In recent years, exogenous ketones have been discussed for their potential benefits in cardiovascular health and diabetes management. A Diabetologia publication now shows that ketone supplements reduce postprandial glucose, lipid and ghrelin concentrations, raising the question of whether they could complement current therapeutic strategies for type 2 diabetes.

“In clinical practice, we frequently see that postprandial hyperglycaemia remains a challenge, even in individuals who are otherwise well treated. We were intrigued by the idea that exogenous ketones could acutely shift metabolism towards a more favourable postprandial substrate profile without intensifying conventional glucose-lowering therapy,” says Nikolaj Rittig, principal investigator at Aarhus University Hospital in Denmark.

For the study, a team around Rittig investigated the effects of pre-meal ketone supplementation in different formulas, timepoints and concentrations, achieving beneficial metabolic results. While they make clear that the current guideline-directed treatments remain the cornerstone of care in type 2 diabetes, exogenous ketones may complement these as a non-pharmacological approach.

“Targeting postprandial metabolic excursions more specifically could represent an additional, physiologically oriented strategy in selected individuals. Our study demonstrates acute metabolic effects, and future work must determine whether these translate into durable clinical benefits,” says Mads B. Bengtsen, co-first author of the study.

Ketones as a pre-meal intervention in two crossover trials

The team conducted two randomised, participant-blind crossover studies using established ketone supplements that are commonly used in sports nutrition. These were either ketone monoesters (KE), i.e. monoesters of the most abundant ketone body, β-hydroxybutyrate (BHB), linked to alcohols, or ketone salts (KS) consisting of racemic BHB bound to mineral ions.

In the first study, 14 participants living with type 2 diabetes (treated with metformin monotherapy or lifestyle interventions) received 30 g of KE, KS or a placebo 30 minutes before a mixed meal test on three separate occasions. Blood samples were collected for three hours postprandially to assess glucose (primary endpoint), as well as BHB, non-esterified fatty acids (NEFAs), triglycerides, lactate, gastrointestinal hormones and acetaminophen (paracetamol; test to measure gastric emptying). Subjective appetite and food intake were also evaluated.

The second study examined the dose-response and timing effects of KE in 10 participants living with type 2 diabetes. Doses of 0 g, 10 g, 20 g and 40 g were administered at different time points (60 min, 30 min or immediately before an oral glucose tolerance test, OGTT), with peak glucose and the incremental area under the curve (iAUC) as the key outcomes.

Postprandial glucose reduction and beyond

In the first study, pre-meal ketone supplementation was found to affect several postprandial metabolic responses. Most notably, glucose exposure, as measured by iAUC, was reduced by 36 % (or 1.5 mmol/l) with KE. KS reduced the iAUC by 22 %. However, this effect was primarily driven by a delay in the postprandial glucose rise without a reduction in peak glucose concentrations (see Figure 1, left).

Both supplements increased circulating BHB and enhanced the suppression of NEFAs and ghrelin. KE also reduced postprandial triglyceride excursions by 53 % (see Figure 1, right). This effect may arise from a delay in lipid absorption, similar to that observed for glucose. In line with this, tracer analyses showed that KE reduced the rate at which meal-derived glucose appeared in the blood, suggesting altered intestinal handling of glucose.

Importantly, the second study revealed that the observed KE effects were dose-dependent and influenced by timing. The greatest reductions in glucose excursions were observed at the highest KE dose (40 g) and when KE were administered 30 to 60 minutes before nutrient intake. Together, these findings suggest that exogenous ketones exert an acute effect on postprandial metabolism, with KE showing a more pronounced impact.

Ketones as metabolic signals

These results highlight the diversity of the metabolic effects induced by ketones – and they raise questions about the underlying mechanisms.

“Beyond their role as fuel, ketones have signalling properties that may influence hepatic glucose output and lipid metabolism. This combination of metabolic and signalling effects made exogenous ketones a compelling strategy to explore in a rigorous clinical setting,” explains co-author Mads V. Svart, outlining the rationale behind the study.

In line with this, the mechanisms underlying the observed effects are likely to be multifactorial.

“The most likely explanation of the reductions in postprandial glucose and lipids involves local effects in the gut, presumably a delayed gastrointestinal transit time, and inhibition of adipose tissue lipolysis,” explains co-first author Maj Bangshaab, pointing out that the observed reduction in NEFA strongly supports decreased lipolytic activity, which in turn may improve postprandial glucose handling. She adds, “Ketones are not only substrates but also signalling molecules, and their interaction with metabolic pathways could enhance insulin sensitivity or alter substrate partitioning.”

According to Bangshaab, the concomitant reduction in ghrelin also suggests an interaction with appetite-regulating pathways, adding an additional physiological dimension to the observed effects. Notably, however, no differences in subjective appetite measures were observed during the study.

An experimental metabolic strategy

The observed reductions in glucose levels are statistically significant and noteworthy. According to the authors, the strongest reduction lies within a clinically relevant range, comparable to that observed with dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin. However, they emphasise that these findings must be interpreted with caution.

From a clinical standpoint, substantial evidence gaps remain before translation into routine care can be considered. 

Rittig and Svart comment, “At this stage, exogenous ketone supplementation should be regarded as an experimental metabolic strategy rather than a ready-to-implement clinical tool. Issues such as formulation, palatability, tolerability, cost and long-term adherence must be carefully addressed.”

From a research perspective, however, their findings suggest new ways of exploring the use of exogenous ketones alongside established type 2 diabetes therapies. In addition to lowering glucose levels, ketones could be employed to influence processes such as lipid metabolism and appetite regulation. They could also potentially improve cardiovascular and cognitive outcomes.

Rittig looks ahead: “The next crucial step is larger and longer-duration trials assessing HbA1c, body weight, cardiovascular risk markers and patient-reported outcomes. First, there has to be sustained evidence of safety and clinically meaningful benefit,” he says. "Only then can the approach realistically be considered for integration into routine diabetes management."

Key points:

• Pre-meal administration of exogenous ketones attenuates postprandial metabolism. In a recent study, ketone monoesters have been shown to reduce glucose exposure by up to 36 %, while also lowering lipids and ghrelin.

• The metabolic effects are dose-dependent and timing-sensitive, with the greatest reductions in glucose observed when ketones are administered 30 to 60 minutes before a meal.

• Mechanistically, the effects possibly involve delayed intestinal nutrient handling and inhibition of lipolysis rather than insulin-driven pathways alone.

• Despite the clinically relevant acute effects, exogenous ketones should currently be regarded as an experimental metabolic strategy rather than a ready-to-implement clinical tool.

Read the original publication here.

Author: Hanna Gabriel, BA MSc. Any opinions expressed in this article are the responsibility of EASD e-Learning.