Glucose and Glycogen Dynamics in Prediabetes (GGD)

Investigating Disturbances in Glucose and Glycogen Dynamics in Prediabetes

The goal of this observational study is to investigate changes in nocturnal and postprandial glucose and glycogen metabolism in individuals with impaired fasting glucose and impaired glucose tolerance compared to healthy, non-diabetic, overweight participants (15 per group). In addition, it will be investigated if reducing gluconeogenesis, by using the challenge agent Acipimox, in people with prediabetes can increase glucose tolerance and fat oxidation by increased reliance on hepatic glycogen. The main questions this project aims to answer are:

• whether there are differences in nocturnal glucose/glycogen metabolism in individuals with impaired fasting glucose, impaired glucose tolerance and healthy overweight controls.
• whether there are differences in postprandial glucose/glycogen metabolism in individuals with impaired fasting glucose, impaired glucose tolerance and healthy overweight controls.

Participants will visit the university for a screening visit and a visit with overnight stay for measurements of gluconeogenesis, glycogen, and substrate oxidation. A subgroup will receive [18F]-FDG to assess tissue-specific postprandial glucose uptake. Thereafter, 20 prediabetic individuals will follow a 4-day treatment with acipimox to decrease gluconeogenesis, followed by a second overnight visit with similar measurements as mentioned for the first visit.

Study Overview

• Status: Recruiting
• Conditions: Pre Diabetes
• Intervention / Treatment: Drug: Acipimox 250 mg Oral Capsule

• Study Type: Observational
• Enrollment (Estimated): 45

Contacts and Locations

• Study Contact: Name: Kay Roumans, PhD; Phone Number: +31433882124; Email: k.roumans@maastrichtuniversity.nl
• Study Contact Backup: Name: Mijke Buitinga, PhD; Phone Number: +31883887286; Email: m.buitinga@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229ER
      • Recruiting
      • Maastricht University
      • Contact: Kay Roumans, PhD; Phone Number: 31 433882124; Email: k.roumans@maastrichtuniversity.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

15 healthy overweight participants, 15 participants with prediabetes characterised by IGT and 15 participants with prediabetes characterised by IFG. All participants will be aged 45-75y, with a BMI between 27-38 kg/m2, stable dietary habets, a sedentary lifestyle and no sign of active disease or excesive alcohol consumption.

Description

Inclusion Criteria for all groups:

• Participants are able to provide signed and dated written informed consent prior to any study specific procedures
• Participants should have suitable veins for cannulation or repeated venipuncture
• Women are post-menopausal (defined as at least 1 year post cessation of menses)
• Aged ≥ 45 and ≤ 75 years
• Body mass index (BMI) 27 - 38 kg/m2
• Stable dietary habits (no weight loss or gain >5kg in the past 3 months)
• Sedentary lifestyle (not more than 2 hours of sports per week)

Inclusion Criteria for Prediabetic groups specifically:

Impaired Fasting Glucose: fasting blood glucose between 6.1 and 6.9 mmol/L and 2-h plasma glucose after ingestion of 75g oral glucose load below 7.8 mmol/L Impaired Glucose Tolerance: fasting blood glucose below 6.1 mmol/L and 2-h plasma glucose after ingestion of 75g oral glucose load between 7.8 and 11.1 mmol/L

Exclusion Criteria for all groups:

• Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator
• Previously diagnosed with type 2 diabetes
• Patients with congestive heart failure and/or severe renal (eGFR <50mL/min) and or liver insufficiency or another condition that may interfere with outcomes measured in this study.
• Any contra-indication MRI scanning
• Alcohol consumption of >2 servings per day for men and >1 servings per day for woman
• Smoking in the past 6 months
• Medication use that may influence main outcome parameters, specifically the following types of medication: Type 2 diabetes medication, corticosteroids, thyroid medication.
• Participation in research or medical examination that included PET scanning in the last 3 months

Exclusion Criteria for Healthy overweight specifically:

- Any of the criteria mentioned above to define prediabetes

Exclusion Criteria for Prediabetic groups who will undergo acipimox treatment:

• Gout
• Hypersensitivity to acipimox or to any of the excipients in the tablet
• Peptic ulcer/dyspepsia
• Medication that interferes with Acipimox (statins, fibrates).

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy overweight volunteers; This group includes 15 healthy overweight volunteers. These participants will undergo two test days with one overnight stay. During these days several tests will be conducted including measurements such as muscle and liver glycogen, whole-body gluconeogenesis, substrate oxidation and postprandial hepatic and muscle glucose uptake will be assessed by 18F-FDG PET combined with an oral glucose tolerance test.
Prediabetes volunteers-IFG; This group will include 15 subjects with impaired fasting glucose (IFG). These participants will undergo two test days with one overnight stay. During these days several tests will be conducted including measurements such as muscle and liver glycogen, whole-body gluconeogenesis, substrate oxidation and postprandial hepatic and muscle glucose uptake will be assessed by 18F-FDG PET combined with an oral glucose tolerance test. A subset of IFG prediabetes individuals with impaired fasting glucose (first 10 subjects enrolled) will receive a 4-day Acipimox treatment (3x 250mg capsules for three days (one with breakfast, one with lunch and one with snack) and 1x 250mg in the morning of day 4. After the intervention the participants will come to the university for two days with an overnight stay for tests (muscle and liver glycogen, whole-body gluconeogenesis, substrate oxidation, oral glucose tolerance test).	Drug: Acipimox 250 mg Oral Capsule; A subset of prediabetes individuals (first 10 IFG and 10 IGT subjects enrolled) will receive a 4-day Acipimox treatment (3x 250mg capsules for three days (one with breakfast,one with lunch and one with snack) and 1x 250mg in the morning of day 4.; Other Names: Olbetam 250 mg oral capsule
Prediabetes volunteers-IGT; This group will include 15 subjects with impaired glucose tolerance (IGT). These participants will undergo two test days with one overnight stay. During these days several tests will be conducted including measurements such as muscle and liver glycogen, whole-body gluconeogenesis, substrate oxidation and postprandial hepatic and muscle glucose uptake will be assessed by 18F-FDG PET combined with an oral glucose tolerance test. A subset of IGT prediabetes individuals with impaired fasting glucose (first 10 subjects enrolled) will receive a 4-day Acipimox treatment (3x 250mg capsules for three days (one with breakfast, one with lunch and one with snack) and 1x 250mg in the morning of day 4. After the intervention the participants will come to the university for two days with an overnight stay for tests (muscle and liver glycogen, whole-body gluconeogenesis, substrate oxidation, oral glucose tolerance test).	Drug: Acipimox 250 mg Oral Capsule; A subset of prediabetes individuals (first 10 IFG and 10 IGT subjects enrolled) will receive a 4-day Acipimox treatment (3x 250mg capsules for three days (one with breakfast,one with lunch and one with snack) and 1x 250mg in the morning of day 4.; Other Names: Olbetam 250 mg oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic and muscle glycogen measured by 13Carbon-Magnetic resonance spectroscopy (13C-MRS)	Difference in overnight and postprandial change of hepatic and muscle glycogen measured by 13C-MRS between healthy overweight volunteers and volunteers with IFG and IGT	During day 1 and day 2
Whole body gluconeogenesis determined by deuterated water	Difference in whole-body gluconeogenesis between healthy overweight volunteers and IFG and IGT volunteers	During day 1 and day 2
Postprandial hepatic and muscle glucose uptake determined by Fluorodeoxyglucose-Positron emission tomography ([18F]-FDG-PET) combined with oral glucose tolerance test (OGTT)	Difference in glucose uptake between healthy overweight volunteers and IFG and IGT volunteers	During day 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral glucose tolerance after acipimox treatment measured by OGTT	Difference in glucose tolerance measured by OGTT before and after 4 days of acipimox treatment in prediabetic volunteers (intra- and inter-group comparisons)	During day 2 and day 6
Hepatic glycogen after acipimox treatment measured by 13C-MRS	Difference in overnight change of hepatic glycogen before and after 4 days of acipimox treatment in prediabetic volunteers (intra- and inter-group comparisons)	During day 1,2, 5 and 6
Whole body gluconeogenesis after acipimox treatment determined by deuterated water	Difference in whole body gluconeogenesis before and after 4 days of acipimox treatment in prediabetic volunteers (intra- and inter-group comparisons)	During day 1,2, 5 and 6

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepatic acetylcarnitine as a measure for hepatic gluconeogenesis determined by H-MRS	Difference in hepatic acetylcarnitine between healthy overweight volunteers and individuals with IGT and IFG and the difference in hepatic acetylcarnitine before and after 4 days of acipimox treatment in prediabetic volunteers (intra- and inter-group comparisons).	During day 1,2, 5 and 6
Substrate oxidation (fat and carbohydrate oxidation) determined by indirect calorimetry	Difference in substrate oxidation (fat and carbohydrate oxidation) between healthy overweight volunteers and IFG and IGT volunteers and the difference in substrate oxidation before and after 4 days of acipimox treatment in IFG and IGT volunteers (intra- and inter-group comparisons).	During day 1,2, 5 and 6
Dynamic water relaxation measurements with 1H-MRS (surrogate glycogen)	Difference in water relaxation measures between healthy overweight volunteers and IFG and IGT volunteers.	During day 1,2, 5 and 6
Anthropometric measurements	weight and height will be combined to report BMI in kg/m^2 (to characterize participants)	During the screening day
Body composition determined by Bodpod	fat mass and fat free mass as % (to characterize participants)	During day 1

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Vera Schrauwen, PhD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2024
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: August 7, 2023
• First Submitted That Met QC Criteria: March 11, 2024
• First Posted (Actual): March 19, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Prediabetic State; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Acipimox
• Other Study ID Numbers: NL84574.068.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data can be obtained with the PI on request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No