered dietitian on a low carbohydrate diet that is high in fats found in the typical American diet. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.
• Поведенческое Dietary Intervention Standard Low Fat Diet
  Assigned participants will receive instruction by a registered dietitian on a low fat diet that is high in complex carbohydrates. Total caloric intake will be adjusted to induce a supervised metabolic challenge defined as weight gain of approximately 2.5 kg over 5 weeks followed by 3-5kg weight loss over 8 weeks.

Первичные конечные точки

• Change from baseline on the 2-stage Steady State Plasma Glucose test [Срок оценки: Peak weight (4 weeks)]
• Change from baseline on the radiographic measurement of visceral to subcutaneous (V:S) fat ratio [Срок оценки: Peak weight (4 weeks)]
• Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition [Срок оценки: Peak weight (4 weeks)]
• Change from peak weight on the 2-stage Steady State Plasma Glucose test [Срок оценки: Post-weight loss (8 weeks)]
• Change from baseline on the radiographic measurement of visceral to subcutaneous (V:S) fat ratio [Срок оценки: Post-weight loss (8 weeks)]
• Change from baseline on the magnetic-resonance based measurement of intrahepatic lipid deposition [Срок оценки: Post-weight loss (8 weeks)]
• Measurement of markers of lipid and carbohydrate metabolism and inflammation from adipose mRNA [Срок оценки: Baseline]
• Quantification of plasma inflammatory cytokine levels in serum samples by Luminex immunoassay [Срок оценки: Baseline]
• Change from baseline in plasma inflammatory cytokine levels in serum samples as measured by Luminex immunoassay [Срок оценки: Peak Weight (4 weeks)]

Критерии участия

Критерии включения

• Age 35-65
• BMI 25-35 kg/m2
• Stable body weight
• Nondiabetic

Критерии исключения

Patients with;

• diabetes
• major organ disease
• history of liposuction or bariatric surgery
• active eating or psychiatric disorder
• pregnancy or lactation, heavy alcohol use
• recent change in weight (over the past 12 weeks)
• use of weight loss medication, statins, or oral steroids

Clinical screening exclusions;

• hematocrit < 33%
• fasting glucose >/= 126 mg/dL
• blood pressure >160/100 mmHg

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Профилактика

Центры проведения

США · 1 центр

• Stanford University — Stanford

Идентификаторы

NCT: NCT05165706 · 40195 · 5R01DK110186-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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