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

Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut, USA.
Diabetes (Impact Factor: 8.1). 03/2009; 58(5):1237-44. DOI: 10.2337/db08-1557
Source: PubMed
ABSTRACT
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.
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.
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.
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.

Full-text

Available from: Rory J Mccrimmon
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,
1
Anne Williamson,
2
Namyi Yu,
3
Ewan C. McNay,
4
James Dzuira,
5
Rory J. McCrimmon,
1
and Robert S. Sherwin
1
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 -hy-
droxybutyrate and octanoate on rat hippocampal synaptic trans-
mission during exposure to low glucose.
RESEARCH DESIGN AND METHODS—A total of 11 inten-
sively treated type 1 diabetic subjects participated in stepped
hyperinsulinemic- (2 mU kg
1
min
1
) euglycemic- (glucose
5.5 mmol/l) hypoglycemic (glucose 2.8 mmol/l) clamp stud-
ies. 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 prepa-
rations 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 back-
wards, and map searching. Ingestion of medium-chain triglycer-
ides reversed these effects. Medium-chain triglycerides also
produced higher free fatty acids and -hydroxybutyrate levels
compared with placebo. However, the increase in cat-
echolamines and symptoms during hypoglycemia was not al-
tered. 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 im-
proves cognition without adversely affecting adrenergic or symp-
tomatic responses to hypoglycemia in intensively treated type 1
diabetic subjects. Medium-chain triglycerides offer the therapeu-
tic advantage of preserving brain function under hypoglycemic
conditions without causing deleterious hyperglycemia. Diabetes
58:1237–1244, 2009
M
aintaining plasma glucose (PG) at near-nor-
mal levels in individuals with type 1 diabetes
reduces the risk for developing long-term
microvascular complications (1). However,
intensive insulin therapy increases the risk of severe
hypoglycemia, which can cause rapid deterioration of
cognitive function and often occurs without warning
symptoms (1,2). As a result, hypoglycemia limits the
ability of patients to achieve target glycemic goals because
the immediate fear of hypoglycemia exceeds the fear of
long-term complications. Therefore, new strategies to pro-
tect the brain from hypoglycemia-induced injury are es-
sential for optimizing the benefits of insulin therapy.
Although the brain relies primarily on glucose, it can use
alternative fuels such as monocarboxylic acids, lactate,
and ketones to maintain energy homeostasis (3–7). Expo-
sure to prolonged fasting or hypoglycemia causes adaptive
changes in the brain, including an enhanced ability to
utilize alternative fuels (3,8,9). Thus, patients with inten-
sively managed type 1 diabetes, by virtue of their in-
creased exposure to hypoglycemia, may develop an
enhanced ability to use alternate fuels, which, in turn,
might provide neuroprotection during hypoglycemia.
Medium-chain triglycerides, constituents of coconut and
palm kernel oils, are medium-chain fatty acid esters of
glycerol. Medium-chain triglycerides have a favorable
safety profile and are used to treat a variety of disorders
(10 –12). They offer a readily available noncarbohydrate
fuel source because they are rapidly absorbed and quickly
metabolized into medium-chain fatty acids (10). Medium-
chain fatty acids do not require chylomicrons for transport
or carnitine for entry into mitochondria (10). As a result,
metabolism of medium-chain fatty acids promotes the
generation of ketones (10). Furthermore, animal data
suggest that medium-chain fatty acids can readily cross
the blood-brain barrier (BBB) and be oxidized by the brain
(13). Thus, medium-chain fatty acids may provide both a
direct and an indirect brain fuel source via the generation
of ketones, offering type 1 diabetic patients a prophylactic
treatment strategy to preserve brain function during hypo-
glycemic episodes without raising blood glucose levels.
To explore this possibility, we evaluated whether oral
medium-chain triglycerides could improve cognitive per-
formance during acute insulin-induced hypoglycemia in
intensively treated type 1 diabetic subjects. In addition, an
in vitro hippocampal slice preparation from nondiabetic
rats was used to assess the ability of -hydroxybutyrate
From the
1
Section of Endocrinology, Yale School of Medicine, New Haven,
Connecticut; the
2
Department of Neurosurgery, Yale School of Medicine,
New Haven, Connecticut;
3
Winthrop University Hospital, Long Island, New
York; the
4
Department of Psychology, State University of New York,
University at Albany, Albany, New York; and the
5
Yale Center for Clinical
Investigation, New Haven, Connecticut.
Corresponding author: Kathleen A. Page, kathleen.page@yale.edu.
Received 10 November 2008 and accepted 4 February 2009.
Published ahead of print at http://diabetes.diabetesjournals.org on 17 Febru-
ary 2009. DOI: 10.2337/db08-1557.
© 2009 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. See http://creativecommons.org/licenses/by
-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
ORIGINAL ARTICLE
DIABETES, VOL. 58, MAY 2009 1237
Page 1
and octanoate to support neuronal activity when the
glucose supply is deficient.
RESEARCH DESIGN AND METHODS
A total of 11 individuals (5 men, 6 women, aged [mean SD] 34.8 8.9 years,
BMI 24.2 3.4 kg/m
2
) with type 1 diabetes for 15.9 9.5 years participated in
the study. Subjects had no medical problems other than type 1 diabetes and
had a normal physical exam and electrocardiogram. Blood tests confirmed
absent C-peptide levels and normal renal and liver function. Subjects were
intensively controlled with insulin (10 with continuous subcutaneous insulin
infusion [CSII] and 1 with multiple daily injections), as reflected by a mean
A1C of 6.9 0.6 and a history of frequent hypoglycemic episodes, defined as
self-reported fingerstick blood glucose 60 mg/dl. The number of hypoglyce-
mic episodes per month was between 1 and 5 in two subjects, between 6 and
10 in two subjects, between 11 and 30 in six subjects, and 30 in one subject.
Subjects gave their written informed consent to participate in this study,
which was approved by the Yale University human investigation committee.
Experimental protocol. Nine subjects underwent two stepwise hyperinsu-
linemic-euglycemic-hypoglycemic clamp studies with ingestion of either the
medium-chain triglycerides or placebo drink in random order in a crossover
design, as described below. Of the 11 subjects, 2 participated in one study
session (1 with placebo and 1 with medium-chain triglycerides). Cognitive
data from all 11 subjects were included in the analysis as permitted by the
mixed model. Paired Student’s t tests were used to compare substrate and
hormone levels between medium-chain triglycerides and control sessions for
the nine subjects who completed both sessions.
Subjects were admitted to the Hospital Research Unit (HRU) of the Yale
Center for Clinical Investigation on the evening before the study. Dinner was
served at 6:00
P.M., and they were fasted overnight until the end of the study
the following day. At approximately 9:00 P.M., an intravenous catheter was
inserted into an antecubital vein for infusion of insulin (regular human insulin;
Novo Nordisk, Bagsvaerd, Denmark) and dextrose to maintain euglycemia
overnight. Subjects who used CSII had the option of being admitted to the
HRU on the morning of each session, at which time their CSII infusion was
suspended, and an intravenous catheter was inserted in an antecubital vein for
insulin and glucose administration. Of the 10 CSII-treated patients, 3 chose
this option and were admitted on the morning of each session. These subjects
reduced their basal insulin dose by 20% and checked blood glucose at home
before bedtime and on awakening. The study was cancelled if blood glucose
was 70 mg/dl based on home glucose measurements.
At approximately 7:30 A.M., a second catheter was placed in a retrograde
fashion into a dorsal vein of the nondominant hand for blood sampling. The
hand was placed in a heated box (50–55°C) to arterialize venous blood. At
time 0, PG was indistinguishable on the placebo (6.8 0.4 mmol/l) and
medium-chain triglyceride days (7.0 0.7 mmol/l). A primed continuous
infusion of insulin was then initiated and maintained at a constant rate of 2.0
mU kg
1
min
1
, and a variable rate of 20% dextrose was infused
concomitantly (Fig. 1). At 75 min, subjects ingested over a 5-min period the
first of a series of three drinks, each in 50-ml volumes, containing either
medium-chain triglycerides or sucralose, a sugar substitute. During the
medium-chain triglycerides session, a total of 40 g of medium-chain triglycer-
ides (derived from coconut oil containing 67% octanoate, 27% decanaote, and
6% other fatty acids; Novartis) was ingested at 25-min intervals with front
loading of 20 g then 10 g twice. During the control session, cherry-flavored
water sweetened with sucralose was ingested at identical time intervals.
Drinks were prepared by the HRU. At 5 min after the first drink, PG (mean
SE) was lowered to 2.8 0.16 mmol/l for the hypoglycemic phase of the
clamp. PG was measured in duplicate every 5 min to ensure a stable glucose
plateau. Blood samples were collected for glucose, lactate, -hydroxybu-
tyrate, glycerol, free fatty acids (FFAs), insulin, glucagon, norepinephrine, and
epinephrine levels at baseline and at 20-min intervals.
During the euglycemic phase (from 45 to 70 min) and again during the
hypoglycemic phase (from 155 to 180 min), subjects completed a battery of
cognitive tasks. Tests of nonmemory function included digit symbol substitu-
tion, Tests of Everyday Attention, telephone book searching, and map
searching in 1 and 2 min. Tests of immediate and delayed verbal memory and
verbal memory recognition were adapted from the Wechsler Memory Scale
logical memory tests (14). Working memory was assessed by modified
versions of the standard Wechsler Memory Scale Digit Span and Letter/
Number Sequencing Tests (14). These cognitive tests have been validated in
studies of the effect of hypoglycemia on cognition (15,16). Hypoglycemic
symptoms were assessed by a self-rating questionnaire during both the
euglycemic and hypoglycemic phases. Symptoms of hypoglycemia were
classified as autonomic (racing heart, sweating, warmness, trembling, hunger,
anxiety) or neuroglycopenic (weakness, tiredness, double vision, difficulty
speaking, difficulty concentrating, drowsiness, confusion, blurry vision); the
total symptom score was equal to the autonomic plus neuroglycopenic
symptom scores.
Measurement of hormones and metabolites. PG and lactate were mea-
sured enzymatically using glucose and lactate oxidase, respectively (Yellow
Springs Instruments, Yellow Springs, OH). Plasma insulin and glucagon were
measured using a double-antibody radioimmunoassay (Millipore, St. Charles,
MO), epinephrine and norepinephrine by high-performance liquid chromatog-
raphy (ESA, Chelmsford, MA), and FFAs using NEFA-HR (Wako Diagnostics,
Richmond, VA). Plasma glycerol was measured by an enzymatic end point
reaction with a CMA 600 analyzer (CMA Microdialysis, Chelmsford, MA) and
-hydroxybutyrate using an ACE chemical analyzer (Wako Diagnostics,
Richmond, VA).
Animal protocol. Standard methods were used for hippocampal slice prep-
aration (17) using adult Sprague-Dawley rats (29 male, 13 female). The
standard artificial cerebrospinal fluid (aCSF) contained (in mmol/l): 124 NaCl,
3 KCl, 2 MgSO
4
, 1.2 NaH
2
PO
4
, 26 NaHCO
3
, 2.0 CaCl
2
, and 10 glucose, pH 7.4.
The slices (400 m) were placed on the stage of an interface recording
chamber (Fine Science Tools, Foster City, CA), where they were superfused
with aCSF and maintained at 32
o
C 0.5.
Local field potentials were recorded in the cell body layer of CA1 using a
low-resistance (3 mol/l) patch pipette filled with aCSF; a twisted bipolar
electrode placed in the Schaffer collaterals was used to evoke synaptic
responses. The baseline response used for the experiment was 50% of the
maximal response recorded in aCSF. The stimulus intensity was not altered
for the balance of the experiment. Synaptic responses were studied both at
low frequencies (0.1 Hz) and after stimulus trains of 10 Hz for 10 s. At rest,
brain slices have lower rates of oxidative phosphorylation than the intact
brain. Therefore, to more accurately simulate the increased neural activity and
metabolic demand seen during hippocampal memory processing (18) and to
model cognitive activation, we used 10-Hz repetitive synaptic stimulation. The
protocol will drive oxidative metabolism in slices (17) without causing
significant synaptic plasticity (19).
Hypoglycemia was induced by a bath applying aCSF containing 2 mmol/l
glucose with 8 mmol/l sucrose added to maintain osmolarity for 30 min. This
concentration of bath glucose results in a tissue glucose of 0.5 mmol/l (20)
compared with 5.0 mmol/l with a bath glucose of 10 mmol/l. The synaptic
responses were delivered at 0.1 Hz during the wash-on period, and stimulus
trains (10 Hz, 10 s) were delivered at 10-min intervals to investigate the
relationship between the metabolic load and synaptic responses.
We examined three experimental conditions: 2 mmol/l glucose 8 mmol/l
-hydroxybutyrate, 2 mmol/l glucose 8 mmol/l octanoate, and 2 mmol/l
glucose 4 mmol/l -hydroxybutyrate 4 mmol/l octanoate. For each
condition, the test compound(s) were bath applied for an additional 30 min
with one stimulus train midway during the wash-on period. Control aCSF (10
mmol/l glucose) was then washed on to determine the ability of the tissue to
recover from hypoglycemia.
Statistical analysis. Data analysis was performed using SAS version 9.2
(Cary, NC). Clamp- and treatment-dependent changes were analyzed indepen-
dently for each cognitive test using a mixed-model ANOVA. In the mixed-
model ANOVA, fixed effects for the treatment order, treatment (medium-chain
triglycerides vs. placebo), glucose (euglycemia vs. hypoglycemia), and their
interactions were included, and correlation between repeated assessments
was modeled using an unstructured covariance pattern (21). Linear contrasts
5.5
2.8
Cognitive
Te s t s
Cognitive
Tests
Time (min)
Drinks
Plasma Glucose (mmol/l)
0 30 60 90 120 150 180
7.0
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.
FATTY ACIDS AND COGNITIVE FUNCTION
1238 DIABETES, VOL. 58, MAY 2009
Page 2
were estimated to test differences in euglycemic to hypoglycemic cognitive
changes between medium-chain triglycerides and placebo. The level of
significance at individual time points was determined by paired Student’s t
tests with a Bonferroni correction for multiple testing. Paired Student’s t tests
were used to compare substrate and hormone levels between medium-chain
triglycerides and control sessions during steady-state euglycemia and hypo-
glycemia. A P value 0.05 was considered significant. Except where noted, all
data are reported as the means SE.
Physiology statistics. The amplitude of the population spike was the
primary measure. Paired Student’s t tests, corrected for multiple comparisons,
were used to test for significance at the different points in the experiment.
RESULTS
PG, insulin, and metabolite concentrations. PG pro-
files were identical throughout medium-chain triglyceride
and control sessions (Fig. 2). During steady-state euglyce-
mia (from 30 to 75 min), PG was 5.5 0.07 mmol/l in
the medium-chain triglycerides and 5.4 0.1 mmol/l in the
control sessions (P 0.4). Similarly, steady-state glucose
levels during the final 40 min of the hypoglycemic phase were
equivalent during the medium-chain triglyceride (2.74 0.05
mmol/l) and control sessions (2.73 0.06 mmol/l; P 0.8).
Plasma insulin also increased comparably in both sessions
99 12 (medium-chain triglycerides) versus 98 11 U/ml
(control; P 0.4).
During the euglycemic phase of both sessions, insulin
suppressed plasma FFAs and -hydroxybutyrate. During
hypoglycemia, both metabolites remained suppressed in
the control study but rose after administration of medium-
chain triglycerides. During the final 40 min of hypoglyce-
mia, plasma FFAs (0.323 0.07 vs. 0.083 0.04 mmol/l,
P 0.01) and -hydroxybutyrate (356 81 vs. 25 1.4
mol/l, P 0.01) were significantly higher after medium-
chain triglycerides compared with placebo. There were no
differences between groups in plasma glycerol (22 7 vs.
31 8 mol/l, P 0.30) or lactate (0.94 0.16 vs. 1.12
0.17 mmol/l, P 0.20) during hypoglycemia.
Cognitive tests. Acute hypoglycemia impaired cognitive
performance in tests of immediate verbal memory (P
0.001), delayed verbal memory (P 0.005), verbal memory
recognition (P 0.001), digit symbol coding (P 0.03),
digit span backwards (P 0.008), and map searching in 1
min (P 0.04) as assessed by the change in performance
from euglycemia to hypoglycemia after placebo ingestion
(Fig. 3 and Table 1). When compared with ingestion of the
placebo drink, medium-chain triglycerides prevented the
decline in cognitive performance during hypoglycemia in
tests of immediate verbal memory (P 0.009), delayed
verbal memory (P 0.001), and verbal memory recogni-
tion (P 0.0008). Medium-chain triglycerides also im-
proved performance during hypoglycemia in digit symbol
coding (P 0.002) and total map searching (P 0.04).
Counterregulatory hormones. Hypoglycemia increased
plasma epinephrine and norepinephrine levels in both
treatment groups (Fig. 4). They were, however, not signif-
icantly different during the final 40 min of hypoglycemia
(epinephrine 233 102 in control subjects vs. 236 90
pg/ml with medium-chain triglycerides, P 0.8; norepi-
nephrine 239 45 in control subjects vs. 272 69 pg/ml
with medium-chain triglycerides, P 0.2). As expected
(22), there was no significant glucagon response to hypo-
glycemia during the control and medium-chain triglycer-
ides sessions (46 7.4 in control subjects vs. 47 8.0
pg/ml with medium-chain triglycerides, P 0.75).
Symptomatic responses. Total hypoglycemic symptom
scores were significantly elevated during hypoglycemia
FIG. 2. AD:PG(A), plasma insulin (B), plasma FFA (C), and plasma -hydroxybutyrate (D) profiles during the euglycemic-hypoglycemic clamp
studies with medium-chain triglycerides or placebo ingestion. f, medium-chain triglycerides; E, placebo. Down arrows indicate drink
administration.
K.A. PAGE AND ASSOCIATES
DIABETES, VOL. 58, MAY 2009 1239
Page 3
compared with euglycemia (control 30.80 3.9 vs. 19.22
1.40, medium-chain triglycerides 35.25 5.8 vs. 21.35
2.3, respectively; P 0.002 for comparison of hypoglyce-
mia to euglycemia). There was no difference in hypogly-
cemic symptoms after medium-chain triglycerides com-
pared with placebo ingestion (Fig. 4).
Rat hippocampal slice studies. -Hydroxybutyrate can
partially substitute for glucose in vitro. Whena2mmol/l
glucose bath was applied for 30 min with intervening
stimulus trains, the field potential amplitude decreased
from 7.1 1.2 to 4.1 0.93 mV and then reached steady
state. Across the population, this represented a 47.7
12.3% decrease (P 0.05, n 21). When -hydroxybu-
tyrate was added iso-osmotically, there was a partial
recovery to 5.74 1.03 mV (83.8 7.8% of control, n
10). This was significantly (P 0.05) different from the 2
mmol/l glucose values alone, but not different from values
in control aCSF. We also assessed whether -hydroxybu-
tyrate could fully substitute for glucose using a bath
applying 8 mmol/l -hydroxybutyrate in 0 mmol/l added
glucose aCSF. In all three slices studied, the synaptic
response was lost after the first stimulus train and was
only partially recoverable upon washing to 10 mmol/l
glucose, indicating the need for a minimal level of glucose
to maintain synaptic transmission under a metabolic load.
-Hydroxybutyrate in 2 mmol/l glucose was also able to
maintain synaptic function during both low- and moderate-
frequency stimulation. In control aCSF, there was a mod-
est decrease in the mean population spike amplitude 9.9
2.5% (first vs. last response) during a 10-Hz train. In
contrast, as shown in Fig. 5, the synaptic response was
reduced by 80.0 6.4% of control in 2 mmol/l glucose (P
0.05). When -hydroxybutyrate was added to the bath, the
ability of the tissue to respond to synaptic stimulation was
restored to 82.0 22.4% (18% depression) of control (n
10). It was also notable that -hydroxybutyrate was able
to prevent the initial depression seen in control studies
(Fig. 5).
Octanoate does not substitute for glucose in
hippocampal slice preparations. In contrast, substitu-
tion of octanoate for glucose using the same experimental
paradigm produced no recovery of synaptic function in
any of the slices tested (n 6). The response only
recovered to 49.6 12.8% of control after washing with 10
mmol/l glucose containing aCSF in three of six cases.
Moreover, unlike -hydroxybutyrate, octanoate did not
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 (f) or placebo (E). *P < 0.01 medium-chain triglycerides vs. placebo.
TABLE 1
Cognitive test scores during euglycemia and hypoglycemia with medium-chain triglycerides or placebo ingestion
Cognitive test
Medium-chain
triglycerides
euglycemia (5.5
mmol l
1
l
1
)
Medium-chain
triglycerides
hypoglycemia (2.8
mmol l
1
l
1
)
Placebo euglycemia
(5.5 mmol l
1
l
1
)
Placebo hypoglycemia
(2.8 mmol l
1
l
1
)
Immediate verbal memory 15.85 0.66 14.97 1.13* 17.36 1.03 13.28 1.04†
Delayed verbal memory 14.82 1.25 14.80 1.31* 15.33 1.40 11.58 0.71†
Verbal memory recognition 13.19 0.53 13.29 0.50* 14.27 0.23 12.14 0.19†
Digit span backwards 0.60 0.05 0.58 0.05 0.64 0.05 0.54 0.05†
Letter/number sequencing 12.04 0.81 10.97 0.76 11.07 0.85 9.92 0.71
Digit symbol coding 72.50 5.27 74.99 4.56* 74.04 4.59 68.56 3.54†
Map search (1 min) 53.11 4.16 48.42 3.19 50.35 3.27 42.94 2.31†
Map search (2 min) 73.30 1.70 75.11 1.51* 75.04 1.92 74.67 1.51
Telephone search 2.86 0.17 3.06 0.20 3.14 0.26 3.46 0.34
Data are least square means SE. *P 0.05 change from euglycemia to hypoglycemia after medium-chain triglycerides vs. placebo; P
0.05 between euglycemia and hypoglycemia.
FATTY ACIDS AND COGNITIVE FUNCTION
1240 DIABETES, VOL. 58, MAY 2009
Page 4
preserve population spike amplitude during the stimulus
train (Fig. 6).
Octanoate improves recovery after hypoglycemia. To
determine whether there was a synergistic effect of -hy-
droxybutyrate and octanoate, they were bath-applied to-
gether (4 mmol/l each) using the same protocol as above.
There was a partial recovery to 75.9 12.6% of control, an
effect not significantly different from that seen with 8
mmol/l -hydroxybutyrate. However, there was an in-
crease in the speed with which the synaptic response
recovered to a stable baseline when washed with control
aCSF compared with -hydroxybutyrate alone (2 mmol/l
glucose 8 mmol/l -hydroxybutyrate, 31.6 8.7 min,
n 7; 2 mmol/l glucose 4 mmol/l -hydroxybutyrate
4 mmol/l octanoate, 21.9 8.2 min, n 5).
DISCUSSION
This study tested the hypothesis that oral medium-chain
triglycerides could provide an alternative fuel source to
prevent the deterioration of higher brain function caused
by acute hypoglycemia in intensively treated type 1 dia-
betic subjects. We used a battery of tasks to assess a range
of cognitive domains. As expected, hypoglycemia impaired
performance in tests of attention, short-term and delayed
verbal memory, and working memory. Medium-chain tri-
glyceride ingestion prevented this decline in performance
in tests of short-term and delayed verbal memory and tests
pertaining to attention. Medium-chain triglycerides’ bene-
ficial effect was most notable on tests of verbal memory,
which to a large extent involves the hippocampus, a brain
region particularly vulnerable to hypoglycemia (18,22–24).
From the therapeutic perspective, it is reassuring that the
cognitive benefit of medium-chain triglycerides was not
associated with an adverse effect on hypoglycemia-in-
duced adrenergic responses or symptoms.
Medium-chain triglycerides, a source of medium-chain
fatty acids, have been widely used for nutritional support
and in patients with malabsorption (10,25). Medium-chain
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. f, medium-chain triglycerides; E, placebo.
FIG. 5. -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 -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 -hydroxybutyrate. Also note that -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: -hydroxybutyrate was applied to 10 of these.
K.A. PAGE AND ASSOCIATES
DIABETES, VOL. 58, MAY 2009 1241
Page 5
fatty acids are rapidly absorbed and oxidized in the liver.
This results in an excess of acetyl-CoA, and in turn the
rapid production of ketones (10), an energy source for the
brain (3,5,7). Furthermore, medium-chain fatty acids
readily cross the BBB and are metabolized by the brain
(13). Therefore, medium-chain fatty acids could directly
and/or indirectly, via the generation of ketones, act to
preserve brain function during hypoglycemia by provision
of alternative fuels without raising blood glucose levels in
patients with type 1 diabetes.
Medium-chain triglyceride ingestion raised plasma -hy-
droxybutyrate and FFA levels during insulin-induced hy-
poglycemia, and thus both fuels might contribute to the
observed effects on cognitive performance. The hippocam-
pal slice data, however, suggest that the predominant
impact of medium-chain fatty acids is mediated via the
generation of ketones. -Hydroxybutyrate supported syn-
aptic transmission both at rest and during stimulus trains
when glucose supply was deficient, whereas octanoate
alone was ineffective. The failure to see an effect of
octanoate in the hippocampal slice preparation reflects a
time-dependent effect, and longer prior exposure to medi-
um-chain fatty acids might have improved neuronal func-
tion. Alternatively, these findings may be explained by
differences in brain metabolism of ketones and medium-
chain fatty acids. Evidence suggests that octanoate is
exclusively metabolized by astrocytes (13,26,27), whereas
ketones are oxidized by both neurons and astrocytes
(28,29). The finding that octanoate was able to improve the
rate of recovery of synaptic function upon restoration of
control glucose concentrations, but not the response to
hypoglycemia itself, is consistent with the hypothesis
that astrocytes may be critical for the restoration of
synaptic function after a metabolic challenge such as
hypoglycemia.
There is significant literature on the effects of alternative
metabolic substrates on synaptic function in brain slice
preparations (30 –32). However, our studies on -hydroxy-
butyrate differ from previous work (30,31) in two impor-
tant aspects. First, we examined -hydroxybutyrate in
lowered (2 mmol/l) glucose compared with aglycemia, and
second, we examined the ability of either -hydroxybu-
tyrate or octanoate to support synaptic transmission under
a metabolic load. In glucose-free medium, -hydroxybu-
tyrate is able to maintain ATP but neither phosphocreatine
levels nor synaptic function in slices prepared from adult
rats (30,31). In contrast, our data indicate that -hydroxy-
butyrate is able to sustain synaptic activity in adult rats
only with some glucose present. It is also important to
note that -hydroxybutyrate is comparable to glucose in
its ability to support synaptic activity under a metabolic
load (Fig. 5). Taken together, these data suggest that there
is an absolute requirement for a low concentration of
glycolytic substrate to sustain robust synaptic transmis-
sion. This possibility is consistent with the data of Kana-
tani et al. (32); however, other investigators (33) have
suggested that lactate can substitute for glucose under
most conditions.
Although medium-chain triglyceride ingestion sustained
cognitive function during acute hypoglycemia, it did not
affect the adrenergic hormonal or symptomatic response
to hypoglycemia. This finding might reflect a specific effect
of medium-chain fatty acids on brain regions involved in
cognition without affecting subcortical regions, such as
the ventromedial hypothalamus, that are involved in the
detection of hypoglycemia and the initiation of counter-
regulatory responses. This is consistent with evidence
suggesting that there are regional differences in the brain’s
capacity to use alternative fuels during hypoglycemia (34).
Evans et al. (34) demonstrated that intralipid infusion
impaired the counterregulatory response to hypoglycemia
without affecting cognitive performance, whereas Rossetti
et al. (35) recently reported that amino acid ingestion
preserved cognitive performance without affecting coun-
terregulatory or symptomatic responses to acute hypogly-
cemia, much as we observed here.
Some studies, however, suggest that lactate and -hy-
droxybutyrate sustain cognitive function while blunting
counterregulatory responses during hypoglycemia (4 6).
Notably, the -hydroxybutyrate concentrations in those
studies using -hydroxybutyrate infusions (5,6) were
much higher than in this study. Therefore, differences in
circulating levels of -hydroxybutyrate could explain the
differences observed. In addition, prior studies (5,6) exam-
ined nondiabetic subjects, whereas we focused on inten-
sively treated type 1 diabetic subjects. Pan et al. (8)
suggest that it takes up to 72 h for ketones to be metabo-
lized in the brain of nondiabetic individuals, probably
because of the time required to increase BBB monocar-
boxylic acid transporters. In keeping with this view, acute
in vitro studies using nondiabetic animals indicate that
ketones can be immediately metabolized in the absence of
the BBB (30). Moreover, it has been reported that brain
acetate transport is increased in type 1 diabetic subjects
receiving intensive insulin therapy compared with nondi-
abetic subjects (9). Thus, adaptive increases in the trans-
port of -hydroxybutyrate into the brain of intensively
managed type 1 diabetic subjects may account for the
ability of medium-chain triglycerides to rapidly attenuate
hypoglycemic effects on cognitive function, and such
adaptations in -hydroxybutyrate transport may be region
specific (36).
A potential limitation of the study is that cognitive
performance may decline over time, thereby contributing
to the deterioration in performance we observed in the
hypoglycemic phase of the study. However, we anticipate
that the dominant effect on cognitive decline was hypogly-
cemia per se, given that both the medium-chain triglycer-
ides and placebo sessions were performed over identical
time intervals in random order, making it highly unlikely
that the specific benefit of medium-chain triglycerides
could be specifically attributed to a time-associated de-
cline in cognitive performance. Of note, all of the type 1
FIG. 6. Octanoate does not support synaptic transmission under hypo-
glycemic conditions. Graph shows the effect of bath application of 2
mmol/l glucose with or without equimolar substitution of either -hy-
droxybutyrate or octanoate. Note that -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 -hydroxybutyrate, n 6 octanoate.
FATTY ACIDS AND COGNITIVE FUNCTION
1242 DIABETES, VOL. 58, MAY 2009
Page 6
diabetic patients selected for this study were receiving
intensive insulin therapy regimens and had a documented
history of hypoglycemia. As a result, they had absent
glucagon and reduced epinephrine responses during the
hypoglycemic clamp. The increase in epinephrine in these
patients was less than half that seen in other studies
reported by our group in nondiabetic individuals (37). Our
aim was to see whether medium-chain triglycerides could
maintain brain function in the face of hypoglycemia in
such individuals. Whether the prophylactic benefits of
medium-chain triglyceride ingestion might differ in pa-
tients with and without hypoglycemia unawareness re-
mains to be determined.
It should be emphasized that long-term effects of medium-
chain triglycerides on cardiovascular risk factors and
glucose metabolism are unknown. Short-term studies of
the effects of medium-chain triglyceride ingestion on se-
rum lipoprotein profiles in nondiabetic subjects are con-
flicting. Some report that medium-chain triglyceride intake
causes only minor changes (38 40) or decreases (41) in
serum lipid profiles, whereas others suggest it increases
serum lipoprotein levels (42). Medium-chain triglycerides
are marketed as a weight loss supplement based on
reports that they increase energy expenditure and fat
oxidation (43– 45) and reduce body weight in animals and
humans (46,47). Short-term studies of medium-chain trig-
lycerides have also suggested beneficial effects on glucose
metabolism in patients with type 2 diabetes (48,49). Whether
similar metabolic effects of medium-chain triglycerides are
observed in type 1 diabetes will require further investigation.
We conclude that ingestion of medium-chain triglycer-
ides improves cognitive function without affecting the
adrenergic hormonal or symptomatic responses to acute
hypoglycemia in intensively controlled type 1 diabetic
patients. These findings suggest that medium-chain triglyc-
erides could be used as prophylactic therapy for such
patients with the goal of preserving brain function during
hypoglycemic episodes, such as when driving or sleeping,
without producing hyperglycemia.
ACKNOWLEDGMENTS
This study was supported in part by a grant from the
Juvenile Diabetes Research Foundation Center for the
Study of Hypoglycemia (4-2004-807), the Yale Center of
Clinical Investigation supported by a Clinical and Transla-
tional Science Awards Grant (UL1 RR024139) from the
National Center for Research Resources, and National
Institutes of Health grants (R37 DK20495, RO1NA045792,
and DK069831).
No potential conflicts of interest relevant to this article
were reported.
This study was presented at the American Diabetes
Association 68th Scientific Sessions, San Francisco, CA,
6 –10 June 2008, abstract no. 15-OR.
We thank Ellen Hintz, Melinda Zgorski, Donna
D’eugenio, Osama Abdelghany, Donna Caseria, Mikhail
Smolgovsky, Ralph Jacob, Aida Groszmann, and Brenda
Wu for their help in executing these studies.
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  • Source
    • "It seems likely that influx of a non-glucose energy substrate plays a role. Recent (neuroimaging) studies found little evidence to support enhanced blood to brain transport of amino acids [135, 136] or lipid substrates transport [138, 139] and Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from… 715 ketones are unlikely candidates because its production is suppressed by insulin. Also, the lower brain glycogen content in patients with type 1 diabetes with impaired awareness of hypoglycemia compared to controls [149] argues strongly against the glycogen supercompensation hypothesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Hypoglycemia is the most frequent complication of insulin therapy in patients with type 1 diabetes. Since the brain is reliant on circulating glucose as its main source of energy, hypoglycemia poses a threat for normal brain function. Paradoxically, although hypoglycemia commonly induces immediate decline in cognitive function, long-lasting changes in brain structure and cognitive function are uncommon in patients with type 1 diabetes. In fact, recurrent hypoglycemia initiates a process of habituation that suppresses hormonal responses to and impairs awareness of subsequent hypoglycemia, which has been attributed to adaptations in the brain. These observations sparked great scientific interest into the brain's handling of glucose during (recurrent) hypoglycemia. Various neuroimaging techniques have been employed to study brain (glucose) metabolism, including PET, fMRI, MRS and ASL. This review discusses what is currently known about cerebral metabolism during hypoglycemia, and how findings obtained by functional and metabolic neuroimaging techniques contributed to this knowledge.
    Preview · Article · Nov 2015 · Cellular and Molecular Life Sciences CMLS
  • Source
    • "Other trials with ketogenic supplements in AD are ongoing (https://clinicaltrials.gov/ct2/ results?term=ketones+Alzheimer%27s\&Search=Search). Conditions involving acute or long-term cognitive problems including post-insulin hypoglycemia (Page et al., 2009) and epilepsy (Cross, 2009; Neal et al., 2008) also respond to a ketogenic diet or supplement. One of the reasons that type 2 diabetes is such an important risk factor for AD may be due to insulin resistance. "
    [Show abstract] [Hide abstract] ABSTRACT: Brain energy metabolism in Alzheimer’s disease (AD) is characterized mainly by temporo-parietal glucose hypometabolism. This pattern has been widely viewed as a consequence of the disease, i.e. deteriorating neuronal function leading to lower demand for glucose. This review will address deteriorating glucose metabolism as a problem specific to glucose and one that precedes AD. Hence, ketones and medium chain fatty acids (MCFA) could be an alternative source of energy for the aging brain that could compensate for low brain glucose uptake. MCFA in the form of dietary medium chain triglycerides (MCT) have a long history in clinical nutrition and are widely regarded as safe by government regulatory agencies. The importance of ketones in meeting the high energy and anabolic requirements of the infant brain suggest they may be able to contribute in the same way in the aging brain. Clinical studies suggest that ketogenesis from MCT may be able to bypass the increasing risk of insufficient glucose uptake or metabolism in the aging brain sufficiently to have positive effects on cognition.
    Full-text · Article · Oct 2015
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    • "Although glucose is the main energy source for neurons, human brain can also utilize ketone bodies from FFA, lactate, pyruvate , glycerol and some aminoacids, as alternative sub- strate [10]. The protective effect of ketone bodies on hypoglycemia-induced neuronal damage has been demonstrated in animal studies [11, 12] and also in patients with type 1 diabetes, in whom the ingestion of mediumchain triglycerides prevented the cognitive deficit induced by hypoglycemia by elevating blood levels of 3-hydroxybutyrate [13]. Ketogenic diet (KD), which provides FFA as alternative fuel to carbohydrates for neuronal energy metabolism, has therefore a strong potential neuroprotective effect. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose. Methods: A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs. Results: We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life. Conclusions: KD could represent an effective treatment to support brain function in selected cases of CHI.
    Full-text · Article · Sep 2015 · Orphanet Journal of Rare Diseases
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