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. 2009 May;58(5):1237-44.
doi: 10.2337/db08-1557. Epub 2009 Feb 17.

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

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

Kathleen A Page et al. Diabetes. .
Free PMC article

Abstract

Objective: We examined whether ingestion of medium-chain triglycerides could improve cognition during hypoglycemia in subjects with intensively treated type 1 diabetes and assessed potential underlying mechanisms by testing the effect of beta-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 x kg(-1) x min(-1)) euglycemic- (glucose approximately 5.5 mmol/l) hypoglycemic (glucose approximately 2.8 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 beta-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 beta-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices beta-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.

Figures

FIG. 1.
FIG. 1.
Variable rate glucose infusion and primed continuous infusion of insulin (2 mU · kg−1 · min−1). Hyperinsulinemic clamps were used to maintain euglycemic conditions for 90 min followed by a 90-min hypoglycemic phase. Cognitive tests were administered during steady-state euglycemia and hypoglycemia. The study drink (medium-chain triglycerides or placebo) was given at time = 75, 100, and 125 min. Upward arrows indicate time of drink administration.
FIG. 2.
FIG. 2.
A–D: PG (A), plasma insulin (B), plasma FFA (C), and plasma β-hydroxybutyrate (D) profiles during the euglycemic-hypoglycemic clamp studies with medium-chain triglycerides or placebo ingestion. ■, medium-chain triglycerides; ○, placebo. Down arrows indicate drink administration.
FIG. 3.
FIG. 3.
Medium-chain triglyceride ingestion preserved cognitive performance under hypoglycemic conditions in tests of verbal memory. A: Immediate verbal memory. B: Delayed verbal memory. C: Verbal memory recognition. Figures show change in test scores (euglycemia-hypoglycemia) after medium-chain triglycerides (■) or placebo (○). *P < 0.01 medium-chain triglycerides vs. placebo.
FIG. 4.
FIG. 4.
A: Symptoms of hypoglycemia were significantly greater during hypoglycemia compared with euglycemia. *P < 0.05. There was no difference in symptoms of hypoglycemia after medium-chain triglyceride ingestion when compared with placebo ingestion. B and C: Plasma epinephrine (B) and plasma norepinephrine (C) profiles during euglycemic-hypoglycemic clamp studies with medium-chain triglycerides or placebo ingestion. ■, medium-chain triglycerides; ○, placebo.
FIG. 5.
FIG. 5.
β-Hydroxybutyrate (BOHB) supports synaptic activity during a stimulus train. Data were taken from the 1st, 10th, and final stimulus during the last of a series of three 10-Hz, 10-s trains delivered under three conditions: control (10 mmol/l glucose), 2 mmol/l glucose, and 2 mmol/l glucose with 8 mmol/l β-hydroxybutyrate. Note that there was a profound decrease in the percent change in the amplitude of the evoked response in 2 mmol/l glucose that was reversed in the presence of 2 mmol/l glucose + 8 mmol/l β-hydroxybutyrate. Also note that β-hydroxybutyrate was able to sustain synaptic activity during the train to a greater degree than 10 mmol/l glucose, as shown by the effect on the 10th stimulus. Data are from a total of 21 slices: β-hydroxybutyrate was applied to 10 of these.
FIG. 6.
FIG. 6.
Octanoate does not support synaptic transmission under hypoglycemic conditions. Graph shows the effect of bath application of 2 mmol/l glucose with or without equimolar substitution of either β-hydroxybutyrate or octanoate. Note that β-hydroxybutyrate was able to substitute for glucose under basal conditions, whereas octanoate had no effect. Data are shown 10 min after the last of three stimulus trains, n = 10 β-hydroxybutyrate, n = 6 octanoate.

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