Glucose and Glycogen Dynamics in Prediabetes

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.

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).