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De Novo Lipogenesis and Insulin Sensitivity in Obese (DELISA)

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ClinicalTrials.gov Identifier: NCT04260542
Recruitment Status : Recruiting
First Posted : February 7, 2020
Last Update Posted : February 7, 2020
Sponsor:
Collaborators:
Faculty Hospital Kralovske Vinohrady
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by (Responsible Party):
Michaela Siklova, Charles University, Czech Republic

Brief Summary:
Disturbances of de novo lipogenesis (DNL) are one of the features of dysfunction of adipose tissue (AT). Disturbances of DNL play a role in development of metabolic complications of obesity. The goal of this project is to investigate novel pathways of DNL regulation. DNL will be studied during nutritional interventions in healthy and obese subjects in exposure to 2-days high carbohydrate diet preceded by a) 2-days fasting b) several weeks´ ketogenic diet. This nutritional protocol creates conditions for the study of prominent changes in DNL: suppression of DNL during fasting or ketogenic diet followed by stimulation during high-carbohydrate diet. Systemic phenotypic features and molecular indices of DNL regulation in AT will be followed during the protocols. Specific attention will be paid to newly reported pathway- hormone sensitive lipase and transcription factor ChREBP. The results will contribute to development of pharmacological approaches in the treatment of metabolic complications of obesity, targeted selectively to AT, without side effects in other tissues.

Condition or disease Intervention/treatment Phase
Insulin Resistance Obesity Behavioral: Fasting/refeeding Behavioral: Ketogenic diet/ fasting Not Applicable

Detailed Description:
The main goal of the proposed project is to characterize the regulation of de novo lipogenesis in AT, a pathway strongly associated with insulin sensitivity in humans. The project should provide information that will bring proof-of-concept for the development of AT DNL-targeting therapeutic strategies to decrease the metabolic risk in obese individuals. Two protocols in lean and obese women to modulate (inhibit/induce) DNL will be implemented: 1) two days of fasting followed by two days of high-carbohydrate diet refeeding (FAST/RF) in lean and obese women; 2) "fasting-mimicking" intervention in obese women with high fat low carbohydrate ketogenic diet followed by two days of high-carbohydrate diet refeeding (KETO/RF). KETO diet should provide long lasting AT DNL inhibition, and as such it should further highlight the processes necessary for DNL activation in the refeeding phase. The unique protocols proposed in the application will allow to investigate in humans the relationship between AT DNL and whole body insulin sensitivity and glucose tolerance. Moreover, the state of the art experimental methodologies applied for the analyses of AT samples should uncover the possible mechanisms of regulation of DNL by ChREBP, HSL and other factors as well as the related AT secretory capacity in humans. The findings obtained in lean subjects will be compared to obese subjects, as the deregulated response of these pathways might be expected. The project will provide a proof-of-principle for the role of AT DNL in the regulation of insulin sensitivity in lean and obese individuals. The results will indicate novel pathways for future development of drugs targeting the relevant sites in AT in the context of treatment of obesity-induced insulin resistance and associated disorders.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Role of De Novo Lipogenesis in Regulation of Insulin Sensitivity in Adipose Tissue in Obese
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy
Drug Information available for: Insulin

Arm Intervention/treatment
Active Comparator: FAST Lean
Short-term fasting (FAST), comparator group of lean subjects
Behavioral: Fasting/refeeding
2-days fasting followed by 2-days of refeeding. During the fasting period the subjects will be hospitalized to control their state of health and ensure fasting compliance. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat).
Other Name: FAST lean

Experimental: FAST Obese
Short-term fasting (FAST), experimental group of obese subjects
Behavioral: Fasting/refeeding
2-days fasting followed by 2-days of refeeding. During the fasting period the subjects will be hospitalized to control their state of health and ensure fasting compliance. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat).
Other Name: FAST obese

Experimental: KETO Obese
Medium-term ketogenic diet intervention (KETO), experimental group of obese subjects
Behavioral: Ketogenic diet/ fasting
1 month of fasting-mimicking ketogenic diet and subsequent 2-days of refeeding. The subjects will be instructed by nutritional specialist to follow isocaloric ketogenic diet consisting of 6% carbohydrates, 17 % of proteins and 77% fat to cover individual energy demand. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat).
Other Name: KETO obese




Primary Outcome Measures :
  1. Insulin sensitivity [ Time Frame: through study completion, an average of 1 year ]
    Change in insulin sensitivity index (ΔiAUC insulin/ΔiAUC glucose from OGTT)

  2. De Novo Lipogenesis in adipose tissue [ Time Frame: through study completion, an average of 1 year ]
    Change in mRNA expression of lipogenic genes and by targeted and non-targeted lipid analysis (ΔCT)


Secondary Outcome Measures :
  1. gene expression profiling of adipose tissue [ Time Frame: through study completion, an average of 1 year ]
    Change in long non-coding RNA analysis by microarrays (ΔCT)


Other Outcome Measures:
  1. Exploratory outcome into adipose tissue lipolysis [ Time Frame: through study completion, an average of 1 year ]
    Change in glycerol, FFA concentration in AT explants



Information from the National Library of Medicine

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Ages Eligible for Study:   25 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • sedentary premenopausal women
  • lean (n=20-25, age 25-40 years, BMI 20-25 kg/m2)
  • obese (n=20-25, age 25-40 years, BMI 30-40 kg/m)

Exclusion Criteria:

  • diagnosed cancer
  • diabetes (T1DM and T2DM)
  • liver and renal diseases
  • major cardiovascular event
  • bariatric surgery
  • allergy to lidocaine
  • positive serology for hepatitis (B and C) and HIV
  • smoking above 10 cigarettes/day, alcohol consumption above 66g/day
  • sleep apnea
  • poor venous status
  • weight-change more than 3kg in last 3 months
  • untreated hyper- or hypo-thyroidism
  • long term use of medication and/or steroids
  • shift workers and individuals with abnormal sleep/wake pattern

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04260542


Contacts
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Contact: Michaela Siklova, PhD +420 267 102 211 michaela.siklova@lf3.cuni.cz
Contact: Lenka Rossmeislova, PhD +420 267 102 211 lenka.rossmeislova@lf3.cuni.cz

Locations
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Czechia
Charles University Recruiting
Prague, Czechia, 100 00
Contact: Michaela Siklova, PhD    +420 267 102 211    michaela.siklova@lf3.cuni.cz   
Contact: Lenka Rossmeislova, PhD    +420 267 102 211    lenka.rossmeislova@lf3.cuni.cz   
Principal Investigator: Michaela Siklova, PhD         
Sub-Investigator: Lenka Rossmeislova, PhD         
Sub-Investigator: Vladimir Stich, prof,MD,PhD         
Sub-Investigator: Jan Gojda, MD, PhD         
Faculty Hospital Kralovske Vinohrady Recruiting
Prague, Czechia
Contact: Jan Gojda, MD, PhD       jan.gojda@fnkv.cz   
Sponsors and Collaborators
Charles University, Czech Republic
Faculty Hospital Kralovske Vinohrady
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
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Principal Investigator: Michaela Siklova, PhD Charles University

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Responsible Party: Michaela Siklova, Deputy head of adipose tissue physiology lab, Charles University, Czech Republic
ClinicalTrials.gov Identifier: NCT04260542    
Other Study ID Numbers: NV19-01-00263
First Posted: February 7, 2020    Key Record Dates
Last Update Posted: February 7, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Michaela Siklova, Charles University, Czech Republic:
adipose tissue
insulin resistance
obesity
ketogenic diet
de novo lipogenesis
Additional relevant MeSH terms:
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Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs