Glucose metabolism and hyperglycemia1–5
Dario Giugliano, Antonio Ceriello, and Katherine Esposito
ABSTRACT
Islet dysfunction and peripheral insulin resistance are both present in
type 2 diabetes and are both necessary for the development of hy-
perglycemia. In both type 1 and type 2 diabetes, large, prospective
clinical studies have shown a strong relation between time-averaged
mean values of glycemia, measured as glycated hemoglobin
(HbA1c), and vascular diabetic complications. These studies are the
basis for the American Diabetes Association’s current recom-
mended treatment goal that HbA1c should be 쏝7%. The measure-
ment of the HbA1c concentration is considered the gold standard for
assessing long-term glycemia; however, it does not reveal any in-
formation on the extent or frequency of blood glucose excursions,
but provides an overall mean value only. Postprandial hyperglyce-
mia occurs frequently in patients with diabetes receiving active treat-
ment and can occur even when metabolic control is apparently good.
Interventional studies indicate that reducing postmeal glucose ex-
cursions is as important as controlling fasting plasma glucose in
persons with diabetes and impaired glucose tolerance. Evidence
exists for a causal relation between postmeal glucose increases and
microvascular and macrovascular outcomes; therefore, it is not sur-
prising that treatment with different compounds that have specific
effects on postprandial glucose regulation is accompanied by a sig-
nificant improvement of many pathways supposed to be involved in
diabetic complications, including oxidative stress, endothelial dys-
function, inflammation, and nuclear factor-␬B activation. The goal
of therapy should be to achieve glycemic status as near to normal as
safely possible in all 3 components of glycemic control: HbA1c, fasting
glucose, and postmeal glucose peak. Am J Clin Nutr 2008;
87(suppl):217S–22S.
KEY WORDS Fasting hyperglycemia, postprandial hypergly-
cemia, glycated hemoglobin, type 2 diabetes, cardiovascular disease
risk, lifestyle
INTRODUCTION
Maintenance of a normal plasma glucose concentration re-
quires precise matching of glucose utilization and endogenous
glucose production or dietary glucose delivery. Glucose is de-
rived from 3 sources: the intestinal absorption that follows the
digestion of dietary carbohydrates, glycogenolysis, and glucone-
ogenesis. Glucose is transported into cells through multiple met-
abolic pathways: it may be stored as glycogen; it may undergo
glycolysis to pyruvate; finally, it may be released into the circu-
lation by the liver and kidneys, the sole organs containing
glucose-6-phosphatase, the enzyme necessary for the release of
glucose into the circulation.
Am J Clin Nutr 2008;87(suppl):217S–22S. Printed in USA. © 2008 American Society for Nutrition
In the fasting condition, plasma glucose concentrations are
relatively stable, which indicates that rates of glucose production
and utilization are equal. They average 2.2 mg 䡠 kgҀ1 䡠 minҀ1
(range: 1.8 to 2.6 mg 䡠 kgҀ1 䡠 minҀ1) in healthy adults after an
overnight fast (1). After a meal, glucose absorption results in
rates of exogenous glucose delivery into the circulation that can
be more than twice the rate of postabsorptive endogenous glu-
cose production, depending on the carbohydrate content of the
meal and the rate and degree of glucose absorption. As glucose is
adsorbed, endogenous glucose production is suppressed, and
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glucose utilization by liver, muscle, and fat accelerates (2). Thus,
exogenous glucose is assimilated, and the plasma glucose con-
centration returns to approximately the fasting state.
Insulin is the dominant glucoregulatory hormone. In the fast-
ing state, it regulates the plasma glucose concentration primarily
by restraining hepatic glucose production; higher concentra-
tions, such as those found after meals, are required to stimulate
glucose utilization (3). Glucagon is a potent hyperglycemic hor-
mone that acts almost exclusively on the liver to increase hepatic
glucose production within minutes. Ingestion of carbohydrate
elicits a prompt rise in insulin concentration and a decrease in
glucagon concentration. The increase in insulin concentrations,
which occurs before the rise in arterial glucose concentrations, is
thought to be mediated largely via hormonal signals arising in the
gastrointestinal tract (incretion effect) (4). The early insulin re-
lease allows increased glucose disposal during absorption and
prevents hyperglycemia. If the rise in insulin concentration oc-
curred only after glucose entered the circulation, much higher
concentrations of the hormone would be required to correct the
large change in glucose concentration that would result if ab-
sorption were unaccompanied by an early increase in utilization.
Islet dysfunction and peripheral insulin resistance are both
present in type 2 diabetes and are both necessary for the devel-
opment of hyperglycemia. Consequent to insulin deficiency (se-
cretion or action), glucagon concentrations rise. A fall in the
insulin-to-glucagon ratio causes increased production of glucose
1
From the Department of Geriatrics and Metabolic Diseases, University
of Naples SUN, Italy (DG and KE), and the Warwick Medical School,
Coventry, United Kingdom (AC).
2
Presented at an ILSI Europe workshop titled “Glycemic Response and
Health,” held in Nice, France, on 6 – 8 December 2006.
3
Supported in part by a Grant (Ricerca di Ateneo) from the Second Uni-
versity of Naples, Italy.
4
Address reprint requests to ILSI Europe. E-mail: publications@
ilsieurope.be.
5
Address correspondence to D Giugliano, Via S Chiara 10/L, 80138
Naples, Italy. E-mail: dario.giugliano@unina2.it.
217S
218S GIUGLIANO ET AL
by the liver (basal hyperglycemia), whereas the absolute de-
crease in plasma insulin concentration or action reduces glucose
utilization in peripheral tissues (postprandial hyperglycemia).
POSTPRANDIAL HYPERGLYCEMIA
The profile of postprandial hyperglycemia is determined by
many factors, including the timing, quantity, and composition of
the meal; the carbohydrate content of the meal; and the resulting
secretion of insulin and inhibition of glucagon secretion. Be-
cause the absorption of food continues for 5 to 6 h after a meal in
persons with and without diabetes, the optimal time to measure
postprandial blood glucose concentrations remains an open
question. Postchallenge hyperglycemia refers to the glucose
peak after a predefined load of glucose, ie, during an oral glucose
tolerance test (OGTT). The 75-g OGTT was standardized by the
World Health Organization (5) and is now the reference test for
categorizing glucose tolerance. The relation between values of
postprandial and postchallenge hyperglycemia is poorly under-
stood, and differences depend in part on the ability of mixed
meals containing amino acids to provoke greater insulin secre-
tion than glucose alone. In one study, glycemia at 2 h after an
OGTT was closely related to 2-h glycemia after a standardized
meal (6), which suggests that subjects with high concentrations
of postchallenge glycemia are also likely to have exaggerated
glucose peaks after a normal meal in daily life.
Diabetes is diagnosed when the fasting plasma glucose con-
centration is consistently 욷7 mmol/L (126 mg/dL) or when the
2-h plasma glucose concentration (after drinking a 75-g glucose
load) is consistently 욷11.1 mmol/L (200 mg/dL). These
thresholds are much higher than the “normal” fasting and 2-h
mean glucose concentrations of 5.1 mmol/L (92 mg/dL) and
5.4 mmol/L (97 mg/dL), respectively. These concentrations
were chosen because they effectively differentiated persons at
high risk of eye disease from persons at low risk (7). It is now
clear that fasting or 2-h glucose concentrations that are well
below the diabetes cutoffs are cardiovascular disease risk
factors (8, 9) and that a progressive relation between glucose
and cardiovascular disease risk extends from normal glucose
concentrations right into the diabetes range with no clear lower
threshold (9, 10).
Diabetes affects an estimated 20.8 million persons in the
United States, 7% of the current population, and the lifetime risk
of developing diabetes for those born in 2000 is 35% (11, 12).
Many of these persons will develop diabetes-specific microvas-
cular pathology in the retina, renal glomerulus, and peripheral
nerve and accelerated atherosclerotic macrovascular disease af-
fecting the arteries that supply the heart, brain, and lower ex-
tremities. In both type 1 and type 2 diabetes, large, prospective
clinical studies have shown a strong relation between time-
averaged mean values of glycemia, measured as glycated hemo-
globin A1c (HbA1c), and diabetic complications (13, 14). These
studies are the basis for the American Diabetes Association’s
current recommended treatment goal that HbA1c should be 쏝7%
(15) However, only about one-third of patients diagnosed as
having diabetes achieve that goal (16) and even fewer reach the
target concentration for HbA1c of 6.5% advocated by the Amer-
ican College of Endocrinology (17).
GLYCATED HEMOGLOBIN AS A CARDIOVASCULAR
DISEASE RISK FACTOR
HbA1c is an easily measured biochemical marker that strongly
correlates with the level of ambient glycemia during a 2- to 3-mo
period. Tests for HbA1c are also inexpensive and can be done at
any time of day. The concentration of HbA1c strongly predicts the
risk of incident eye, kidney, and nerve disease in persons with
type 1 and type 2 diabetes mellitus. Epidemiologic evidence also
indicates that HbA1c is a progressive risk factor for cardiovas-
cular disease in both persons with diabetes and those without
diabetes. Selvin et al (18) performed a meta-analysis of 10 cohort
studies involving 7435 persons with type 2 diabetes and 3 cohort
studies involving 1688 persons with type 1 diabetes. For type 2
diabetes, a 1–percentage point absolute increase in HbA1c was
associated with a significant 18% increase in the risk of coronary
heart disease or stroke and a 28% increase in the risk of peripheral
vascular disease. Khaw et al (19) analyzed the relation of one
HbA1c measurement to incident cardiovascular events in a 6-y
cohort study of 10 232 diabetic and nondiabetic men and women
aged 45-79 y. After adjustment for other risk factors, there was a
significant 21% increase in cardiovascular events for every
1–percentage point increase in HbA1c concentration above 5%.
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Similar relations were observed for total mortality (22% for men
and 28% for women). These results indicate that the HbA1c
concentration is an independent progressive risk factor for
incident cardiovascular events, regardless of diabetes status.
These reports also show that the HbA1c concentration can now
be added to the list of other clearly established indicators of
cardiovascular disease risk, such as blood pressure and cho-
lesterol concentration. As suggested by Gerstein (20), the
presence or absence of diabetes is likely to become less im-
portant than the concentration of HbA1c in the assessment of
cardiovascular disease risk (similar to the fact that a diagnosis of
hyperlipidemia has become less important than the concentration
of LDL cholesterol).
GLYCATED HEMOGLOBIN AND GLUCOSE
EXCURSIONS
The measurement of HbA1c concentrations is considered the
gold standard for assessing long-term glycemic control at present
and is regarded as a key therapeutic target for the prevention of
diabetes-related complications. The HbA1c concentration, al-
though a useful measure of metabolic control and the efficacy of
diabetes therapeutic interventions, is an integrated summary of
circadian blood glucose concentrations during the preceding
6 – 8 wk (21). It therefore does not reveal any information on the
extent or frequency of blood glucose excursions but provides an
overall mean value only. This being the case, one can argue that
the HbA1c concentration is not necessarily the best or most clin-
ically useful glycemic indicator of the risk of complications,
particularly at the lower end of elevated HbA1c concentrations.
For instance, in patients in whom glucose concentrations fluctu-
ate markedly, the HbA1c concentration may indicate adequate
metabolic control; however, such patients are exposed to the
risks of hypoglycemia and the possibly harmful effects of exces-
sive postprandial hyperglycemic excursions.
The contribution of the postprandial glucose concentration to
overall glycemic control in persons with diabetes remains largely
undetermined. The best determinant of HbA1c concentrations in
 GLUCOSE METABOLISM AND HYPERGLYCEMIA
patients with types 1 and 2 diabetes is mean daily glycemia (22,
23). However, studies indicate that postprandial hyperglycemia
contributes up to70% of total daytime hyperglycemia (24, 25)
Therefore, it is not surprising that in the large cohort of patients
with type 1 diabetes in the Diabetes Control and Complications
Trial, postprandial hyperglycemia was predictive of HbA1c con-
centrations in a manner similar to that of mean daily glycemia
(22). In type 2 diabetes, a positive correlation with HbA1c con-
centration was reported for postprandial and preprandial glucose
concentrations (23). An explanation for apparent discrepancies
in the data was recently provided by a study showing that the
contribution of postprandial glucose excursions changes with the
degree of control: the contribution of postprandial glucose in
HbA1c concentration predominates in patients with fairly good
control, whereas the contribution of fasting hyperglycemia in-
creases as glycemic control worsens (26).
POSTPRANDIAL HYPERGLYCEMIA AND
CARDIOVASCULAR DISEASE RISK
Many epidemiologic data show that the 2-h glucose concen-
tration measured during an OGTT is an independent cardiovas-
cular disease risk factor, whereas fasting glucose is not (8, 27–
31). Clearly, the OGTT is nonphysiologic and cannot be equated
to the consumption of a meal. However, 2 studies have confirmed
that postprandial hyperglycemia is an independent risk factor for
cardiovascular diseases in type 2 diabetes in the clinical setting.
The Diabetes Intervention Study showed that in type 2 diabetes
the 1-h postprandial glucose concentration can be used to predict
the risk of myocardial infarction (32). More recently, a prospec-
tive study with a mean follow-up of 5 y showed that PPG is an
independent risk factor for coronary heart disease in patients with
type 2 diabetes, particularly in women (33).
Interventional trials also suggest a link between postprandial
hyperglycemia and cardiovascular disease risk. The STOP-
NIDDM trial showed that treatment of subjects with impaired
glucose tolerance with the ␣-glycosidase inhibitor acarbose, a
compound that specifically reduces postprandial hyperglycemia,
is associated with a 36% reduction in the risk of progression to
diabetes (34), a 34% risk reduction in the development of new
cases of hypertension, and a 49% reduction in the risk of cardio-
vascular events (35), particularly silent myocardial infarction
(36). Furthermore, in a recent meta-analysis of type 2 diabetic
patients, acarbose treatment was associated with a significant
reduction in cardiovascular events compared with placebo treat-
ment, also after adjustment for other risk factors (37). Very re-
cently, the effects of 2 insulin secretagogues, repaglinide and
glyburide, which are known to have different efficacy on post-
prandial hyperglycemia, on carotid intima-media thickness, and
on markers of systemic vascular inflammation in type 2 diabetic
patients have been evaluated (38). After 12 mo, the postprandial
glucose peak was 148 앐 28 mg/dL in the repaglinide group and
180 앐 32 mg/dL in the glyburide group (P 쏝 0.01). HbA1c
showed a similar decrease in both groups (0.9%). Carotid intima-
media thickness regression, defined as a decrease of 쏜0.020 mm,
was observed in 52% of the diabetic subjects receiving repaglin-
ide and in 18% of those receiving glyburide (P 쏝 0.01).
Interleukin-6 (P ⫽ 0.04) and C-reactive protein (P ҃ 0.02)
decreased more in the repaglinide group than in the glyburide
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group. The reduction in carotid intima-media thickness was as-
sociated with changes in postprandial but not fasting hypergly-
cemia. Therefore, evidence is emerging and suggests that treat-
ing postprandial hyperglycemia may positively affect the
development of cardiovascular disease.
MECHANISMS OF HYPERGLYCEMIA-INDUCED
VASCULAR DAMAGE
At least 4 major pathways are involved in hyperglycemia-
induced vascular damage: enhanced polyol activity, causing sor-
bitol and fructose accumulation; increased formation of ad-
vanced glycation end products; activation of protein kinase C and
nuclear factor ␬B; and increased hexosamine pathway flux.
There are many reasons to think that hyperglycemic states trigger
all of these deleterious metabolic events through a single process:
overproduction of superoxide by the mitochondrial electron-
transport chain. This elegant and unifying theory developed by
Brownlee (39) seems to indicate that activation of oxidative
stress by hyperglycemia plays a major role in the pathogenesis of
diabetic complications. Because all these metabolic alterations
occur more particularly in endothelial cells, it has been postu-
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lated that they can result in endothelial dysfunction and contrib-
ute to vascular damage (40).
Activation of oxidative stress plays a pivotal role in the effects
of the above-mentioned mechanisms and risk factors associated
with, or induced by, sustained hyperglycemia. However, evi-
dence is increasing that other glycemic disorders such as rapid
glucose swings might play an important role. Emphasis has been
given to the relation between postprandial hyperglycemia and,
more generally, hyperglycemic spikes and diabetic complica-
tions. For instance, it has been established that postprandial hy-
perglycemia induces an overproduction of superoxide that, after
reacting with nitric oxide, produces a subsequent nitrosative
stress with generation of such metabolic derivatives as peroxyni-
trite and nitrotyrosine. The toxicity of these substances can lead
to endothelial damage and, furthermore, to microvascular and
macrovascular complications. By reducing postprandial excur-
sions, oxidative and nitrosative stress can be diminished (41).
Nitrotyrosine is thought to be a relatively specific marker of
oxidative damage mediated by peroxynitrite (42) and was re-
cently shown to be an independent predictor of cardiovascular
disease (43). Nitrotyrosine formation is detected during acute
hyperglycemia in the artery wall of monkeys (44), in working
hearts from rats during hyperglycemia (45), and in the plasma of
healthy and diabetic subjects (46, 47). Thus, oxidative stress,
irrespective of atherosclerotic disease stages, seems to represent
a key phenomenon in acute vascular disease progression.
Glucose variations over time are not limited to postprandial
hyperglycemic excursions, because blood glucose concentra-
tions in patients with diabetes are always fluctuating from hy-
perglycemic peaks to glucose nadirs. Such fluctuations are par-
ticularly marked in type 1 diabetes and, to a lesser degree, in
patients with type 2 diabetes treated with insulin. However, pa-
tients with type 2 diabetes can also experience such peak and
trough patterns with acute glucose variations. Peaks usually cor-
respond to maximum values after meals, particularly at mid-
morning (48), whereas troughs are observed over interprandial
periods (49), especially in patients who are treated with insulin
secretagogues and who are at risk of hypoglycemic episodes
(50).
220S GIUGLIANO ET AL
In one study involving patients with type 2 diabetes, Monnier
et al (51) measured 24-h excretion of 8-iso-prostaglandin F2␣, an
indicator of free radical production, while patients used a con-
tinuous blood glucose monitoring system; fasting glucose con-
centrations and HbA1c also were determined. There was a linear
correlation between increased free radical production and the
magnitude of glucose fluctuations, but not with the 24-h mean
glucose concentration, fasting plasma glucose concentrations, or
even the HbA1c concentration. 8-iso-Prostaglandin F2␣ concen-
trations were 4 times higher in patients with the greatest glycemic
variability than in patients having the lowest glycemic variabil-
ity. We reported that exposure of lean nondiabetic subjects to the
same magnitude of glycemic excursion reported by Monnier et al
(51) doubled circulating nitrotyrosine concentrations (46).
Moreover, oscillatory hyperglycemia causes more acute incre-
ments in plasma concentrations of some proinflammatory cyto-
kines, such as interleukin-6, interleukin-18, and tumor necrosis
factor-␣, than does chronic hyperglycemia in both healthy and
glucose-intolerant subjects (52). All this seems strictly related to
the ability of hyperglycemic spikes to reduce the availability of
nitric oxide (53).
POSTPRANDIAL HYPERGLYCEMIA: A TARGET OF
THERAPY
The precise relevance of postprandial hyperglycemia in the
daily life of persons with diabetes was recently quantified (54).
Self-assessed daily blood glucose curves were obtained over a
1-wk period, including 18 glucose readings before and 2 h after
meals, from 3284 unselected outpatients with non-insulin-
treated type 2 diabetes mellitus who attended 500 different dia-
betes clinics operating throughout Italy. A postprandial blood
glucose value 쏜8.89 mmol/L (160 mg/dL) was recorded at least
once in 84% of patients, which indicated that postprandial hy-
perglycemia is a frequent phenomenon in patients with type 2
diabetes mellitus receiving active treatment and can occur even
when metabolic control is apparently good. In another study, 401
patients with type 2 diabetes were requested to monitor home
blood glucose on 3 nonconsecutive days during a period of 1 mo
(38). In particular, they assessed blood glucose just before and
every 30 min after the main meal of the day for 2 h. The mean
FIGURE 1. Meal-related home blood glucose monitoring obtained on 3
nonconsecutive days in 401 subjects with type 2 diabetes. The profile of the
blood glucose curves did not differ significantly, and the glucose peaks
occurred between 30 and 60 min after the meal. From reference 38.
value of the postmeal incremental glucose peak was 70 앐 42
mg/dL. Most importantly, all patients had the glucose peak be-
tween 30 and 60 min after meal (Figure 1). Obviously, this
contrasts with the current belief that the glucose peak occurs later
after a meal and the recommendation of the American Diabetes
Association to measure blood glucose 2 h after a meal (55).
Therefore, it is not surprising that treatment with various dif-
ferent compounds that have specific effects on postprandial glu-
cose regulation, such as fast-acting insulin analogues, secreta-
gogues acting on first-phase insulin secretion, amylin analogues,
and acarbose, is accompanied by significant improvements, not
only in oxidative stress (56 –58) but also in endothelial dysfunc-
tion (59 – 61), myocardial blood flow (62), inflammation (37),
and nuclear factor-␬B activation (63).
Evidence also suggests that both postprandial hypertriglycer-
idemia and hyperglycemia induce endothelial dysfunction,
through induction of oxidative stress (47, 64). Studies show
independent but cumulative effects of postprandial hypertriglyc-
eridemia and hyperglycemia on endothelial function, which sug-
gests oxidative stress as the common mediator (65). This sup-
ports a specific and direct role of postprandial hyperglycemia,
independent of lipidemia, in cardiovascular disease. Interest-
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ingly, it was shown recently that hyperlipidemia acts to generate
oxidative stress in the mitochondria through the same pathways
as hyperglycemia (66). The evidence described up to now proves
that hyperglycemia can induce acute alterations in normal human
homeostasis. Diabetic subjects also have basal hyperglycemia,
and it can be hypothesized that the acute effects of mealtime
hyperglycemia can exacerbate those produced by chronic hyper-
glycemia, thus contributing to the overall complexity of diabetes.
Therefore, at present, given the tendency for rapid variations
in hyperglycemia throughout the life of patients with diabetes
(above all in the postprandial phase), it is appropriate to think that
this may exert an important influence on the onset of diabetes-
associated complications. Thus, correcting postprandial hyper-
glycemia should form part of the strategy for the prevention and
management of cardiovascular disease in diabetes.
LIFESTYLE CHANGES
Unhealthy diets and a lack of physical activity have contrib-
uted to a worldwide increase in the prevalence of obesity, type 2
diabetes, and the metabolic syndrome (67). But this epidemic is
not inevitable. We know that lifestyle intervention can dramat-
ically reduce the incidence of diabetes and slow the HbA1c in-
crease in both nondiabetic and diabetic persons (68 –70). More-
over, some recent studies deal specifically with the effect of
lifestyle changes on the resolution of the metabolic syndrome, a
forerunner of type 2 diabetes and cardiovascular diseases (71).
The first study was published in 2004 on 180 overweight subjects
with the metabolic syndrome (72). After a 2-y lifestyle program
focusing mainly on a Mediterranean-style diet, the net reduction
in prevalence of the syndrome was 48%. In the participants in the
Diabetes Prevention Program (73) who had impaired glucose
tolerance at baseline, 18% of the placebo group and 38% of the
lifestyle group no longer had the syndrome at 3 y. The Dietary
Approaches to Stop Hypertension (DASH) diet used in the Ira-
nian study (74) is similar to a Mediterranean-style diet. The
weighed mean resolution of the syndrome was 24.4% for life-
style changes (Figure 2). In 2 studies, resolution of the syndrome
was dependent on reduction in waist circumference and weight
 GLUCOSE METABOLISM AND HYPERGLYCEMIA
FIGURE 2. Resolution of the metabolic syndrome (patients who did not
fulfill the criteria of the syndrome anymore) in randomized controlled trials
of lifestyle changes. Numbers indicate the size of the intervention and the
placebo groups, respectively. DPP, Diabetes Prevention Program; DASH,
Dietary Approaches to Stop Hypertension. From reference 71.
loss (73, 74); in others, it was independent of weight changes
(71).
Although there is no proof that these lifestyle changes are
ultimately proven to reduce cardiovascular disease in our soci-
ety, public health approaches to facilitate them urgently need to
be implemented. The search for more and more effective drugs
for the control of hyperglycemia will continue. In the meantime,
lifestyle modifications may be a good companion to drugs for
reducing the metabolic and cardiovascular burden of type 2 di-
abetes and associated hyperglycemias.
The contributions of the authors were as follows—DG: collection of data,
analysis of data, writing of the manuscript; AC: significant advice and con-
sultation; and KE: analysis of data and writing of the manuscript. None of the
authors had any financial or personal conflicts of interest.
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