Ketone Esters in T2DM

Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease associated with an increased prevalence of cardiovascular events, and therefore represents a significant global health concern. The aetiology of the disease is complex and involves the interaction of both non-modifiable (i.e., genetic predisposition) and modifiable (e.g., physical activity levels, diet, body mass) risk factors. Individuals with T2DM have an impaired ability to utilise glucose, the body's most efficient energy substrate (providing 2.58 ATP per molecule of oxygen), due to a decreased capacity to produce and/or utilise insulin. Consequently, there is an increased reliance on the metabolism of less efficient fuel sources, predominantly the metabolism of the free fatty acid palmitate, which produces 2.33 ATP per molecule of oxygen and thereby increases oxygen requirements by approximately 10% relative to glucose metabolism. This increased oxygen cost that manifests at rest and during exercise, increases the effort required to perform physical tasks which may discourage physical activity, further exacerbating the disease state and the prevalence of associated cardiovascular co-morbidities, and may ultimately reduce quality of life.

Whereas at high concentrations, ketone bodies are known to be toxic, at a low dose ß hydroxybutyrate, one of the most common ketone bodies produced, can be used as a metabolic substrate. Although not an efficient store of energy per se, the energy can be released at a lower O2 cost than free fatty acids, generating 2.50 units of ATP per unit of O2 consumed. Theoretically, this 7% improvement in efficiency would be of benefit to those with heart disease and diabetes. Whilst there are several studies demonstrating the theoretical benefit of this improvement in efficiency in vitro or in animal models, to date this has not been demonstrated in humans.

Sodium glucose transporter 2 (SGLT-2) inhibitors, a class of anti-hyperglycaemic agents, have been shown to suppress insulin production whilst stimulating glucagon, an action that engenders mild hyperketonaemia. Interestingly, recent trials have suggested the use of SGLT-2 inhibitors have a cardio-protective effect indicated by a significant reduction in cardiovascular related death in people with type 2 diabetes. It is hypothesised that this benefit is mediated through alternate substrate utilisation. These medications, however cannot be used for all individuals. They are not licensed for, nor are likely to be effective for people with impaired renal function, which is common among people with heart failure and diabetes. The associated risk of genital infections is over 10% even in those who have been prescribed the SGLT-2 inhibitors medication.

Exogenous ketone supplements can be ingested in the form of ketone esters and have been proven efficient in improving metabolic profile by decreasing circulating glucose and free fatty acids. More specifically a ketone monoester (Kme) supplement has been shown to provide a rapid increase in blood ß-hydroxybutyrate levels within 30 min in healthy humans. Importantly, once ingested, Kme is metabolised into ß-hydroxybutyrate, which is the isoform produced by endogenous ketogenesis. Therefore, the oral consumption of Kme may be an interesting alternative for increasing ß hydroxybutyrate and therefore improving metabolic efficiency and cardiovascular function in individuals with T2DM.