Effects of β-hydroxybutyrate on cognition in patients with type 2 diabetes

Abstract

Objective Cognitive impairment in type 2 diabetes is associated with cerebral glucose hypometabolism. Providing a glucose substitute such as ketone bodies might restore metabolic balance in glucose-compromised neurones and improve cognitive performance. We aimed to investigate if β-hydroxybutyrate (ketone body) infusion acutely affects cognitive performance, measured by a neuropsychological test battery, in patients with type 2 diabetes. Design Randomised, placebo-controlled, double-blind cross-over trial. Methods Eighteen patients with type 2 diabetes received i.v. ketone body (β-hydroxybutyrate) and placebo (saline) infusion in a randomised order on two separate occasions. On both days of examination, blood glucose was clamped at 7.5 mmol/L and a neuropsychological test battery was used to assess global cognitive performance (primary outcome) and specialized cognitive measures of verbal memory, working memory, executive function, psychomotor speed, and sustained attention. Results During neurocognitive testing, β-hydroxybutyrate concentrations were 2.4 vs 0.1 mmol/L. Working memory assessed by Wechsler Adult Intelligence Scale letter-number-sequencing significantly improved by 1.6 points (95% CI: 0.7, 2.4; non-adjusted P < 0.001) corresponding to a 17% increase in performance during ketone infusion compared to placebo. There was no change for global cognitive performance or any other cognitive measure after adjusting for multiple comparisons. Blood concentrations of β-hydroxybutyrate and glycaemic status did not associate with test performance; however, insulin resistance measured by HOMA was related to improved working memory performance during ketone infusion (β = 4%; 95% CI: 1.1, 7.7; P = 0.012). Conclusions Ketone infusion specifically improved working memory performance in patients with type 2 diabetes in the absence of changes in global cognition.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

“…infusion of BHB (blood levels of 2.4 mM), significantly improved working memory performance when compared to a placebo infusion. However, no change in a global cognitive score was found [87]. Further, in elderly persons without dementia, a single ketogenic meal of MCFA improved performance in several cognitive domains, with improvements correlating to levels of circulating BHB [89].…”

“…A number of approaches to increase ketone body availability have been applied in elderly individuals and in diseases affecting cognition. These approaches include both acute interventions of BHB infusion [87] or a single meal/drink of MCFA [88][89][90], and also long-term treatments with continued MCFA supplementation as an add-on to the regular diet [91][92][93][94][95][96] or complete conversion to a ketogenic diet [97][98][99]. A predominance of studies has been conducted in patients with mild cognitive impairment and AD and apply the MCFA supplementation approach to achieve ketonemia.…”

A Systematic Review of Intravenous β-Hydroxybutyrate Use in Humans – A Promising Future Therapy?

“…The improvements in cerebral blood flow and altered oxygen metabolism may improve working memory in patients with Type 2 Diabetes mellitus. Jensen et al administered a racemic formulation of BHB that was associated with a 17% improvement in working memory (although there was no change in global cognitive function) ( 20 ).…”

Comparative Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs Ketosis-Inducing Diet

“…Glycogen stores are depleted, and the organism is forced to enter metabolic changes, mainly: gluconeogenesis (endogenous glucose production) and ketogenesis (ketone bodies production by the liver) [23]. Ketone Bodies (KB) are lipid driven molecules (beta-oxidation), and they act as alternative substrates for energy production during fasting and low-carb diets [24]. KB act as powerful anorexigenic agents, reducing cerebral neuropeptide Y, maintaining Cholecystokinin (CCK) meal response and decreasing circulating ghrelin, with a general reduction of perceived hunger and food intake, increasing weight loss and diet tolerability [25].…”