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

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 beta-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. Design: Randomised, placebo-controlled, double-blind cross-over trial. Methods: Eighteen patients with type 2 diabetes received i.v. ketone body (beta-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, beta-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 beta-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 (p = 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.