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ARTICLE
The insulin resistance phenotype (muscle or liver) interacts
with the type of diet to determine changes in disposition index
after 2 years of intervention: the CORDIOPREV-DIAB
randomised clinical trial
Ruth Blanco-Rojo
1,2,3,4
&Juan F. Alcala-Diaz
1,2,3,4
&Suzan Wopereis
5
&
Pablo Perez-Martinez
1,2,3,4
&Gracia M. Quintana-Navarro
1,2,3,4
&Carmen Marin
1,2,3,4
&
Jose M. Ordovas
6,7
&Ben van Ommen
5
&Francisco Perez-Jimenez
1,2,3,4
&
Javier Delgado-Lista
1,2,3,4
&Jose Lopez-Miranda
1,2,3,4
Received: 28 July 2015 /Accepted: 8 September 2015
#Springer-Verlag Berlin Heidelberg 2015
Abstract
Aims/hypothesis The aim of the study was to determine
whether basal insulin resistance (IR) phenotype (muscle and/
or liver) determines the effect of long-term consumption of a
Mediterranean diet or a low-fat diet on tissue-specific IR and
beta cell function.
Methods The study was performed in 642 patients included in
The effect of an olive oil rich Mediterranean diet on type 2
diabetes mellitus risk and incidence study (CORDIOPREV-
DIAB). A total of 327 patients were randomised to a
Mediterranean diet (35% fat; 22% from monounsaturated fatty
acids) and 315 to a low-fat diet (<28% fat). At baseline, the
patients were classified into four phenotypes according to the
type of IR: (1) no IR; (2) muscle IR; (3) liver IR; (4) muscle+
liver IR. The hepatic insulin resistance index (HIRI), muscular
insulin sensitivity index (MISI) and disposition index were
analysed at baseline and after 2 years of follow-up.
Results At baseline, 322 patients presented no IR, 106
presented muscle IR, 109 presented liver IR, and 105
presented muscle+ liver IR. With both dietary interven-
tions, HIRI decreased in all patients (p<0.001) and MISI
increased in muscle IR and muscle+liver IR patients
(p<0.01). Long-term intake of the Mediterranean diet in-
creased the disposition index and insulinogenic index in
the muscle IR patients (p=0.042 and p=0.044, respective-
ly) and the disposition index in the muscle+ liver IR pa-
tients (p=0.048), whereas the low-fat diet increased the
disposition index in the liver IR patients (p= 0.017).
Conclusions/interpretation Although both diets improve in-
sulin sensitivity, there are differences based on basal IR phe-
notypes. Moreover, according to insulinogenic and disposi-
tion index data, a low-fat diet might be more beneficial to
patients with liver IR, whereas patients with muscle IR and
muscle+ liver IR might benefit more from a Mediterranean
diet.
Trial registration ClinicalTrials.gov NCT00924937
Funding The study was supported by the Ministerio de
Economia y Competitividad (AGL2012/39615) and by the
Ministerio de Ciencia e Innovacion (PIE14/00005 and PI13/
00023)
Ruth Blanco-Rojo and Juan F. Alcala-Diaz contributed equally to this
study.
Javier Delgado-Lista and Jose Lopez-Miranda are joint senior authors.
Electronic supplementary material The online version of this article
(doi:10.1007/s00125-015-3776-4) contains peer-reviewed but unedited
supplementary material, which is available to authorised users.
*Jose Lopez-Miranda
jlopezmir@uco.es
1
Lipids and Atherosclerosis Research Unit, Reina Sofia University
Hospital, Avda Menendez Pidal, s/n, 14004 Cordoba, Spain
2
Nutrigenomics and Metabolic Syndrome, Maimonides Institute for
Biomedical Research at Cordoba (IMIBIC), Cordoba, Spain
3
Department of Medicine, University of Cordoba, Cordoba, Spain
4
CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN),
http://www.ciberobn.es/
5
TNO, Zeist, the Netherlands
6
Nutrition and Genomics Laboratory, Jean Mayer US Department of
Agriculture Human Nutrition Research Center on Aging, Tufts
University, Boston, MA, USA
7
IMDEA Food Institute, Madrid, Spain
Diabetologia
DOI 10.1007/s00125-015-3776-4
Keywords Beta cell function .Dietary intervention .Insulin
resistance .Low-fat diet .Mediterranean diet
Abbreviations
CHD Coronary heart disease
CORDIOPREV Coronary Diet Intervention with Olive Oil
and Cardiovascular Prevention
CORDIOPREV-
DIAB
The effect of an olive oil rich Mediterra-
nean diet on type 2 diabetes mellitus risk
and incidence study
CRP C-reactive protein
HIRI Hepatic insulin resistance index
IFG Impaired fasting glucose
IGI Insulinogenic index
IGT Impaired glucose tolerance
IR Insulin resistance
ISI Insulin sensitivity index
MISI Muscular insulin sensitivity index
Introduction
Cardiovascular disease and type 2 diabetes are currently con-
sidered the main causes of disability and death worldwide [1].
Both are complex metabolic disorders, and their simultaneous
presence considerably increases the risk of macrovascular
complications and death. In diabetic patients with a previous
heart attack, the 7 year incidence of subsequent myocardial
infarction is more than double that of non-diabetic individuals
with previous myocardial infarction. Similarly, the recurrence
rate of major atherosclerotic complications in type 2 diabetic
patients with a prior cardiovascular event is very high: around
6% per year [2]. Therefore, prevention of type 2 diabetes
should be a priority in cardiovascular patients.
Insulin resistance (IR) reflects defective insulin action pre-
dominantly in skeletal muscle and liver, which are the main
insulin-sensitive target tissues [3]. As a consequence, insulin
secretion increases to maintain normoglycaemia, a situation
that could compromise pancreatic beta cell function and result
in type 2 diabetes [4]. There is compelling clinical trial evi-
dence that type 2 diabetes can be prevented or delayed by
lifestyle interventions: among these, modification of the diet
has been established as one of the most important contributing
factors [5]. Two dietary approaches have been suggested as
good alternatives to delay the onset of type 2 diabetes: first,
the Mediterranean diet, rich in olive oil, seems to provide
cardiovascular benefits and increase insulin sensitivity; it has
been recently linked to lower type 2 diabetes incidence [6,7].
The other alternative is a low-fat diet, with a content of <30%
energy from total fat, which has been demonstrated to prevent
type 2 diabetes [5] and has been recommended by the ADA
[8].
Although the development of type 2 diabetes is tightly
related to IR, it is unclear whether IR develops simultaneously
in multiple organs and whether its severity varies depending
on the organ. Moreover, there is evidence that interventions
that increase insulin sensitivity are organ specific [9,10].
However, to the best of our knowledge, no long-term compar-
isons of different dietary patterns in individuals at risk of
diabetes that take into account the extent of IR in target organs
have been reported.
The present work aims to determine whether basal IR phe-
notype (muscle and/or liver) determines the effect of long-
term consumption of a Mediterranean diet or a low-fat diet
on tissue-specific IR and beta cell function.
Methods
Participants The Coronary Diet Intervention with Olive Oil
and Cardiovascular Prevention (CORDIOPREV) study is an
ongoing prospective, randomised, open, controlled trial of
1,002 patients receiving conventional treatment for coronary
heart disease (CHD) who had their last coronary event more
than 6 months before enrolment in one of two different dietary
models (a Mediterranean diet and a low-fat diet) over a period
of 5 years. The patients were recruited between November
2009 and February 2012, mostly at the Reina Sofia University
Hospital, Cordoba, Spain. The eligibility criteria, design and
methods of the CORDIOPREV clinical trial have been reported
elsewhere [11,12], and the protocol is registered at
ClinicalTrials.gov (registration no. NCT00924937). The
outcome investigated in this study relates to the one of the
secondary outcomes of the CORDIOPREV study: metabolic
control of carbohydrates (CORDIOPREV-DIAB).
Patients who had not had a diabetes diagnosis and/or were
not receiving glucose-lowering treatment before the beginning
of the study underwent an OGTT as part of the protocol of the
CORDIOPREV-DIAB study. Patients were asked about their
medical diagnosis and glucose-lowering treatment in an inter-
view with an internal medicine physician and their response
was confirmed by electronic medical records, which are avail-
able for all patients in Andalucía, Spain. According to the base-
line OGTT, 242 patients had normal glucose tolerance (fasting
glucose <5.5 mmol/l, 2 h glucose <7.7 mmol/l, HbA
1c
<47.5 mmol/mol [6.5%]); 77 had impaired fasting glucose
(IFG; fasting glucose 5.6–6.9 mmol/l), 80 had impaired glucose
tolerance (IGT; 2 h glucose 7.8–11.0 mmol/l); 53 had both IFG
and IGT; and 190 had type 2 diabetes (fasting glucose
≥7 mmol/l, 2 h glucose ≥11.1 mmol/l or HbA
1c
≥47.5 mmol/
mol [6.5%]). Once in the study, patients who received a
biochemical diagnosis of diabetes, but who were not put on
pharmacological treatment by their physicians, continued in
the study. Patients who initiated pharmacological treatment
for diabetes were excluded from the study.
Diabetologia
A total of 642 patients were randomised to two dietary
treatment groups: 327 to a Mediterranean diet group and 315
to a low-fat diet group. There were no significant differences
in the demographic and metabolic characteristics between the
groups (see electronic supplementary material [ESM]
Tab le 1). Patients lost before follow-up at 2 years are detailed
in ESM Fig. 1.
The local ethics committees approved the trial protocol and
its amendments, which follow the Declaration of Helsinki and
good clinical practice. The experimental protocol conforms to
international ethical standards [13]. Written informed consent
was obtained from all study participants.
Study diets The low-fat diet comprised <28% of energy from
fat (12% monounsaturated, 8% polyunsaturated and 8% satu-
rated fatty acids), 57% from carbohydrates and 15% from
proteins. The Mediterranean diet comprised 35% of energy
from fat (22% monounsaturated, 6% polyunsaturated and
7% saturated fatty acids), 50% from carbohydrates and 15%
from proteins. To ensure that the main fat source of the
Mediterranean diet (extra-virgin olive oil) was identical for
all patients in this group, the olive oil was given to the
participants by the research team. Food packs, including
low-fat foods (cereals, legumes, pasta, etc.) were provided
for the patients randomised to the low-fat diet group.
Dietary assessment and anthropometric measurements
The CORDIOPREV study was supervised by a team of
registered dietitians. At the beginning of the study and every
year, the dietitian had a face-to-face interview with each patient,
during which was carried out a 137-item semi-quantitative food
frequency questionnaire, validated in Spain [14], and a
validated 14-item questionnaire of adherence to the Mediterra-
nean diet to determine a Mediterranean diet score [15]. Partici-
pants in each intervention group received the same intensive
dietary counselling. The dietitian adapted the participants’
customary diet to the Mediterranean diet or to the low-fat diet,
focusing on the overall daily diet rather than on isolated nutri-
ents. Weight, height and waist circumference were also mea-
sured at baseline and again each year according to standardised
protocols.
Biochemical measurements Venous blood for analysis of the
participants’biochemical variables was collected in tubes
containing EDTA after a 12 h overnight fast at baseline and
after 2 years of follow-up. Lipid variables, serum insulin,
plasma glucose and plasma concentration of C-reactive protein
(CRP) were determined as previously reported [11,12].
Estimation of IR, insulin secretion and beta cell function
indices Patients underwent a standard OGTT at baseline and
after 2 years of follow-up. After an overnight fast, blood was
sampled from a vein before oral glucose intake (0 min) and
again after a 75 g flavoured glucose load (Trutol 75; Custom
Laboratories, Baltimore, MD, USA). Blood samples were
taken at 30, 60, 90 and 120 min to determine glucose and
insulin concentrations [16].
The following indices were then estimated. The indices
used to determine tissue-specific IR were: the hepatic insulin
resistance index (HIRI) and the muscle insulin sensitivity in-
dex (MISI). HIRI was estimated by the validated method of
Matsuda and DeFronzo [16], expressed as fasting insulin
(pmol/l)×fasting glucose (mmol/l). MISI was measured
according to the method of Abdul-Ghani et al [17]:
MISI=(dG/dt) /mean plasma insulin concentration, where
dG/dt is the rate of decay of plasma glucose concentration
from its peak value to its nadir during the OGTT. Other IR
indices determined were: insulin sensitivity index (ISI)=
10,000/√[(fasting insulin [pmol/l]× fasting glucose
[mmol/l])×(mean OGTT insulin [pmol/l])×(mean OGTT
glucose [mmol/l])] [16]; and HOMA-IR [18]. Insulin secre-
tion was measured by the insulinogenic index (IGI):
IGI= [30 min insulin−fasting insulin (pmol/l)]/ [30 min glu-
cose−fasting glucose (mmol/l)] [19]. Finally, beta cell func-
tion was estimated by calculating the disposition index as
follows: disposition index= ISI ×[AUC
30 min insulin
/
AUC
30 min glucose
], where AUC
30 min
is the area under the
curve between baseline and 30 min of the OGTT for insulin
(pmol/l) and glucose (mmol/l) measurements, respectively,
calculated by the trapezoidal method [20].
Determination of muscle and liver IR groups At baseline,
the patients were distributed into four groups according to the
presence or absence of muscle and/or liver IR. For this purpose,
we used a method based on that described by Abdul-Ghani et al
[21]. The patients were divided into tertiles according to HIRI
and MISI. The highest tertile of HIRI and the lowest tertile of
MISI were considered to indicate IR in each organ. A second
operational definition based on the median value for IR in
skeletal muscle and liver gave similar results.
Statistical analyses Normal distribution was tested for all
measured variables, and skewed variables were normalised
by log
10
. Statistical analysis was carried out using SPSS soft-
ware version 18.0 for Windows (SPSS, Chicago, IL, USA).
The data were presented as mean±SD for continuous
variables and as frequencies for categorical variables. In the
statistical tests, age, sex, BMI and change in weight were
included as covariates. The statistical significance of the dif-
ferences in mean values at baseline according to IR groups
was assessed by a univariate general linear model. A repeated
measures ANOVA test was used to determine the statistical
differences between variables at baseline and after 2 years of
follow-up. The mean percentage change in each variable was
calculated as follows: ([V
2
−V
0
]/V
0
)×100, where V
0
is the
value of each variable at baseline and V
2
is the value after
Diabetologia
2 years of follow-up. A negative value of mean percentage
change indicates that the variable has decreased after 2 years
of follow-up, and a positive value indicates that the variable
has increased. Bonferroni’s test was used in all cases where
post hoc analyses were required, in which p<0.05 was
considered to be significant.
Results
Study population Tab le 1shows the demographic and
metabolic characteristics at baseline of the patients according
to the basal IR phenotype. A group of 322 patients presented
no muscle or liver IR, 106 had muscle IR, 109 had liver IR,
and 105 presented both muscle and liver IR.
Patients with muscle IR, liver IR and muscle+liver IR
showed significant differences compared with those with no
IR in several variables. Patients with muscle IR were signifi-
cantly older than those in the other groups (p<0.001). As
regards anthropometric measurements, patients with liver IR
and muscle +liver IR showed significantly greater weight,
BMI and waist circumference than those with muscle IR and
those with no IR (p< 0.001). Serum triacylglycerol values
were higher in patients with liver IR and muscle+ liver IR than
in those with no IR (p<0.001). HDL-cholesterol was lowest in
patients with liver IR and muscle+liver IR compared with the
other groups (p=0.017). Patients with liver IR and muscle+
liver IR showed significantly greater HbA
1c
, fasting glucose
and fasting insulin than those with muscle IR and those with
no IR (p<0.001).
With respect to the OGTT-derived indices (Table 1), HIRI
was highest in patients with muscle+liver IR, and progres-
sively decreased in the liver IR, muscle IR and no IR groups
(p<0.001). ISI was lowest, however, in patients with muscle+
liver IR, and progressively increased in the liver IR, muscle IR
and no IR groups (p<0.001). MISI was lower in patients with
muscle+ liver IR and muscle IR compared with those with
liver IR and no IR (p<0.001), whereas IGI was higher in
patients with muscle+ liver IR and muscle IR compared with
those with liver IR and no IR (p<0.001). The muscle+liver IR
Tabl e 1 Demographic and metabolic characteristics of the patients by IR phenotype
Characteristic No IR Muscle IR Liver IR Muscle+liver IR pvalue
a
n322 106 109 105
Men/women (n) 275/47 85/21 96/13 87/18 NS
Age (years) 58.49±9.43 61.35±9.00*
‡§
56.30±9.40 57.04± 8.68 <0.001
Weight (kg) 80.35±12.23 79.10±12.03 91.51±14.04*
†
89.45±14.17*
†
<0.001
BMI (kg/m
2
) 29.30 ±3.95 29.62 ±3.66 32.28 ±4.28*
†
32.67±4.71*
†
<0.001
Waist circumference (cm) 100.4±10.1 100.2±10.3 109.3±9.6*
†
108.0±11.1*
†
<0.001
Serum triacylglycerols (mmol/l) 1.30 ±0.69 1.34±0.64 1.62±0.71* 1.74±0.75*
†
<0.001
Total cholesterol (mmol/l) 4.17±0.80 4.16±0.80 4.15± 0.79 4.31± 0.85 NS
HDL-cholesterol (mmol/l) 1.16±0.25 1.11±0.22 1.06±0.21*
†
1.06±0.23*
†
0.017
LDL-cholesterol (mmol/l) 2.38±0.66 2.41±0.66 2.26±0.59 2.42±0.67 NS
CRP (nmol/l) 20.29±19.62 21.43±18.38 23.81±17.33 22.00±14.38 NS
HbA
1c
(%) 5.99±0.47 6.04±0.47 6.39 ±0.77*
†
6.21±0.55*
†
<0.001
HbA
1c
(mmol/mol) 42.0±5.1 42.5±5.1 46.3±8.4*
†
44.4±6.0*
†
<0.001
Fasting glucose (mmol/l) 5.24± 0.67 5.25± 0.74 6.01± 1.22*
†
5.65±0.80*
†
<0.001
Fasting insulin (pmol/l) 45.4± 24.3 55.5± 29.8 103.8± 80.1*
†
108.7±56.8*
†
<0.001
HIRI 261± 98 311±94*
‡§
710± 419*
†§
824± 489*
†‡
<0.001
MISI 0.029± 0.022 0.005± 0.003*
‡
0.027±0.022 0.005±0.003*
‡
<0.001
ISI 14.95 ±7.42 10.51 ±4.50*
‡§
6.55±2.85*
†§
4.71±1.71*
†‡
<0.001
HOMA-IR 1.90±0.75 2.27±0.72* 5.22±3.14*
†
6.07±3.66*
†
<0.001
IGI 76.7±59.4 120.1± 108.2*
‡
84.3 ±69.1 129.7 ±90.8*
‡
<0.001
Disposition index 1,106±926 1,176±1,104 594± 484*
†
678± 489*
†
<0.001
Data are mean±SD unless indicated
a
Univariate model adjusted for age and sex, followed by Bonferroni’stest
*p<0.05vsnoIR
†p<0.05 vs muscle IR
‡p<0.05 vs liver IR
§p<0.05 vs muscle+ liver IR
Diabetologia
and liver IR groups presented higher HOMA-IR than muscle
IR, and these three groups all had higher HOMA-IR compared
with patients with no IR (p<0.001). Finally, the disposition
index was lower in patients with muscle+ liver IR and liver IR
than in those with muscle IR and no IR (p<0.001).
Comparative effect of the Mediterranean vs the low-fat
diet on variables of glycaemic control according to IR sub-
groups At baseline, there were no significant differences in
the variables studied between the patients who were
randomised to a low-fat diet or to a Mediterranean diet within
each IR subgroup (Table 2).
HIRI significantly decreased after 2 years of follow-up
with both dietary treatments in all subgroups (p<0.001).
However, patients with liver IR and muscle+ liver IR present-
ed a greater improvement in HIRI compared with those with
no IR, measured as the mean percentage change. Specifically,
HIRI decreased more in the low-fat and Mediterranean diet
groups in patients with liver IR than in those with no IR
(−44.1% vs −16.8%, p=0.002; −38.5% vs −13.7%,
p=0.017, respectively). On the other hand, HIRI decreased
more in patients with muscle+liver IR consuming the low-
fat diet than in those with no IR consuming the low-fat diet
(−42.4% vs −16.8%, p=0.012) (Table 2). MISI significantly
increased in the muscle IR and muscle+ liver IR groups after
2 years of follow-up with both dietary treatments (p<0.001
and p=0.003, respectively), whereas it significantly decreased
in the liver IR group with both dietary treatments (p=0.001).
In terms of mean percentage change, there were also signifi-
cant differences between IR subgroups. Patients with muscle
IR consuming the low-fat and Mediterranean diets presented a
greater increase in MISI compared with those with no IR
(172.9% vs −6.0%, p<0.001; 204.4% vs −3.3%, p<0.001,
respectively) and with liver IR (172.9% vs −30.5%,
p<0.001; 204.4% vs −12.5%, p<0.001, respectively). By
contrast, MISI increased more in patients with muscle+ liver
IR consuming the low-fat diet than in those with no IR
(147.5% vs −6.0%, p<0.001) and with liver IR (147.5% vs
−30.5%, p<0.001) (Table 2).
HbA
1c
significantly decreased after 2 years of follow-up
with both dietary treatments in all subgroups (p<0.001), ex-
cept in those with liver IR who consumed the Mediterranean
diet (Table 2).
IGI decreased significantly from baseline to 2 years of
follow-up in patients with muscle+liver IR (p=0.015) con-
suming the low-fat diet. In terms of mean percentage change,
there was a significant difference in the muscle IR group
(p=0.044) between those who consumed the low-fat diet
(in whom IGI decreased) and those who consumed the
Mediterranean diet (in whom IGI increased).
Finally, long-term consumption of the Mediterranean diet
for 2 years led to an increase indisposition index that was only
significant in muscle IR (p=0.042) and muscle+ liver IR
patients (p=0.048), whereas consumption of the low-fat diet
led to an increase in disposition index that was only significant
in liver IR patients (p=0.017). Moreover, there were differ-
ences in the values of mean percentage change in the disposi-
tion index (Fig. 1). In muscle IR and muscle+ liver IR patients,
consumption of the Mediterranean diet led to a higher increase
in disposition index compared with the low-fat diet (55.0% vs
26.5%, p=0.020 and 41.0% vs 14.8%, p=0.040, respective-
ly). By contrast, in liver IR patients the increase in disposition
index was higher in those consuming the low-fat diet than in
those consuming the Mediterranean diet (67.3% vs 20.3%,
p=0.014).
ISI and HOMA-IR values significantly improved after
2 years of follow-up with both dietary treatments and in all
subgroups (ESM Table 2).
Dietary intake and anthropometric measurements At base-
line, there were no significant differences in Mediterranean diet
score between the Mediterranean diet and the low-fat diet
groups and between the IR subgroups (Table 3). After 2 years
of follow-up, the Mediterranean diet score significantly de-
creased in patients following the low-fat diet but significantly
increased in patients following the Mediterranean diet, in all
subgroups. Accordingly, the change in mean percentage change
in Mediterranean diet score was significantly greater in the
Mediterranean diet group, for all the IR subgroups (p<0.001).
As regards the anthropometric measurements, no IR, mus-
cle IR and liver IR patients following the low-fat diet present-
edadecreaseinweightandBMI(p<0.05) (Table 3). No IR
and liver IR patients consuming the low-fat diet also showed a
significant decrease in waist circumference (p<0.05). No
changes were observed in anthropometric measurements in
patients consuming the Mediterranean diet.
Discussion
This study provides new evidence that different dietary
approaches (a Mediterranean diet or a low-fat diet) may
provide extra benefits in improving beta cell function in
patients with CHD, depending on the presence or absence of
muscle and/or liver IR. Our findings suggest that, although
both diets improve insulin sensitivity, there are some differ-
ences based on basal IR phenotypes. MISI increased only in
patients who presented muscle IR at baseline (alone or com-
bined with liver IR), whereas HIRI presented a greater de-
crease in patients with baseline liver IR relative to the other
groups. Moreover, according to IGI and disposition index
data, a low-fat diet might be of more benefit to patients with
liver IR, whereas a Mediterranean diet might be more
beneficial to patients with muscle IR and muscle+ liver IR.
There is compelling clinical trial evidence to show that the
most cost-effective method to prevent type 2 diabetes is
Diabetologia
Tab l e 2 Glucose metabolism variables at baseline and after 2 years of follow-up of a low-fat diet or a Mediterranean diet, and mean percentage change in values by IR phenotype
Variable No IR Muscle IR Liver IR Muscle+ liver IR pvalue
(low-fat diet)
a
pvalue
(Mediterranean diet)
a
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
n156 166 47 59 57 52 55 50
HIRI
Baseline 252± 100 268± 97 332± 80 294± 101 686± 280 644±228 798± 286 717±239
2years
b
205± 146* 222± 139* 257 ±128* 219± 162* 378 ±225* 379± 226* 371 ±236* 460±226*
Mean change (%) −16.8± 4.5 −13.7± 4.0 −22.1±5.9 −22.8 ±4.9 −44.1 ±4.3
‡
−38.5± 4.5
‡
−42.4± 4.8
‡
−34.4± 4.7 0.001 0.017
MISI
Baseline 0.033± 0.027 0.026± 0.017 0.005± 0.003 0.005 ±0.003 0.030 ±0.025 0.024± 0.018 0.004± 0.003 0.005 ±0.003
2years
c
0.027±0.023 0.024± 0.017 0.015±0.011* 0.019±0.026* 0.015±0.013* 0.021 ±0.020* 0.014±0.015* 0.011 ±0.008*
Mean change (%) −6.0± 1.2 −3.3± 0.9 172.9± 42.3
‡§
204.4±64.07
‡§
−30.5± 11.7 −12.5±5.8 147.5± 49.5
‡§
93.9± 23.3 <0.001 <0.001
HbA
1c
(%)
Baseline 5.96± 0.46 6.01± 0.48 6.09 ±0.47 6.04± 0.47 6.48 ±0.61 6.26±0.57 6.30 ±0.54 6.15±0.53
2years
b
5.69± 0.51* 5.76± 0.49* 5.80±0.55* 5.73± 0.47* 6.17± 0.65* 6.15 ±0.68 5.85± 0.58* 5.95 ±0.46*
Mean change (%) −4.3± 0.1 −4.2± 0.1 −4.7± 0.1 −5.1± 0.1 −5.2±0.1 −2.6± 0.1 −6.3±0.2 −3.4±0.1 NS NS
HbA
1c
(mmol/mol)
Baseline 42.0± 5.0 42.0±5.2 43.0 ±5.1 43.0 ±5.1 47.0 ±6.7 45.0± 6.2 45.0± 5.9 44.0± 5.8
2years
b
39.0± 5.6* 39.0±5.4* 40.0± 6.0* 39± 5.1* 44.0 ±7.1* 44.0 ± 7.4 40.0±6.3* 42.0± 5.0*
Mean change (%) −4.3± 0.1 −4.2± 0.1 −4.7± 0.1 −5.1± 0.1 −5.2±0.1 −2.6± 0.1 −6.3±0.2 −3.4±0.1 NS NS
IGI
Baseline
d
73.5± 61.6 82.1±57.3 105.9 ±85.4 109.1±87.5 92.9 ±81.1 98.3 ±64.8 139.4± 97.3 148.1 ±97.3
2years
e
83.2± 67.0 83.2±67.7 87.56 ±56.21 124.3 ±65.9 83.2± 79.2 86.4± 78.9 107.0± 67.0* 130.8 ±88.6
Mean change (%) 7.0± 0.7 1.3± 0.7 −20.9± 7.7 12.1± 6.3
†
−11.5± 4.5 −13.71± 1.6 −30.3± 7.3 −13.22± 8.7 NS NS
Disposition index
Baseline
d
1,120±1,360 1,097± 1,519 1,029 ±1,022 1,032 ±996 548± 772 636 ±870 633±607 704 ±688
2years
e
1,311± 1,103 1,207±730 1,321± 899 1,480±967* 918± 464* 798± 509 727± 461 993± 499*
Mean change (%) 20.3± 2.1 16.6± 1.5 26.5 ±1.2 55.0±2.1 67.3 ±3.7 20.3±3.0 14.8± 1.7 41.0± 1.5 NS NS
Data are mean± SD
a
Significant differences (p<0.05) in mean percentage change in values between IR subgroups within each dietary treatment, analysed using a univariate model adjusted for age, sex, baseline BMI and
change in weight, followed by Bonferroni’stest:
‡
p<0.05 vs no IR;
§
p<0.05 vs liver IR
b
Data from 539 patients
c
Data from 436 patients
d
Data from 600 patients
e
Data from 447 patients
*p<0.05 between baseline and after 2 years of follow-up in each variable (of each dietary treatment and IR subgroup), analysed using repeated measures ANOVA, adjusted for age, sex, baseline BMI and
change in weight
†
p<0.05 in mean percentage change in values between the low-fat diet and the Mediterranean diet within each IR group, analysed using a univariate model adjusted for age, sex, baseline BMI and change in
weight
Diabetologia
lifestyle intervention, which includes changes in exercise and
dietary habits [22–24]. In several of these long-term interven-
tion studies, the main dietary goals in the intervention groups
were a low-fat, calorie-restricted diet with a low content of
saturated fatty acids and a higher dietary fibre intake. As a
consequence, participants in the active treatment groups
achieved significant weight loss, which appeared to be the
main factor in reducing incident diabetes compared with con-
trol groups. Other prospective studies have demonstrated that
greater adherence to a Mediterranean diet is associated with a
significant reduction in the risk of diabetes [25,26]. In this
context, the Effects of the Mediterranean Diet on the Primary
Prevention of Cardiovascular Diseases (PREDIMED) trial
performed a long-term intervention, with a median follow-
up of 4.1 years, in non-diabetic individuals comparing three
dietary interventions: a Mediterranean diet supplemented with
extra-virgin olive oil; a Mediterranean diet supplemented with
mixed nuts; and a control diet consisting of advice to reduce
intake of all types of fat. The authors concluded that a
Mediterranean diet enriched with extra-virgin olive oil but
without energy restrictions reduced type 2 diabetes incidence
compared with the other two diets [27]. Despite the success of
these studies, two recent reviews highlighted the need to
0
10
20
30
40
50
60
70
80
No IR Muscle IR Liver IR Muscle + Liver IR
Mean change (%)
*
*
*
Fig. 1 Mean percentage change in values of disposition index between
baseline and after 2 years of follow-up by IR phenotype. *p<0.05 be-
tween low-fat diet (white bars) and Mediterranean diet (black bars) in
each IR subgroup analysed using a univariate model adjusted for age,
sex, baseline BMI and change in weight
Tabl e 3 Mediterranean diet adherence score and anthropometric measurements at baseline and after 2 years of follow-up of a low-fat diet or a
Mediterranean diet, and mean percentage change in values by IR phenotype
Variable No IR Muscle IR Liver IR Muscle+liver IR
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
Low-fat diet Mediterranean
diet
Mediterranean diet score
Baseline 8.67±2.06 8.96± 2.00 8.79± 1.84 8.95±2.37 8.50 ±1.99 8.68± 1.96 8.35± 1.79 8.92± 2.02
2 years 7.57± 1.68* 11.62± 1.71* 7.53±1.71* 11.45±1.79* 7.40± 1.65* 11.36±2.03* 7.60± 1.51* 12.00±1.29*
Mean change
(%)
−9.3±2.6 38.2±4.5
†
−11.4±2.4 36±5.7
†
−11.5±2.2 41.0± 7.2
†
−5.9±3.1 40.7±4.0
†
Weight (kg)
Baseline 79.93±12.49 80.72±12.02 80.43± 9.94 78.04±13.46 91.20±14.81 91.87±13.23 88.86± 15.23 90.09±13.04
2 years 78.57±12.47* 79.64±12.11 78.72± 10.30* 79.30±14.49 90.22± 13.32* 90.38±14.15 87.34±17.74 91.31±15.12
Mean change
(%)
−2.4±0.5 −1.7±0.6 −1.9± 0.6 0.1±1.1 −2.2±0.4 −0.8±0.7 −0.9± 0.5 0.4± 1.4
BMI (kg/m
2
)
Baseline 29.08±3.90 29.49± 3.99 30.08±3.24 29.26±3.95 32.35±4.77 32.20±3.67 32.73±5.07 32.59±4.32
2 years 28.56±4.04* 29.21±4.32 29.25± 3.24* 29.69±4.70 31.97± 4.48* 31.85±3.87 32.04± 5.46 33.02±4.84
Mean change
(%)
−2.2±0.5 −1.2±0.4 −1.7± 0.4 0.5±0.8 −1.9±0.7 −0.6±0.9 −1.0± 0.5 0.9± 1.2
Waist circumference (cm)
Baseline 100.2±10.1 100.6± 10.1 101.1±8.2 99.6± 11.8 109.6± 10.9 109.0±7.9 108.5±11.5 107.4±10.7
2 years 98.4± 10.3* 99.3 ±10.0 100.5±8.4 100.1± 11.9 108.0± 10.4* 107.4±8.8 107.9±11.8 107.9±11.6
Mean change
(%)
−2.2±0.7 −1.4±0.6 −1.5± 0.6 −1.7±0.6 −1.7± 0.5 −2.0±0.5 −0.8± 0.6 0.6±0.8
Data are mean±SD
There were no significant differences between the IR groups within each dietary treatment (the low-fat diet or the Mediterranean diet) for all the variables
*p<0.05 between baseline and after 2 years of follow-up in each variable (of each dietary treatment and IR subgroup), analysed using repeated measures
ANOVA, adjusted for age, sex, baseline BMI and change in weight
†
p<0.05 in mean percentage change in values between the low-fat diet and the Mediterranean diet within each IR group, analysed using a univariate
model adjusted for age, sex, baseline BMI and change in weight
Diabetologia
perform intervention trials in order to determine specific die-
tary patterns to offer recommendations to vulnerable indi-
viduals [5,26]. The approach of the present study goes
further, since it also takes into account the fact that the
different pathophysiology of the distinct prediabetic states
(muscle IR, liver IR and muscle+ liver IR) might provide a
basis for the development of individualised prevention of
type 2 diabetes [28]. Therefore, we consider that our find-
ings may have important clinical and public health applica-
tions, especially in the field of personalised medicine.
The diets studied in the intervention (Mediterranean and
low-fat diets) are considered healthy diets [5]: both are rich
in whole grain foods, fruit and vegetables, with a moderate
consumption of fish and low-fat dairy products, and are low in
saturated fat, meat and simple sugars. We observed that levels
of HbA
1c
were significantly reduced, which indicates that
both diets improve glycaemic control [29] and is in agreement
with results found in several intervention studies [30,31]. We
also found that both diets improved insulin sensitivity, al-
though with differences according to tissue-specific IR. HIRI
decreased in all patients with both diets, although this im-
provement seemed to be greater in liver IR and muscle+liver
IR patients. By contrast, MISI was increased only in patients
with muscle IR or muscle+liver IR after 2 years of follow-up
of both diets.That is relevant, since the disposition index takes
into account insulin secretion and insulin sensitivity, and the
calculation itself is affected by tissue-specific IR [32].
Low-fat diets, with a content of <30% of energy from total
fat, are considered the best suited for type 2 diabetes preven-
tion, according to many scientific societies, including the
ADA and the Diabetes and Nutrition Study Group of the
European Association for the Study of Diabetes [8,33].
According to our results, this recommendation may be espe-
cially encouraged in patients with liver IR, whose disposition
index was increased on the low-fat diet compared with those
on the Mediterranean diet. It is important to note that, although
neither diet in this study was calorie-restricted, the weight,
BMI and waist circumference of the patients on the low-fat
diet significantly decreased during follow-up, especially in
those in the liver IR group. Our results agree with those of
other intervention studies, which related weight loss to
reduced diabetes incidence, even when the difference in
weight was minimal [34]. In addition, it has been shown that
a relatively small decrease in BMI is associated with a consid-
erable reduction in hepatic triacylglycerol content, which
might be related to a reduction in the severity of IR [35].
Therefore, this weight loss could diminish hepatic triacylglyc-
erol content and IR, and thus enhance gluconeogenesis and
favour beta cell function in our liver IR patients.
Recent research supports the idea that a traditional
Mediterranean dietary pattern, even without energy restric-
tion, can also help in type 2 diabetes prevention [27,36].
The main differences between the low-fat and the
Mediterranean diets, which were reflected in the adherence
questionnaire, were found in certain unique characteristics
of the Mediterranean diet, such as the moderate consump-
tion of wine and nuts and the widespread use of extra-virgin
olive oil, which means that it is considered a high-
unsaturated fat diet (>35% of energy from fat, of which
22% were monounsaturated fatty acids). We found a spe-
cific extra benefit of consuming the Mediterranean diet in
patients with muscle IR, who presented a significant
increase in IGI and disposition index compared with pa-
tients who consumed the low-fat diet; this was the case in
muscle+liver IR patients, who also presented an increase in
disposition index. This could be linked to the fact suggested
in previous works that a diet high in monounsaturated fatty
acids downregulates genes involved in lipogenesis and
tends to decrease muscle triacylglycerol and
diacylglycerol levels in skeletal muscle from insulin-
resistant individuals [37]. This may be supported by the
improvement in insulin sensitivity and beta cell function
that we observed in our muscle IR and muscle+ liver IR
patients. Moreover, it has been reported that extra-virgin
olive oil consumption, compared with a low-fat meal,
enhances the glucagon-like peptide-1 response [31]. This
hormone has been shown to suppress endogenous glucose
production potentially via effects on insulin pulsatility, but
there is also some evidence that it promotes peripheral
glucose uptake mostly related to neural mechanisms [38].
Some limitations of the current study must be mentioned.
Type 2 diabetes prevention was not the primary endpoint of
the CORDIOPREV trial, but was a secondary analysis con-
ducted in the subgroup of cardiovascular patients not treated
with glucose-lowering drugs at baseline (CORDIOPREV-
DIAB study). However, there are no reasons to believe that
the randomisation would not have worked in such a large
subset of participants. Another point is that the study sample
consisted of older white patients with CHD, which limits the
generalisation of our results to clinically healthy individuals
and to other age groups or ethnicities. Finally, we experienced
greater losses during follow-up in the low-fat diet group,
although this seems not to have affected the results after
2 years of follow-up.
In spite of these limitations, to the best of our knowledge
this study is the first long-term intervention comparing the
effects of two dietary patterns (Mediterranean diet or low-fat
diet) on tissue-specific IR and beta cell function in cardiovas-
cular patients not treated for diabetes, according to muscle
and/or liver IR. Our findings suggest that, although both diets
improve insulin sensitivity, there are differences based on
basal IR phenotypes. Moreover, according to IGI and dispo-
sition index data, the low-fat diet might be more beneficial to
patients with liver IR, whereas the patients with skeletal
muscle IR and those with both liver and muscle IR might
benefit more from a Mediterranean diet. Although further
Diabetologia
studies are needed to confirm these results in other population
groups, such as in healthy individuals at risk of progression to
diabetes and in those with different ethnicity, these findings
may guide the implementation of personalised dietary inter-
ventions tailored to the different states of IR, thus achieving
more efficient prevention of type 2 diabetes in vulnerable
patients.
Acknowledgements The authors would like to thank to Fundacion
Patrimonio Comunal Olivarero and the Escuela Andaluza de Salud
Publica (EASP), Granada, Spain, which carried out the randomisation
process of this study; and also the volunteers who participated in the
study.
Funding The present study was supported by the Ministerio de
Economia y Competitividad (AGL2012/39615 to JL-M) and by the
Ministerio de Ciencia e Innovacion (PIE14/00005 to JL-M and
PI13/00023 to JD-L). It was also partly supported by a research grant
from the European Commission (NUTRITECH European Integrated Pro-
ject-289511). RB-R is supported by an ISCIII postdoctoral research con-
tract (Sara Borrell) and JFA-D is supported by an Instituto de Salud
Carlos III research contract (Programa Rio-Hortega).
Duality of interest The authors declare that there is no duality of inter-
est associated with this manuscript.
Contribution statement JL-M, JD-L and FP-J conceived and designed
the study; RB-R, JFA-D, GMQ-N, JD-L, PP-M and CM performed the
experiments and participated in the acquisition of data; RB-R, JFA-D,
SW, BvO, JMO and JL-M analysed and interpreted the data; RB-R and
JL-M drafted the manuscript; JD-L, PP-M, JMO and BvO provided crit-
ical revision of the paper for the main intellectual content. All authors
contributed substantially to aspects of study design or acquisition of data,
to drafting of the article, or to critical revision for important intellectual
content. All authors have given their final approval of the version to be
published. JL-M is the guarantor of this work.
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