A ketone ester for diabetes mellitus

Thesis

Various studies have reported that type 2 diabetes mellitus (T2DM) may be reversed by following a ketogenic diet, although it is not clear if this is due to carbohydrate restriction or a consequence of elevating the concentration of ketone bodies in the blood (ketosis). A recently developed ketone ester (KE) drink, which elevates human circulating D-βhydroxybutyrate (βHB) levels by ~3 mM within minutes, allows to isolate the effects of ketosis and carbohydrate restriction.

The aims of the work described in this thesis were to determine; if sustained exogenous ketosis is safe and well tolerated in healthy adults, L-Alanine’s contribution to the glucose-lowering effect of ketone bodies, the impact of acute ketosis on myocardial energetics and, if sustained ketosis is safe and tolerated in patients living with T2DM. In the first study (Chapter 3), twenty-four healthy adults (1:1 sex ratio, between 18 to 70 years old) drank 25 ml of the KE three times a day for 28 days. Anthropomorphic measurements, plus blood and urine biochemistry remained unaltered. All adverse effects of the KE were mild according to the participants.

In the experiments presented in Chapter 4, ten healthy adults fasted for 24 hours prior to the ingestion of 25 ml of the KE with or without 2gr of L-Alanine. Raising L-Alanine blood concentration attenuated the KE glucose-lowering effect by almost 50% (p<0.01). No significant differences in blood βHB, Free Fatty Acids (FFA), lactate and C-peptide were found when adding L-Alanine to the KE drink.

The work described in Chapter 5, involved twelve healthy adults who fasted for 24 hours and afterwards, drank 25 ml of the KE. Myocardial Phosphocreatine/Adenosine Triphosphate ratio (PCr/ATP) was measured before and 30 minutes after the KE drink using ³¹P Magnetic Resonance Spectroscopy at 7 Teslas. No significant differences in PCr/ATP were detected between measurements.

Finally, in Chapter 6, twenty-one type 2 diabetes patients, drank 25 ml of the KE three times a day for 28 days. Glycated haemoglobin (HbA_1c) dropped from 7.7% to 7.2% and fructosamine concentrations from 335 to 290 µM. Overall time in the euglycemic range was assessed using continuous glucose monitors and improved by 2.3% (p < 0.01) while drinking the KE. Once again, anthropomorphic measurements, blood and urine biochemistry remained unaltered. All adverse effects of the KE were mild according to the participants and no events of ketoacidosis were documented.

In summary, the work described in this thesis has demonstrated; a close interaction between blood L-Alanine, ketone bodies and glucose concentrations and that a single KE drink has no effect on myocardial PCr/ATP in healthy participants. This work is the first to demonstrate, in the general population and in patients with T2DM, that sustained exogenous ketosis, is safe, well-tolerated, and may improve glucose control in T2DM.

Authors: Soto mota, LA

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: ketosis; ester; Beta-hydroxybutyrate; diabetes mellitus; ketone bodies
• Subjects: Physiology; Diabetes; Biochemistry; Human metabolism