Pre-meals of 3-hydroxybutyrate in Type 2 Diabetes (PreKetone)

Pre-meals of 3-hydroxybutyrate for People With Type 2 Diabetes

Hyperglycemia following meals in patients with type 2 diabetes mellitus (T2DM) is a common problem. Recently, our group found that oral consumption of the ketone metabolite, 3-hydroxybutyrate (3-OHB), effectively stimulates insulin secretion and delays gastric emptying.The aim of this study is to investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 20 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes)

Study Overview

• Status: Completed
• Conditions: Ketosis; Postprandial Hyperglycemia; Glucose Metabolism Disorders (Including Diabetes Mellitus)
• Intervention / Treatment: Dietary supplement: 3-hydroxybutyrate (3-OHB)

Detailed Description

Hyperglycemia following meals in patients with type 2 diabetes mellitus (T2DM) is a common problem, which can cause discomfort and fatigue but may also lead to diabetic complications. Small servings of macronutrients, especially protein-rich products, before a main meal (= pre-meals) has been shown to significantly lower postprandial glucose excursions in both healthy individuals and patients with T2DM. The reductions are primarily attributed the fact that protein stimulates insulin secretion and delays gastric emptying. The timing and dose of a premeal are essential for the glycemic reductions following a meal 4. Unfortunately, it often requires a rather large amount of protein (> 50 g) to facilitate clinically relevant reductions in postprandial glucose levels and a large protein intake may be unwanted for some patients (i.e., chronic kidney disease). Recently, our group found that oral consumption of the ketone metabolite, 3- hydroxybutyrate (3-OHB), effectively stimulates insulin secretion and delays gastricemptying. We have also shown that 3-OHB inhibits gluconeogenesis 6, which may further contribute to glucose-lowering effects. Two other clinical studies have shown that serving 3- OHB before an oral glucose tolerance test (OGTT) lowered glucose excursions in healthy volunteers and persons with impaired glucose tolerance. There are no current data available about the effect of 3-OHB premeals in T2DM patients, but we have preliminary data from an ongoing trial showing that 30 g of 3-OHB served 40 min before a mixed meal test effectively lowers postprandial glucose levels (around 3 mM) in patients with T2DM. The optimal dose and timing of 3-OHB pre-meals is unknown but important before initiating long-term clinical trials. We hypothesize that pre-melas of 3-OHB will affect postprandialglucose excursions in a time-dependent matter and servings 30 minutes before an OGTT is Deleted: 4 optimal in order to lower postprandial glucose excursions. The aim of this study is therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 20 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes). The primary endpoint is glucose trajectories following the OGTT. This study will give important insight into the optimal dose and timing for potential future clinical long-term studies in patients with metabolic diseases (i.e., T2DM, obesity)

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mads Bisgaard Bengtsen, MD, PhD; Phone Number: 004529277453; Email: madsbengtsen@clin.au.dk
• Study Contact Backup: Name: Nikolaj Rittig, MD, PhD

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Department of Endocrinology and Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Older than 18 years of age
• Type 2 diabetes diagnosis
• No antiglycemic treatment or monotherapy with metformin

Exclusion Criteria:

• Hba1c > 70
• Severe liver disease (Child-Pugh score >10) or kidney disease (eGFR< 40 ml/min)
• Anemia (Hgb < 6.5 mM)
• History with pancreatitis
• Practicing ketogenic diets (i.e., low-carb diet, fasting regime)
• Inability to understand Danish or English
• Ongoing cancer or other acute/chronic serious diseases (PI will determine)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 0 gram 3-OHB 30 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).
Experimental: 10 gram 3-OHB 30 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).
Experimental: 20 gram 3-OHB 30 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).
Experimental: 40 gram 3-OHB 30 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).
Experimental: 20 gram 3-OHB 0 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).
Experimental: 20 gram 3-OHB 60 minutes before an OGTT	Dietary supplement: 3-hydroxybutyrate (3-OHB); The aim of this study was therefore to i) investigate the dose/response relationship between 3-OHB servings of 0, 10, 20 and 40 grams 30 minutes before an OGTT and, ii) investigate the role of timing by serving 25 grams of 3-OHB at different timepoints ahead of an OGTT (0, 30 and 60 minutes).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood glucose following the OGTT	Change in blood glucose following the OGTT and compared between the different visits. Incremental change (delta) from baseline to peak. Measured with laboratory kits.	Blood samples will be obtained -60, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150, 180 minutes from the OGTT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentrations of 3-OHB, insulin, C-peptide, glucagon like peptide-1 (GLP-1), cholecystokinin (CCK), acetaminophen, free fatty acids along others.	Incremental change (delta) from baseline to peak in plasma concentrations of 3-OHB, insulin, C-peptide, glucagon like peptide-1 (GLP-1) following the OGGT and compared between the different visits. Measured with laboratory kits.	Blood samples will be obtained -60, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150, 180 minutes from the OGTT

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
• Investigators: Study Director: Niels Møller, Professor, professor

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2023
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 14, 2022

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Metabolic Diseases; Glucose Metabolism Disorders
• Other Study ID Numbers: V4_03052022

Drug and device information, study documents

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