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diabetes research and clinical practice 89 (2010) 97102

Contents lists available at ScienceDirect

Diabetes Research
and Clinical Practice
journ al h omepage: www .elsevier.co m/lo cate/diabres

Review

Prevention and control of type 2 diabetes by Mediterranean


diet: A systematic review
Katherine Esposito a, Maria Ida Maiorino a, Antonio Ceriello b, Dario Giugliano a,*
a
b

Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
IDIBAPS, Barcelona (A.C.), Spain

article info

abstract

Article history:

We conducted a systematic review of the available studies that assessed the effect of a

Received 15 February 2010

Mediterranean diet in type 2 diabetes. We searched publications up to 30 November 2009.

Received in revised form

Seventeen studies were included. Two large prospective studies report a substantially lower

21 April 2010

risk (83% and 35%, respectively) of type 2 diabetes in healthy people or in post-infarct

Accepted 26 April 2010

patients with the highest adherence to a Mediterranean diet. Five randomized controlled

Published on line 23 May 2010

trials have evaluated the effects of a Mediterranean diet, as compared with other commonly
used diets, on indices of glycaemic control in subjects with type 2 diabetes. Improvement of

Keywords:

fasting glucose and HbA1c levels was greater with a Mediterranean diet and ranged from 7 to

Mediterranean diet

40 mg/dl for fasting glucose, and from 0.1 to 0.6% for HbA1c. No trial reported worsening of

Type 2 diabetes

glycaemic control with a Mediterranean diet. Two controlled trials in a secondary preven-

Prevention

tion setting demonstrated that post-infarct patients, including diabetic patients, had car-

Glycaemic control

diovascular benefits from a Mediterranean diet. The evidence so far accumulated suggests

Cardiovascular risk

that adopting a Mediterranean diet may help prevent type 2 diabetes, and also improve
glycaemic control and cardiovascular risk in persons with established diabetes.
# 2010 Elsevier Ireland Ltd. All rights reserved.

Contents
1.
2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Evidence acquisition . . . . . . . . . . . . . . . . .
2.2. Study selection . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Diabetes prevention. . . . . . . . . . . . . . . . . .
3.2. Glycaemic control of diabetes . . . . . . . . . .
3.2.1. Glucose and HbA1c levels (Fig. 1) .
3.2.2. Insulin sensitivity (Fig. 1) . . . . . . .
3.3. Cardiovascular risk . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Second University of Naples, 80138 Naples, Italy. Tel.: +39 081 5665054; fax: +39 081 5665054.
E-mail address: dario.giugliano@unina2.it (D. Giugliano).
0168-8227/$ see front matter # 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2010.04.019

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1.

diabetes research and clinical practice 89 (2010) 97102

Introduction

The term Mediterranean diet essentially refers to a primarily


plant-based diet whose greater consumption has been
associated with higher survival for lower all cause mortality
[1,2]. The Mediterranean diet was first described in the 1960s
by Ancel Keys, based on his observation of food habits of some
populations in the Mediterranean region [3]: the traditional
dietary patterns typical of Crete, much of the rest of Greece,
and southern Italy in the early 1960s were considered to be
largely responsible for the good health observed in these
regions. There is no single Mediterranean diet, as 20 countries
have a coastline in the Mediterranean basin; moreover, social,
political, religious, and economic differences introduce variations to the Mediterranean diet both between and within these
countries. Despite this, a high consumption of foods of
vegetable origin, such as fruits, vegetables, legumes, nuts,
cereals and whole-grains; olive oil as the principal source of
fat; fish and poultry consumed in low-to-moderate amounts;
relatively low consumption of red meat; and moderate
consumption of wine, normally with meals, could be considered important characteristics of this dietary pattern [4].
Adherence to the Mediterranean diet is normally assessed
with a score, such as that created by Trichopoulou et al. [1] which
is extensively used because it is simple and has variants created
to evaluate multiple diet-health relations. For those components supposed to be protective, such ratio of monounsaturated
to saturated fat fatty acid, legumes, whole grains, fruits,
vegetables, or fish, participants receive one point if their intake
is over the sample median; moreover, participants receive one
point if the intake of components supposed to be detrimental
(dairy products or meat) is below the median. For alcohol one
point is scored if consumption is 1050 g/day for men or 525 g/
day for women. If participants meet all the characteristics of the
Mediterranean diet, their score is the highest (9 points),
reflecting maximum adherence. If they meet none of the
characteristics the score is minimum, reflecting no adherence at
all. The score developed by Panagiotakos et al. [5] is based on
daily consumption of non-refined cereals and products (whole
grain bread, pasta, brown rice, etc.), fruits (46 servings/day),
vegetables (23 servings/day), olive oil (as the main added lipid)
and non-fat or low-fat dairy products (12 servings /day); weekly
consumption: of fish, poultry, potatoes, olives, pulses, and nuts
(46 servings/week), and eggs and sweets (13 servings/week);
and monthly consumption: of red meat and meat products (45
servings/month). Thus, the reported monthly frequency consumption of these food groups allowed to calculate a diet score
that assessed adherence to the Mediterranean diet (range 055).
The aim of this study was to do a systematic review of all
the available studies that have assessed the effect of a
Mediterranean diet in human diabetes, including diabetes
prevention, and metabolic and cardiovascular outcomes.

2.

Methods

2.1.

Evidence acquisition

We searched PubMed, Embase, and the Cochrane Central


Register of Controlled Trials databases up to 30 November

2009, using a search strategy that included both truncated free


text and exploded MeSH terms. MeSH headings included
Mediterranean, diet, diabetes, type 2 diabetes, type
1 diabetes, prevention, dietary pattern, glycemic
control, HbA1c, insulin resistance, insulin sensitivity,
HOMA, cardiovascular disease, coronary heart disease,
prospective, follow-up, or cohort, and their variants.
The search strategy had no language restrictions. We also
consulted references from the extracted articles and reviews
to complete the data bank. We assessed the relevance of
studies by using a hierarchical approach based on title,
abstract, and the full manuscript.

2.2.

Study selection

We identified studies that evaluated the association of an a


priori score used for assessing adherence to a Mediterranean
diet and incidence of diabetes. We excluded the studies if they
had a casecontrol design, if they analyzed adherence to a
non-specific dietary pattern or to a recommended dietary
guideline and not to a Mediterranean diet. We also identified
cross-sectional or prospective studies, and controlled clinical
trials that evaluated the effects of a Mediterranean diet on
indices of glycaemic control, including HbA1c, and insulin
sensitivity (HOMA), as well as cardiovascular outcomes in
diabetic patients. We excluded studies with less than 15
patients or with a follow-up less than 3 months.
Two investigators (DG, KE) collected the data, and
disagreements were solved by consensus and by the opinion
of a third author (AC), if necessary. We assessed the quality of
the studies according to the number of participants, the
duration of follow-up, and adjustment for potential confounders. We considered studies with a high number of participants, long duration of follow-up, and adjustment for
confounders including demographic, anthropometric, and
traditional risk factors to be of high quality.

3.

Results

Our initial search yielded 62 reports, of which we excluded 24


on the basis of the title or abstract. Of the remaining 38
articles, we excluded 21 for the following reasons: a nonspecific dietary pattern, instead of a Mediterranean diet, was
evaluated (n = 7); a case control design was used (n = 1); the
study population was not diabetic (n = 5); the study population
consisted of less than 15 subjects (n = 4), including the only
study we found in type 1 diabetic subjects; the follow-up was
less than 3 months (n = 1); duplicate publications (n = 3).
Seventeen studies [622] were included.

3.1.

Diabetes prevention

The link between Mediterranean diet and the risk of developing type 2 diabetes has been explored in one cross-sectional [6]
study and two prospective studies [7,8]. A cross-sectional
study of 1514 men and 1528 women from Greece found a 21%
lower odds of diabetes for a 10-unit increase in the
Mediterranean diet score [6]. In 13,380 Spanish university
graduates without diabetes at baseline followed up for a

diabetes research and clinical practice 89 (2010) 97102

99

median of 4.4 years, participants who adhered closely to a


Mediterranean diet had a 83% lower risk of diabetes (OR: 0.17,
95% CI 0.040.72) compared with those with the lowest
adherence score [7]. The Mediterranean score included
legumes, grains, fruits and nuts, vegetables, fish, meat and
meat products, alcohol, milk and dairy products, ratio of
monounsaturated to saturated fat. In the large postinfart GISSI
PREVENZIONE trial including 8291 Italian patients with a
recent myocardial infarction followed up for 3.5 years [8], a
Mediterranean diet protected against new diabetes (OR: 0.65,
95% CI 0.490.85, highest quintile vs lowest quintile of
adherence). The Mediterranean score was based on consumption of cooked and raw vegetables, fruit, fish, and olive oil.

3.2.

Glycaemic control of diabetes

3.2.1.

Glucose and HbA1c levels (Fig. 1)

In the cross-sectional analysis of a population of 901 outpatients with type 2 diabetic patients attending diabetes
clinics located in South Italy [9], adherence to a Mediterranean-type diet was inversely associated with post-prandial
glucose levels measured at home in a free living condition,
independent of variations in age, adiposity, energy intake,
physical activity, and other potential confounders: 2-h postmeal glucose levels were significantly lower in diabetic
patients with high adherence to a Mediterranean-type diet
than those with low adherence (difference: 2-h glucose,
2.2 mmol/L, 95% CI 0.82.9 mmol/L, P < 0.001). Moreover, mean
HbA1c concentration was significantly lower in diabetic
patients with high adherence to a Mediterranean-type diet
than those with low adherence (difference: HbA1c, 0.9%, 95%
CI 0.51.2%, P < 0.001).
Five randomized controlled trials [1014] have evaluated
the effects of Mediterranean diet, as compared with other
commonly used diets, on indices of glycaemic control in
subjects with type 2 diabetes. Toobert et al. [10] randomized
postmenopausal women with type 2 diabetes (n = 279) to
either usual care (control) or comprehensive lifestyle selfmanagement program (MLP) that also included a Mediterranean low-saturated fat diet. For the MLP women, HbA1c
decreased from a baseline level of 7.437.07% (P = 0.001) at 6
months, whereas that of the control subjects remained at 7.4%
during the same period. However, the relative role of the
Mediterranean diet in the context of the program that also
included stress management training, exercise, group support, and smoking cessation, is unclear. Estruch et al. [11]
evaluated the short term effects of two Mediterranean diets
(supplemented with either 1 l/week of virgin olive oil or 30 g/
day of tree nuts), and a low-fat diet in 772 high risk persons,
including 421 (54.5%) diabetic patients: after 3 months, the
Mediterranean diet groups had lower fasting glucose ( 7 mg/
dl, 95% CI 13 to 1.3 mg/dl) than the low-fat diet group. There
was no separate analysis for the diabetic patients; however, no
difference in outcome for subgroups analysis was found. In a
2-year trial, Shai et al. [12] compared 3 weight-loss diets in 322
moderately obese subjects, including 46 diabetic patients:
among the participants with diabetes, there was a significant
decrease in fasting glucose concentration ( 32.8 mg/dl) in the
Mediterranean diet group and an increase (12.1 mg/dl) in the
low-fat diet group. There was no change in fasting glucose

Fig. 1 Controlled clinical trials assessing the effect of


Mediterranean diet on indices of glycaemic control and
insulin sensitivity in type 2 diabetic patients. The circles
represent the net effect of the dietary interventions
(Mediterranean diet minus comparative diet). Where not
indicated, 95% CI were not provided: in this case, a value of
significance is given. The HOMA index was: insulin (U/
ml) T fasting glucose (mmol/liter)/22.5.

levels in the non-diabetic participants in any of the three diet


groups. Moreover, there was no difference in HbA1c decrease
between the groups assigned to the Mediterranean diet as
compared with the low-fat diet ( 0.5  1.1 vs 0.4  1.3%,
P = 0.45). Esposito et al. [13] evaluated the metabolic effects of a
Mediterranean diet and a low fat diet in 215 patients with
newly diagnosed type 2 diabetes: at year 1, fasting glucose
decreased more in the Mediterranean diet group than in lowfat diet group (difference: 21 mg/dl, 95% CI: 30 to 13 mg/dl,
P = 0.01); moreover, HbA1c levels were lower in the Mediterranean diet group than the low fat diet group (difference: 0.6%,
95% CI 0.9 to 0.3%). In a comparative study of lowcarbohydrate Mediterranean diet vs the American Diabetes
Association diet in 116 type 2 diabetic patients on stable
antihyperglycaemic drug therapy, Elhayany et al. [14] found a
non-significant decrease in fasting glucose ( 20 mg/dL,
P = 0.08), and a significantly greater reduction in HbA1c level

100

diabetes research and clinical practice 89 (2010) 97102

( 2% vs 1.6%, respectively, P = 0.02) in those allocated to the


Mediterranean diet.

3.2.2.

Insulin sensitivity (Fig. 1)

One cross-sectional study evaluated the association between


insulin sensitivity and a Mediterranean diet [15]. In a Greek
adult population, an inverse association has been found
between adherence to a Mediterranean diet and indices of
glucose homeostasis, the higher the adhesion, the lower the
insulin resistance, as assessed by HOMA (homeostasis model
assessment). This association, however, was only evident in
non-diabetic people.
Three clinical controlled trials [1214], carried out in people
with type 2 diabetes, with follow-up ranging from 3 months to
2 years, have evaluated insulin sensitivity (HOMA index) with
a Mediterranean diet, as compared with control diets, for the
most low-fat diets. In the study of Shai et al. [12], among the
participants with diabetes, the decrease in HOMA-IR at 24
months was significantly greater in those assigned to the
Mediterranean diet than in those assigned to the low-fat diet.
In the 215 patients with newly diagnosed type 2 diabetes
studied by Esposito et al. [13], the HOMA index was lower in the
Mediterranean diet group at year 1 than the low fat diet group
(difference between diets: 1.0, 95% CI 1.6 to 0.5). By
contrast, Elhayany et al. [14] found no difference in HOMA
index at 12 months by comparing a low-carbohydrate
Mediterranean diet vs the ADA diet in 116 type 2 diabetic
patients on stable antihyperglycaemic drug therapy.

3.3.

Cardiovascular risk

There are 2 controlled trials [13,14] that specifically evaluated


the effects of Mediterranean diet on cardiovascular risk factors
in type 2 diabetic patients. These trials reported that diabetic
people allocated to a Mediterranean diet presented, as
compared with diabetic subjects receiving a control diet,
more marked improvement of traditional cardiovascular risk
factors, including systolic blood pressure, triglycerides, ratio of
total to HDL-cholesterol, and HDL-cholesterol. A post hoc
analysis [16] of a quasi-randomised (allocation by alternation),
controlled trial, in type 2 diabetic patients (n = 259) allocated to
an ADA diet, a low glycemic index diet, or a modified
Mediterranean diet found that at 12 months mean alanine
aminotransferase levels were lowest in the Mediterranean
arm, leading the authors to suggest that a Mediterranean diet
may have a beneficial effect on liver steatosis in type 2
diabetes.
A short-term interventional trial [17] compared the effects
of two different Mediterranean diets on immune cell activation and soluble inflammatory markers in 112 older subjects
with type 2 diabetes (60%) or with 3 or more cardiovascular risk
factors. After 3 months, monocyte expression of adhesion
molecules, and circulating concentrations of interleukin-6 and
soluble intercellular adhesion molecule-1 decreased after both
Mediterranean diets, but not after the low fat diet. By contrast,
a 1-year randomized trial in 101 patients with coronary heart
disease, including a small percentage (69%) of type 2 diabetic
patients, was unable to find any effect of Mediterranean diet,
as compared with control diet, on markers of inflammation,
including C-reactive protein and fibrinogen [18].

One cross-sectional study [19] evaluated the association


between adherence to Mediterranean diet and the risk of
peripheral artery disease (PAD) in 944 Italian patients with
type 2 diabetes. In multivariate analysis, a higher Mediterranean diet score was independently associated with a significant reduction in PAD risk (odds ratio = 0.44; 95% CI 0.240.83).
We found no prospective or controlled clinical trials that
specifically assessed the role of a Mediterranean diet in
reducing cardiovascular events and mortality in diabetes.
There are, however, three randomized trials [2022] that
included diabetic patients. Singh et al. [20] tested an IndoMediterranean diet in 1000 patients in India with existing
coronary disease or at high risk for coronary disease, including
190 people with diabetes in the intervention arm. As compared
with the control diet, the intervention diet characterized by
increased intake of mustard or soybean oil, nuts, vegetables,
fruits, and whole grains reduced the rate of fatal myocardial
infarction by one third and the rate of sudden death from
cardiac causes by two thirds. A total of 11,323 men and
women, including 1700 diabetic subjects, with myocardial
infarction from 172 centers in Italy were included in the GISSIPrevenzione clinical trial [21]. All patients received advice to
increase their consumption of Mediterranean foods, including
fish, fruit, raw and cooked vegetables and olive oil. Compared
with people in the worst dietary score quarter, the odds ratio of
mortality for those in the best score quarter was 0.51 (95% CI
0.440.59). In a small controlled trial [22] of 2-y follow-up in
survivors of a first myocardial infarction (20% had diabetes),
both a Mediterranean (n = 51) and low-fat (n = 50) diet were
equally better than a control diet in reducing (78% reduction)
the composite primary end-point. However, the Mediterranean-style diet was only distinguished by greater omega-3 fat
intake.
Because an expression of concern [23] has been issued
about the study of Singh et al. [20], this paper is usually not
considered in support to the Mediterranean diet-heart
hypothesis.

4.

Conclusions

This review shows that greater adherence to a Mediterranean


diet is significantly associated with a reduced risk of type 2
diabetes in the general population and in patients with preexisting myocardial infarction. Randomized controlled trials
demonstrate that type 2 diabetic patients allocated to a
Mediterranean diet have, as compared with diabetic patients
following a control diet, better glycaemic control (lower fasting
glucose and HbA1c levels), associated with reduced insulin
resistance (lower HOMA). In secondary prevention of cardiovascular disease, there is evidence that Mediterranean diet
may increase survival also in diabetic patients.
A particular feature of the Mediterranean diet is the
abundant use of virgin olive oil for cooking, frying, spreading
on bread, or dressing salads. This leads to a high ratio of
monounsaturated fatty acids (MUFA) to saturated fatty acids.
A recent review [24] of published studies on dietary fat and
diabetes suggests that replacing saturated fats and trans fatty
acids with unsaturated (polyunsaturated and/or monounsaturated) fats has beneficial effects on insulin sensitivity and is

diabetes research and clinical practice 89 (2010) 97102

likely to reduce risk of type 2 diabetes. One recent long-term


clinical study [25] in overweight type 2 diabetic patients,
however, was unable to find difference on glycaemic control
(fasting glucose, HbA1c and HOMA index) between a high
MUFA diet (46% of total energy as carbohydrate and 38% as fat)
as compared with a high-carbohydrate diet (54% of total
energy as carbohydrate and 28% as fat).
Adiponectin is an adipose tissue-secreted, metabolically
active cytokine that is inversely associated with obesity and
central adiposity and that has been shown to improve insulin
sensitivity and to have anti-inflammatory properties. In the
Nurses Health Study median plasma adiponectin concentrations were 23% higher in diabetic women who most closely
followed a Mediterranean-type diet than in low adherers after
adjustment for age and energy intake [26]. Higher adiponectin
levels are consistently associated with a lower risk of type 2
diabetes in 13 prospective studies of diverse populations, with
a relative risk of 0.72 (95% CI 0.670.78) per 1 log mg/mL
increment in adiponectin levels [27]. This may be in line with
the available literature showing that a combination of dietary
factors, such as, in the Mediterranean diet, may retard
inflammation, possibly by nutrient-nutrient synergy [2830].
A recent meta-analysis [31] comprising more than 1.5
million healthy subjects followed for a time ranging from 3 to
18 years and 40,000 fatal and non-fatal events, shows that
greater adherence to Mediterranean diet is significantly
associated with a reduced risk of both overall and cardiovascular mortality. We were unable to find such prospective
studies in type 2 diabetic patients; however, the results of 2
interventional studies comprising a significant proportion of
type 2 diabetic patients demonstrated that people allocated to
a Mediterranean diet after a recent myocardial infarction may
have a better survival and reduced cardiovascular events.
Certain limitations of our review warrant consideration.
The few controlled trials specifically designed to evaluate the
metabolic and cardiovascular outcomes of Mediterranean diet
in type 2 diabetes remain a major limitation. Adherence to a
Mediterranean diet is usually based on a score which always
involves some level of arbitrary decision in the type and
number of foods to be included and assignment of points to
different levels of intake. Moreover, an analysis of this type
cannot provide universally applicable results, because diet
varies across populations and also between sections of the
same population. In general, dietary pattern scores, such as
the Mediterranean diet score, tend to generate fairly consistent results with respect to health benefits, whereas studies
focusing on the component foods or food groups are often
contradictory [32]. Most clinical studies of Mediterranean diet
focused on surrogate markers for early risk assessment which
may be misleading. On the other hand, there are at least 2
outcome-based trials that demonstrated benefits in terms of
reduction of cardiovascular and total mortality in patients
with recent myocardial infarction, including more than 1700
patients with type 2 diabetes, assigned to a Mediterraneanstyle diet [21,22]. A recent systematic search of MEDLINE for
prospective cohort studies or randomized trials investigating
dietary exposures in relation to coronary heart disease
concludes that among the dietary exposures with strong
evidence of causation, only a Mediterranean dietary pattern is
related to coronary heart disease in randomized trials [33].

101

In conclusion, current evidence is insufficient to assess in


full the healthy benefits of Mediterranean diet in subjects with
type 2 diabetes. However, the evidence so far accumulated
suggests that adopting a Mediterranean diet may help prevent
type 2 diabetes in the population and also improve glycaemic
control and cardiovascular risk in persons with established
diabetes.

Conflict of interest
There are no conflicts of interest.

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