Endocrine
DOI 10.1007/s12020-012-9830-9
REVIEW
Pathophysiology of prediabetes and treatment implications
for the prevention of type 2 diabetes mellitus
Michael Bergman
Received: 1 October 2012 / Accepted: 23 October 2012
Ó Springer Science+Business Media New York 2012
Abstract Type 2 diabetes and other non-communicable
diseases (NCD) are a growing public health challenge
globally. An estimated 285 million people, corresponding
to 6.4 % of the world’s adult population has diabetes. This
is expected to reach 552 million by 2030, 7.8 % of the
adult population, with the African region expected to
experience the greatest increase. A much larger segment of
the world’s population, approximating 79 million individ-
uals in the US alone, has prediabetes. Multiple factors
including genetic predisposition, insulin resistance,
increased insulin secretory demand, glucotoxicity, lipo-
toxicity, impaired incretin release/action, amylin accumu-
lation, and decreased b-cell mass play a causative role in
the progressive b-cell dysfunction characteristic of predi-
abetes. Interventions preventing progression to type 2
diabetes should therefore delay or prevent b-cell failure.
This article will first review the principal pathophysiolog-
ical mechanisms underlying prediabetes and subsequently
address treatment considerations based on these in the
prevention of type 2 diabetes. In view of long-standing
safety data with demonstrated efficacy and cost-effective-
ness in the prevention of type 2 diabetes in high-risk
individuals, metformin should be considered as initial
therapy for those unable to comply with or lifestyle mod-
ification or where the latter has been ineffective in
decreasing progression to type 2 diabetes.
M. Bergman (&)
Department of Medicine, Division of Endocrinology,
NYU School of Medicine, 345 East 37th Street, Suite 313,
New York, NY 10016, USA
e-mail: Michael.Bergman@nyumc.org
KeyWords Prediabetes
Diabetes prevention

Impaired fasting glucose
Impaired glucose tolerance

Glucolipotoxicity
Incretin effect
Pathophysiology of prediabetes and treatment
implications for the prevention of type 2 diabetes
mellitus
Type 2 diabetes and other non-communicable diseases
(NCD) are a growing public health challenge globally. An
estimated 285 million people, corresponding to 6.4 % of
the world’s adult population has diabetes. This is expected
to reach 552 million by 2030 corresponding to 7.8 % of the
adult population with the African region expected to
experience the greatest increase [1].
A much larger segment of the world’s population,
approximating 79 million individuals in the US alone, has
prediabetes. Prediabetes, in which blood glucose concentra-
tions are higher than normal but not meeting the absolute
definition of diabetes, represents a high-risk state for diabetes
development. According to World Health Organization
(WHO), individuals at risk have one or both prediabetic
conditions: impaired fasting glucose (IFG), defined as a
fasting plasma glucose (FPG) concentration C6.1 (110 mg/
dl) and \7.0 mmol/L (126 mg/dl), and/or impaired glucose
tolerance (IGT), defined by a FPG concentration \6.1 mmol/
L (110 mg/dl) and a 2 h post-load plasma glucose concen-
tration between C7.8 (140 mg/dl) and \11.1 mmol/L
(199 mg/dl) measured during a 75 g oral glucose tolerance
test (OGTT) [2]. The American Diabetes Association (ADA)
applies the same post-load threshold values for IGT, but uses
a lower cutoff value for IFG with a FPG 5.6–6.9 mmol/L
(100–125 mg/dl). Furthermore, the ADA recommends that a
glycated hemoglobin A1c (HbA1c) between 5.7 and 6.4 % as
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another measure for diagnosing prediabetes. The ADA and
WHO both recognize a HbA1c level [6.5 % as indicative of
diabetes [2–7].
IFG and IGT differ in their pathophysiologic mecha-
nisms which will be discussed below. Individuals with both
IFG and IGT have a more severe dysglycemic condition
and are especially at high-risk for type 2 diabetes.
[8].5–10 % of individuals with prediabetes develop dia-
betes annually with up to 70 % eventually developing
diabetes [9, 10].
A meta-analysis of randomized controlled clinical trials
reported reductions in the risk of developing diabetes after
lifestyle or drug-based interventions although it is unclear
whether in so-doing major cardiovascular events are affected
[11]. Prediabetes can revert to normoglycemia as well. In the
Diabetes Prevention Program Outcome Study, reversion to
normal glucose, even when transient, was associated with a
significant 56 % reduced risk of future diabetes independent
of previous treatment [12]. Diabetes risk reduction was
strongly associated with the number of times normal glucose
regulation was achieved and was highest in those who
remained with prediabetes despite lifestyle intervention.
It is also vital to note that diabetes risk substantially
increases in those with glucose values at the higher end of the
defined normal range [13]; therefore risk prediction might be
more accurately determined if glucose parameters are treated
as a continuous rather than categorical process [14]. Fur-
thermore, incorporation of post-load glucose into a model that
already includes FPG can improve prediction [15]. The
combination of HbA1c and FPG levels has been shown to
improve risk prediction for developing diabetes [16]. In
postpartum women, the OGTT was superior to FPG or HbA1c
in postpartum screening demonstrating the importance of
measuring a post-load glucose level in this population [17].
Multiple factors including genetic predisposition, insulin
resistance, increased insulin secretory demand, glucotox-
icity, lipotoxicity, impaired incretin release/action, amylin
accumulation, and decreased b-cell mass play a causative
role in the progressive b-cell dysfunction [9]. Interventions
preventing progression to type 2 diabetes should therefore
delay or prevent b-cell failure [9].This article will first
review the principal pathophysiological mechanisms
underlying prediabetes and subsequently address treatment
considerations based on these in the prevention of type 2
diabetes.
Pathophysiology of prediabetes
Trajectories of glycemic changes in prediabetes
Blood glucose levels are strictly regulated in healthy
individuals. With the evolution toward type 2 diabetes,
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Endocrine
abnormalities in glucose and insulin concentrations and
dynamics occur continuously and insidiously over many
years [18, 19]. Trajectories of fasting and post-load glucose
levels as well as insulin sensitivity and insulin secretion
(b-cell function) preceded the development of type 2 dia-
betes in the British Whitehall II study [10]. Increased
glucose values were observed as early as 13 years before
diagnosis, although these seemed to be tightly regulated
within the normal range until 2–6 years before diagnosis, at
which time abrupt deterioration occurred. Insulin sensi-
tivity was already reduced 13 years before onset of dia-
betes, with a steeper fall noted 5 years before diagnosis.
Insulin secretion (b-cell function) was steady throughout
the 13 year observation period and showed a substantial
compensatory increase 3–4 years before diagnosis before
decreasing steeply before conversion to diabetes. These
results indicate that insulin resistance starts many years
before diabetes development and that decreased b-cell
function is already present in the prediabetic stage.
Of note, the glucose levels that define IGT occurred
rather late during the lengthy observation period, just
before conversion to diabetes. Hence, similar to FPG,
postprandial concentrations also follow a continuum and it
is therefore plausible that by intervening much earlier,
before achieving the defined absolute IGT thresholds,
could delay or prevent progression to diabetes. As Tirosh
et al. [13] pointed out that individuals with glucose levels
approximating 94 mg/dl (5.2 mmol.l), considered as nor-
mal and below the IFG threshold, are at increased risk for
developing diabetes, it is conceivable that postprandial
glucose levels below 140 mg/dl (7.8 mmol/l), the cut point
for defining IGT, confer increased risk for developing
diabetes. Therefore, individuals with even subtle abnor-
malities in either fasting or post-load glucose levels should
be identified as early as possible, well before achieving
critical thresholds for IFG or IGT especially if they have
associated risk factors for progression to prediabetes.
Multistage model of diabetes development
Weir [19] described a multistage model of diabetes
development that corresponds to progression of diabetes,
each stage marked by changes in b-cell mass, phenotype
and function.The first stage is defined by a long period of
insulin resistance accompanied by a compensatory
increased rate of insulin secretion and increased b-cell
mass. The second stage constitutes the stable adaptation
period when b cells no longer fully compensate for
increased insulin resistance and is accompanied by changes
in b-cell phenotype demonstrated by changes in gene and
protein expression; thus, fasting and post-load glucose
values are not completely maintained. Glucose levels rise
to 5.0–6.5 mmol/l (89–116 mg/dl).This period is usually
Endocrine
accompanied by a decrease in acute insulin secretion at
FPG concentrations of 5.6 mmol/l (100 mg/dl). Acute
glucose stimulated insulin secretion drops off considerably
and disappears completely when fasting glucose levels
increase to 6.3 mmol/l (114 mg/dl). The second phase of
insulin secretion is partially preserved. These observations
correspond to the concept of glucotoxicity by which
modestly high-glucose levels creates an unfavorable envi-
ronment leading to alteration in b-cell function (see
below).
During the unstable early decompensation period—the
third stage of diabetes development — b cells become
unable to compensate for insulin resistance when glucose
levels approximate 7.3 mmol/l (130 mg/dl) and conse-
quently glucose concentrations start to increase rapidly, as
was seen in Whitehall II. This period probably extends
from prediabetes to manifest diabetes during which the
subsequent two stages, stable and severe decompensation,
occur.
Glucose dysregulation
Glucose dysregulation has been reviewed by Vasudevan
and Garber [20]. In the fasting state, hepatic glucose output
(HGO) results from both glycogenolysis and gluconeo-
genesis accounting for approximately 90 % of the glucose
released into the circulation. Conversely, in the postpran-
dial state, HGO is suppressed to help limit the rise in
plasma glucose levels and the liver stores fuel by conver-
sion to glycogen. These effects are mediated in the fasting
state by an increase in gluconeogenic substrate, a reduction
in insulin concentration and an increase in other hormones
such as glucagon with the converse changes occurring
postprandially. Insulin directly reduces HGO by inhibition
of gluconeogenic enzymes, such as phosphoenolpyruvate
carboxykinase. Indirectly, insulin may reduce HGO via its
antilipolytic action, as a strong correlation exists between
plasma free fatty-acid (FFA) levels and HGO.FFA stimu-
late gluconeogenesis by increasing ATP and NADH, gen-
erated from their oxidation in the liver. Insulin inhibition of
HGO has been shown to correlate with suppression of
plasma FFA levels.
Endogenous glucose production is greatly suppressed in
individuals with normal glucose tolerance postprandially
by insulin release, whereas this is less pronounced in pre-
diabetes and diabetes. In the basal state, 30 % of glucose
uptake is insulin mediated, whereas in the post-prandial
state, this increases to 85, 80–90 % of which occurs in
skeletal muscle [21, 22]. In type 2 diabetes, total body
glucose disposal is decreased, 85–90 % of which is related
to insulin resistance in muscle. If insulin secretion was able
to compensate for insulin resistance perfectly, no obser-
vable changes in glucose concentration would occur. This
implies that b-cell dysfunction is already present in the
prediabetic phase.
b-cell function cannot be characterized solely on the
basis of insulin secretion without considering underlying
insulin resistance. b- cells respond to an increase in
glucose concentration with a rise in insulin secretion that
is dependent on whole body insulin sensitivity. Accord-
ingly, the relation between insulin secretion and insulin
sensitivity is hyperbolic (‘‘Hyperbolic Law of Glucose
Tolerance’’) [23], and the ratio of incremental insulin to
incremental glucose divided by insulin resistance is
described by a constant known as the disposition index
(DI), the so-called ‘‘gold-standard’’ for b-cell function
[8]. This index, higher in healthy individuals and lower in
prediabetes and diabetes, therefore represents the ability
of the glucose regulating system to compensate for
insulin resistance by increasing plasma insulin [8, 23].
When the plasma insulin response to oral glucose is
related to the glycemic stimulus and severity of insulin
resistance, there is a progressive decline in b-cell func-
tion that begins in NGT individuals (2–hour plasma
glucose [100 mg/dl (5.6 mmol/l) during a 75 gram
OGTT [24]. A reduced DI, representative of compro-
mised b-cell function, is a harbinger of type 2 diabetes
[23]. Studies using different measures of b-cell function
have reported severely abnormal (up to 80 % decreased)
insulin secretion in prediabetes, findings supported by
autopsy reports describing a 50 % decrease in b-cell
volume in IFG.
Skeletal muscle glucose metabolism
Aside from impaired insulin action, kinetic defects in
insulin action in obesity have also been demonstrated
whereby the rate of activation of insulin’s effect to stim-
ulate glucose disposal is decreased and the rate of deacti-
vation of insulin’s effect is increased [21]. In physiologic
circumstances, insulin is secreted post-prandially in a
phasic rather than a steady-state manner. It is therefore
likely that kinetic defects in insulin action are of functional
importance and steady-state measurements of insulin
action underestimate alterations in insulin sensitivity. Pul-
satility and/or rapid oscillation of insulin secretion is lost or
disordered in first-degree relatives of individuals with type
2 diabetes who show minimal glucose intolerance or NGT,
and in those with IGT [25–28]. A loss of coordinated
insulin secretory responses to oscillatory glucose infusion
is found in individuals with IGT, indicating a defect in the
ability of the b-cell to properly sense and respond to par-
allel changes in the plasma glucose level [27]. These
abnormalities in the dynamics of insulin secretion represent
an early manifestation of b-cell dysfunction that precedes
the development of type 2 diabetes.
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Defects in muscle glycogen synthesis have been dem-
onstrated in insulin resistant states, with a 50 % reduction
observed in type 2 diabetes. As glycogen synthesis is
known to account for the majority of non-oxidative glucose
metabolism, a defect in glucose incorporation into glyco-
gen is an important manifestation of insulin resistance. The
impairment in skeletal muscle glycogen synthesis has been
attributed to defects in glucose transport, hexokinase and
glycogen synthase [21].
Pancreatic b-cell function
Chronic hyperglycemia impairs glucose-induced pancreatic
insulin secretion and insulin gene expression through
mechanisms that impact glucose desensitization, ß-cell
exhaustion, and glucotoxicity [29]. Glucose desensitization
is applied to the rapid and reversible refractoriness of
pancreatic b-cell insulin exocytosis subsequent to sustained
hyperglycemia, whereas b-cell exhaustion refers to deple-
tion of the intracellular insulin pool available for rapid
release following prolonged exposure to a secretagogue. In
contrast, glucotoxicity refers to the progressively irrevers-
ible effects of chronic hyperglycemia on b-cell function.
b-cell secretory defects are reversible up to a point and
become irreversible thereafter, suggesting that there is a
continuum between b-cell exhaustion and glucotoxicity,
with the latter occurring more predictably after sustained
hyperglycemia. Chronic hyperglycemia also decreases
pancreatic b-cell mass by promoting islet cell apoptosis.
b-cell mass may also be affected by accumulation of amyloid
plaques although this is unlikely to be a causal factor for
onset of hyperglycemia in type 2 diabetes in man [29, 30].
Insulin resistance in IFG and IGT
Individuals with isolated IFG differ from those with iso-
lated IGT in their fasting and 2 h post-load glucose values
and by the shape of their glucose concentration curves
during an OGTT [8, 10]. Both groups present with insulin
resistance but the site of insulin resistance differing. Ele-
vated hepatic insulin resistance is a typical finding in IFG,
with almost normal skeletal muscle sensitivity. Individuals
with IFG have moderate hepatic insulin resistance and
impaired early (1–30 min) insulin response exocytosis of
insulin from secretory vesicles docked to the membrane
[30] during the OGTT [8]. Because the late-phase plasma
insulin response is intact and muscle sensitivity is normal
or near-normal, the 2 h plasma glucose returns to the initial
FPG level [8]. Those with IGT have moderate-severe
muscle insulin resistance with small changes in liver
sensitivity [8] and impaired early and late insulin
(60–120 min) response (granule translocation and matura-
tion) during OGTT [31]. Although FPG is not elevated,
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Endocrine
there is a progressive, sustained plasma glucose rise during
OGTT and the 2 h level remains well-above the fasting
level [8]. This concept is supported by the finding that total
body glucose disposal can gradually worsen from normal
glucose tolerance to IFG to IGT and then to type 2
diabetes.
Although individuals with IFG have 2-hour values
during an OGTT comparable to those with NGT, the
1-hour level may nonetheless be elevated. Similarly, the
1-hour level in those with IGT exceeds those with NGT
and is higher than the 2-hour values during an OGTT [32].
Abdul-Ghani et al. [33, 34] demonstrated that the 1 h
glucose concentration exceeding 150 mg/dl (8.33 mmol/l)
during the OGTT is a strong predictor of future risk for
type 2 diabetes. In the Botnia [35] and San Antonio Heart
Studies [33, 34], a 1-hr plasma glucose of at least 155 mg/
dl was the best predictor of future type 2 diabetes in
individuals with IGT. About 40 % of those, who develop
type 2 diabetes have normal glucose tolerance (NGT) at
baseline [34]. In one study [34], 16.7 % of those with NGT
having a1-hour glucose level [ 155 mg/dl (8.61 mmol/l)
developed type 2 diabetes over 7–8 years. The group of
individuals with NGT having a 1-hour level [ 155 mg/dl
(8.61 mmol/l) fulfilling the ATP III criteria for the meta-
bolic syndrome had a 4.3 % annual risk for future type 2
diabetes [34]. The risk in the latter group for progression
exceeds that of individuals with IFG or IGT and their odds
ratio for developing diabetes is double that of IGT subjects
with a 1-hour value \155 mg/dl (8.61 mmol/l). Each
individual with combined glucose intolerance (IFG ?
IGT) had a 1-hour value [155 mg/dl (8.61 mmol/l). The
1-hour plasma glucose concentration during the OGTT
correlates more strongly with insulin secretion, insulin
resistance and insulin secretion/insulin resistance index
than the 2-hour plasma glucose concentration [33]. The
1-hour value of 155 mg/dl had greater sensitivity (75 %)
compared to the 2-hour level (51 %) as a threshold for
predicting future type 2 diabetes although specificity was
greater with the 2-hour value (92 % vs 79 %). Thus, high-
risk individuals with IGT with additional risk factors for
progression to type 2 diabetes, can be screened using the
1-hour plasma glucose to further identify those for poten-
tial pharmacologic therapy [8].
When comparing HbA1c levels between 5.7–6.4 % with
the OGTT for diagnosing individuals at risk for developing
diabetes, a 1-hour post-load glucose level of 155 mg/dl
(8.61 mmol/l) could identify more individuals with early
glucose abnormalities than the 2-hour post-load level
of 140 mg/dl (7.8 mmol/l) (unpublished, Bergman). The
1-hour post-load glucose level diagnosed dysglycemic
states as more severe than did the 2-hour level in both
low (5.7–5.9 %) and high (6.0–6.4 %) HbA1c groups.
Approximately 60 % of individuals in the low and 70 %
Endocrine
in the high-HbA1c group had abnormal 1-hour glucose
readings. This decreased to about 40 % in both low and
high HbA1c groups using the 2-hour post-load value
reflecting the increased sensitivity of the 1-hour level.
Although these findings need to be confirmed, individuals
in the low HbA1c group may already be at risk for
developing diabetes based on the 1-hour post-load level
and might benefit from lifestyle intervention at this stage
when b –cell function is still relatively intact.
Glucolipotoxicity
The relation between glucose and lipid toxicity with insulin
resistance and b-cell toxicity has been reviewed [22, 29].
Lipid accumulation in the liver appears to be a principal
mechanism associated with obesity-related insulin resis-
tance and type 2 diabetes [36]. Altered metabolism of tri-
glyceride-rich lipoproteins is an integral part of the
atherogenic dyslipidemia in insulin resistant prediabetic
individuals and in type 2 diabetes, and is characterized
typically by elevated serum triglyceride levels and
decreased high-density lipoprotein cholesterol (HDL-c).
Increased hepatic secretion and decreased clearance of
VLDL and intestinally derived chylomicrons result in
prolonged plasma retention of these particles and accu-
mulation of highly atherogenic partially lipolyzed choles-
terol-enriched intermediate density lipoprotein (IDL)
remnants and small dense LDL particles. Excess triacyl-
glycerols beyond the oxidative needs of lean tissue (stea-
tosis) leads to a ‘‘spill over’’ effect in liver, skeletal muscle,
cardiac muscle, and endocrine pancreas, resulting in tissue
dysfunction or lipotoxicity, largely due to potentially toxic
end products of non-oxidative FFA metabolism. This
eventually leads to lipoapoptosis or lipid-induced cell
death. This tissue toxic effect has been attributed to the
generation of specific proapoptotic lipid species or signal-
ing molecules such as reactive oxygen species generation,
de novo ceramide synthesis, nitric oxide generation,
decreases in phosphatidylinositol-3-kinase, and primary
effects on mitochondrial structure or function. Long-chain
fatty acids (LCFA) may also suppress antiapoptotic factors
such as Bcl-2.
FFAs, resulting from hydrolysis of stored triacylglyce-
rols, result in decreased glucose transport via inhibition of
key glucose transporters in insulin responsive tissues such
as skeletal muscle, resulting in insulin resistance. FFA
oxidation stimulates the activity of key gluconeogenic
enzymes (pyruvate carboxylase, phosphoenolpyruvate
carboxykinase, glucose-6-phodphastase). [37]. Thus, lipo-
toxicity results in pancreatic (insulin secretory) and
peripheral (insulin resistance) defects eventually resulting
in sustained hyperglycemia.
Fatty acids and glucose constitute the primary oxidative
fuels that support muscle contractility and their relative
utilization can be adjusted to match energy supply and
demand. Metabolic fuel switching mediated the ability of
lipid and carbohydrate pathways to regulate each other
[22]. Isolated hyperglycemia or elevated circulating FFAs
may not be detrimental to the b cell. Elevated glucose
levels alone results in oxidation and isolated elevation in
FFAs are oxidized instead of glucose. However, when both
glucose and FFA levels are elevated, progressive tissue
toxicity may ensue [20]. FFAs impair b-cell function,
particularly in the setting of elevated glucose levels. FFAs
act via multiple, ultimately converging, pathways that
include suppression of cellular proliferation, impairments
in b-cell gene transcription, alterations in glycerolipid/free
fatty-acid cycling, and elevations in reactive oxidative
species (ROS) production leading to a phenomenon known
as endoplasmic reticulum stress [38]. b-cells have limited
capacity to cope with oxidative stress, and given the central
role of the ER in the production of secreted proteins such as
insulin, are therefore especially prone to ER stress.
Enhanced FFA flux, uptake and oxidation inhibit glycol-
ysis (intrahepatic substrate competitive cycle) and stimulate
gluconeogenesis [37].When both FFA and glucose levels are
elevated, FFA-derived long-chain fatty acyl-CoA ester lev-
els are high, yet they cannot be oxidized because glucose-
derived malonyl-CoA is elevated as well. Malonyl-CoA
regulates mitochondrial cytosolic lipid partitioning (the
relative fluxes of FFA oxidation and esterification) through
its inhibitory action on carnitine palmitoyltransferase-1
(CPT-1), which catalyzes the rate-limiting step leading to
mitochondrial b-oxidation of fatty acids [21, 22]. An
increase in malonyl-CoA inhibits CPT-1 and hence FFA
oxidation which leads to their accumulation in the cytoplasm
with subsequent deleterious effects on insulin action.
Alternatively, if LCFA-CoAs are not transported into the
mitochondria they may be re-esterified via diacylglyercol
(DAG) to form triglycerides and phospholipids [20, 21].
Palmitoyl-CoA may also be converted into ceramide which
may be toxic and result in insulin resistance [22].
Intramyocellular triglyceride content is increased in
obesity and type 2 diabetes has been shown to be a strong
predictor of insulin resistance. It is likely that increased in-
tramyocellular triglyceride content may not in itself impair
insulin signaling, but serves as a marker of increased intra-
cellular LCFA-CoAs and lipid intermediates. There are
several mechanisms by which fatty-acid intermediates can
induce insulin resistance. Both LCFA-CoAs and DAG can
activate protein kinase C (PKC), especially novel PKC iso-
zymes such as PKC h leading in turn to serine phosphory-
lation of insulin receptor substrate-1(IRS-1), impairing its
ability to associate with the insulin receptor, and interfering
with PI3 K activation and insulin signaling [22, 29].
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Altered fat distribution
Body fat distribution is an additional factor that mitigates
insulin resistance. Independent total body fat mass, accu-
mulation of adipose tissue within the visceral/abdominal
region and liver accentuates insulin resistance. The latter
may be related to inflammatory changes in adipose depots
with release of cytokines [37]. Intraperitoneal (visceral)
adipose tissue may be particularly deleterious as it drains
directly to the liver via the portal vein, therefore exposing
the liver to high concentrations of FFA [21]. Furthermore,
visceral adipocytes appear to be more responsive to cate-
cholamine-stimulated lipolysis and less so to suppression
of lipolysis by insulin. This could lead to increased FFA
flux into muscle and liver contributing to increased intra-
myocellular and hepatic triglyceride content and insulin
resistance.
Changes in glucose homeostasis have been linked to
altered partitioning of fat in skeletal muscle and abdominal
adipose tissue in obese children and adolescents with IGT
[39].These children were found to have profound periph-
eral insulin resistance with major defects in the non-oxi-
dative pathway of glucose metabolism, no compensatory
increase in insulin secretion and low adiponectin concen-
trations. Adiponectin, a possible mediator of triglyceride
accumulation, appears to have an important role in the
genesis of insulin resistance. These children also displayed
suppression of total body lipid oxidation, plasma fatty
acids, and glycerol turnover.
Altered distribution of fat between the abdominal sub-
cutaneous and visceral compartments is associated with
IGT. The visceral-to-subcutaneous ratio appears to be
greater in those with IGT. Intramyocellular lipid accumu-
lation and increased visceral fat mass are related to insulin
resistance in children with prediabetes supporting the view
that increased lipid content in myocytes is a marker of
impaired insulin action. Hence, intra-myocellular and intra-
abdominal fat accumulation is strongly related to post-glu-
cose hyperglycemia in obese prediabetic young individuals.
As discussed above, over accumulation of long-chain fatty
acyl-CoA interferes directly with insulin signaling and glu-
cose transport. Selective depletion of intramyocellular fat
stores appears to restore normal insulin sensitivity despite
persistent excess of total body fat.
Impaired incretin effect
Abnormalities in the incretin axis are important in pro-
gressive b-cell failure in type 2 diabetes [40]. Glucagon-
like peptide-1 (GLP-1) is an incretin hormone that results
in glucose-dependent insulin secretion, suppression of
glucagon secretion, a delay in gastric emptying, and a
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Endocrine
decrease in caloric intake likely secondary to centrally
mediated signaling [41]. Glucose-dependent insulinotropic
polypeptide (GIP) as well as GLP-1 potentiate glucose-
induced insulin release. Both GLP-1 and GIP mediate the
b-cell by activation of adenylate cyclase and ATP con-
version to cAMP amplifying the insulin secretory response
activated by hyperglycemia. In the absence of hypergly-
cemia, neither incretin increases insulin secretion. They
also have other important effects on the b-cell including
increasing Pdx-1 gene expression and stimulate gene
transcription [9] resulting in replenishment of insulin
stores, prevention b-cell exhaustion and preserving b-cell
function. GLP-1 increases glucose transporter 2 and glu-
cokinase expression, leading to improved b-cell sensitivity
to glucose.
Both incretins have short half-lives as they are rapidly
cleared by several peptidases, particularly dipeptidyl pep-
tidase IV (DPP-4). Sitagliptin, a DPP-4 inhibitor, augments
incretin levels and improves glycemic control by lowering
the appearance of glucose (augmenting splanchnic reten-
tion in enterocytes or hepatocytes), postprandial endoge-
nous glucose release, and glucagon response and by
improving insulin sensitivity and b-cell cell glucose sens-
ing [27]. Enhanced insulin release, in concert with a
reduction in glucagon concentration, reduces the post-
prandial rise in glucose concentrations. Although it is still
somewhat uncertain whether and to what extent the GLP-1
response is reduced in type 2 diabetes, the incretin effect,
defined as the potentiation of insulin release by oral versus
IV glucose underlying 60–70 % of insulin secretion in
normal healthy individuals [42], is compromised in type 2
diabetes. This correlates with reduced insulin secretion and
severe b-cell resistance to the stimulatory effect of GLP-1
on insulin secretion [8]. Although the secretion of GLP-1 is
often reduced, the insulinotropic effect of both GLP-1 and
GIP appears to be severely compromised.
Treatment implications for the prevention of type 2
diabetes mellitus
Treatment paradigms for the treatment of prediabetes have
been previously reviewed [8, 10, 43–46].It is assumed that
in preventing type 2 diabetes, microvascular and macro-
vascular complications should consequentially be averted
[45]. This premise has recently been addressed in a recent
meta-analysis [11] of diabetes prevention trials demon-
strating that all-cause mortality or cardiovascular mortality
was not reduced which may have been impacted by the
sample size, low cardiovascular risk of the groups studied
or the presence of other risk factors in individuals with
IGT. However, a borderline statistically significant reduc-
tion in fatal and non-fatal stroke was observed. It should be
Endocrine
noted that none of the prevention studies were designed to
assess the benefits on cardiovascular events [47]. Further
studies are therefore required in this area.
1. Diet and Physical exercise
Lifestyle modification, which improves insulin sensi-
tivity and b-cell function, should serve as the cornerstone
of treatment focusing on diet, 7 % weight loss, and
150 min per week of moderate physical activity [10]. In the
Finnish Diabetes Prevention Study and the US DPP [48], a
58 % risk reduction in progression to diabetes was
observed. These effects were sustained in long-term fol-
low-up although the initial benefit was reduced [47].
Maintaining weight loss and physical activity is difficult to
sustain over extended time periods [8] shown in the US
DPP where weight was regained at the termination of this
study. Similarly pharmacological induced weight loss is
also followed by weight regain. Even when weight loss is
achieved, only 50–60 % will avert progression to type 2
diabetes [8] indicating that lifestyle intervention alone is
insufficient to prevent diabetes in a large number of
individuals.
When lifestyle modification is ineffective, pharmaco-
logic treatment should be considered although there are no
approved pharmacologic treatments for prediabetes [49].
The ‘‘key’’ to diabetes prevention resides in the preserva-
tion of b-cell function [8]. Pharmacological treatment
combined with diet and exercise that improve and preserve
b-cell function and enhance insulin sensitivity may there-
fore be appropriate for treating high-risk individuals [8].
2. Metformin
Metformin, a biguanide, has been shown to have bene-
ficial effects on body mass index (BMI) and lipid param-
eters [10] and is safe without serious side-effects although
contraindicated if the serum creatinine is [1.5 mg/dl in
males and 1.4 mg/dl in females [8]. It reduces FPG and
HbA1c by inhibiting hepatic glucose production and
improving insulin sensitivity [8] and does not stimulate
insulin secretion or preserve b-cell function. Although
in vitro evidence exists for improved b-cell function and
prevention of apoptosis, in vivo data from the UK Pro-
spective Diabetes Study (UKPDS) fail to support these
observations [40]. Only minor gastrointestinal side-effects
have been observed, with 10–15 % of individuals not tol-
erating metformin [8]. In the US DPP, 1750 mg daily of
metformin reduced conversion to type 2 diabetes by 31 %,
which was less effective than lifestyle with greater effect in
those with higher baseline BMI and FPG. The ADA
Consensus Conference recommended that high-risk indi-
viduals (HbA1c [6.0 %, BMI [30 kg/m2, age \60 years)
with IGT or IFG be treated with metformin [50]. Further-
more, data derived from the DPP Research Group
concluded that metformin was cost-effective from the
perspective of a health system and society especially when
using generic formulation [8].
3. Thiazolidinediones (TZD)
Thiazolidinedione agents in high-risk individuals are
capable of stabilizing b-cell function over a prolonged
period [49]. TZD act through the peroxisome proliferator-
activated receptor-c by increasing hepatic and peripheral
insulin sensitivity and preserving insulin secretion. These
agents mobilize fat from muscle, liver, and b-cell thereby
improving lipotoxicity [40]. Improved muscle insulin
sensitivity is related to reduced FFA/intramyocellular lipid
content, altered fat topography [8]. TZD have been shown
to effectively reduce and maintain a durable reduction in
HbA1c in type 2 diabetes in long-term studies implying
preservation of b-cell function. Rosiglitazone (8 mg)
showed a 60 % reduction in incident diabetes but was
associated with a significant increase in weight (approxi-
mately 2 kg) and increased risk of heart failure. Low dose
(2 mg twice daily) rosiglitazone in combination with
metformin was studied to determine if side-effects would
be reduced. The risk of diabetes was reduced by 66 %, but
diarrhea was more prevalent than in controls (16 % vs
6 %) [47].
Pioglitazone reduced the risk of diabetes in obese indi-
viduals with IGT by more than 70 % with improved dia-
stolic blood pressure and HDL-cholesterol and a reduced
rate of carotid intima-media thickening. However, these
benefits were associated with greater incidence of edema
and weight gain (about 3 kg). Pioglitazone has also been
associated with congestive heart failure. As the fat weight
gain and fluid retention are dose-related, limiting the dose
to 30 mg/d may provide most of the efficacy while mini-
mizing side-effects [8]. An increased incidence of trauma-
related fractures have been observed in postmenopausal
women treated with pioglitazone and should therefore be
used with caution in this population. A possible-link with
bladder cancer has recently been suggested and it was not
found to be more effective than lifestyle alone in the Indian
DPP-2 study [47]. Troglitazone was withdrawn in Europe
due to hepatotoxicity and rosiglitazone removed because of
concerns pertaining to increased cardiovascular risk.
4. a-glucosidase inhibitors
a-glucosidase inhibitors reduce the rate of polysaccha-
ride digestion from the proximal intestine and lower pri-
marily postprandial glucose without causing hypoglycemia
and have been evaluated in diabetes prevention trials [8,
10, 50–53]. In the STOP-NIDDM study, acarbose resulted
in a 25 % relative-risk reduction for diabetes in individuals
with IGT with a suggested decrease in cardiovascular
disease and hypertension risk. However, about a third of
123
 Endocrine

the acarbose-treated individuals could not complete the 7. Insulin secretagogues

trial because of gastrointestinal side-effects [51]. Vogli-
Although sulfonylureas (glyburide,glimepiride, and gli-
bose, another a-glucosidase inhibitor, showed a 40 %
clazide) are effective in lowering glucose levels associated
reduction in incident diabetes in a high-risk Japanese
with increased risk for hypoglycemia, they have not been
population [52]. a-glucosidase inhibitors have also been
studied in the prevention of diabetes. Nonetheless, based on
shown to augment incretin secretion as well as altering gut
evidence from the treatment of type 2 diabetes, they have
micobiota flora, which may partially explain their benefi-
been associated with a progressive decline in b-cell function
cial effects [53].
[40]. There is a consistent loss of glycemic control after
5. GLP-1 analogs 18 months of therapy demonstrating the lack of durability of
sulfonylureas and loss of glucose control is associated with
The GLP-1 analogs exenatide and liraglutide produced
progressive b-cell failure. Furthermore, nateglinide, a short-
weight loss in obese individuals and reversion from pre-
acting insulin secretagogue showed no benefit in diabetes
diabetes to normoglycemia which was accompanied by
prevention or cardiovascular outcomes in 9,000 individuals
nausea and vomiting [8, 10]. Liraglutide decreased con-
with IGT in the NAVIGATOR Study [54].
version to type 2 diabetes by 84–96 % in a 20 week study
of 564 obese, non-diabetic individuals, 31 % of whom had 8. Insulin
IGT [8]. Exenatide was found to improve b-cell function
When used to target normal fasting plasma glucose
and when continued for 3 years, a persistent beneficial
levels for more than 6 years, glargine had a neutral effect
effect was found even when it was discontinued for
on cardiovascular outcomes and cancers [55]. In the pre-
1 month. In vivo rodent and in vitro cultured human islet
diabetic cohort (12 % of the study population), glargine
cell studies have shown that exenatide can expand b-cell
slowed the progression to type 2 diabetes (assessed by
mass and prevent apoptosis of islets [41]. GLP-1 analogs
repeat OGTT 6 and 12 weeks after study end) representing
also impact liver function with reduced hepatic glucose
a 28 % reduction in risk. The implications of this finding,
production, a-cell function with a reduction in glucagon
however, remain questionable. Although reducing new-
secretion, the gut by improvement of the GLP-1 response,
onset diabetes, glargine also increased hypoglycemia and
and the brain by a reduction in appetite with weight loss.
modestly increased weight (1.6 kg). Whether the decrease
The insulin stimulatory effects wanes as normoglycemia is
in incident diabetes will affect future microvascular or
achieved thereby minimizing the risk for hypoglycemia
other outcomes remains unknown. These findings therefore
[41].
do not support changing standard therapies for early dys-
As GLP-1 analogs effectively reduce IGT conversion to
glycemia [55].
type 2 diabetes, improve b-cell function, promote weight
loss, improve cardiovascular risk factors and do not cause 9. Other medications
hypoglycemia, they may be ideally suited for treating IGT
Other medications often used to treat cardiovascular risk
[8]. The major side-effects of GLP-1 receptor agonists are
factors in those with prediabetes include angiotensin-con-
nausea and vomiting which occur in 20–30 % of individ-
verting enzyme (ACE) inhibitors, angiotensin receptor
uals and are generally mild and transient. Approximately
blockers (ARBs), thiazides, b-blockers and statins.
5 % of individuals cannot tolerate these agents. While
Hypertension is 2–3 times more common in those with
pancreatitis has been listed as a potential side-effect, an
prediabetes [56]. As the effectiveness of ACE inhibitors
increased incidence of the latter has not been substantiated
and ARBs is not limited to blood pressure reduction and
[8]. In considering their potential suitability for use in the
these agents do not only pejoratively glucose-control but
prevention of diabetes, the considerable costs of these
also have a specific effect on prevention of diabetic
agents requires cost effectiveness studies should they ulti-
nephropathy [57, 58], their primary use in prediabetes is
mately be approved for this indication.
recommended [58], whereas thiazide diuretics and
6. DPP-IV inhibitors b-blockers have been associated with a higher risk of
incident diabetes [59–61]. Finally, as prediabetes and dia-
Based on their mechanism of action discussed earlier,
betes are cardiovascular risk equivalents, treatment goals
agents in this class could in principle be beneficial in dia-
for LDL-C should be similar [58]. Although statin therapy
betes prevention although there are no long-term studies
has been associated with a small, increased risk of devel-
available examining the enhancement of insulin secretion
opment of diabetes [62], benefit in individuals at high
into preservation of b-cell function [42]. Hypoglycemia,
cardiovascular risk favors their use as part of a multifac-
weight loss or appetite suppression is not associated with
torial approach to risk factor management even when dia-
their use. Cost effectiveness of these agents need to be
betes is diagnosed [62–64].
taken into consideration as well.

123
Endocrine
Conclusion
As we have seen, certain therapeutic classes may be useful
for the treatment of prediabetes-based on their specific role
in the complex pathophysiologic mechanisms described
earlier. However, in view of long-standing safety data with
demonstrated efficacy and cost-effectiveness in the pre-
vention of type 2 diabetes in high-risk individuals, met-
formin should be considered as initial therapy for those
unable to comply with or lifestyle modification or where
the latter has been ineffective in decreasing progression to
type 2 diabetes. The use of a-glucosidase inhibitors,
despite their marked gastrointestinal intolerance, may
present another reasonable option. At the present time,
these options would be preferable to other agents lacking
long-term efficacy data, have the potential for side-effects
and where costs limit their usage in the prediabetic popu-
lation. First line therapies for reducing cardiovascular risk
factors in prediabetes include ACE inhibitors or ARBs for
hypertension and statins for hypercholesterolemia, with
therapeutic targets similar to those with established
diabetes.
Conflict of Interest The author has no conflicts to report.
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