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Prediabetes in youths: mechanisms and biomarkers

Ram Weiss, Nicola Santoro, Cosimo Giannini, Alfonso Galderisi, Giuseppina Rosaria Umano, Sonia Caprio

Obesity has been estimated to decrease life expectancy by as little as 08 years to as much as 7 years, and is the second Lancet Child Adolesc Health 2017
leading cause of preventable deathafter smokingin the USA. Alongside the increase in the prevalence of obesity, Published Online
prediabetes and type 2 diabetes have become more common in adolescents. Yet, little is known about the pathogenesis September 26, 2017
of these conditions in the paediatric population and how prediabetes could be detected at an early stage to prevent
progression towards overt diabetes. In this Review, we summarise knowledge on the pathophysiology of prediabetes
Department of Pediatrics,
and type 2 diabetes in adolescents, and describe how biomarkers of -cell function might help to identify individuals Ruth Rappaport Childrens
at risk of progression from normal glucose tolerance towards prediabetes and overt type 2 diabetes. To better Hospital, Rambam Medical
understand and treat this disease, new therapeutic strategies will need to be explored and developed, and more Center, Haifa, Israel
(R Weiss MD); Division of
sensitive and specific biomarkers are needed to allow earlier detection of prediabetes.
Pediatric Endocrinology,
Department of Pediatrics, Yale
Introduction is not specifically within at-risk groups.1014 For example, University School of Medicine,
In paediatric populations, the increasing prevalence of the prevalence of impaired fasting glucose in obese New Haven, CT, USA
(N Santoro MD, C Giannini MD,
obesity is being accompanied by a rise in the prevalence of children ranges from 1% in Italy15 and 4% in Germany,
A Galderisi MD, G R Umano MD,
type 2 diabetes. The SEARCH for Diabetes in Youth study to 17% in Sweden (all with the use of ADA criteria);14 in Prof S Caprio MD); and
group1 estimated that the prevalence of type 2 diabetes in the USA, reported prevalence ranges from 29% (WHO Department of Womens and
young people (<20 years) in the USA might almost criteria) to 1547% (ADA criteria).11,16,17 Impaired fasting Childrens Health, University of
Padova, Padova, Italy
quadruple between 2010 and 2050. Type 2 diabetes in glucose was reported in a small proportion (<5%) of
(A Galderisi)
children and adolescents is highly heterogeneous in terms the obese paediatric population in Mexico,18 India,19
Correspondence to:
of disease onset and progression. Since onset is and mainland China,20 compared with 28% of obese Prof Sonia Caprio, Division of
progressive, overt diabetes is preceded by a range of adolescents in Taiwan.21 In the United Arab Emirates, Pediatric Endocrinology,
glucose-related phenotypes characterised by a progressive which has one of the highest prevalences of adult type 2 Department of Pediatrics, Yale
University School of Medicine,
decline in -cell function. These conditions clinically diabetes worldwide, 12% of overweight and obese
New Haven, CT 06520, USA
define a state known as prediabetes, and are highly children have impaired fasting glucose.10 Several
prevalent in obese children and adolescents.2 In this challenges arise when attempting to compare and
Review, we will focus on the main elements that alter interpret these prevalence data, since the sample
glucose metabolism early in the course of diabetes populations were recruited from different settings
development and on genetic and developmental factors (eg, whole population vs obesity clinic). Additionally, in
that predispose an individual to prediabetes and diabetes. epidemiological studies involving large samples, some
participants might not have truly fasted when fasting
Prevalence of youth-onset prediabetes glucose was measured, causing an overestimation of the
Prediabetes is a broad expression that describes multiple prevalence. Similarly, the presence of impaired glucose
facets of altered glucose metabolism, including impaired tolerance can vary across repeated sampling within a
fasting glucose, impaired glucose tolerance, elevated timeframe of weeks,22 possibly because whole-body
glycated haemoglobin (HbA1c), or combinations of these.3,4 insulin sensitivity can be affected by participant
Each of these conditions, whether detected in childhood or characteristics, such as minor infection or phases of the
adulthood, confers an increased risk of developing type 2 menstrual cycle. However, arguably, a single detection
diabetes, as well as cardiovascular diseases, over time.
Importantly, these conditions are not interchangeable and
each represents specific alterations in glucose metabolism. Key messages
The emerging rise in the prevalence of prediabetes in Prediabetes in obese children involves inadequate insulin
children and adolescents has paralleled the rise in secretion in the presence of substantial insulin resistance
childhood obesity seen over the past three decades.5 Strong associations between lipid partitioning in
The recorded prevalence of prediabetes depends on insulin-responsive tissues (such as the liver and muscle)
the conditions and tools chosen for screening, the and whole-body insulin resistance have been identified
population studied, pubertal status, andimportantly The development of prediabetes consists of multiple
the definitions used. Impaired fasting glucose is defined metabolic defects that involve gut-hormone profiles,
as above 56 mmol/L by the American Diabetes hyperglucagonaemia, and reduced glucose effectiveness
Association (ADA)6 and above 61 mmol/L by WHO.7 Genome-wide association studies have identified
As a result, the recorded prevalence of impaired glucose single-nucleotide polymorphisms that are associated with
tolerance in obese children and adolescents ranges tissue-specific insulin resistance, -cell dysfunction, or
from 1% to 30%,2,8,9 whereas the prevalence of impaired both, making individuals with these variants more prone
fasting glucose has a broader range in not only obese to the adverse metabolic effects of obesity
children, but also the general adolescent population that Published online September 26, 2017 1


of impaired glucose tolerance, even if not repeated, coordinated hormonal (insulin and glucagon), neural,
already indicates that the cells of the individual have and metabolic activity in all organs and tissues involved
inadequate function and pronounced insulin resistance. in glucose metabolism. Insulin secreted from cells
Because the detection of prediabetes is highly dependent and glucagon secreted from cells regulate glucose
on the tools used and the population studied (including metabolism. The timely secretion of insulin and its
their pubertal status), prediabetes should not be viewed as target organ action lead to the clearance of glucose from
a single entity. To this end, in 2010, the ADA published the circulation, thus preventing hyperglycaemia. This
revised recommendations on the use of HbA1c to diagnose clearance also provides a source of energy for immediate
prediabetes and diabetes.23 These recommendations were use or for storage in muscles, adipose tissues, and the
based on results from cross-sectional and longitudinal liver. Normal glucose metabolism depends on the
studies showing an association between elevated HbA1c physiological interaction between insulin secretion and
and diabetes at baseline, or a long-term association insulin action; for type 2 diabetes to develop, defects in
between increased HbA1c and the risk of diabetes and both are usually present.30
diabetes-related comorbidities in adults.2426 In
1156 otherwise healthy adolescents, 21% were found to be The role of insulin secretion
within the at-risk for diabetes range (5764%; 3946 Insulin secretion is a biphasic process (figure 1), in which
mmol/mol).27 Furthermore, the diagnosis of diabetes the first phase is the immediate release of a restricted
using HbA1c has been proven not to overlap completely amount of insulin prepackaged in secretory granules in
with that assessed by the oral glucose tolerance test.27 In response to increasing plasma glucose concentrations.
fact, HbA1c combined with 2 h glucose is the strongest This first phase is measured within the first 10 min of
predictor for the development of prediabetes or diabetes a hyperglycaemic clamp. Second-phase secretion is
in young, at-risk individuals27 and an independent the prolonged response to persistently elevated glucose
predictor of cardiovascular risk in non-diabetic adults.28,29 concentrations, and it involves a longer process of
Therefore, absolute HbA1c concentrations should not trafficking of insulin from the Golgi system to secretory
be viewed as the only biomarker for the detection of granules and out of the cell.31 This second phase is
prediabetes in youths. The combination of several such measured mainly within 10120 min of a hyperglycaemic
biomarkers can shed light on the pathogenesis of altered clamp. First-phase and second-phase insulin secretions
glucose metabolism and its complications in children can be accurately quantified only in response to a non-
and adolescents, and might provide potential targets for physiological intravenous glucose stimulus (a hyper
intervention. glycaemic clamp or an intravenous glucose tolerance
test), but both phases can be modelled from the response
Pathophysiology of altered glucose metabolism to a more physiological oral glucose load. Despite this
Glucose concentrations are normally restricted within limitation, the measurement of phasic insulin dynamics
a narrow range between fasting and postprandial is crucial because defects in first-phase secretion have
conditions. Maintenance of glucose concentrations been shown to precede the development of overt type 2
within this range depends on the intricate interplay of diabetes.32 Obese adolescents with impaired fasting
glucose or impaired glucose tolerance, or both, have been
Normal glucose tolerance shown to have reduced first-phase insulin secretion
300 Impaired glucose tolerance
Type 2 diabetes
compared with those with normal glucose metabolism.33
In a study using C-peptide modelling of oral glucose
tolerance test results, glucose sensitivity of first-phase
insulin secretion was shown to decline progressively as
glucose metabolism of obese adolescents deteriorated
Insulin (U/mL)

from isolated impaired fasting glucose or impaired

glucose tolerance to both conditions.34 Alterations in
100 second-phase insulin secretion occur later in disease
development and have been reported only in obese
adolescents with both impaired fasting glucose and
impaired glucose tolerance, or overt type 2 diabetes.35
0 This observation implies that an isolated defect in first-
0 10 20 40
phase secretion is an early manifestation of prediabetes,
First phase Second phase whereas a combination of first-phase and second-phase
Time (min) secretion defects might represent profound -cell
dysfunction, which is the prelude for overt type 2 diabetes.
Figure 1: Insulin secretion during a hyperglycaemic clamp
Compared with individuals with normal glucose tolerance, those with impaired glucose tolerance have reduced
The deterioration of cells usually occurs faster in
first-phase insulin secretion and preserved second-phase insulin secretion. Those with type 2 diabetes have defects children and adolescents than in adults. In fact, the
in both first-phase and second-phase insulin secretion. transition from prediabetes towards type 2 diabetes takes

2 Published online September 26, 2017


about 10 years in adults with a roughly 7% reduction in 8 Normal glucose tolerance (n=2568)
-cell function per year, whereas in obese adolescents the Impaired glucose tolerance (n=693)
cells deteriorate at around 2030% per year,36 with a Type 2 diabetes (n=72)

mean transition time from prediabetes to overt diabetes of

about 25 years.37 Insulin secretion defects in obese youths
highlight an inability to compensate for the profound

Insulinogenic index
ambient insulin resistance. Despite -cell deterioration,
obese youths show much higher insulin concentrations
during oral glucose tolerance tests than do obese adults.
Such seemingly supra-physiological insulin concentrations
are still not enough to overcome the marked insulin
resistance of these youths.
Whole-body insulin sensitivitythe action of the
hormone in all insulin-responsive tissues and organs 0 1 2 3 4 5
declines in obese children and adolescents with impaired Whole-body insulin sensitivity index
glucose tolerance when compared with equally obese
youth with normal glucose tolerance.35,38 Importantly, Figure 2: The disposition index across glucose tolerance categories
Data are from youths (aged 821 years) followed up at the Yale Obesity-Diabetes Clinic, New Haven, CT, USA
obese children with impaired glucose tolerance have (unpublished). At any given degree of insulin sensitivity, obese youths with normal glucose tolerance (body-mass
uniformly high insulin resistance, whereas those with index [BMI] z score 224 [SD 061]) have greater insulin secretion than those with impaired glucose tolerance
normal glucose tolerance can range from highly insulin (BMI z score 238 [048]) and those with type 2 diabetes (BMI z score 237 [062]). Although less prominent in
insulin-sensitive individuals, at lower levels of insulin sensitivity (ie, greater insulin resistance), these differences
sensitive to highly resistant.39 Reduced insulin sensitivity
are substantial and insulin secretion is insufficient to maintain normal glucose metabolism.
in obese children is, in most cases, associated with a
typical lipid partitioning profile generally characterised by
increased intra-abdominal (visceral), intrahepatic, and substantial increases in both fasting and 2 h glucose
intramyocellular lipid deposition.40 This lipid depot concentrations.45 These glucose concentrations can be
distribution pattern might differ between obese youths of within the normal glucose tolerance range, yet they
different ethnic backgrounds (eg, African-American still reflect an increased demand on the stressed cell,
youths have a lower visceral to subcutaneous adipose because even appropriate -cell compensation requires a
tissue ratio and a lower risk of intrahepatic fat continuous glucose stimulus to maintain enhanced
accumulation than white and Hispanic youths). The insulin secretion. In obese children, normal glucose
ability of an obese child to compensate for low insulin tolerance is a continuous spectrum, therefore a worsening
sensitivity by increasing insulin concentrations is the of the disposition index accompanies increases in
determinant of actual glucose tolerance. To increase postprandial glucose concentrations even within the
circulating insulin concentrations, two parallel normal range.44 In other words, major defects in -cell
compensatory mechanisms are activated: enhanced function might exist in obese youths with 2 h glucose
insulin secretion and reduced insulin clearance by the concentrations, as measured by the oral glucose tolerance
liver.41 In children with very low insulin sensitivity, hepatic test, at the upper end of the normal range.
insulin clearance is probably reduced to a minimum In a cohort study of around 1600 obese youths (aged
beyond which insulin action within the liver could be 821 years) from various ethnic backgrounds,44 we showed
compromised, thus leaving further increasing insulin that 37% had 2 h glucose concentrations of 101119 mg/dL,
secretion as the sole compensation mechanism aimed at and 47% had concentrations of 120139 mg/dL, whereas
maintaining euglycaemia.41 only 20% had a 2 h glucose concentration lower than
The mathematical relation of insulin sensitivity and 100 mg/dL.44 Moreover, we observed a decline in insulin
secretion is best described as hyperbolic, such that the sensitivity and secretion across the spectrum of the
product of insulin sensitivity and insulin secretion equals disposition index, which in turn was associated with an
a constant (figure 2).42 This product has been named the increased risk of progressing to impaired glucose tolerance
disposition index, and reflects -cell function in the later in life.44 These observations indicated that -cell
context of ambient insulin sensitivity. The disposition function relative to insulin sensitivity is impaired even in
index has been shown to be the strongest predictor of the youths with high 2 h glucose concentrations within the
development of diabetes over time.43 Obese children with non-pathological range. Notably, baseline disposition index
impaired glucose metabolism have a lower disposition could be used to predict the risk of developing prediabetes
index than their counterparts with normal glucose or type 2 diabetes over time.44,46
tolerance, reflecting defects in -cell function that precede The disposition index is probably affected by genetic
the development of hyperglycaemia in the diabetic and epigenetic factors that limit the ability of obese
range.34,44 For a given disposition index, exposure to lower children to compensate for insulin resistance. Indeed,
insulin sensitivity (ie, being on the left of the hyperbolic children whose mother had gestational diabeteswhich
disposition index curve) is accompanied by slight yet reflects a genetic background of type 2 diabetes and Published online September 26, 2017 3


in-utero exposure to hyperglycaemiahave a lower poor -cell compensation is more pronounced in

disposition index than their counterparts matched for African-American adolescents than in Hispanic
obesity status and are at risk of deteriorating glucose adolescents, suggesting that the association between
tolerance over time.47 fatty liver and insulin sensitivity might be modulated by
race and ethnicity.53 Results from a longitudinal study54
The role of insulin resistance showed that baseline hepatic fat content is associated
The link between obesity and prediabetes is ectopic fat with changes in glucose metabolism over time and that
accumulation. Such fat accumulation in key insulin- it correlates with 2 h glucose, insulin sensitivity, and
responsive organs such as skeletal muscle and liver insulin secretion at 2 year follow-up. These data indicate
alters the insulin signalling pathway, leading to increased that intrahepatic fat accumulation is more deleterious
insulin resistance. This resistance is characterised by for glucose metabolism than ectopic fat accumulation.55
defects in the non-oxidative pathway of glucose Of note, transition through pubertal phases needs to be
metabolism, an increased intramyocellular lipid content, taken into account. Mid-puberty (Tanner stage 3) is
and high visceral and hepatic fat content.48 Fat characterised by a roughly 30% reduction in whole-body
accumulation in the liver is an important trigger of insulin sensitivity,56 which can be completely or partly
insulin resistance, and its severity is associated with the recovered by the end of puberty (Tanner stage 5).57 This
presence of prediabetes in adolescents.49 The associations issue is of major importance when assessing insulin
between lipid accumulation in insulin-responsive sensitivity and glucose tolerance in adolescents because
tissues and tissue-specific insulin resistance might be glucose tolerance in some obese youths who are tested at
bidirectional. On the one hand, acute delivery of free mid-puberty might improve when retested at a later
fatty acids causes an important reduction in muscle pubertal stage.
insulin sensitivity.50 On the other hand, insulin resistance
in the liver can lead to further hyperinsulinaemia and Glucose effectiveness
additional hepatic lipid deposition.51 Glucose has the ability to facilitate its own uptake via a
The role of fatty liver in insulin resistance and mass effect in peripheral tissues and to suppress
metabolic syndrome has been shown in several hepatic glucose production depending on basal insulin
paediatric studies. In a multiethnic group of 118 obese concentrations.58 This property is known as glucose
youths, the severity of fatty liver disease was associated effectiveness, and it tends to increase with greater insulin
with a decline in -cell function and increased occurrence concentrations.59 Since glucose effectiveness is difficult to
of prediabetes.49 Moreover, increasing amounts of measure, its major role in glucose metabolism tends to be
intrahepatic fat were paralleled by an increased overlooked. The contribution of glucose effectiveness to
prevalence of metabolic syndrome, suggesting that fatty whole-body glucose disposal in fasting conditions (fasting
liver disease might be a predictive factor of metabolic or basal insulin concentrations) is estimated to be
syndrome in children.49 Importantly, DAdamo and around 70% of the total, whereas in typical postabsorptive
colleagues52 showed that, in obese adolescents, the insulin concentrations imposed during a hyper
negative effect of fatty liver on insulin sensitivity was insulinaemiceuglycaemic clamp, the contribution of
independent of the degree of visceral fat and glucose effectiveness to whole-body glucose disposal drops
intramyocellular lipid content. This study included to nearly 30%. Therefore, the contribution of insulin-
23 obese adolescents with fatty liver and 20 obese independent glucose disposal (ie, glucose effectiveness) to
adolescents without fatty liver, matched for age, Tanner the maintenance of glucose homoeostasis in typical
stage, body-mass index (BMI) z score, and percentage of physiological postabsorptive conditions is estimated to be
body fat, visceral fat, and intramyocellular lipid.52 similar to that of insulin-dependent mechanisms.59
Although baseline hepatic glucose production was When glucose tolerance deteriorates, glucose effective
similar between the groups, the suppression of hepatic ness is impaired, such that blood glucose concentrations
glucose production in the presence of similar insulin could not be reduced via suppression of hepatic glucose
concentrations was significantly lower in adolescents production or acceleration of muscle glucose uptake,
with fatty liver than in those without, indicating hepatic independent of increased insulin concentrations.
insulin resistance. Additionally, the group with fatty liver Defects in both glucose effectiveness and -cell insulin
had higher muscle insulin resistance, expressed as the secretion promote a further rise in circulating blood
glucose disposal rate, than the group without fatty liver. sugar concentrations. Glucose effectiveness is reduced
The investigators also showed that individuals with fatty in adult patients with type 2 diabetes60 and in children
liver have a reduced ability to suppress glycerol turnover, and adolescents with altered glucose metabolism.61 Of
indicating adipose insulin resistance. These data clearly note, the baseline levels and dynamics of glucose
suggest that intrahepatic fat accumulation is a major effectiveness are independent predictors of changes in
determinant of liver, muscle, and adipose tissue insulin 2 h glucose concentrations over time,61 emphasising the
resistance.52 Moreover, Alderete and colleagues53 showed role of this factor in the development of altered glucose
that the association of high intrahepatic fat content and metabolism in obese children.

4 Published online September 26, 2017


The role of gut-derived incretins and glucagon lower concentrations in individuals with greater degrees
Incretins are hormones released from the of obesity than in those who are not obese.69 Adiponectin
gastrointestinal tract in response to food intake, and receptors are present in the major insulin-responsive
they regulate pancreatic islet hormone secretion. The tissues related to glucose metabolism, and activation
two major incretins identified are glucose-dependent of these receptors culminates in increased fat oxidation.
insulinotropic polypeptide (GIP) and glucagon-like Unsurprisingly, concentrations of this hormone are
peptide-1 (GLP-1). Both incretins potentiate glucose- negatively associated with intramyocellular,70 intrahepatic,71
induced insulin secretion and decrease the release of and visceral fat depots38 in obese children. Moreover, low
glucagon from the pancreatic islets,62 which manifest as concentrations of adiponectin were shown to be associated
an enhanced insulin response to oral glucose compared with higher C-reactive protein concentrations and with
with intravenous glucose administration when both are components of the metabolic syndrome, such as low HDL
matched for plasma glucose concentrations. Obesity cholesterol and a high triglyceride:HDL cholesterol ratio.72
and altered glucose metabolism in children are Thus, adiponectin might be one of the signals linking
associated with reduced fasting and variable inflammation and obesity. Although concentrations of
postprandial GLP-1 concentrations.63 Obese children adiponectin in obese adolescents are known to vary
with impaired glucose tolerance and type 2 diabetes with ethnicity, adiponectins tight relation with insulin
have a significantly reduced incretin effect compared sensitivity, independent of the amount of visceral fat,
with those with normal glucose metabolism in the is consistent.73
presence of similar GIP and GLP-1 concentrations.64 Leptin is a hormone also secreted from adipose tissue
Moreover, obese African-American children seem to but, by contrast with adiponectin, its concentrations rise
have a reduced GLP-1 response during oral glucose with increasing amounts of adipose tissue. Leptin
tolerance test compared with obese white children.65 concentrations are associated with insulin sensitivity in
The role of GIP is less clear in the context of altered obese youths, independently of body fat,74 and leptin has
glucose metabolism in childhood, because this incretin been shown to induce fatty-acid oxidation, thus reducing
has been shown to be released in similar amounts in triglyceride concentrations in the liver75 and cells.76
both lean and obese children, and in euglycaemic and Therefore, leptin can be considered beneficial in the
postprandial hyperglycaemic conditions.66 Fasting GLP- context of childhood obesity. Obese adolescents with type 2
1 concentrations have been associated with increased diabetes have lower leptin concentrations than in matched
resting energy expenditure and fat oxidation in adults.67 obese adolescents with normal glucose metabolism,77
Further investigation is needed to decipher whether the suggesting that hypoleptinaemia in obese youths could be
reduced fasting concentrations of GLP-1 observed in a biomarker of an adverse metabolic phenotype.
obese youths might provide a mechanism for the
development of altered glucose metabolism that is Prediabetes and the progression to type 2
associated with adiposity in childhood, and whether this diabetes
could be a therapeutic target in the future. Although prediabetes is a high-risk state for developing
Intra-islet communications between cells and cells, overt diabetes, many people with prediabetes will not
via adjacent cell junctions and paracrine effects, ensure a progress to severe glucose intolerance.6,7 The prevalence
coordinated secretion of insulin and glucagon. Type 2 of prediabetes and diabetes in the obese paediatric
diabetes is characterised by disinhibited glucagon population also varies substantially across different
secretion in systemic hyperinsulinaemia.30 Weiss and countries and ethnicities.11,16,18,78,79 On the one hand,
colleagues68 showed that, before the development of progression of impaired fasting glucose to overt type 2
overt type 2 diabetes in obese youths, basal glucagon diabetes appear to be slower in the paediatric obese
concentrations are increased, and are less suppressed by population than in the general adult population.80 On the
hyperinsulinemia in individuals with impaired glucose other hand, the transition from impaired glucose
tolerance than in those with normal glucose tolerance. tolerance to type 2 diabetes has been shown to be more
Moreover, among obese children with normal glucose rapid in children and adolescents than in adults.37 The
tolerance, those who were more insulin resistant had prediabetic stages of impaired glucose tolerance and
greater basal glucagon concentrations than those who impaired fasting glucose do not necessarily coexist,10,15,79
were more insulin sensitive. In this study, deterioration which emphasises that these two conditions are distinct
from normal to impaired glucose tolerance over time metabolic complications.34 Therefore, the additive effect
was accompanied by significantly increased fasting of impaired fasting glucose and impaired glucose
glucagon concentrations. tolerance means that individuals with both conditions are
more likely to progress to overt type 2 diabetes than those
The role of fat-derived hormones and cytokines with only one of those conditions.81 Importantly, although
Adipose tissue is characterised by a unique profile of the reproducibility of prediabetes detection with an oral
secreted hormones and cytokines (figure 3). Adiponectin glucose tolerance test in obese children is not ideal,
is a fat-derived hormone that, paradoxically, is found at the presence of elevated glucose concentrations after Published online September 26, 2017 5



Adipose tissue hypertrophy

High visceral to
abdominal ratio

Skeletal muscle Liver

Increased intramyocellular fat Increased circulating free fatty acids Decreased insulin clearance
Increased muscular insulin resistance Ectopic fat deposition Increased heptatic insulin resistance
Decreased glucose uptake Inflammation Increased glycogenolysis and
Altered cytokine secretion gluconeogenesis

Decreased adiponectin Increased leptin

Decreased -oxidation Decreased insulin resistance

Increased inflammation Increased -oxidation
Increased ectopic fat deposition

Figure 3: Interplay between fat-derived hormones and cytokines

An excess of visceral adipose tissue is linked to ectopic fat deposition and abnormal secretion of adipokines. Obese patients with high visceral to subcutaneous fat
ratio have decreased adiponectin and leptin concentrations, despite equivalent body-mass index and body fat percentages. Lowered adiponectin concentrations are
associated with increased ectopic fat deposition in skeletal muscle and liver. Decreased leptin concentrations are associated with lower insulin sensitivity.

oral load, even on just one test, probably indicates the factor in adults. In our cohort study of 955 obese children
presence of substantial defects in glucose metabolism.22 and adolescents,85 we found that each copy of the T allele
of the rs7903146 SNP was associated with an almost
Genetic markers of paediatric prediabetes twotimes increased odds of having impaired glucose
Results from several genome-wide association studies tolerance, and this risk genotype is associated with an
have helped to highlight the genetic basis of type 2 increased risk of maintaining impaired glucose tolerance
diabetes and to identify single-nucleotide polymorphisms or progressing towards type 2 diabetes. To unravel
(SNPs)eg, in genes involved in insulin metabolism and the mechanisms underlying the genotypephenotype
the inflammatory responseassociated with type 2 association, we used the oral minimal model to assess
diabetes.82 Most variants associated with prediabetes and insulin secretion, the ratio of circulating fasting proinsulin
type 2 diabetes are in genes expressed in cells. Because to C-peptide to evaluate proinsulin processing, and an
of the difficulty in recruiting large paediatric cohorts, most euglycaemic clamp coupled with tracer methods to
genome-wide association studies have been done in measure hepatic and peripheral insulin sensitivity. We
adults, and information about the genetics of prediabetes observed that the T allele of TCF7L2 rs7903146 has
in youths is therefore insufficient. Barker and colleagues83 profound effects on -cell function, as shown by a reduced
genotyped 16 SNPs previously associated with diabetes in disposition index (and altered proinsulin secretory
6000 children and adolescents and determined their efficiency). The effect of the TCF7L2 rs7903146 probably
association with fasting glucose concentrations. They involves the liver, by reducing the ability of insulin to
observed that nine loci were indeed associated with fasting suppress hepatic endogenous glucose production.85
glucose concentrations, including five previously
discovered SNPs and four additional loci. In another study Conclusions and future perspectives
of 714 obese adolescents,84 common variants in or near In summary, altered glucose metabolism in obese children
genes modulating insulin secretion were found to be is preceded by early defects in insulin secretion that results
associated with a high risk for developing prediabetes. from low insulin sensitivity and inadequate suppression of
The co-occurrence of risk alleles in or near genes glucagon. These defects can be detected in individuals at
expressed in cells is associated with defects in insulin the upper range of normal glucose concentrations,
secretion that could lead to the development of prediabetes emphasising that glucose tolerance is a continuous
when severe insulin resistance occurs.84 Although the spectrum. A combination of low insulin sensitivity tightly
number of susceptibility genes for type 2 diabetes has linked to adverse lipid partitioning patternsalong with
risen over the past decade, the rs7903146 SNP in the inadequate -cell compensation, impaired glucose
TCF7L2 gene remains the strongest known genetic risk effectiveness, and elevated basal glucagon secretion

6 Published online September 26, 2017


(R01-HD028016) to SC. NS is funded by the American Heart Association

Search strategy and selection criteria through 13SDG14640038 and 16IRG27390002, and by the Allen
Foundation award. AG received a Research Fellowship from the
We searched PubMed using the search terms prediabetes, International Society for Pediatric and Adolescent Diabetes. This work
impaired fasting glucose, and impaired glucose tolerance was also made possible by a grant from the National Institute of
from Jan 1, 1980, to April 30, 2017. We included studies Diabetes and Digestive and Kidney Diseases (DK045735) to the Yale
Diabetes Research Center, and Clinical and Translational Science Awards
written in English that preferably used gold standard Grant UL1-RR-024139 from the National Center for Advancing
methods to assess insulin sensitivity and secretion (ie, clamps Translational Sciences, a component of the National Institutes of Health
or intravenous glucose tolerance tests) in individuals aged (NIH), and NIH Roadmap for Medical Research. This Reviews contents
18 years or younger. We selected prevalence studies from are solely our own responsibility and do not necessarily represent the
official view of NIH.
across the globe on the basis of the sample size.
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We declare no competing interests. 18 Yamamoto-Kimura L, Posadas-Romero C, Posadas-Sanchez R,
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This work has been made possible by grants from the National Institute Prevalence and interrelations of cardiovascular risk factors in
of Diabetes and Digestive and Kidney Diseases (R01-DK111038) and the urban and rural Mexican adolescents. J Adolesc Health 2006;
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