Metabolic effects of 3-hydroxybutyrate infusion in individuals with type 1 diabetes compared with healthy control participants: a randomised crossover trial showing intact feedback suppression of lipolysis

Aims/hypothesis

Diabetic ketoacidosis remains a severe complication in type 1 diabetes, arising from insufficient insulin levels and accelerated lipolytic rate, leading to increased β-oxidation of NEFA and ketone body production in the liver. The ketone body 3-hydroxybutyrate (3-OHB) inhibits lipolysis in healthy individuals. The current study aimed to test whether this feedback suppression of lipolysis by 3-OHB is disrupted in individuals with type 1 diabetes.

Methods

We used a single-blind, randomised, crossover design to study ten men diagnosed with type 1 diabetes and ten healthy control participants. Eligibility criteria were male sex, age ≥18 years, BMI of 19–26 kg/m² and no severe comorbidities/diseases. Following an overnight fast, each participant received two 3 h i.v. infusions: (i) sodium-d/l-3-OHB and (ii) iso-osmolar saline (NaCl), separated by a 1 h washout period. The order of the two interventions was assigned by randomisation for each participant. Participants were blinded to the allocation throughout the study day, but investigators were aware of the assigned intervention order. We evaluated the lipolytic rate and glucose turnover using [9,10-³H]palmitate and [3-³H]glucose tracers. Additionally, adipose tissue signalling was quantified using western blotting techniques in subcutaneous abdominal adipose tissue biopsies. The primary endpoint measure was palmitate flux (lipolytic rate).

Results

During the infusion of 3-OHB, the d/l-3-OHB blood concentrations increased to 3.3 ± 0.7 mmol/l in participants with type 1 diabetes compared with 2.9 ± 0.5 mmol/l in control participants (p=0.03). The infusion effectively suppressed the lipolytic rates by more than 50% (p<0.001) and reduced circulating NEFA by approximately 0.5 mmol/l (p<0.001) compared with NaCl in both participants with type 1 diabetes and control participants. In adipose tissue, 3-OHB reduced protein kinase A phosphorylation of perilipin (p<0.001) and hormone-sensitive lipase phosphorylation at Ser660 (p<0.001) and Ser563 (p<0.01) similarly in participants with type 1 diabetes and control participants. Indices of glucose metabolism remained unaffected throughout in both groups.

Conclusions/interpretation

Our findings indicate that, in individuals with type 1 diabetes, the suppression of lipolysis, blood NEFA concentrations and adipose tissue signalling activity in response to 3-OHB remains intact compared with healthy control participants. These findings imply that derailment of receptor signalling by 3-OHB is unlikely to be involved in the development of diabetic ketoacidosis.

Trial registration: ClinicalTrials.gov NCT04656236

Funding

Open access funding provided by Aarhus Universitet. This study was supported by the Novo Nordisk Foundation (NNF19OC0058872) and the Health Research Foundation of Central Denmark Region.

Graphical Abstract