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Amyotrophic Lateral Sclerosis
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Impaired glucose tolerance in patients with amyotrophic lateral sclerosis
Pierre-Francois Pradat a; Gaelle Bruneteau a; Paul H. Gordon a; Luc Dupuis bc; Dominique Bonnefont-
Rousselot de; Dominique Simon fg; Francois Salachas a; Philippe Corcia h; Vincent Frochot i; Jean-Marc
Lacorte i; Claude Jardel j; Christiane Coussieu i; Nadine Le Forestier a; Lucette Lacomblez akl; Jean-Philippe
Loeffler bc; Vincent Meininger ak
a APHP, Hôpital de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux, Paris b INSERM U692,
Faculté de Médecine, Strasbourg c Université de Strasbourg, Strasbourg d APHP, Hôpital de la Pitié-
Salpêtrière, UF de Biochimie des Maladies Métaboliques, Paris e Faculté de Pharmacie, Département de
Biochimie, Université Paris Descartes, Paris f APHP, Hôpital de la Pitié-Salpêtrière, Service de Diabétologie,
Paris g INSERM, Villejuif h Hôpital Bretonneau, Service de Neurologie, Tours i APHP, Hôpital de la Pitié-
Salpêtrière, Service de Biochimie Endocrinienne et Oncologique, Paris j APHP, Hôpital de la Pitié-Salpêtrière,
Service de Biochimie Métabolique, k UPMC, Faculté de Médecine, Hôpital de la Pitié-Salpêtrière, l INSERM,
Faculté de Médecine, Paris, France
First Published on: 20 March 2009
To cite this Article Pradat, Pierre-Francois, Bruneteau, Gaelle, Gordon, Paul H., Dupuis, Luc, Bonnefont-Rousselot, Dominique, Simon,
Dominique, Salachas, Francois, Corcia, Philippe, Frochot, Vincent, Lacorte, Jean-Marc, Jardel, Claude, Coussieu, Christiane,
Forestier, Nadine Le, Lacomblez, Lucette, Loeffler, Jean-Philippe and Meininger, Vincent(2009)'Impaired glucose tolerance in
patients with amyotrophic lateral sclerosis',Amyotrophic Lateral Sclerosis,
To link to this Article: DOI: 10.1080/17482960902822960
URL: http://dx.doi.org/10.1080/17482960902822960
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ORIGINAL ARTICLE
Impaired glucose tolerance in patients with amyotrophic lateral
sclerosis
PIERRE-FRANCOIS PRADAT
1
, GAELLE BRUNETEAU
1
, PAUL H. GORDON
1
,
LUC DUPUIS
2
, DOMINIQUE BONNEFONT-ROUSSELOT
3
, DOMINIQUE SIMON
4
,
FRANCOIS SALACHAS
1
, PHILIPPE CORCIA
5
, VINCENT FROCHOT
6
,
JEAN-MARC LACORTE
6
, CLAUDE JARDEL
7
, CHRISTIANE COUSSIEU
6
,
NADINE LE FORESTIER
1
, LUCETTE LACOMBLEZ
1,8,9
,
JEAN-PHILIPPE LOEFFLER
2
& VINCENT MEININGER
1,8
1
APHP, Ho
ˆpital de la Pitie
´-Salpe
ˆtrie
`re, Fe
´de
´ration des Maladies du Syste
`me Nerveux, Paris,
2
INSERM U692, Faculte
´de
Me
´decine, Strasbourg, and Universite
´de Strasbourg, Strasbourg,
3
APHP, Ho
ˆpital de la Pitie
´-Salpe
ˆtrie
`re, UF de Biochimie des
Maladies Me
´taboliques, Paris and Universite
´Paris Descartes, Faculte
´de Pharmacie, De
´partement de Biochimie, Paris,
4
APHP, Ho
ˆpital de la Pitie
´-Salpe
ˆtrie
`re, Service de Diabe
´tologie, Paris and INSERM U 780, Villejuif,
5
Ho
ˆpital Bretonneau,
Service de Neurologie, Tours,
6
APHP, Ho
ˆpital de la Pitie
´-Salpe
ˆtrie
`re, Service de Biochimie Endocrinienne et Oncologique,
Paris,
7
APHP, Ho
ˆpital de la Pitie
´-Salpe
ˆtrie
`re, Service de Biochimie Me
´tabolique,
8
UPMC, Faculte
´de Me
´decine, Ho
ˆpital de la
Pitie
´-Salpe
ˆtrie
`re, and
9
INSERM U678, Faculte
´de Me
´decine, Paris, France
Abstract
Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association
with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test
in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate
ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and
adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher’s exact tests
assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with
ALS (7.41 mmol/l91.68) compared to controls (6.0591.44, p0.006). ALS patients with impaired glucose tolerance
(IGT) according to WHO criteria (n7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to
patients with normal glucose tolerance (0.77 nmol/l90.30 vs. 0.5790.19, p0.04). IGT was not associated with disease
duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with
increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may
be multifactorial and deserves further investigation.
Key words: Amyotrophic lateral sclerosis, fatty acids, diabetes mellitus, glucose intolerance
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegen-
erative disorder characterized by the progressive loss
of motor neurons in the spinal cord, brainstem, and
motor cortex. There is increasing evidence, however,
that the disease has systemic features beyond the
nervous system; studies in patients (1) and transgenic
mice (2,3) indicate a potential role of alterations in
energy homeostasis (4,5). Abnormalities of carbohy-
drate metabolism have been inconsistently reported
since the 1980s (68) and there is a postulated role
for lipid alterations in ALS (13). The prognosis of
ALS, while poor overall, is widely variable among
patients. Considerable effort is being expended to
determine predictors of clinical phenotype. The
objective of our study was to analyse glucose home-
ostasis in a series of ALS patients. We also investi-
gated whether abnormalities of carbohydrate
metabolism are associated with modifications in lipid
parameters or with clinical features.
Correspondence: P.-F. Pradat, Fe´de´ration des Maladies du Syste`me Nerveux, Centre re´fe´rent maladie rare SLA, Hoˆ pital de la Pitie´-Salpeˆ trie`re, 4783,
Boulevard de l’Hoˆpital, 75651 Paris, France. Fax: 33 1 44 24 32 69. E-mail: pierre-francois.pradat@psl.aphp.fr
(Received 2 January 2009; accepted 15 Februar y 2009)
Amyotrophic Lateral Sclerosis.
2009, 16, iFirst article
ISSN 1748-2968 print/ISSN 1471-180X online #2009 Informa UK Ltd. (Infor ma Healthcare, Taylor & Francis AS)
DOI: 10.1080/17482960902822960
Downloaded By: [BIUS Jussieu/Paris 6] At: 15:53 6 April 2009
Patients and methods
Subjects and clinical evaluation criteria
A series of 21 consecutive patients aged 18 to 75
years with sporadic ALS were recruited from the
Paris ALS Centre (Table I). The local ethics
committees approved the study and patients signed
an informed consent form consistent with institu-
tional guidelines. All patients met the El Escorial
World Federation of Neurology criteria for diagnosis
of definite or probable ALS (http://www.wfnals.org)
(9). Patients with known diabetes or drugs interfer-
ing with glucose metabolism, such as steroids, were
excluded from the study. Demographic data in-
cluded age, sex, body mass index (BMI), site of
onset (bulbar or limb) and disease duration from the
onset of symptoms. Clinical evaluation criteria
included a muscle atrophy score (0: none, 1:
moderate, 2: severe, for each limb, range 08),
manual muscle testing MRC score (a total of
14 muscles of upper and lower limbs were tested
bilaterally plus flexion and extension of the neck,
range 080) and a measure of functional impairment
(ALSFRSR, range 048) (10).
Controls (n21) were randomly selected from
the Telecom Study, which recruited 3240 consecu-
tive France Telecom employees working in the Paris
area, who voluntarily attended a centre for preventive
medicine (11).They were sex- and age-matched with
ALS patients, and control subjects with known
diabetes were excluded. Controls and ALS popula-
tions were also similar in BMI (Table I).
Biological investigations in patients
Glucose homeostasis after glucose load. A standard oral
glucose tolerance test (OGTT) was performed by
administering 75 g of oral glucose to participants
after a 12-h overnight fast. Blood glucose and
plasma insulin levels were determined before and
30, 60, 90 and 120 min after the glucose bolus.
Plasma glucose and insulin were measured on
Modular Hitachi (Roche Diagnostics†) by glucose
oxidase method and IMMULITE 2000 (Siemens†),
respectively. We defined diabetes mellitus and im-
paired glucose tolerance according to the criteria
adopted by the World Health Organization (WHO)
(12). Diabetes mellitus was diagnosed if the fasting
plasma glucose (FPG) exceeded 7.0 mmol/l or the 2-
h post-load blood glucose concentration exceeded
11.0 mmol/l. Impaired FPG was defined as FPG of
6.17.0 mmol/l. Impaired glucose tolerance (IGT)
was defined as FPG less than 7.0 mmol/l and 2-h
blood glucose of 7.811.0 mmol/l. Exploration of
carbohydrate metabolism also included measures of
fasting glucagon.
Other laboratory investigations. Lipid investigations
included the following: serum total cholesterol
(TC), unesterified cholesterol, cholesteryl esters
(CE) and esterification ratio, HDL-cholesterol
(HDL-C), LDL-cholesterol (LDL-C), triglycerides,
lipoprotein(a), apolipoproteins (AI, AII, B, CII,
CIII, E), free fatty acids (FFAs), glycerol, phospho-
lipids, TC/phospholipids ratio and lipoproteino-
gram. The response to oral glucose load was
determined by measuring lipids parameters before
and 120 min and 240 min after the glucose load. A
lactate/pyruvate ratio was also measured during
fasting and 60 min and 120 min after glucose load.
Other laboratory investigations included serum
proinflammatory cytokines (tumour necrosis fac-
tor-alpha and interleukin-6) and adipocytokines
(leptin and adiponectin) that are associated with
adipose tissue and insulin resistance (13).
Biological investigations in controls
A standard OGTT was performed with the same
protocol (75 g oral glucose after a 12-h overnight
fast). Blood glucose was determined before and
120 min after the glucose bolus.
Statistical analysis
Mann-Whitney U-tests compared continuous data
and Fisher’s exact tests analysed categorical data
between those with and without IGT. Statistical
analysis was conducted with Xlstats software
Table I. Characteristics of patients with ALS and control subjects.
ALS patients Controls p-value
Number of patients 21 21 NA
Age (mean, SD) (years) 53.2 (12.7) 53.1 (12.9) 0.99
Patients over 50 years of age (%) 62% 62% 1.00
Sex ratio (men/women) 18/3 18/3 1.00
Body mass index (mean, SD) (kg/m
2
) 23.8 (3.4) 25.3 (3.0) 0.23
Site of onset (limb/bulbar) 19/2 NA NA
Disease duration (mean, SD) (months) 19.4 (11.0) NA NA
ALSFRSR score (mean, SD) 35.3 (6.8) NA NA
Testing (mean, SD) (total MRC score) 118.6 (24.7) NA NA
Atrophy score (mean, SD) 4.20 (2.0) NA NA
NA: non applicable.
2P.-F. Pradat et al.
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(Addinsoft, version 2008.5.02). The level of signifi-
cance was set at p0.05.
Results
Biological investigations
Blood glucose determined 120 min after the glucose
bolus was significantly higher in patients with ALS
(7.41 mmol/l91.68) compared to controls (6.059
1.44, p0.006). The prevalence of IGT according
to WHO criteria was 7/21 (33%) in ALS patients
and 2/21 (9.5%) in controls (p0.13). The results
of measures of carbohydrate metabolism are indi-
cated in Table II and those of other biological
parameters in Table III and in Supplementary
Table 1. Serum insulin levels were significantly
increased in ALS patients with IGT compared to
patients with normal glucose tolerance (NGT) at 60
and 90 min after glucose loading (p0.045 and
0.044, respectively). Lipid investigations showed
that mean fasting FFA levels were elevated in ALS
patients (0.6490.25 mmol/l) compared with the
reference value (0.100.60 mmol/l). FFA levels
were higher in patients with IGT than patients
with NGT (p0.04). Levels of fasting glycerol
tended to be elevated in the IGT patients (p
0.059). Other lipid measures, including TC, trigly-
cerides, HDL-C and LDL-C were not significantly
different between groups. After glucose load, there
was a significant decrease in FFA levels compared to
fasting values (p0.00001), an expected event since
insulin inhibits lipolysis. In this case, no difference
was noted between patients with IGT and patients
with NGT. Fasting and post-glucose lactate-pyru-
vate ratios were also not significantly different
between both groups. Proinflammatory cytokines
(tumour necrosis factor-alpha and interleukin-6)
and adipocytokines (leptin and adiponectin) were
in the normal range and mean levels were similar in
patients with IGT and NGT.
Association with clinical measures
There were no significant differences between ALS
patients with IGT and NGT for the following
clinical parameters: BMI (23.793.5 kg/m
2
vs.
23.893.3 kg/m
2
,p0.93), site of onset (limb/
bulbar: 5/2 vs. 14/0, p0.14), disease duration
(17.4911.4 months vs. 20.4910.7 months, p
0.62), ALSFRSR score (35.096.4 vs. 35.596.9,
p0.89), total MRC score (118.6916.6 vs.
Table III. Main results of biological investigations performed in addition to the study of carbohydrate metabolism.
All patients IGT NGT p-value Normal values
Number of patients 21 7 14
TC (mmol/l) 5.85 (0.91) 6.01 (0.65) 5.78 (0.98) 0.57 4.14-7.51
Triglycerides (mmol/l) 1.36 (0.67) 1.44 (0.50) 1.32 (0.73) 0.40 0.51-2.17
HDL-C (mmol/l) 1.58 (0.34) 1.57 (0.34) 1.55 (0.34) 0.78 1.04-2.33
LDL-C (mmol/l) 3.65 (0.72) 3.78 (0.54) 3.60 (0.78) 0.65 1.55-4.14
Glycerol (mmol/l) 0.10 (0.12) 0.17 (0.18) 0.07 (0.06) 0.059 0.03-0.15
FFAs (mmol/l) 0.64 (0.25) 0.77 (0.30) 0.57 (0.19) 0.043 0.10-0.60
Lactate-pyruvate ratio 10.8 (2.4) 12.2 (3.4) 10.3 (1.6) 0.43 B15
TNF-alpha (ng/l) 1.29 (0.54) 1.19 (0.52) 1.34 (0.54) 0.64 0.78-1.53*
Il-6 (ng/l) 1.28 (0.64) 1.50 (0.43) 1.17 (0.70) 0.12 0.29-1.90*
Leptin (mg/l) 10.71 (9.45) 12.34 (5.77) 9.89 (10.74) 0.15 0.5-16.9*
Adiponectin (mg/l) 8.29 (3.66) 8.95 (2.66) 7.96 (4.02) 0.36 4.4918*
Abbreviations: F: female; M: male; FFAs: free fatty acids; TC: total cholesterol.
* Normal values for patients with BMI B25kg/m
2
.
Table II. Carbohydrate metabolism investigations (mean, SD) and comparison between patients with impaired glucose tolerance (IGT) and
normal glucose tolerance (NGT). The normal range for each test reflects the geometric mean92 standard deviations (i.e. 95% interval), as
obtained from the reference laboratory.
All patients IGT NGT p-value Normal values
Number of patients 21 7 14
Glucose (mmol/l) Fasting 4.89 (0.54) 5.01 (0.63) 4.82 (0.49) 0.42 3.90-5.80
30 min 8.82 (1.09) 8.91 (1.09) 8.77 (1.09) 0.52 ND
60 min 8.91 (1.85) 9.75 (1.79) 8.55 (1.76) 0.41 ND
90 min 8.18 (1.72) 9.91 (1.68) 7.31 (0.87) 0.001 ND
120 min 7.41 (1.68) 9.21 (1.33) 6.51 (0.86) 0.0003 ND
Insulin (pmol/l) Fasting 58.53(19.85) 70.37 (9.74) 56.51 (20.42) 0.26 43.3-165.99
30 min 291.93 (110.49) 294.45 (64.30) 291.13 (120.88) 0.81 ND
60 min 402.42 (156.32) 651.70 (59.90) 347.07 (110.49) 0.045 ND
90 min 398.59 (201.35) 669.02 (25.26) 330.97 (166.28) 0.044 ND
120 min 352.69 (193.49) 514.93 (269.27) 293.66 (107.75) 0.300 ND
Glucagon (ng/l) Fasting 100.43 (56.98) 75.14 (11.65) 113.07 (65.75) 0.15 60-200
ND: not determined.
Impaired glucose tolerance in ALS 3
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118.7927.9, p0.50) and muscle atrophy score
(3.7292.0 vs. 4.2892.0, p0.81).
Discussion
This study shows that ALS patients present with
abnormal glucose tolerance compared to a population
of controls comparable in age, sex and BMI. Glucose
intolerance could be a primary abnormality in ALS or
result from muscle wasting or physical inactivity.
Abnormal glucose tolerance occurs in other neuro-
muscular disorders and may result from a decrease in
functional muscle mass leading to the inability to
promptly store a large glucose load (14). Similarly,
prolonged inactivity can induce insulin resistance
(15,16), but we found no association between glucose
intolerance and the degree of muscle atrophy or
weakness, functional impairment or whether the
patient could walk. Nor did we find statistical relation-
ships with other factors that have been reported in
people without ALS such as BMI, low HDL choles-
terol and high triglycerides levels (17,18).
The mechanisms responsible for alteration in
glucose homeostasis during ALS may be multi-
factorial. We did detect a significant increase of
fasting FFAs concentration in the subgroup of
patients with IGT compared to the NGT group.
This is consistent with the widely documented role
of elevated FFA in the pathogenesis of insulin
resistance (19). Elevated FFAs could alter glucose
metabolism by affecting access to insulin-sensitive
cells (adipose and muscle), and/or by impairing
glucose transport or metabolism within cells directly;
increased FFA levels could result from increased
lipolysis in white adipose tissue or decreased uptake
by different tissues, mainly skeletal muscle and
heart. Given that ALS patients are hypermetabolic
(20), it seems unlikely that they consume less FFAs.
Alternatively, increased adipose lipolysis has also
been documented in ALS mice (2) and is consistent
with decreased fat mass and increased frequency of
hyperlipidaemia in ALS patients (1). Further studies
are required to evaluate potential metabolic altera-
tions in the adipose tissue of ALS patients.
Supplementary Table 1. Other biological investigations (mean, SD) and comparison between patients with impaired glucose tolerance
(IGT) and normal glucose tolerance (NGT). The normal range for each test reflects the geometric mean 92 standard deviations (i.e. 95%
interval), as obtained from the reference laboratory.
All patients IGT NGT p-value Normal values
Number of patients 21 7 14
TC (g/l) Fasting 2.26 (0.35) 2.32 (0.25) 2.23 (0.38) 0.57 1.60-2.90
120 min 2.11 (0.32) 2.10 (0.14) 2.11 (0.38) 0.99
240 min 2.16 (0.36) 2.18 (0.17) 2.16 (0.42) 0.75
Unesterified C (g/l) Fasting 0.79 (0.12) 0.81 (0.08) 0.77 (0.14) 0.39 0.40-1.00
Cholesteryl esters (g/l) Fasting 1.47 (0.25) 1.51 (0.18) 1.45 (0.27) 0.56 0.90-1.90
Cholesteryl esterification ratio Fasting 0.65 (0.02) 0.65 (0.01) 0.65 (0.02) 0.48 0.60-0.70
Triglycerides (g/l) Fasting 1.2 (0.6) 1.3 (0.4) 1.2 (0.6) 0.40 0.45-1.90
120 min 1.1 (0.6) 1.1 (0.4) 1.1 (0.7) 0.78
240 min 1.1 (0.5) 1.0 (0.4) 1.2 (0.6) 0.77
HDL-C (g/l) Fasting 0.61 (0.13) 0.61 (0.13) 0.60 (0.13) 0.78 0.40-0.65
120 min 0.57 (0.13) 0.56 (0.12) 0.58 (0.13) 0.52
240 min 0.61 (0.13) 0.61 (0.12) 0.60 (0.14) 0.95
LDL-C (g/l) Fasting 1.41 (0.3) 1.46 (0.2) 1.39 (0.3) 0.65 0.90-1.60
120 min 1.31 (0.25) 1.31 (0.14) 1.31 (0.29) 0.82
240 min 1.32 (0.28) 1.36 (0.12) 1.31 (0.32) 0.77
Glycerol (g/l) Fasting 0.09 (0.11) 0.15 (0.16) 0.06 (0.05) 0.052 0.03-0.19
120 min 0.07 (0.07) 0.09 (0.06) 0.06 (0.07) 0.12
240 min 0.08 (0.06) 0.11 (0.07) 0.07 (0.06) 0.13
Free fatty acids (mmol/l) Fasting 0.64 (0.25) 0.77 (0.30) 0.57 (0.19) 0.043 0.10-0.60
120 min 0.10 (0.06) 0.09 (0.03) 0.10 (0.07) 0.65
240 min 0.50 (0.30) 0.31 (0.18) 0.58 (0.30) 0.063
Phosholipids (g/l) Fasting 2.30 (0.20) 2.39 (0.18) 2.26 (0.20) 0.14 1.30-2.90
TC/Phospholipids Fasting 0.98 (0.10) 0.97 (0.07) 0.98 (0.11) 0.58 0.90-1.10
Apo A1 (g/l) Fasting 1.60 (0.24) 1.60 (0.27) 1.61 (0.22) 0.63 1.20-1.85
Apo B (g/l) Fasting 1.13 (0.23) 1.16 (0.18) 1.11 (0.25) 0.68 0.6-1.35
Apo A-II (mg/dl) Fasting 31.21 (4.82) 29.82 (4.34) 31.81 (4.89) 0.65 3254
Apo E (mg/dl) Fasting 3.87 (0.82) 4.01 (0.86) 3.81 (0.79) 0.68 2.30-6.30
Apo C2 (mg/dl) Fasting 3.00 (0.64) 2.99 (0.44) 3.00 (0.72) 0.76 1.50-6.50
Apo C3 (mg/dl) Fasting 8.79 (1.55) 9.33 (1.04) 8.53 (1.68) 0.48 7.50-20.50
Lp(a) (mg/dl) Fasting 0.31 (0.38) 0.32 (0.38) 0.31 (0.38) 0.88 0.01-0.35
Lactate-pyruvate ratio Fasting 10.80 (2.41) 11.77 (3.07) 10.30 (1.65) 0.43 B15
60 min 11.38 (2.29) 12.39 (1.76) 10.94 (2.35) 0.26
120 min 11.34 (2.56) 13.07 (2.99) 10.60 (1.92) 0.17
Abbreviations: C: cholesterol; TC: total cholesterol.
4P.-F. Pradat et al.
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Contrasting with our results, a previous study
failed to detect impaired glucose tolerance in a series
of 21 patients with ALS compared to control
patients (8). However, seven out of the 10 control
subjects were inpatients who suffered from ischae-
mic stroke. Impaired insulin sensitivity has been
shown to be highly prevalent among non-diabetic
patients with recent ischaemic stroke (21). The
discrepancy between their results and ours may
thus result from the high prevalence of insulin
resistance in their control group.
Carbohydrate metabolism disturbances in our
series of patients with sporadic ALS are different
from those reported in transgenic mice expressing
ALS-linked SOD1 mutations (2). Glucose tolerance
tests in ALS mice show that they clear glucose more
efficiently than wild- type mice. This difference
might be due, at least in part, to inter-species
differences in energy metabolism. Alternatively,
since our cohort only included non-SOD1 linked
sporadic ALS patients, this discrepancy might in-
dicate differences in the underlying pathogenic
mechanisms between sporadic and SOD1-linked
ALS.
Our findings are in line with findings of insulin
resistance in other neurodegenerative diseases
(22,23) such as Huntington’s disease (24), Alzhei-
mer’s disease (23,25) and Parkinson’s disease (26).
In these conditions, the possible link between lipid
abnormalities, particularly elevations of FFAs, and
insulin resistance, as suggested in our study in ALS
patients, has never been investigated. Whether
insulin resistance is a cause or a consequence of
neurodegeneration, and represents a risk factor for
these disorders remains unsolved.
In conclusion, our study suggests the existence of
glucose homeostasis abnormalities in ALS patients
and the potential role of lipid abnormalities, further
supporting the emerging concept of a close relation-
ship between ALS and energy metabolism. Future
studies are needed to determine if glucose metabo-
lism abnormalities may contribute to motor neuron
vulnerability and if therapeutic interventions with
nutritional or glucose lowering agents may be
beneficial.
Acknowledgements
We thank Vanessa Pibiri, Rene´e Fouchet (Hoˆpital de
la Pitie´-Salpeˆtrie` re, Paris, France) and Ce´line Lange
(INSERM U 780, Villejuif, France) for their tech-
nical contribution and Alexis Elbaz (INSERM U
708, Paris, France) for helpful discussions about
epidemiological issues.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
References
1. Dupuis L, Corcia P, Fergani A, Gonzalez de Aguilar JL,
Bonnefont-Rousselot D, Bittar R, et al. Dyslipidaemia is a
protective factor in amyotrophic lateral sclerosis. Neurology.
2008;70:10049.
2. Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL,
Loeffler JP. Evidence for defective energy homeostasis in
amyotrophic lateral sclerosis: benefit of a high-energy diet in a
transgenic mouse model. Proc Natl Acad Sci U S A.
2004;101:1115964.
3. Fergani A, Oudart H, Gonzalez de Aguilar JL, Fricker B,
Rene F, Hocquette JF, et al. Increased peripheral lipid
clearance in an animal model of amyotrophic lateral sclerosis.
J Lipid Res. 2007;48:157180.
4. Gonzalez de Aguilar JL, Dupuis L, Oudart H, Loeffler JP.
The metabolic hypothesis in amyotrophic lateral sclerosis:
insights from mutant Cu/Zn superoxide dismutase mice.
Biomed Pharmacother. 2005;59:1906.
5. Gonzalez de Aguilar JL, Echaniz-Laguna A, Fergani A, Rene
F, Meininger V, Loeffler JP, et al. Amyotrophic lateral
sclerosis: all roads lead to Rome. J Neurochem.
2007;101:115360.
6. Perurena OH, Festoff BW. Reduction in insulin receptors in
amyotrophic lateral sclerosis correlates with reduced insulin
sensitivity. Neurology. 1987;37:13759.
7. Reyes ET, Perurena OH, Festoff BW, Jorgensen R, Moore
WV. Insulin resistance in amyotrophic lateral sclerosis. J
Neurol Sci. 1984;63:31724.
8. Harno K, Rissanen A, Palo J. Glucose tolerance in amyo-
trophic lateral sclerosis. Acta Neurol Scand. 1984;70:4515.
9. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial
revisited: revised criteria for the diagnosis of amyotrophic
lateral sclerosis. Amyotroph Lateral Scler Other Motor
Neuron Disord. 2000;1:2939.
10. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D,
Thurmond B, et al. The ALSFRSR: a revised ALS functional
rating scale that incorporates assessments of respiratory
function. BDNF ALS Study Group (Phase III). J Neurol
Sci. 1999;169:1321.
11. Simon D, Senan C, Garnier P, Saint-Paul M, Papoz L.
Epidemiological features of glycated haemoglobin A1c-
distribution in a healthy population. The Telecom Study.
Diabetologia. 1989;32:8649.
12. Report of the Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus. Diabetes Care.
1997;20:118397.
13. Tilg H, Moschen AR. Inflammatory mechanisms in the
regulation of insulin resistance. Mol Med. 2008;14:22231.
14. Collis WJ, Engel WK. Glucose metabolism in five neuro-
muscular disorders. Neurology. 1968;18:91525.
15. Goodyear LJ, Kahn BB. Exercise, glucose transport, and
insulin sensitivity. Annu Rev Med. 1998;49:23561.
16. Stuart CA, Shangraw RE, Prince MJ, Peters EJ, Wolfe RR.
Bed-rest-induced insulin resistance occurs primarily in mus-
cle. Metabolism. 1988;37:8026.
17. Tripathy D, Carlsson M, Almgren P, Isomaa B, Taskinen
MR, Tuomi T, et al. Insulin secretion and insulin sensitivity
in relation to glucose tolerance: lessons from the Botnia
Study. Diabetes. 2000;49:97580.
18. Lindahl B, Weinehall L, Asplund K, Hallmans G. Screening
for impaired glucose tolerance. Results from a population-
based study in 21,057 individuals. Diabetes Care. 1999;
22:198892.
19. Bergman RN, Ader M. Free fatty acids and pathogenesis of
type 2 diabetes mellitus. Trends Endocrinol Metab.
2000;11:3516.
20. Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM,
Beaufrere B, et al. Factors correlated with hypermetabolism
in patients with amyotrophic lateral sclerosis. Am J Clin Nutr.
2001;74:32834.
Impaired glucose tolerance in ALS 5
Downloaded By: [BIUS Jussieu/Paris 6] At: 15:53 6 April 2009
21. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata
DM, Shulman GI, et al. Impaired insulin sensitivity among
non-diabetic patients with a recent TIA or ischaemic stroke.
Neurology. 2003;60:144751.
22. Ristow M. Neurodegenerative disorders associated with
diabetes mellitus. J Mol Med. 2004;82:51029.
23. Sabayan B, Foroughinia F, Mowla A, Borhanihaghighi A.
Role of insulin metabolism disturbances in the development
of Alzheimer’s disease: mini review. Am J Alzheimers Dis
Other Demen. 2008;23:1929.
24. Lalic NM, Maric J, Svetel M, Jotic A, Stefanova E, Lalic K, et
al. Glucose homeostasis in Huntington’s disease: abnormal-
ities in insulin sensitivity and early-phase insulin secretion.
Arch Neurol. 2008;65:47680.
25. Ronnemaa E, Zethelius B, Sundelof J, Sundstrom J, Deger-
man-Gunnarsson M, Berne C, et al. Impaired insulin
secretion increases the risk of Alzheimer’s disease. Neurology.
2008;71:106571.
26. Sandyk R. The relationship between diabetes mellitus and
Parkinson’s disease. Int J Neurosci. 1993;69:12530.
6P.-F. Pradat et al.
Downloaded By: [BIUS Jussieu/Paris 6] At: 15:53 6 April 2009