Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia

Abstract

OBJECTIVE-We examined whether ingestion of mediumchain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of ␤-hydroxybutyrate and octanoate on rat hippocampal synaptic transmission during exposure to low glucose.RESEARCH DESIGN AND METHODS-A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic-(2 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) euglycemic-(glucose ϳ5.5 mmol/l) hypoglycemic (glucose ϳ2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests. In vitro rat hippocampal slice preparations were used to assess the ability of ␤-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced.RESULTS-Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and ␤-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices ␤-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations.CONCLUSIONS-Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia. Diabetes

Bezafibrate Mildly Stimulates Ketogenesis and Fatty Acid Metabolism in Hypertriglyceridemic Subjects

“…Experimental ketonemia of approximately 0.3 to 0.4 mM induced by MCT ingestion has beneficial effects on cognition in AD (Henderson et al, 2009) and in type 1 diabetics during acute hypoglycemia (Page et al, 2009). With bezafibrate, we did not reach this level during fasting, but we did reach 0.3 to 0.4 mM ␤-OHB at the end of the metabolic day.…”

“…Ingestion of a drink containing MCT raises plasma ␤-OHB and is associated with better performance on cognitive tests in AD (Reger et al, 2004;Henderson et al, 2009) and in experimental hypoglycemia in type 1 diabetics (Page et al, 2009). One possible method to induce mild ketonemia without markedly changing the habitual diet is to target the peroxisome proliferator-activated receptor (PPAR)-␣ (Cullingford, 2004), which is a central nuclear receptor in lipid homeostasis (Issemann and Green, 1990) and is expressed in hepatocytes and astrocytes (Edmond et al, 1987).…”

Ketogenic diet and its impact on mental processes of working population

“…Neurons are adapted to using many different substrates for energy: glutamine, glutamate, lactate, pyruvate, KB. This is especially useful for people with regular hypoglycaemic episodes (Amaral, 2013), causing cognitive dysfunction, sensory disturbances and memory defects (Costantini et al, 2008), verbal memory, digit symbol coding, digit span backwards, and map searching (Page et al, 2009). Lack of energy due to hypometabolism and mitochondriopathies can be replaced by KB (Currais, 2015).…”

“…However, with patients without ApoE4 allele one of the nutritional options to improve mild cognitive impairments is adding medium chain triglycerides to the diet (Page et al, 2009, Farias et al, 2014, Sharma et al, 2014, Fernando et al, 2015, Hertz et al, 2015, Ohnuma et al, 2016.…”

Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial

“…In humans, after the first MCT meal, MCFA comprised 8% of the total chylomicron triglyceride fatty acids in plasma (25). At 2 h after the addition of MCTs in type 1 diabetic patients, an increase in plasma free fatty acids was observed with an improved cognitive test score (26). It is conceivable that in addition to the leucine and cholecalciferol, after the addition of the MCTs, blood concentrations of ketone bodies and MCFAs might be further increased and eventually improve brain function.…”