Glucose metabolism and hyperglycemia15

Dario Giugliano, Antonio Ceriello, and Katherine Esposito

KEY WORDS
Fasting hyperglycemia, postprandial hyperglycemia, glycated hemoglobin, type 2 diabetes, cardiovascular disease
risk, lifestyle

INTRODUCTION

Maintenance of a normal plasma glucose concentration requires precise matching of glucose utilization and endogenous
glucose production or dietary glucose delivery. Glucose is derived from 3 sources: the intestinal absorption that follows the
digestion of dietary carbohydrates, glycogenolysis, and gluconeogenesis. Glucose is transported into cells through multiple metabolic pathways: it may be stored as glycogen; it may undergo
glycolysis to pyruvate; finally, it may be released into the circulation by the liver and kidneys, the sole organs containing
glucose-6-phosphatase, the enzyme necessary for the release of
glucose into the circulation.

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 kg1 min1
(range: 1.8 to 2.6 mg kg1 min1) 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 glucose 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
glucose utilization by liver, muscle, and fat accelerates (2). Thus,
exogenous glucose is assimilated, and the plasma glucose concentration returns to approximately the fasting state.
Insulin is the dominant glucoregulatory hormone. In the fasting state, it regulates the plasma glucose concentration primarily
by restraining hepatic glucose production; higher concentrations, such as those found after meals, are required to stimulate
glucose utilization (3). Glucagon is a potent hyperglycemic hormone 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 release allows increased glucose disposal during absorption and
prevents hyperglycemia. If the rise in insulin concentration occurred 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 absorption 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 development of hyperglycemia. Consequent to insulin deficiency (secretion 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 University 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.

Am J Clin Nutr 2008;87(suppl):217S22S. Printed in USA. 2008 American Society for Nutrition

217S

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ABSTRACT
Islet dysfunction and peripheral insulin resistance are both present in
type 2 diabetes and are both necessary for the development of hyperglycemia. 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 Associations current recommended treatment goal that HbA1c should be 7%. The measurement of the HbA1c concentration is considered the gold standard for
assessing long-term glycemia; however, it does not reveal any information on the extent or frequency of blood glucose excursions,
but provides an overall mean value only. Postprandial hyperglycemia occurs frequently in patients with diabetes receiving active treatment and can occur even when metabolic control is apparently good.
Interventional studies indicate that reducing postmeal glucose excursions 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 surprising that treatment with different compounds that have specific
effects on postprandial glucose regulation is accompanied by a significant improvement of many pathways supposed to be involved in
diabetic complications, including oxidative stress, endothelial dysfunction, 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):217S22S.

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GIUGLIANO ET AL

by the liver (basal hyperglycemia), whereas the absolute decrease in plasma insulin concentration or action reduces glucose
utilization in peripheral tissues (postprandial hyperglycemia).

POSTPRANDIAL HYPERGLYCEMIA

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 cardiovascular 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 1percentage 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
1percentage point increase in HbA1c concentration above 5%.
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 cholesterol concentration. As suggested by Gerstein (20), the
presence or absence of diabetes is likely to become less important 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, although 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 clinically 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 fluctuate 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 excessive 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

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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. Because 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 understood, and differences depend in part on the ability of mixed
meals containing amino acids to provoke greater insulin secretion 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 concentration is consistently 7 mmol/L (126 mg/dL) or when the
2-h plasma glucose concentration (after drinking a 75-g glucose
load) is consistently 11.1 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 microvascular pathology in the retina, renal glomerulus, and peripheral
nerve and accelerated atherosclerotic macrovascular disease affecting the arteries that supply the heart, brain, and lower extremities. In both type 1 and type 2 diabetes, large, prospective
clinical studies have shown a strong relation between timeaveraged mean values of glycemia, measured as glycated hemoglobin A1c (HbA1c), and diabetic complications (13, 14). These
studies are the basis for the American Diabetes Associations
current recommended treatment goal that HbA1c should be 7%
(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 American College of Endocrinology (17).

GLYCATED HEMOGLOBIN AS A CARDIOVASCULAR

DISEASE RISK FACTOR

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 concentrations in a manner similar to that of mean daily glycemia
(22). In type 2 diabetes, a positive correlation with HbA1c concentration 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 increases as glycemic control worsens (26).

Many epidemiologic data show that the 2-h glucose concentration measured during an OGTT is an independent cardiovascular 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 prospective 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 STOPNIDDM 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 cardiovascular 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 treatment, also after adjustment for other risk factors (37). Very recently, the effects of 2 insulin secretagogues, repaglinide and
glyburide, which are known to have different efficacy on postprandial 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 28 mg/dL in the repaglinide group and
180 32 mg/dL in the glyburide group (P 0.01). HbA1c
showed a similar decrease in both groups (0.9%). Carotid intimamedia thickness regression, defined as a decrease of 0.020 mm,
was observed in 52% of the diabetic subjects receiving repaglinide and in 18% of those receiving glyburide (P 0.01).
Interleukin-6 (P 0.04) and C-reactive protein (P 0.02)
decreased more in the repaglinide group than in the glyburide

group. The reduction in carotid intima-media thickness was associated with changes in postprandial but not fasting hyperglycemia. Therefore, evidence is emerging and suggests that treating postprandial hyperglycemia may positively affect the
development of cardiovascular disease.
MECHANISMS OF HYPERGLYCEMIA-INDUCED
VASCULAR DAMAGE

At least 4 major pathways are involved in hyperglycemiainduced vascular damage: enhanced polyol activity, causing sorbitol and fructose accumulation; increased formation of advanced 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 electrontransport 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 postulated that they can result in endothelial dysfunction and contribute 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, evidence 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 complications. For instance, it has been established that postprandial hyperglycemia induces an overproduction of superoxide that, after
reacting with nitric oxide, produces a subsequent nitrosative
stress with generation of such metabolic derivatives as peroxynitrite and nitrotyrosine. The toxicity of these substances can lead
to endothelial damage and, furthermore, to microvascular and
macrovascular complications. By reducing postprandial excursions, 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 recently 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 concentrations in patients with diabetes are always fluctuating from hyperglycemic peaks to glucose nadirs. Such fluctuations are particularly marked in type 1 diabetes and, to a lesser degree, in
patients with type 2 diabetes treated with insulin. However, patients with type 2 diabetes can also experience such peak and
trough patterns with acute glucose variations. Peaks usually correspond to maximum values after meals, particularly at midmorning (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).

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POSTPRANDIAL HYPERGLYCEMIA AND

CARDIOVASCULAR DISEASE RISK

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GIUGLIANO ET AL

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-insulintreated type 2 diabetes mellitus who attended 500 different diabetes clinics operating throughout Italy. A postprandial blood
glucose value 8.89 mmol/L (160 mg/dL) was recorded at least
once in 84% of patients, which indicated that postprandial hyperglycemia 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 42

mg/dL. Most importantly, all patients had the glucose peak between 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 different compounds that have specific effects on postprandial glucose regulation, such as fast-acting insulin analogues, secretagogues 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 dysfunction (59 61), myocardial blood flow (62), inflammation (37),
and nuclear factor-B activation (63).
Evidence also suggests that both postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction,
through induction of oxidative stress (47, 64). Studies show
independent but cumulative effects of postprandial hypertriglyceridemia and hyperglycemia on endothelial function, which suggests oxidative stress as the common mediator (65). This supports a specific and direct role of postprandial hyperglycemia,
independent of lipidemia, in cardiovascular disease. Interestingly, 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 hyperglycemia, 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 diabetesassociated complications. Thus, correcting postprandial hyperglycemia 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 contributed 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 dramatically reduce the incidence of diabetes and slow the HbA1c increase in both nondiabetic and diabetic persons (68 70). Moreover, 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 Iranian study (74) is similar to a Mediterranean-style diet. The
weighed mean resolution of the syndrome was 24.4% for lifestyle changes (Figure 2). In 2 studies, resolution of the syndrome
was dependent on reduction in waist circumference and weight

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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 continuous blood glucose monitoring system; fasting glucose concentrations 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 concentrations were 4 times higher in patients with the greatest glycemic
variability than in patients having the lowest glycemic variability. 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 increments in plasma concentrations of some proinflammatory cytokines, 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).

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.

The contributions of the authors were as followsDG: collection of data,

analysis of data, writing of the manuscript; AC: significant advice and consultation; 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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