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"The Role of the Liver for Interorgan Metabolic Crosstalk in Type 2 Diabetes"

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ClinicalTrials.gov Identifier: NCT04088851
Recruitment Status : Recruiting
First Posted : September 13, 2019
Last Update Posted : September 13, 2019
Sponsor:
Collaborator:
Prof. Dr. Gerald Shulman, Yale University, New Haven, Conneticut, USA
Information provided by (Responsible Party):
German Diabetes Center

Brief Summary:

WP 1: Working hypothesis: The gluconeogenic flux rates from pyruvate (lactate, alanine) and glycerol are higher in patients with T2D compared to the healthy control group.

WP2: Working Hypothesis: The gluconeogenic flux rates of lactate and glycerol are reduced in patients with T2D by acute inhibition of the redox shuttle.


Condition or disease Intervention/treatment Phase
Type2 Diabetes Drug: Metformin Not Applicable

Detailed Description:
Type 2 diabetes (T2D) is characterized by insulin resistance and inadequate insulin secretion leading to hyperglycemia. Current concepts indicate that insulin resistant adipose tissue releases metabolites, which stimulate hepatic gluconeogenesis (GNG), lipid deposition and secretion. Failure of compensation by ß cell function will favour muscle insulin resistance and fasting/postprandial hyperglycemia. The investigators have previously provided evidence for abnormal ATP synthesis and mitochondrial efficiency, but it remains unknown, how and which substrate fluxes account for excessive GNG in T2D. For this reason, the main objective of this project is to adress the multi-system challenges of T2D, by examining interorgan metabolic crosstalk with an emphasis on liver as orchestrator of interorgan substrate fluxes and driver of the transition from normo- to hyperglycemia. This proposal aims at investigating hepatic glucose and energy flux in T2D with focus on gluconeogenic contribution of lactate to hepatic mitochondrial substrate flux, the activity of the redox shuttle and mitochondrial ATP synthase flux, also after inhibition by metformin by using a novel combination of positional isotopomer nuclear magnetic resonance (NMR) analysis (PINTA) with multinuclei magnetic resonance spectroscopy (MRS).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: "Non-invasive Measurement of Hepatic Substrate Flux Rates in Patients With Diabetes Mellitus Type 2"
Actual Study Start Date : September 11, 2019
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : February 20, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metformin - T2D
Patients with type-2 diabetes and from their GP described Metformin Therapy (1 g per day) will undergo MRS and PINTA measurement.
Drug: Metformin
Type 2 Diabetics with prescribed Metformin therapy (1 g / day) will pause the medication for 2 weeks and then continue the anti-diabetic treatment again. Aim is to measure the gluconeogenic precursor fluxes with and without metformin therapy.

Placebo Comparator: No Metformin - T2D
Patients with type-2 diabetes and from their GP described Metformin Therapy (1 g per day) will pause the medication for 2 weeks and undergo MRS and PINTA measurement. After their visit they will continue the anti-diabetic treatment according to the GP's presription.
Drug: Metformin
Type 2 Diabetics with prescribed Metformin therapy (1 g / day) will pause the medication for 2 weeks and then continue the anti-diabetic treatment again. Aim is to measure the gluconeogenic precursor fluxes with and without metformin therapy.

No Intervention: No Metformin - Healthy Controls
Healhy controlls will undergo the MRS and PINTA measurments, matched in BMI and age.



Primary Outcome Measures :
  1. The gluconeogenic flux rates from pyruvate (lactate, alanine) and glycerol are higher in patients with T2D compared to the healthy control group. [ Time Frame: 2 weeks ]

    The present study tests the hypothesis that the GDP redox-shuttle is overactive and responsible for excessive GNG in human T2D what could be enhanced by adipocines secreted from inflammed adipose tissue in obese.

    It is a randomized controlled trial investigating liver energy metabolism in patients with T2D with and without inhibition of redox shuttle in patients with T2D and compared to a healthy control group (age- and BMI corrected). Patients and healthy controls are included prospectively. The combination of PINTA method and MRS determines the flux rates of pyruvate (lactate and alanine) and glycerol as well as gluconeogenesis and glycogenolysis. In addition, acute cellular changes after acute inhibition of the redox shuttle are investigated.




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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • T2D + metformin therapy
  • healthy volunteers

Exclusion Criteria:

  • no metformin therapy

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): NCT04088851


Locations
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Germany
German Diabetes Center Recruiting
Duesseldorf, NRW, Germany, 40225
Contact: Theresia C Sarabhai, MD    00492113382689    theresia.sarabhai@ddz.de   
Sponsors and Collaborators
German Diabetes Center
Prof. Dr. Gerald Shulman, Yale University, New Haven, Conneticut, USA

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Responsible Party: German Diabetes Center
ClinicalTrials.gov Identifier: NCT04088851     History of Changes
Other Study ID Numbers: IMPACT
First Posted: September 13, 2019    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs