Effect of Meal Timing in T2D on Hepatocytes SRIT1 and Clock Genes

NCT ID: NCT04405895

Last Updated: 2020-05-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-31
• Study Completion Date: 2020-10-20

Brief Summary

This study is undertaken to explore in T2D, the effect of meal timing on serum induced SIRT1 and Clock Genes mRNA expression in cultured hepatocytes. Fasting serum samples were collected from T2D participants, following two different meal timing schedules, either a diet with large breakfast and lunch with small dinner Breakfast Diet (3Mdiet) or an isocaloric diet with 6 small meals evenly distributed along the day Allday Diet (6Mdiet). The researchers will use an ex-vivo/in-vitro approach in which cultured medium will be conditioned with the fasted human serum collected from the two groups of T2D participants at baseline, after 2 weeks and after 12 week of the diet intervention.

Detailed Description

The timing of many physiological processes, including glucose metabolism, is coordinated by the circadian clock gene system. The circadian clock regulation, optimize glucose metabolism for the consumption of high energy and carbohydrate (CH) meals in the early hours of the day and for fasting at evening and night. Circadian disruption which occurs when the meal timing is not aligned with the circadian clock rhythms like skipping breakfast, overeating CH at night or eating CH all day, lead to desynchronized clock genes and can result in adverse health outcomes like insulin resistance, obesity hyperglycemia and T2D. Although the clock genes are disseminated in almost all peripheral tissues, those localized in the liver, are particularly important for the regulation of glucose metabolism, influencing the enzymatic determinants of the hepatic glucose output, by enhancing glycogen storage and suppressing nocturnal hepatic glucose production (glycogenolysis and gluconeogenesis sequentially).Therefore, the disruption of the hepatic clock genes lead to fasting, nocturnal, and to postprandial hyperglycemia in T2D. The researchers had previously shown in T2D, that compared to 6Mdiet, the 3Meal diet timing schedule, was most effective in reducing body weight, HbA1c, overall hyperglycemia, and led to up-regulation of SIRT1 and Clock Genes mRNA expression in leukocytes. However, this effect of meal timing had never been explored in liver cells. The investigators hypothesized that compared to Allday Diet (6Mdiet), the serum collected from T2D participants following Breakfast Diet (3Mdiet) will up-regulate SIRT1 and Clock Genes oscillatory mRNA expression in cultured hepatocytes.

Conditions

Type 2 Diabetes; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Breakfast Diet (3Mdiet)

The Breakfast Diet (3Mdiet) will consist in 3 meals with distribution of calories: breakfast 50%, lunch 33% and dinner 17%.

Group Type: EXPERIMENTAL

Breakfast Diet

Intervention Type: OTHER

Breakfast Diet (3Mdiet) consist on high-energy breakfast and reduced in energy and carbohydrate (CH) dinner. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 3Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 3Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.

Allday Diet (6Mdiet)

The Allday Diet (6Mdiet) will consist on 6 meals (breakfast, lunch and dinner and 3 snacks) with distribution of calories: breakfast 15%, lunch 25%, dinner 30% and 10% in each of the three snacks.

Group Type: ACTIVE_COMPARATOR

Allday Diet

Intervention Type: OTHER

Allday Diet (6Mdiet) consist in 6 small meals: breakfast, lunch and dinner and 3 snacks, with calories and carbohydrates (CH) evenly distributed throughout the day. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 6Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 6Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.

Interventions

Breakfast Diet

Breakfast Diet (3Mdiet) consist on high-energy breakfast and reduced in energy and carbohydrate (CH) dinner. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 3Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 3Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.

Intervention Type: OTHER

Allday Diet

Allday Diet (6Mdiet) consist in 6 small meals: breakfast, lunch and dinner and 3 snacks, with calories and carbohydrates (CH) evenly distributed throughout the day. Participants fasting serum to provide serum to for the in ex-vivo cell studies, will be collected at fasting (8:00), at start (day 0), after 2 weeks and at the end of 6Mdiet intervention (12 weeks). The participants serum is added to culture medium (as serum conditioned medium) to treat during 48 hours the cultured hepatocytes. After 48 hours of serum treatment, the mRNA extraction for the assessment of SIRT1 and Clock Gene expression will be performed at 00:00, 06:00, 12:00 and at 18:00 to assess SIRT1 and the Clock Genes circadian oscillation in hepatocytes. The 6Mdiet efficacy on reducing the overall glycemic excursions is assessed with continuous monitoring system at baseline after 2 weeks month of diet intervention.

Intervention Type: OTHER

Other Intervention Names

3Mdiet; 6Mdiet

Eligibility Criteria

Inclusion Criteria

• T2D patients with stable treatment for at least 3 month preceding the study.
• HgA1c >7.5 %.
• Age > 30 years.
• BMI: 27-34 kg/m2.
• Treatment with antidiabetic drugs (i.e. metformin, DPP4 inhibitors, glinides) and GLP-1 analogs, will be allowed
• Anti-hypertensive treatment will be allowed.
• Lipid-lowering medication also allowed

Exclusion Criteria

• Type 1 diabetes.
• Major illnesses (liver, heart, kidney, infectious, neurological, psychiatric, immunological, active malignancy).
• Change in weight of > 4.5 kg within 3 month prior the diet onset.
• Night or rotating shift workers.
• Those who crossed more than 2 time zones during 2-week period prior to study onset.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tel Aviv University

OTHER

Sponsor Role: lead

Responsible Party

Daniela Jakubowicz

Daniela Jakubowicz, MD: Clinical Profesor Head of Obesity Clinic at Diabetes Unit.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Daniela Jakubowicz, MD

Role: PRINCIPAL_INVESTIGATOR

Wolfson Medical Center

Shani Tsameret, RD

Role: PRINCIPAL_INVESTIGATOR

E. Wolfson Medical Center.

Locations

Wolfson Medical Center

Holon, Please Select, Israel

Countries

Israel

Central Contacts

Daniela Jakubowicz, MD

Role: CONTACT

daniela.jak@gmail.com

+972508105552

Zohar Landau, MD

Role: CONTACT

landau.zohar@gmail.com

+972544822792

Facility Contacts

Daniela Jakubowicz, MD

Role: primary

daniela.jak@gmail.com

0508105552

Zohar Landau, MD

Role: backup

landau.zohar@gmail.com

972544822792

Other Identifiers

0118-20-WOMC

Identifier Type: -

Identifier Source: org_study_id