Review

Precision nutrition for prevention and management of

type 2 diabetes
Dong D Wang, Frank B Hu

Precision nutrition aims to prevent and manage chronic diseases by tailoring dietary interventions or recommendations Lancet Diabetes Endocrinol 2018
to one or a combination of an individual’s genetic background, metabolic profile, and environmental exposures. Published Online
Recent advances in genomics, metabolomics, and gut microbiome technologies have offered opportunities as well as February 9, 2018
http://dx.doi.org/10.1016/
challenges in the use of precision nutrition to prevent and manage type 2 diabetes. Nutrigenomics studies have
S2213-8587(18)30037-8
identified genetic variants that influence intake and metabolism of specific nutrients and predict individuals’
Department of Nutrition
variability in response to dietary interventions. Metabolomics has revealed metabolomic fingerprints of food and (D D Wang ScD, Prof F B Hu MD),
nutrient consumption and uncovered new metabolic pathways that are potentially modified by diet. Dietary and Department of
interventions have been successful in altering abundance, composition, and activity of gut microbiota that are relevant Epidemiology (Prof F B Hu),
Harvard T H Chan School of
for food metabolism and glycaemic control. In addition, mobile apps and wearable devices facilitate real-time
Public Health, and Channing
assessment of dietary intake and provide feedback which can improve glycaemic control and diabetes management. Division of Network Medicine
By integrating these technologies with big data analytics, precision nutrition has the potential to provide personalised (Prof F B Hu), Department of
nutrition guidance for more effective prevention and management of type 2 diabetes. Despite these technological Medicine, Brigham and
Women’s Hospital and Harvard
advances, much research is needed before precision nutrition can be widely used in clinical and public health settings.
Medical School, Boston, MA,
Currently, the field of precision nutrition faces challenges including a lack of robust and reproducible results, the USA
high cost of omics technologies, and methodological issues in study design as well as high-dimensional data analyses Correspondence to:
and interpretation. Evidence is needed to support the efficacy, cost-effectiveness, and additional benefits of precision Prof Frank B Hu, Department of
nutrition beyond traditional nutrition intervention approaches. Therefore, we should manage unrealistically high Nutrition, Harvard T H Chan
School of Public Health, Boston,
expectations and balance the emerging field of precision nutrition with public health nutrition strategies to improve
MA 02115, USA
diet quality and prevent type 2 diabetes and its complications. nhbfh@channing.harvard.edu

Introduction guidelines based on population averages may not be

In 2017, 425 million adults worldwide were living with
diabetes, a vast majority of whom had type 2 diabetes.1
The pronounced increase in prevalence during the past
few decades is a consequence of the global pandemic of
obesity driven by urbanisation and its related lifestyle
changes.2 Substantial evidence indicates that type 2
diabetes can be largely prevented through adherence to a
healthy lifestyle, which includes consumption of a
high-quality diet, regular exercise, and maintenance of a
healthy bodyweight.3 Type 2 diabetes is clinically
managed by healthy diets and lifestyles combined with
glucose-lowering agents that aim to prevent or delay both
acute symptoms of hyperglycaemia and complications of
the disease.4 As recommended by the Dietary Guidelines
for Americans5 and the American Diabetes Association,6
a healthy dietary pattern that protects against
type 2 diabetes is rich in fruits, vegetables (except
potatoes), whole grains, nuts, and legumes, and low in
refined grains, red or processed meats, and sugar-
sweetened beverages.7 Along with this dietary pattern, an
improvement in the quality of fats and carbohydrates
consumed is important.7 In practice, this can be achieved
by replacing saturated fat and high-glycaemic index
carbohydrates with unsaturated fats and carbohydrates
with a lower glycaemic index and higher fibre content.
Current dietary recommendations are based on
population averages and often do not take into account
individual variability in response to nutritional
components. Although successful in reducing the
population-level chronic disease burden,8 dietary
best suited for a given individual. In addition,
type 2 diabetes is a heterogeneous disease from a
genetic, pathophysiological, and clinical viewpoint.9
Current understanding of the pathophysiological
mechanisms of type 2 diabetes remains insufficient to
explain the large variability between individuals in both
the development and the clinical manifestations of the
disease.10,11 In addition, individual responses to dietary,
lifestyle, and pharmaceutical interventions varies
considerably. Recently, the concept of precision nutrition
(also known as personalised nutrition) has gained a
great deal of interest in the scientific community and
the general public.12 In this Review, we examine
precision nutrition and relevant evidence from
population-based studies, and we discuss promises and
challenges in the context of dietary prevention and
management of type 2 diabetes.
Goals of precision nutrition
The Precision Medicine Initiative, launched in 2015, aims
to provide safer and more effective ways to prevent and
treat disease.13 A key mission of this initiative is to “tailor
treatment and prevention strategies to people’s unique
characteristics, including their genome sequence,
microbiome composition, health history, lifestyle, and
diet”.14 Analogous to precision medicine, precision
nutrition adapts nutrition interventions and recom­
mendations on the basis of individual characteristics to
prevent and manage chronic diseases such as
type 2 diabetes. In a broader sense, precision nutrition

www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8 1

 Review

can also enable more precise dietary assessment and
disease risk stratification, both of which are fundamental
for more effective targeting of dietary approaches for
prevention and management of type 2 diabetes.
Recent advances in omics technologies and wearable
devices have improved the prospect of applying precision
nutrition to prevention and management of type 2 diabetes
(figure 1). The huge increase in genome-wide association
studies (GWAS) in the past decade has generated extensive
new knowledge about the genetic architecture of the
disease.15 High-throughput next-generation sequencing
technology has made whole-exome and whole-genome
sequencing studies feasible and has underpinned studies
of biological axes beyond the genome, such as the
transcriptome, epigenome, and microbiome. Mass
spectrometry and nuclear magnetic resonance have been
applied to analyse small-molecule metabolites in
biospecimens, allowing for a comprehensive assessment
of an individual’s metabolic status. Meanwhile, mobile
technologies and wearable devices can facilitate real-time
data collection of diet, lifestyle, and biochemical variables
and encourage individuals to actively participate in their
own behaviour change and disease management.
Precision nutrition can integrate data from emerging
technologies and traditional nutritional assessments into
epidemiological or dietary intervention studies of
type 2 diabetes to achieve several goals: to better under­
stand the mechanisms underlying different res­ponses by
individuals to a dietary exposure or inter­vention, in terms
of the risk of type 2 diabetes and glycaemic outcomes; to
achieve better assessment of dietary intakes and
nutritional status in free-living populations; to identify
novel biomarkers that are more effective than traditional
biomarkers at predicting risk of disease and its
complications; to identify new targets for lifestyle and
pharmacological interventions; and to provide person­
alised dietary and lifestyle guidance for more effective
prevention and management.

Diet and type 2 diabetes Measurement and mechanism Data integration and analysis Translation and intervention

9
Diet Questionnaires
5
Healthy 
eating 

plate  Precision nutrition

6
7 Big data analytics
Omics

13
2
Physical activity

4 10

3
Medication

8 11
Wearable devices 14

22·0 17·0

Type 2 diabetes

12
15

Figure 1: Conceptual framework for precision nutrition in prevention and management of type 2 diabetes
(1) General recommendations for healthy diets. (2) Dietary intake interacts with level of physical activity. (3) Dietary approaches interact with antidiabetic
medications in management of type 2 diabetes. (4) Various omics technologies, such as genomics, metabolomics, metagenomic and metatrascriptomic analysis of
the gut microbiota, and epigenomics, provide powerful tools for deep phenotyping individual characteristics and understanding mechanisms underlying diet and
type 2 diabetes. (5) Validated questionnaires such as food frequency questionnaires are the most important and feasible tools for measuring long-term usual diet in
nutritional epidemiological research. (6) Wearable devices and mobile apps provide objective and real-time diet and physical activity measurements. (7) Application
of omics technologies to improve dietary assessment in free-living populations. (8) Wearable devices provide continuous measures of blood glucose and other
physiological variables. Data input from (9) self-reported questionnaire-based dietary assessment tools in epidemiological studies, (10) omics studies, (11) wearable
devices, and (12) conventional clinical measures, such as fasting glucose and lipids. (13) Results derived by use of big-data analytics inform development and
application of precision nutrition. (14) Wearable devices and mobile apps provide useful tools for monitoring and implementing precision nutrition. (15) Precision
nutrition aims to provide personalised nutrition guidance to achieve more effective dietary prevention and management of type 2 diabetes.

2 www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8


Overview of recent advances in type 2 diabetes
omics studies
GWAS, and more recently exome sequencing studies,
have identified more than 100 loci reproducibly associated
with risk of type 2 diabetes and glycaemic traits.16 Most
identified loci have a small effect size and are com­
mon across populations, with a few low-frequency
exceptions.15,17,18 Causal variants have only been identified
for a few loci. These GWAS loci collectively explain less
than 10% of the heritability of the disease.19 Overall,
GWAS have not yet led to meaningful clinical advances
in prevention or management of type 2 diabetes.
Researchers have also discovered genetic variants directly
related to dietary intake and nutrient metabolism, such
as polyunsaturated fat intake,20,21 macronutrient intake,22
alcohol drinking,23 coffee consumption,24 and zinc
transport.25 Interestingly, many BMI loci identified
through GWAS are linked to hypothalamic function and
energy homoeostasis, and therefore closely related to
food intake.26 These findings suggest that taking into
account individual genotypes when formulating dietary
recommendations may be more effective in improving
nutritional status.
Studies on diet and changes in transcription and
methylation patterns have elucidated potential causal
variants of type 2 diabetes and the biological basis
underlying the effect of dietary exposure on predisposition
to the disorder. Most transcriptomic studies using
unbiased microarray and RNASeq approaches have
focused on changes in the transcriptome induced by
dietary interventions during a brief time period, such as
several days. A few studies have evaluated transcriptomic
response to long-term dietary interventions, such as the
Mediterranean diet,27 or they have examined differentially
expressed transcripts due to different habitual dietary
exposures.28 Genome-wide DNA methylation studies
comparing patients who have type 2 diabetes with healthy
controls found varying levels of DNA methylation in
pancreatic islets for thousands of CpG sites, corresponding
to a large number of genes, including many known
type 2 diabetes loci such as TCF7L2, FTO, and PPARG.29–31
Some genes implicated in these identified CpG sites also
displayed altered mRNA expression. These findings shed
light on the mechanisms underlying epigenetic regulation
of transcriptional activity contributing to β-cell function,
insulin secretion, and the development of type 2 diabetes.32
In recent years, high-throughput metabolomics has
been widely applied in population-based research on
type 2 diabetes. In a meta-analysis33 of eight prospective
studies including 8000 individuals (1940 cases of
type 2 diabetes), our group found statistically significant
positive associations of plasma concentrations of
branched-chain aminoacids (BCAAs), including leucine
and valine, and aromatic aminoacids (AAAs), including
tyrosine and phenylalanine, but inverse associations
with glycine and glutamine, with type 2 diabetes. These
metabolites are influenced by both dietary intake and
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Review
metabolism and therefore could be nutritional inter­
vention targets for prevention.
The application of next-generation sequencing
technologies (eg, shotgun metagenomic and meta­
transcriptomic sequencing) for comprehensive mapping
of microbes has offered new insights into the role of gut
microbiota in glycaemic control and pathobiology of
type 2 diabetes.34 Accumulating evidence suggests an
association between the overall composition and diversity
of the gut microbiota and type 2 diabetes,35 although
causality remains uncertain. In addition, the relative
abundance of specific gut microbes is linked to risk of
the disease.36 For example, increased abundance of
Akkermansia muciniphila has been associated with
improvement in glucose control and lower risk of type 2
diabetes.37,38
In summary, recent genomics studies have identified a
large number of type 2 diabetes loci that can be used to
characterise an individual’s genetic predisposition to
the disease. Metabolomics studies have identified
metabolites associated with type 2 diabetes that can be
potentially modified by diet. There is also increasing
evidence that the gut microbiome plays a role in
glycaemic control and pathophysiology of the disease.
These findings provide a scientific basis for the use of
personalised risk characterisation and stratification in
dietary interventions.
Dietary assessment in free-living populations
and causal inference
Dietary assessment in free-living populations is
challenging because of random and systematic errors in
commonly used self-report tools. Omics technologies
offer the potential for more accurate assessment of
dietary intake and nutritional status. Improvements in
the quantification of dietary intake, characterisation of
dietary patterns, and assessment of adherence to dietary
interventions are fundamental in building an evidence
base to support precision nutrition.
Metabolomics analysis has the potential to capture the
complexity of habitual diet better than do traditional
single biomarkers. New metabolomics technologies are
able to profile a large number of metabolites derived from
ingestion and absorption of foods, measure endogenous
biotransformation of nutrients by both the host and gut
microbiota, and uncover diet-induced metabolic response.
Several studies have identified new biomarkers for acute
food exposure, short-term food or nutrient intake, and
long-term dietary intake.39,40 Urinary proline betaine and
4-hydroxy-proline betaine have been identified as
biomarkers for citrus foods. Plasma ether-linked
phospholipids and plasmalogens, dihexosylceramide,
and GM3 ganglioside are biomarkers that can distinguish
between major dietary fat sources. Plasma and urinary
anserine is a marker for chicken whereas plasma and
urinary trimethylamine-N-oxide and carnitines are
markers for red meat and fish.41,42 More recently,
 Review
Garcia-Perez and colleagues43 identified a combination of
multiple metabolites, including those showing higher
intake of fruits (eg, hippurate, tartrate, and glycolate),
vegetables (eg, N-acetyl-S-methyl-cysteine sulphoxide and
S-methylcysteine sulphoxide), fish (dimethylamine), and
lean white meat (1-methylhistidine and 3-methylhistidine).
These metabolite combinations were indicative of overall
dietary pattern in a controlled crossover feeding study
and were validated in a subpopulation of cohort studies.43
Andersen and colleagues44 identified combinations of
urinary metabolites that quantified compliance to either a
new Nordic diet or an average Danish diet.
Several studies have used metabolomics to uncover
novel dietary patterns and understand the role of diet in
prevention of type 2 diabetes.45–49 Floegel and co-
workers46 made use of serum metabolites previously
linked to risk of type 2 diabetes to derive dietary patterns
in the EPIC-Potsdam study.46 A dietary pattern with high
intake of red meat and low intake of whole-grain bread
and tea was associated with a metabolic profile high in
BCAAs and AAAs. A second dietary pattern with high
intake of coffee, cake, cookies, and canned fruit and fish
was linked to a metabolic profile (including many
phosphatidylcholines with a high degree of unsatu­
ration) associated with low risk of type 2 diabetes.
Metabolomics analysis has also been applied to assess
long-term adherence to the dietary intervention in the
PREDIMED trial.50 In this trial, Vazquez-Fresno and
colleagues found multiple urinary metabolites,
including BCAAs, creatine, creatinine, oleic acid, and
metabolites related to carbohydrate and gut microbiota
metabolism, that could reflect adherence to the
Mediterranean diet during the 3 year intervention.
Overall, current metabolomics platforms show only
modest ability to distinguish different dietary patterns
and have not yielded biomarkers with high sensitivity and
specificity for food or nutrient intake. This failure is partly
because metabolites reflect not only dietary intakes, but
also metabolic activity, the microbiome, and genetic
background. Therefore, these technologies are unlikely to
replace traditional assessment tools such as validated
dietary questionnaires and well established nutritional
biomarkers. However, they can serve as complementary
tools for measuring dietary intakes in observational
studies and assessing compliance to dietary interventions.
Recently, the Mendelian randomisation method has
become popular in nutritional epidemiological studies to
determine the causal effect of dietary intake as predicted
by genotypes on health outcomes. Mendelian random­
isation mimics a natural randomised controlled trial
because genotypes are assigned to individuals randomly at
birth. Therefore, this method can largely eliminate
unmeasured confounding and reverse causation, which
are two major biases in epidemiological studies. A recent
study used a single nucleotide polymorphism (rs6754311)
as a proxy for milk intake; each allele increment was
associated with a 66 g increase in daily milk consumption.51
4 www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8
Genetically predicted milk intake was not significantly
associated with risk of type 2 diabetes or multiple glycaemic
traits. Genetic markers may also be indicators of variation
in nutrient metabolism. Several research groups have used
genetic variants in the fatty acid desaturases gene family as
surrogates of the activity of Δ5 desaturase (FADS1) and Δ6
desaturase (FADS2), key enzymes in the metabolism of
polyunsaturated fatty acids. Genotype-predicted
Δ5 desaturase activity was inversely associated with risk of
type 2 diabetes whereas genotype-predicted Δ6 desaturase
activity was positively associated,52 suggesting a causal
effect of the activity of these enzymes on development of
the disease and a mediating role in the effect of
polyunsaturated fatty acid intake on risk.
It is noteworthy that only a few genetic variants have
been found to strongly predict and thus serve as good
proxies for dietary intake and nutritional status. In
addition, Mendelian randomisation analyses can be
subject to confounding by population stratification,
pleiotropy of genetic effects, and inadequate statistical
power.53
Identification of susceptible or responsive
individuals through gene–diet interactions
Type 2 diabetes is a complex phenotype that is influenced
by both genetic and environmental factors as well as
their interactions.54 Studies that apply gene–diet inter­
action findings to precision nutrition could provide a
scientific basis for genotype-based precision nutrition.
Some classic examples of translating genetic information
into personalised nutrition are dietary modifications for
individuals with mutations in the phenylalanine
hydroxylase gene that lead to phenylketonuria55 and
mutations in the lactase gene affecting lactase
persistence.56 However, the genetic basis of these dietary
modifications usually involves single-gene mutations
with large effect sizes, whereas such clear examples do
not exist for type 2 diabetes.
Earlier studies of gene–diet interactions for type 2
diabetes focused on candidate genetic variants.57 This
approach did not generate robust evidence,58 as shown by
Li and colleagues,59 who were unable to replicate eight
published statistically significant inter­ actions between
single-gene variants and macro­nutrient intake in relation
to type 2 diabetes in a large cohort from the EPIC-InterAct
study. Since 2008, investigators have been using polygenic
scores, which are combinations of multiple susceptibility
loci identified by GWAS. That these scores reflect the
polygenic nature of type 2 diabetes is crucial when
exploring gene–diet interactions for this disease. Some
evidence supports an interaction between a polygenic
score of ten type 2 diabetes risk alleles and a western
dietary pattern, characterised by high intakes of red and
processed meat, butter, high-fat dairy products, and refined
grains.60 In a recent study, Langenberg and co-workers61
tested the interaction between a polygenic score of
49 type 2 diabetes loci and a Mediterranean dietary pattern

in EPIC-InterAct but found no statistically significant
interaction effect. However, healthy dietary patterns have
been found to mitigate the effects of genetic variants on
obesity62 and coronary heart disease.63 On the other hand,
unhealthy diet habits, such as regular consumption of
sugar-sweetened beverages, fried food, and saturated fat
intake, were found to exacerbate the effects of genetic
variants on obesity.64–67 Evidence on gene–diet interactions
for obesity is crucial for prevention of type 2 diabetes given
that a small reduction in bodyweight will lead to clinically
meaningful improvement in glycaemic control.68 In
addition, robust evidence indicates that the FTO variant
can modify the association between physical activity,
another major lifestyle risk factor of type 2 diabetes, and
body adiposity.69 These findings imply that individuals with
greater genetic predispositions might benefit more from
interventions to improve diet quality or physical activity,
although this hypothesis has not been explicitly tested in
randomised trials.
In the Diabetes Prevention Program (DPP), Florez and
colleagues70 found that lifestyle intervention and
metformin treatment attenuated the effect of the TCF7L2
genotype on the progression from prediabetes to
type 2 diabetes, although the interaction between the
genotype and interventions was not statistically significant
(table). The POUNDS LOST trial investigated interactions
between intervention diets varying in macronutrient
composition and type 2 diabetes genetic risk scores on
markers of glucose homoeostasis.71,72 Among white
participants, those with a lower genetic risk score showed
more favourable responses to low-protein diets, including
greater decreases in fasting insulin, HbA1c, and
homoeostatic model assessment (HOMA) for insulin
resistance, and a lesser increase in HOMA for β-cell
function, than did those with a higher risk score
within 2 years of follow-up.71 In response to low-fat diets,
participants with a lower genetic risk score showed more
positive responses in fasting glucose, insulin resistance,
and insulin sensitivity during 6 months of follow-up.72
Only a few observational studies and randomised
controlled trials have tested gene–diet interactions in
relation to type 2 diabetes and glycaemic traits. Although
there is some indication that individuals with varying
genotypes respond differently to dietary interventions in
terms of glycaemic markers, few independent
replications exist. Overall, current evidence is not
sufficient to make personalised dietary recommendations
for diabetes prevention or manage­ment based on genetic
information. Several limitations of current studies are
worth noting. First, some studies were cross-sectional
and therefore were susceptible to reverse causation and
had insufficient control of confounding factors. Second,
measurement errors in self-reported dietary intake,
pathological heterogeneity of type 2 diabetes, and modest
effect sizes of genetic variants collectively lead to limited
statistical power that may obscure true interaction
effects, leading to false negative findings. Third,
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Review
gene–diet interactions have been difficult to replicate,
probably because of heterogeneity in diet and lifestyle
across populations, insufficient statistical power, and
lack of standardisation in dietary assessment and
analytical approaches.
Identification of nutritional intervention
targets for prevention of type 2 diabetes
In addition to assessing individual metabolic state,
metabolomics can capture metabolic changes in response
to extrinsic exposures such as dietary intake and can
uncover metabolic pathways through which dietary
exposures influence risk of type 2 diabetes. Floegel and
colleagues78 identified several metabolic networks that
correlated with both dietary intake and metabolic disease
outcomes. For example, metabolic networks consisting of
particular metabolites within the subclasses of phos­
pholipid, sphingomyelin, lyso-phosphatidylcholines, and
acyl alkyl-phosphatidylcholines were positively associated
with coffee intake, but inversely associated with risk of
obesity and type 2 diabetes,78,79 delineating potential
pathways through which coffee may be protective.
Recent studies within randomised controlled trials have
used metabolomics to provide novel evidence to explain
heterogeneity in individual responses to a specific dietary
intervention. In a study based on two weight-loss trials—
the POUND LOST trial and the DIRECT trial—weight-
loss diets decreased metabolites that were associated with
risk of type 2 diabetes, including BCAAs and AAAs.74
More importantly, the observed decreases in the
circulating aminoacid metabolites were predictive of
improvement in insulin resistance inde­pendent of weight
loss. In the DPP, Walford and colleagues75 found that a
lifestyle intervention that incorporated dietary
modification was effective in in­ creasing betaine
concentration from baseline to 2 year follow-up, which
predicted lower risk of type 2 diabetes. In a subpopulation
from the PREDIMED trial, a Mediter­ranean diet rich in
extra-virgin olive oil decreased plasma concentrations of
BCAA (Ruiz-Canela M, University of Navarra, personal
communication). Moreover, a decrease in BCAA
concentrations from baseline to year 1 predicted lower risk
of disease in the remainder of the follow-up period,
whereas baseline BCAA concentrations modified the
effect of the Mediterranean diet intervention on risk of
type 2 diabetes.
Metabolomics techniques are powerful tools for
uncovering novel biomarkers linking dietary components
and risk of type 2 diabetes, which can be useful for
distinguishing responders from non-responders to a
dietary intervention. However, current studies have
generally focused on several candidate metabolites or a
limited number of targeted metabolites, and there are
few independent replications of findings. Whether the
iden­tified metabolites represent causal biological
pathways linking dietary intake to risk of the disease is
largely unknown. Metabolomics studies that cover all
 Review

Topic Study population Intervention Duration Key findings

Florez et al70 Interaction between
polymorphisms of TCF7L2
and lifestyle intervention
Huang et al71 Interaction between genetic
risk score of 31 type 2
diabetes GWAS SNPs and
dietary intervention varying
in protein content
Wang et al72 Interaction between a genetic 733 overweight or obese nondiabetic
risk score of 14 fasting adults from the POUNDS LOST trial
glucose-associated SNPs and
dietary intervention varying
in fat content
The Look Interaction between
AHEAD Research glutamate-ammonia ligase
Group73 gene polymorphism and
lifestyle intervention
Zheng et al74 Effect of dietary intervention
varying in protein content on
circulating metabolites and
subsequent effect on glucose
homoeostasis
Walford et al75 Effect of lifestyle intervention
on circulating metabolites
and subsequent effect on risk
of type 2 diabetes
Ruiz-Canela Effect of Mediterranean diet
(University of intervention on circulating
Navarra, metabolites and subsequent
personal effect on risk of type 2
communication) diabetes
Kovatcheva- Identification of gut microbial 39 healthy individuals
Datchary76 signatures in response to
barley kernel-based bread
intervention
Zeevi et al77 Comparison of effect of a
personalised diet with
traditional dietary advice
3548 overweight adults with elevated Lifestyle (including intensive
fasting glucose and impaired glucose training in diet) vs placebo pills; no
tolerance but without diabetes from the intensive motivational counselling
Diabetes Prevention Program on lifestyle
596 overweight or obese non-diabetic Low-protein vs high-protein diets
white adults from the POUNDS LOST trial
Low-fat vs high-fat diets
3845 overweight or obese participants Intensive lifestyle intervention
with type 2 diabetes from the Look AHEAD (including dietary modification) vs
trial diabetes support and education
programme
774 adults from the POUNDS LOST trial Average-protein diets vs high-
and 318 adults from the DIRECT trial; all protein diets
participants were overweight or obese
without diabetes
757 overweight adults with elevated Lifestyle (including intensive
fasting glucose and impaired glucose training in diet) vs placebo pills; no
tolerance but without diabetes from intensive motivational counselling
Diabetes Prevention Program on lifestyle
892 participants with baseline high Mediterranean diet rich in extra-
cardiometabolic risk but nondiabetic from virgin olive oil vs low-fat diet
the PREDIMED trial
Barley kernel-based bread vs white
wheat flour bread (crossover
design)
800 participants (initial cohort); A personalised diet designed with a
100 participants (validation cohort); machine-learning algorithm that
26 participants (randomised controlled trial) integrated blood variables, dietary
habits, anthropometric data,
physical activity, and gut
microbiota, compared with
traditional dietary advice
3 years Effect of risk-conferring TT genotype at
(average) rs7903146 was stronger in the placebo group
than in the lifestyle-intervention group, but
no significant genotype-intervention
interaction in relation to incident type 2
diabetes
2 years Significant interactions between
intervention diet varying in protein content
and a diabetes genetic risk score on fasting
insulin, HbA1c, HOMA-B, and HOMA-IR at
2 years (pinteraction= 0·02, 0·04, 0·01, and 0·05,
respectively).
2 years Significant interaction between genetic risk
score and dietary fat on 6 month changes in
fasting glucose, HOMA-IR, and insulin
resistance after multivariable adjustment
(pinteraction=0·007, 0·045, and 0·028,
respectively)
Median No significant interaction between lifestyle
9·6 years intervention and the gene for the incidence
of cardiovascular disease among individuals
with type 2 diabetes
2 years Average-protein diets showed stronger effects
than did high-protein diets on reducing
concentrations of BCAAs and AAAs at
6 months independent of weight change.
Decreases in circulating aminoacid metabolites
were predictive of improvement in insulin
resistance independent of weight loss
3 years Lifestyle intervention that incorporated
(average) dietary modification was effective in
increasing betaine level from baseline to
2 year follow-up, which predicted lower
incidence of type 2 diabetes
4·8 years Mediterranean diet rich in extra-virgin olive oil
(average) led to a decrease in plasma BCAA and
attenuated the positive association between
baseline BCAA and incidence of
type 2 diabetes. Changes in BCAA from
baseline to year 1 were positively associated
with risk of type 2 diabetes
3 days Increased abundance of Prevotella copri after
consumption of barley kernel-based bread
1 week Personalised diets showed better
performance in lowering postprandial blood
glucose, fluctuations in blood glucose, and
maximum postprandial blood glucose,
compared with traditional dietary advice

GWAS=genome-wide association study. SNPs=single nucleotide polymorphisms. HOMA-B=homoeostasis model assessment of β-cell function. HOMA-IR=homoeostasis model assessment of insulin resistance.
BCCAs=branched-chain aminoacids. AAAs=aromatic aminoacids.

Table: Summary of key randomised controlled trials on precision nutrition and prevention and management of type 2 diabetes

detectable, untargeted metabolites are needed to provide
a less biased understanding of potential metabolic
pathways. Addition­ally, replication of statistically signifi­
cant findings in independent populations, and functional
studies of iden­tified metabolites are needed to provide
causal evidence supporting the role of meta­bolites as
intervention targets.
Recent studies have demonstrated that both short-term
dietary changes and long-term habitual diet could
influence the composition of gut microbiota.76,80–83 In a
5 day feeding study, David and coworkers80 showed that
high intakes of animal fat and protein increased
bile-resistant bacteria including genera of Alistipes,
Bilophila, and Bacteroides, and decreased types of bacteria

6 www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8


with an enhanced capacity to ferment polysaccharides,
including Roseburia spp, Eubacterium rectale, and
Ruminococcus bromii. Two recent studies found that
long-term intakes of various dietary factors were
associated with the diversity and composition of gut
microbiota.81,83 Hallmarks of a western-style dietary
pattern, including sugar-sweetened beverages, higher
energy intake, snacking, and whole milk were associated
with lower microbiota diversity, whereas consumption of
coffee, tea, and red wine was associated with high
microbiota diversity.
Recent evidence suggests that dietary interventions
may affect glycaemic control through modification of the
composition of gut microbiota. After a 6 week calorie-
restricted diet enriched with fibre and protein,38 the
abundance of A muciniphila, a mucin-degrading
bacterium, was inversely associated with measures of
fasting glucose and insulin sensitivity in 49 participants
in France. Baseline abundance of this organism appeared
to modify the effect of diet on insulin sensitivity markers.
In a study of 39 healthy participants in Sweden,
Kovatcheva-Datchary and colleagues76 found that the ratio
of Prevotella spp to Bacteroides spp was statistically
significantly higher in participants who showed improved
glucose metabolism after the 3 day intervention of barley
kernel-based bread than in those who did not show
improved glucose metabolism.
By combining metabolomics and the gut microbiome,
Wu and colleagues84 provided some early mechanistic
evidence to explain heterogeneous responses to dietary
pattern in a cross-sectional study of 15 vegans and
six omnivores. The investigators found that a plant-based
diet was necessary but not sufficient for the bacterial
production of short-chain fatty acids, a group of metabolites
implicated in host metabolic regulation and risk of
type 2 diabetes.85 A high yield of short-chain fatty acids
required high enrichment of genera such as Prevotella, but
low abundance of Ruminococcus bromii.
Thus, there is increasing evidence that diet has both
short-term and long-term influences on composition of
the gut microbiota. Certain dietary interventions,
particularly plant-based high-fibre diets, may be able
to modify specific types of gut microbes implicated
in regulation of glucose metabolism. Integrating meta­
bolomics and gut microbiome technologies can reveal
the functional activity of gut microbiota and the role of
gut microbes in modifying individual responses to a
dietary exposure. However, research on gut microbiota is
still at a nascent stage and is not ready for translation
into clinical practice. Existing studies are limited by
insufficient statistical power, cross-sectional study
design, and lack of information on functional activity and
strain-level variation of the gut microbiota. Future large
studies within prospective cohorts and long-term
randomised controlled trials are needed to examine the
modifiable capacity of the gut microbiome and its role in
the prevention and management of type 2 diabetes.
www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8 7
Review
Personalised nutrition for the management of
type 2 diabetes
The use of omics tools to elucidate differing individual
responses to dietary exposures, in terms of the progression
of type 2 diabetes or the onset of associated complications,
seems highly relevant for personalised nutrition for the
management of the disease. However, such evidence is
very sparse. The Look AHEAD randomised trial compared
the effect of an intensive lifestyle intervention with
diabetes support and an education programme on
cardiovascular disease in patients with type 2 diabetes. A
recent study investigated whether the effect of the
intensive lifestyle intervention varied across different
genotypes of a genetic variant (s10911021) related to
coronary heart disease, but failed to identify statistically
significant interaction effects.73 Numerous antidiabetic
medications with different mechanisms of action add
another layer of complexity to studies on personalised
nutrition in patients with type 2 diabetes.86 For example,
metabolomics studies have found that metformin and
sulphonylurea affect the circulating metabolome pro­
foundly.75,87,88 Some of the identified metabolites, such as
sphingomyelins, overlap with metabolomic signatures of
dietary intakes, suggesting that antidiabetic medications
may potentially interfere with the effects of dietary intakes
on multiple metabolic pathways. Additionally, recent
studies suggest that a large proportion of the previously
identified gut microbial signatures associated with
type 2 diabetes can be explained by metformin use89 and
that the effects of dietary interventions on gut microbiota
are masked by metformin.90 Beyond these glucose-lowering
agents, some specific characteristics of type 2 diabetes,
such as duration, severity, comorbidities (eg, renal or
hepatic impairment), and pathophysiology of the disease
(eg, the relative contributions of the defect in insulin
secretion and insulin resistance), are also important
considerations for studying and designing personalised
nutrition approaches for the management of type 2
diabetes. However, to our knowledge, no studies have
comprehensively explored how these factors modify the
responses of the human body to dietary interventions to
influence the progression of the disease.
Integrated omics technologies and big-data
analytics
Precision nutrition requires integration of multiple kinds
of omics data as well as information from both traditional
sources, such as questionnaire interviews and standard
clinical tests, and modern sources such as electronic
medical records, mobile apps, and wearable devices.91,92
New bioinformatics tools for data analysis and
visualisation, such as big-data analytics, are imperative
given the recent increase in the volume and complexity of
available data. However, integration of data from multiple
disparate sources and the application of big-data analytics
have not yet provided valuable physiological insights that
can be used in clinical practice. Researchers using these
 Review

A
Per person profiling Computational analysis
Gut microbiome Diary (food, sleep, physical activity)
16S rRNA Using smartphone-adjusted website Main cohort PPGR prediction
Metagenomics 5435 days, 46 898 meals, 9·8 million calories, 2532 exercises
100 Continuous glucose monitoring
Blood tests Using a subcutaneous sensor (iPro2)
130 000 hours, 1·56 million glucose measurements 800 participants
Questionnaires
Standardised meals (50 g available carbohydrates)
Food frequency Validation cohort Dietary intervention
Lifestyle Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Medical
G G F

Anthropometrics Bread Bread Bread Bread Glucose Glucose Fructose

and and 100 participants 26 participants
butter butter

B C
* † ‡ ‡ ‡ * ‡ * † ‡ ns ns * ‡ * * ‡ ns † † § § § ns ‡ ns ‡ ‡
140 100
Bad diet week
120 Good diet week
80
PPGR (iAUC, mg/dL.h)

PPGR (iAUC, mg/dL.h)

100

80 60

60 40
40
20
20

0 0
P6 P10 P3 P8 P2 P5 P9 P4 P1 P11 P7 P12 E8 E7 E9 E4 E14 E11 E10 E12 E5 E3 E2 E1 E6 E13

rt
or

pe
ict

Ex
ed
Predictor-based arm Expert-based arm

Pr
Figure 2: Personalised nutrition in reducing postprandial blood glucose
(A) Illustration of the experimental design of Zeevi and colleagues.77 (B) Left, mean postprandial glycaemic responses to personalised dietary intervention (good diet)
vs control diet (bad diet), and right, traditional dietary advice (good diet) vs control diet (bad diet) at each timepoint of intervention period (by weeks). (C) Left, mean
postprandial glycaemic responses to personalised dietary intervention vs control diet, and right, traditional dietary advice vs control diet. PPGR=postprandial glucose
response. Good diet=meals predicted to have low postprandial glycaemic responses. Bad diet=meals predicted to have high postprandial glycaemic responses.
*p<0·001, †p<0·01, ‡p<0·05, §p<0·1, ns=not significant (Mann-Whitney U test). iAUC=incremental area under the curve. Adapted from Zeevi and colleagues,77 by
permission of Elsevier.

new methods have faced challenges including issues with continuous glucose monitor, physical examinations, blood
incomplete and unreliable input data, as well as tests, and 16S rRNA metagenomics profiling. The
misleading interpretations of findings owing to a lack of investigators reported that nutrition interventions based
expert knowledge. In addition, big data usually require on this algorithm were more effective in reducing
many statistical tests which create an increased chance of postprandial blood glucose than was traditional dietary
false-positive results. Therefore, independent replication advice. Although this proof-of-concept study is an
of findings has become even more important.93 important first step, several methodological issues
Several recent studies combined multiple data sources complicated the interpretation and translation of the
and applied big-data analytics to inform personalised findings. One of the key limitations was that the authors
nutrition interventions. In one example, Price and were unable to demonstrate whether the observed high
colleagues94 showed the benefits of combining infor­mation variability in postprandial glycaemic responses was due to
collected by genomics, metabolomics, proteomics, intra-individual or interindividual variability.95 The clinical
microbiome analysis, and wearable devices in an integrated applications of this approach are challenging because of
framework to develop personalised dietary interventions. the huge amounts of data that need to be collected,
In another study, Zeevi and co-workers77 examined the analysed, and interpreted. In addition, although wearable
utility of personalised nutrition in reducing postprandial devices showed the potential for scalable use in
blood glucose (figure 2). They developed a machine- continuously monitoring health behaviours and motivating
learning algorithm for predicting postprandial glycaemic behavioural changes of participants in the short term, little
responses based on integrated data on dietary intake, is known about their sustainability and effectiveness in the
biomarkers, physical activity, sleep, anthropometric long term.96 Long-term studies of this type that have a
variables, and gut microbiota that were collected through more refined study design as well as simple and
instruments including questionnaires, smartphones, a cost-efficient data collection tools are clearly needed.

8 www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8


Conclusions and future directions
Rapidly evolving omics technologies have offered
unparalleled opportunities to assess individual charac­
teristics including the genome, epigenome, metabolome,
and microbiome, which can be integrated into nutritional
epidemiological studies and dietary intervention trials. In
addition, mobile apps and wearable devices have the
potential to improve real-time assessment of dietary intake
and provide feedback, thus improving glycaemic control
and management of type 2 diabetes (figure 1). Despite
these advances, precision nutrition is still in its infancy
and much research is needed before it can be widely used
in clinical and public health settings. Major challenges
exist in applying precision nutrition to the prevention and
management of type 2 diabetes, including a lack of robust
and reproducible results, the high cost of omics
technologies, and methodological issues in study design
and high-dimensional data analyses. The cutting-edge
omics technologies have not yet delivered reliable and
clinically scalable biomarkers for predicting both disease
outcomes and interindividual variability to a specific
dietary exposure. For example, when biomarkers recently
identified by GWAS and metabolomics studies were added
to a risk prediction model of traditional risk factors, the
model showed only a modest improvement in predicting
risk of type 2 diabetes.97 Likewise, metabolomics and
microbiome technologies are not yet sensitive and specific
enough for use in clinical management of type 2 diabetes,
although they are rapidly evolving and might be
incorporated into personalised nutrition in the future, as
demonstrated by the proof-of-concept study done by Zeevi
and colleagues.77 Various commercial companies have
started to market personalised nutrition assessment and
treatment based on genotypes, but the benefits of such
approaches on improving diet quality and health outcomes
have not been demonstrated. Appropriately designed
intervention studies are needed to perform head-to-head
comparisons between personalised nutrition interventions
and traditional approaches such as nutrition advice
targeting behavioural changes. Furthermore, the value of
personalised nutrition depends on whether the additional
cost and complexity incurred by new laboratory tests and
modification of interventions can be offset by its benefits.98
However, no comprehensive attempts have been made to
rigorously evaluate efficacy, cost-effectiveness, and sus­
tainability of personalised nutrition in the prevention and
management of type 2 diabetes.
To use precision nutrition to prevent and manage
type 2 diabetes, it is important to address the current
challenges by establishing a solid evidence base. This can
be accomplished through the emphasis of more rigorous
study design, integration of high-dimensional big data
from various sources, development of computational
approaches for handling big data, and reduction in the cost
of the omics analyses. Although this Review is focused on
biomarkers identified by omics technologies, individual
dietary choices are likely to depend on a range of broader
www.thelancet.com/diabetes-endocrinology Published online February 9, 2018 http://dx.doi.org/10.1016/S2213-8587(18)30037-8 9
Review
Search strategy and selection criteria
We searched PubMed and Google Scholar, mainly for original
research articles and meta-analyses or systematic reviews
written in English, published from inception to July 31, 2017.
We used the search terms “type 2 diabetes”, “nutrition”,
“diet”, “prevention”, “diabetes management”, “genetics”,
“genomics”, “metabolomics”, “gut microbiome”,
“microbiota”, “gastrointestinal microbiome”,
“metagenomics”, “transcriptomics”, and “epigenetics”. We
mainly selected publications in the past 5 years but did not
exclude frequently referenced and highly relevant older
publications. Additionally, we screened the references of the
studies identified by this search strategy and selected those
articles that we judged relevant to our review.
influences including health-related lifestyles (eg, exercise,
television watching, and sleep) and socioeconomic
characteristics (eg, income, education, social networks,
and neighbourhood food environment).99 These factors
may play a more important role than biomarkers in
modifying an individual’s response to a dietary exposure
and should receive equal or even higher priority in the
process of developing evidence-based precision nutrition.
Thus, it is essential that population-wide, public health
approaches, such as nutrition education, food and health
policy, and government regulation and legislation, remain
fundamental strategies for improving overall diet quality
and nutritional status. It is important to ensure that
investment in precision nutrition is balanced against the
limited resources available for public health nutrition.
Contributors
DDW performed the literature search. DDW and FBH designed the
study and wrote the manuscript.
Declaration of interests
FBH reports personal fees from Metagenics and grants from California
Walnut Commission, outside the submitted work. DDW declares no
competing interests.
Acknowledgments
DDW’s research is supported by a postdoctoral fellowship from the
American Heart Association (16POST31100031). FBH’s research is
supported by National Institutes of Health grants HL60712, HL118264,
and DK102896.
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