Ketones Derived from Dietary Medium-Chain Triglycerides Support Brain Function and Metabolism in Tightly-Controlled Type 1 Diabetic Patients Under Hypoglycemia

Presentation Number: OR12-3
Date of Presentation: April 4th, 2017

Domenico Tricò*, Daniel Spicer, Kathleen Page, Renata Belfort De Aguiar, Sarita Naik, Mary Savoye, Jagriti Arora, Lihong Jiang, Douglas Rothman, Todd Constable, Robert Sherwin and Raimund Herzog
Yale University School of Medicine, New Haven, CT

Abstract

The benefits of tight glycemic control in type 1 diabetes mellitus (T1DM) are limited by an increased risk of insulin-induced hypoglycemia, which can lead to brain energy deficit and rapid deterioration of higher cognitive function. We examined whether dietary medium-chain triglycerides (MCTs) could support brain function and metabolism under hypoglycemia by providing a readily available source of non-glucose alternative fuels, namely β-hydroxybutyrate (BHB) and free fatty acids (FFAs).

Tightly-controlled T1DM patients after either a 4-week MCT-supplemented diet (MCT-diet group, n=8) or a standard diet (n=8) completed cognitive testing and underwent functional MRI examination during clamped hypoglycemia (target glucose 2.75 mmol/l). The MCT-diet group showed higher cognitive performance than T1DM controls particularly in high-load challenges, such as the Sternberg 6-digit task (accuracy 95±3 vs. 90±2 %, p=0.035), as well as enhanced activation of related brain regions, including bilateral anterior prefrontal cortex, left pars opercularis of the inferior frontal gyrus, and dorso-ventral anterior cingulate cortex (p<0.04). Glucagon, Epinephrine and Cortisol profiles throughout the clamp were similar between the two groups, thus excluding potential adverse effects of MCTs on hypoglycemia-induced counterregulatory hormone responses. Cognitive function and brain activation were strongly correlated to each other and to circulating BHB and FFA concentrations, which were increased after the MCT-enriched diet (AUC BHB 23±5 vs. 8±1 mmol/l/min, p<0.001; AUC FFA 36±6 vs. 15±4 mmol/l/min, p=0.037).

To verify whether plasma BHB may directly contribute to brain energy homeostasis under acute hypoglycemia, 6 healthy subjects and 5 tightly-controlled T1DM patients underwent magnetic resonance spectroscopy measurement of 13C-[2,4]-BHB brain metabolism during a hyperinsulinemic-hypoglycemic clamp. All subjects showed increased 13C-glutamate and 13C-glutamine concentrations, indicating utilization of 13C-[2,4]-BHB by neurons and astrocytes, respectively. The contribution of BHB to brain metabolism was higher in T1DM than in healthy subjects in both main cellular compartments (neuronal TCA-cycle flux 6.3±0.1 vs. 5.3±0.1 %, p<0.0001; astrocytic TCA-cycle flux 11.0±1.4 vs. 8.4±1.1 %, p=0.01), suggesting the presence of adaptive changes to recurrent hypoglycemia in tightly-controlled T1DM patients.

In conclusion, a MCT-enriched diet sustains brain metabolism and function under insulin-induced hypoglycemia by increasing availability of BHB and FFAs in T1DM patients. These data suggest that dietary MCT supplementation may represent a novel prophylactic strategy to implement tighter glycemic control in T1DM patients without increasing the risk of hypoglycemia-induced brain injury.

 

Nothing to Disclose: DT, DS, KP, RB, SN, MS, JA, LJ, DR, TC, RS, RH