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Antidiabetic Drugs: Mechanisms of Action and Potential Outcomes on Cellular

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3606 Current Pharmaceutical Design, 2015, 21, 3606-3620

Antidiabetic Drugs: Mechanisms of Action and Potential Outcomes on Cellular

Metabolism

Maria J. Meneses1,2, Branca M. Silva1, Mário Sousa2,3, Rosália Sá2, Pedro F. Oliveira1,2 and Marco G. Alves1*

1
CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; 2Department of
Microscopy, Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Insti-
tute of Biomedical Sciences, University of Porto – UMIB/ICBAS/UP; 3Centre for Reproductive Genetics Professor
Alberto Barros, Porto, Portugal

Abstract: Diabetes mellitus (DM) is one of the most prevalent chronic diseases and has been a leading cause of
death in the last decades. Thus, methods to detect, prevent or delay this disease and its co-morbidities have long
been a matter of discussion. Nowadays, DM patients, particularly those suffering with type 2 DM, are advised to
alter their diet and physical exercise regimens and then proceed progressively from monotherapy, dual therapy, and
multi-agent therapy to insulin administration, as the disease becomes more severe.
Although progresses have been made, the pursuit for the “perfect” antidiabetic drug still continues. The complexity
of DM and its impact on whole body homeodynamics are two of the main reasons why there is not yet such a drug. Moreover, the mo-
lecular mechanisms by which DM can be controlled are still under an intense debate. As the associated risks, disadvantages, side effects
and mechanisms of action vary from drug to drug, the choice of the most suitable therapy needs to be thoroughly investigated. Herein we
propose to discuss the different classes of antidiabetic drugs available, their applications and mechanisms of action, particularly those of
the newer and/or most widely prescribed classes. A special emphasis will be made on their effects on cellular metabolism, since these
drugs affect those pathways in several cellular systems and organs, promoting metabolic alterations responsible for either deleterious or
beneficial effects. This is a crucial property that needs to be carefully investigated when prescribing an antidiabetic.
Keywords: Antidiabetics, cell metabolism, diabetes mellitus, drug therapy, insulin resistance.

INTRODUCTION
In the last decades, the number of diabetic patients has alarm-
ingly increased, particularly due to the increased rates of type 2
diabetes mellitus (T2DM). Besides the health problems, this is as-
sociated with severe economic and sociologic problems. The treat-
ment of diabetic individuals involves high costs and the amount of
money spent every year in their treatment is increasing. There are
several antidiabetic drugs in the market that can be used either in
monotherapy or in combination. The mechanisms of action for each
compound are different and may vary depending on several condi-
tions, including the doses. The antidiabetic drugs aim to control
glucose metabolism and, in a non-specialized approach, we can
affirm that their gold objective is to lower blood glucose levels.
Therefore, most of their mechanisms of action are intimately linked
with glucose metabolism. Unfortunately, most of these compounds
compensate loss of insulin sensitivity, of insulin action or of insulin
secretion, as well as other mechanisms responsible for the disease,
but are unable to avoid or treat some of the deleterious effects. In
addition, this is a field of research in constant change with the de-
velopment of new products and intense research.
Glycemic control in diabetic patients is sometimes quite diffi-
cult to attain. Therefore, it is urgent that the scientific community
provides new and better options to improve the use of the current
available drugs and to highlight the most suitable therapies. Of
particular relevance is the study of the pathophysiological altera-
tions that diabetic individuals suffer and how the available drugs
may affect those processes. There are several options for the treat-
ment of diabetic patients, with distinct modes of action. Notably,
some of those compounds were developed or are in development to
*Address correspondence to this author at the CICS-UBI, Health Sciences
Research Centre, University of Beira Interior, Av. Infante D. Henrique,
6201-506 Covilhã, Portugal; Tel: +351 275329077; Fax: +351 275329099;
E-mail: alvesmarc@gmail.com
treat other diseases, particularly obesity, which is a major cause for
the establishment of diabetes mellitus (DM). Thus, the complexity
of compounds available, their modes of action and their biological
activities are hot topics of debate for multiple areas of the human
health, particularly for cardiovascular, renal, neurologic and even
cancer pathologies.
DM is a multifactorial disease, which indicates that a complex
analysis is needed when searching for new targets to treat this dis-
ease or the mode of action of compounds with potential antidiabetic
activity. Moreover, several of these compounds, if not all, have the
ability to alter cellular metabolism in a way that may be of benefit
in some organs, but cause damage in others. This is a tricky prob-
lem that hampers the development of new drugs and obliges to a
constant monitoring of how the patients take each compound alone
or how combination therapies may evolve. In the last years, thou-
sands of compounds have emerged and there is an extensive litera-
ture on each. Herein we propose to discuss the mode of action of
the most used families of antidiabetic drugs and how they are cur-
rently used. Since these compounds act on insulin sensitivity, insu-
lin action or insulin secretion, they also alter cellular metabolism.
Thus, we also aim to discuss some mechanisms by which these
compounds act on modulating cells metabolism.
DIABETES MELLITUS IN BRIEF
DM is one of the most prevalent chronic diseases and a leading
cause of morbidity and mortality on developed and in developing
countries. It is estimated that 382 million of people have DM and,
according to a recent report, the number of diabetic patients will
reach 592 million by the year 2035 [1]. Therefore, it urges the study
of this pathology and its consequences to cells, organs and whole
body. DM is described as a group of metabolic disorders character-
ized by chronic hyperglycemia resulting from defects in insulin
action, insulin secretion, or both [2]. This deficiency leads to dis-
turbances in the metabolism of carbohydrates, fat and protein,

1873-4286/15 $58.00+.00 © 2015 Bentham Science Publishers

Antidiabetic Drugs
which causes systemic complications and co-morbidities namely
cardiovascular and renal failure. The most predominant types of
DM are type 1 diabetes mellitus (T1DM) and T2DM. T1DM is a
chronic autoimmune disease caused by the pathogenic action of T
lymphocytes on insulin-producing
-cells [3]. This leads to a dra-
matic reduction or even elimination of insulin production. Thus,
patients with T1DM are dependent on exogenous insulin to survive
[4]. Typically, the symptoms of T1DM appear in patients with less
than 30 years, being known as juvenile-onset diabetes. The inci-
dence of T1DM has been globally rising and, if present trend con-
tinues, it is predicted a doubling of new cases in European children
younger than 5 years between 2005 and 2020. Additionally, it is
expected that the prevalence of cases in individuals younger than 15
years of age will rise by 70% during that period [5].
T2DM is characterized by hyperglycemia that results from insu-
lin resistance plus variable degrees of insufficient insulin secretion
[2]. Although new lifestyles of modern societies seem to be the
triggering pathogenic elements, genetic factors are also reported to
be involved in the pathogenesis of T2DM [6]. In early stages of the
disease, insulin production is disproportionately low for the degree
of insulin sensitivity, which is usually increased. Thus, the ability of
pancreatic
-cells to produce adequate amounts of insulin in post-
prandial glycemia is profoundly compromised. These cells’ func-
tional inability is the main determinant of hyperglycemia and is
known to progress over time [7]. As a result, most patients with
T2DM will gradually need more complex therapeutic procedures to
control hyperglycemia. Normally, the alterations start in diet and
exercise regimens and progress to monotherapy, dual therapy, or
multi-agent therapy followed by insulin administration in combina-
tion or not with other antidiabetic drugs [8]. Thus, the demand for
antidiabetic drugs is very high and new products are regularly pre-
sented. Although its safety is assured, these drugs have multiple
modes of action and effects throughout the body. Furthermore, the
complexity of T2DM led to the establishment of an intermediate
state, often called as pre-diabetes. In this prodromal stage of T2DM,
the patients present glycemic values higher than normal, but lower
than T2DM thresholds [9, 10]. Moreover, pre-diabetic patients pre-
sent impaired fasting glycemia and/or impaired glucose tolerance
[11]. This pre-diabetic condition may be triggered by sedentary
lifestyle and the ingestion of high fat and saturated fatty acid diets
[11, 12]. As a consequence, several metabolic changes in organs
and cellular systems occur [13]. These patients have increased risk
for T2DM as well as for cardiovascular disease [14]. However, this
pre-diabetic stage does not imply the progression to T2DM, which
can be prevented or delayed by lifestyle and drug-based interven-
tions [15, 16] illustrating the relevance of an early diagnostic and of
the study of this prodromal stage of T2DM.
ANTIDIABETIC DRUGS
Inhibitors of
-Glucosidases
Carbohydrates are central constituents of western diets [17].
Complex carbohydrates are enzymatically degraded to monosac-
charides by the action of
-galactosidases [18],
-amylase and
-
glucosidases [19]. Thus, inhibitors of intestinal
-glucosidase en-
zymes modulate the rate of digestion of complex carbohydrates and
disaccharides by competitively and reversibly inhibiting
-
glucosidases present in the brush border membrane of enterocytes
that line the intestinal villi [19, 20]. Consequently, the digestion of
carbohydrates and absorption of monosaccharides in the proximal
jejunum are decreased or incomplete in the distal jejunum and il-
eum (Table 1). Therefore, the rise in postprandial plasma glucose
levels is diminished and/or delayed.
-glucosidase inhibitors allow
the pancreatic
-cell more time to augment insulin secretion in re-
sponse to the increase in plasma glucose level [21, 22]. Due to its
mechanism of action,
-glucosidase inhibitors should be taken at
the beginning of the main meals. Notably, its effectiveness in de-
creasing postprandial glycemia will be determined by the amount of
Current Pharmaceutical Design, 2015, Vol. 21, No. 25 3607
complex carbohydrates present in the meal [22]. Importantly, it
presents some adverse effects. The most common are flatulence,
diarrhoea, and abdominal discomfort caused by altered bacterial
metabolism of disaccharides in the colon [23, 24]. Some other dis-
advantages include negligible effect on cholesterol, and potential
elevation in liver hepatic enzymes. Presently, there are three avail-
able
-glucosidase inhibitors used as antidiabetic drugs: acarbose
[25], miglitol [26, 27] and voglibose [23, 28]. While acarbose is
widely available, miglitol was approved by Food and Drug Admini-
stration and voglibose is only available in Japan.
Acarbose was the first
-glucosidase inhibitor described [29]
and is the most prescribed one [30]. It is a pseudotetrasaccharide of
microbial origin (Actinoplanes utahensis) [31], consisting of a mal-
tose molecule linked to acarvosine with a nitrogen bound between
the first and second glucose unit [19, 20, 27]. This modification of a
natural tetrasaccharide is important for its high affinity for active
centres of
-glucosidases of the small intestine brush border, as
well as for its stability [22]. Acarbose is mostly effective against
glucoamylase, being less effective against sucrase, maltase, and
dextrinase [32]. It also inhibits
-amylase, but has no effect on
-
glucosidases [20]. Absorption of acarbose is negligible because it is
mostly degraded by intestinal bacteria and by amylases present in
the small intestine [27, 33]. The recommended dose is 50 mg three
times a day, before the main meals, increasing until a maximum
dose of 100 mg three times daily [20].
Miglitol is the first pseudomonosaccharide
-glucosidase in-
hibitor derived from 1-deoxynojirimycin and presents a structure
very similar to glucose [34]. Unlike acarbose, it is almost com-
pletely absorbed in the upper section of the small intestine, has low
tissue penetration and is excreted unchanged by the kidneys [35]. It
is mostly effective against sucrase, inhibiting also glucoamylase,
isomaltase, lactase and trehalase [36]. The normal administration of
miglitol is usually 50 mg though it may be increased to 100 mg
three times per day after a few weeks, which is the maximal rec-
ommended daily dosage [20, 27].
Voglibose is a valiolamine derivative [37], which is produced
by Streptomyces Hygroscopicus [38]. Similarly to acarbose, vogli-
bose is slowly and poorly absorbed, being rapidly excreted [39].
Like the other
-glucosidases inhibitors [40], voglibose also stimu-
lates an increase of endogenous glucagon-like peptide-1 (GLP-1),
an incretin hormone with antihyperglycemic properties [39, 41].
Voglibose should be administered in a single oral dose of 0.2 mg
three times a day and, if not sufficient, the dose can be uptitrated to
0.3 mg [20, 41].
Biguanides
Several glucose-lowering guanidine derivatives were intro-
duced in the 1920s, due to the finding that Galega officinalis, a
traditional herb historically used as treatment for DM, was rich in
guanidine [42]. These agents were almost forgotten as insulin be-
came widely available and used [43]. It was not until the 1950s that
biguanides were re-investigated for the treatment of DM. In the late
1950s, three biguanides with antidiabetic action were reported:
phenformin [44], buformin [43] and metformin [45]. The use of
phenformin and buformin has been discontinued in many countries
due to a high incidence of lactic acidosis [46], leaving metformin as
the main biguanide used worldwide [43, 47]. Indeed, metformin has
been used to treat T2DM for over 50 years. It is usually described
as the first line treatment to this disorder, along with diet and exer-
cise [48]. Metformin is an insulin-sensitizing drug that exerts its
antihyperglycemic effects by blocking liver gluconeogenesis [49]
through regulation of the gluconeogenic flux, rather than direct
inhibition of gluconeogenic gene expression [50]. It also increases
skeletal muscle uptake of glucose [51] and reduces the absorption
of glucose in the intestinal mucosa [52] (Table 1). Despite almost
60 years of research, the exact mechanisms of metformin action
remain to be unveiled [53]. Nevertheless, it is known that met-
3608 Current Pharmaceutical Design, 2015, Vol. 21, No. 25
formin has no effect on stimulating insulin secretion in pancreatic

-cell [43]. In recent years, studies provided evidence that met-
formin acts as an inhibitor of complex I of the electron transport
chain [54, 55], inducing activation of AMP-activated protein kinase
(AMPK) sensitive signalling [51]. AMPK acts as a regulator of
glucose and lipid metabolism, as well as of cellular energy, through
phosphorylation of some key proteins [56]. The increase in its ac-
tivity results in several biological alterations including: the stimula-
tion of glucose uptake in muscle; fatty acid oxidation in liver and
muscle; inhibition of hepatic glucose production, cholesterol and
triglyceride synthesis; and lipogenesis [57]. Another suggested
effect for metformin is that it increases plasma levels of GLP-1, an
incretin hormone with antihyperglycemic properties, and induces
islet incretin receptor gene expression, through a mechanism that is
dependent on peroxisome proliferator-activated receptor
(PPAR
)
[58]. Metformin has a main advantage over other biguanides, which
is the very low probability to promote lactic acidosis [59]. How-
ever, it has some disadvantages, such as adverse gastrointestinal
effects [59]. Although considered the first-line pharmacological
agent for T2DM individuals, in many patients the administration of
this drug is insufficient to reach glycemic control and a second
agent is added to the treatment [20, 60, 61].
Sulfonylureas
An incidental observation of hypoglycemia episodes during
treatment with sulfonamides in the 1940s, led to the concept and
development of sulfonylureas as agents to stimulate insulin secre-
tion [62]. By 1955, sulfonylureas became the first pharmacological
option to treat non-insulin-dependent DM, besides insulin injections
[63]. The first sulfonylureas developed were tolbutamide, chlor-
propamide, acetohexamide and tolazamide [64, 65]. These first-
generation agents have been largely set aside by the newer second-
generation agents gliclazide, glipizide and glibenclamide (gly-
buride) [65]. The most recent sulfonylurea, glimepiride, is consid-
ered by some researchers as a second generation of sulfonylureas
[64], while others classify it as third-generation [66]. Sulfonylureas
perform their secretagogue action by activating
-cell sulfonylurea
receptor 1 (SUR 1), leading to closure of ATP-dependent potassium
channels [67, 68] (Table 1). Thus, the potassium flow across the
plasma membrane is stopped leading to depolarization, which opens
voltage sensitive calcium channels. Consequently, there is an up-
take of extracellular calcium, activating a cytoskeletal system,
which causes translocation of secretory granules to the cell surface
and extrusion of insulin through exocytosis [69, 70]. Exocytosis
results in the fusion of the secretory granule with the plasma mem-
brane, leading to the release of insulin into the extracellular space to
reach the capillary blood flow [71, 72]. Hence, sulfonylureas ad-
ministration must be carefully monitored since it can lead to hypo-
glycemia, weight gain [73] and hyperinsulinemia [59].
Meglitinides
Meglitinides are insulin secretagogues with a similar mecha-
nism of action to sulfonylureas, acting on ATP-dependent potas-
sium channels [61] (Table 1). Therefore, they fail to have any effect
in patients who have already been treated with maximal therapeutic
dosage of sulfonylureas [74]. Considering this, they offer an alter-
native to sulfonylurea treatment, but have almost the same disad-
vantages and a more complex dosing schedule [59]. To date, three
meglitinides have been used in clinical practice: nateglinide [75],
repaglinide [76] and mitiglinide [77].
Repaglinide, a carbamoylmethyl benzoic acid derivative, was
the first meglitinide analogue to become available for clinical use
[78]. It promotes insulin secretion by closing ATP-dependent potas-
sium channels in the membrane of pancreatic
-cells, but is ineffec-
tive in the absence of extracellular calcium [79]. Repaglinide binds
to a nearby location of the receptor site for sulfonylureas drugs
[80], but generates a more rapid reaction [81]. Nevertheless, the
Meneses et al.
duration of the glucose lowering effect of repaglinide is shorter than
that of some sulfonylureas. Consequently, the risk of having hypo-
glycemia is lower [82]. Repaglinide should be taken before each
meal at least twice daily and the maximum daily dosage is 16 mg
[83]. After oral administration, repaglinide is rapidly absorbed [84]
and has a bioavailability of approximately 63% [85]. It is metabo-
lised in the liver [86] to inactive metabolites and is predominantly
excreted via the bile into the faeces, thus being a viable option for
patients with renal failure [84, 87]. However, cautions should be
taken in patients with liver disease since the pharmacokinetics of
this drug may be significantly modified [88]. Protein binding can be
reduced due to administration of other drugs. Although it can be
used in combination with metformin [76] or thiazolidinediones
[89], patients receiving multiple drugs must be carefully monitored
[61].
Nateglinide, a D-phenylalanine derivative [90], quickly and
reversibly binds to the SUR 1 like sulfonylureas and has specificity
for pancreatic SURs [80]. Thus, the binding site differs from that of
repaglinide. Nateglinide inhibits the ATP-dependent potassium
channels faster than repaglinide but, on the other hand, there is a
more rapid reversal of the inhibition of the channel when taking
nateglinide in comparison with repaglinide [91]. Like repaglinide,
nateglinide is effective in combination with metformin [92] or thia-
zolidinediones [93]. It should be taken before each meal (60 mg)
regardless of the meal composition [94]. Nateglinide is rapidly
absorbed in a dose-dependent manner and is mostly excreted in
urine [95].
GLP-1 Receptor Agonists and DPP-4 Inhibitors
In the early 1990s, it was reported that the incretin hormone
GLP-1 could be a potential target in the treatment of T2DM due to
its antihyperglycemic properties, in contrast to another incretin
glucose-dependent insulinotropic polypeptide (GIP) [96]. GLP-1 is
secreted from endocrine L-cells [97] in the small intestine and is
released after meal ingestion, especially those rich in fats and car-
bohydrates [98]. Once released, GLP-1 exerts direct effects in sev-
eral organs, due to interaction with its receptor located in organs
such as pancreas, brain, heart, lung, stomach, intestine, and kidney
[99]. On pancreatic
-cells, this interaction leads to activation of
adenylate cyclase and production of cAMP, that mediates its stimu-
latory effect on insulin secretion via protein kinase A [100]. How-
ever, GLP-1 stimulates insulin secretion via several other mecha-
nisms, including a direct inhibition of ATP-dependent potassium
channels. As sulfonylureas, this leads to an increase in intracellular
levels of calcium and a rise in mitochondrial ATP synthesis which
leads to a further membrane depolarization. Finally, it causes insu-
lin granule exocytosis from pancreatic
-cells [101]. It was previ-
ously shown that GLP-1 inhibits gastric emptying [102] and in-
duces satiety [103] (Table 1). Furthermore, it may also increase
-
cell mass, through inhibition of apoptosis and promotion of
neogenesis and proliferation. Thus, GLP-1 has several effects that
are of potential value in the treatment of T2DM. Still, GLP-1 is
rapidly degraded and inactivated by the enzyme dipeptidyl pepti-
dase-4 (DPP-4) [104]. DPP-4 cleaves the two N-terminal amino
acids of GLP-1, and the resultant metabolite lacks the insulinotropic
and glucagonostatic effects of GLP-1. Consequently, two therapeu-
tic strategies have emerged to take advantage of the beneficial ef-
fects of GLP-1: the use of GLP-1 receptor agonists, which are more
resistant to the action of DPP-4 [105]; and the development of DPP-
4 inhibitors, which prevent inactivation of GLP-1 [106, 107].
DPP-4 inhibitors competitively and reversibly inhibit DPP-4
providing up to 90% inhibition of its activity during a 24-hour pe-
riod [108]. Therefore, DPP-4 inhibitors promote insulin secretion
and inhibit glucagon secretion [109], being these actions dependent
on the presence of glucose (Table 1). DPP-4 inhibition also in-
creases
-cell mass, as demonstrated in rodent models of T2DM
[110, 111]. In vitro and animal studies have revealed that GLP-1
Antidiabetic Drugs
also increases
-cell mass by stimulating islet cell neogenesis and
by inhibiting apoptosis of islets [112, 113]. Thus, the pharmacol-
ogical potential of these drugs is very relevant. Since 2006, there
are some DPP-4 inhibitors being marketed, namely sitagliptin, vil-
dagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin and alo-
gliptin. Although they share the same mechanism of action, they are
a heterogeneous group that diverges in terms of half-life, systemic
exposure, bioavailability, protein binding, metabolism, presence of
active metabolites and excretion routes [114, 115]. These differ-
ences are extremely important when considering patients that be-
sides T2DM have renal or hepatic impairment, as well as when
combined therapy is considered.
Importantly, these two drug classes present some interesting
differences that must be taken into consideration when choosing the
antidiabetic class to use. While DPP-4 inhibitors allow the increase
of GLP-1 physiological levels, GLP-1 receptor agonists increase the
pharmacological levels of GLP-1 leading to different side effects of
these classes [105, 108].
Thiazolidinediones
Thiazolidinediones, also termed glitazones, are a class of oral
antidiabetic agents that were originally developed in the early 1980s
as antioxidants [116]. The blood glucose-lowering potential of this
class of drugs was observed after the synthesis of ciglitazone, the
first thiazolidinedione. This effect was particularly pronounced in
animals with genetic insulin resistance [117]. Thiazolidinediones
were considered insulin sensitizers [118], as biguanides. This was
established after observing that glycemia improved in the absence
of increasing insulin levels and that it did not affect insulin-
deficient animals. However, due to liver toxicity, ciglitazone and
englitazone were never subjected to clinical studies [119]. Troglita-
zone, the first marketed thiazolidinedione, was introduced in Japan
and USA in 1997, but was subsequently withdrawn due to hepatox-
icity side effects [120]. Today, two thiazolidinediones are available
for clinical use: rosiglitazone and pioglitazone. These drugs are
very similar in their effect on hyperglycemia, side effects and
mechanism of action. Interestingly, both are also available in com-
bination with other antidiabetic drugs such as metformin or glime-
piride [121]. Importantly, an adverse effect of this class is fluid
retention, making thiazolidinediones contraindicated in patients
with heart failure, which is one of the leading causes of death
among T2DM patients [33] (Table 1). In addition, the therapeutic
effect is only observed after 3 to 4 months of therapy, having a slow
onset of action compared with the other available pharmacological
treatments [59].
Thiazolidinediones are potent synthetic activators of the nuclear
receptor peroxisome proliferator-activated receptor  (PPAR)
[122]. PPAR is abundantly expressed in key target tissues for insu-
lin action such as adipose tissue, but is also present in muscle, liver,
endothelium and pancreatic
-cells [123]. It heterodimerizes with
retinoid X receptor and binds to nuclear responsive elements, thus
modulating the transcription of genes that play a role in the metabo-
lism of glucose and lipids [124]. Notably, this stimulation promotes
differentiation of pre-adipocytes, which enhance local effects of
insulin. It is also discussed that signals resultant from the adipose
tissue, e.g adiponectin or leptin, may mediate the improvement in
skeletal glucose disposal induced by thiazolidinediones [125].
Pioglitazone, a potent PPAR agonist [126], increases insulin-
stimulated glucose uptake in peripheral tissues as well as insulin
sensitivity in hepatic and adipose tissue [127]. It also causes a mi-
nor activation of PPAR
, which is related with anti-inflammatory
effects, as well as with the decrease of plasma triglyceride levels
[128]. Pioglitazone has an oral bioavailability of approximately
83%, which is not modified by the presence of food on the gastroin-
testinal tract [129]. Furthermore, it is rapidly absorbed and exten-
sively metabolized by hydroxylation and oxidation in the liver,
forming active and inactive metabolites [130, 131]. Pioglitazone
Current Pharmaceutical Design, 2015, Vol. 21, No. 25 3609
blood glucose-lowering effect evolves gradually over a period of
weeks in a dose-dependent manner [132]. Pioglitazone administra-
tion must be started at 15 mg once a day to a maximum daily dos-
age of 45 mg [121]. Although pioglitazone is not reported to cause
hepatoxicity, it is debated if it might elevate the risk of bladder
cancer through an unknown mechanism [133]. Some evidences
suggest an effect associated with crystal formation and bladder
irritation, rather than a pharmacologic effect through PPAR [126].
However, there is some controversy since other studies reported
that pioglitazone should not be associated with an increased risk of
bladder cancer [134]. Notably, pioglitazone is reported to possess
multiple beneficial effects on lipid metabolism [135], immune func-
tion as well as in endothelial function [136].
Rosiglitazone belongs to the thiazolidinediones class but has a
different side chain from those of troglitazone and pioglitazone
[137]. It reaches a 99% oral bioavailability and is extensively me-
tabolised in the liver [138]. Thus, rosiglitazone is contraindicated
for patients with liver disease. The major excretion routes of rosigli-
tazone are via the urine and faeces [138]. To achieve a significant
antihyperglycemic efficacy, rosiglitazone should be given once or
twice a day at a starting dosage of 4 mg/day, which may be in-
creased, if required, to 8 mg/day, in combination with diet and ex-
ercise [139]. Intriguingly, the risk of bladder cancer appears to be
specifically associated with pioglitazone, and not with rosiglitazone
[140]. At a cardiovascular level, it has been suggested, based on a
systematic review and meta-analysis of observational studies, that
rosiglitazone presents a higher risk of complications (e.g. conges-
tive heart failure and myocardial infarction) when comparing with
pioglitazone [141].
Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibi-
tors
Sodium-dependent glucose co-transporters (SGLTs) are a large
class of proteins that facilitate the transport of sugars and sodium
across the plasma membrane of cells from an extensive variety of
tissues [142]. More specifically, two members of SGLT family
mediate reabsorption of glucose in the kidney. SGLT2 is a high-
capacity and low-affinity transporter, responsible for nearly 90% of
the active renal glucose reabsorption, while SGLT1 reabsorbs the
remaining 10% [143]. SGLTs promote reabsorption of glucose
from the proximal tubules, which is then passively diffused into the
circulation via glucose transporters (GLUTs). SGLT2 is almost
exclusively expressed in renal proximal tubules, unlike SGLT1 that
is also found in the gastrointestinal tract, and its inhibition is there-
fore unlikely to affect other organs [144]. Thus, inhibition of
SGLT2 limits renal glucose reabsorption, promoting its urinary
excretion and the reduction of plasma glucose levels (Table 1).
Thereby, SGLT2 inhibitors use a novel mechanism of action, since
they do not interfere with insulin secretion [145].
Phlorizin has played a pivotal role in clarifying the mechanism
of renal glucose reabsorption. It is a potent inhibitor of both,
SGLT1 and SGLT2, through a nonselective inhibition [146]. How-
ever, subsequent studies have shown that it cannot be used as an
antidiabetic therapy due to a poor intestinal absorption and, conse-
quently, a low bioavailability [146]. Moreover, phlorizin also suf-
fers
-glucosidase degradation and hydrolysis in the gut, producing
phloretin [143]. This metabolite inhibits glucose transporters,
namely GLUT2, leading to gastrointestinal side effects, such as
diarrhoea, and impairment in glucose absorption [147].
Dapagliflozin was the first SGLT2 inhibitor to be approved for
clinical use in adults with T2DM by European Medicine Agency
and the second to be approved by Food and Drug Administration. It
presents resistance to
-glucosidase in the gastrointestinal tract,
which makes it appropriate for oral administration. In addition, it
has 1200-fold selectivity for SGLT2 over SGLT1 [148]. An in vitro
study showed that dapagliflozin exhibited approximately 30
times
greater potency versus SGLT2 than phlorizin, and about 4fold less
3610 Current Pharmaceutical Design, 2015, Vol. 21, No. 25
potency versus phlorizin against SGLT1 [149]. By reducing the
tubular glucose reabsorption, dapagliflozin results in urinary glu-
cose excretion [150]. Moreover, total urinary glucose losses are
proportional to glucose concentration in plasma, so that glucose
elimination in urine is greater in patients with hyperglycemia. Usu-
ally, 10 mg of dapagliflozin per day will increase the amount of
glucose excreted in the urine of a patient with T2DM by 50–80
g/day [151]. Interestingly, it can be used as monotherapy, or in
combination with other antidiabetic drugs, such as metformin [152].
Exogenous Insulin
Insulin is a hormone secreted by the pancreatic
-cells into the
blood, in response to increased glucose concentration [153]. Be-
sides the direct involvement with glucose metabolism (Table 1),
insulin has a controlling influence on the metabolism of fats and
proteins [154]. When the body is unable to produce insulin or de-
velops insulin resistance, one of the possible treatments is the ad-
ministration of an exogenous supply of this hormone [155]. Usu-
ally, when insulin is injected into the body, its molecules form hex-
amers with zinc. For diffusion through interstitial fluid and penetra-
tion into the bloodstream, these hexamers need to dissociate into
dimers and monomers [156]. However, pharmacokinetics (follow-
ing administration via subcutaneous injection) of the structurally
unchanged regular insulin preparations makes it very difficult to
maintain normoglycemia during a whole day [157]. Therefore,
various types of insulin have been developed with diverse action
times in accordance with the patient needs: rapid acting insulin;
short acting insulin; intermediate acting insulin and long acting
insulin. Rapid acting insulin analogues have a molecular structure
that slightly differs from human insulin, with one or two amino acid
modification. These changes allow them to be absorbed more
quickly than human insulin, once they destabilize insulin hexameri-
zation [158]. To achieve an optimum level of insulin, these rapid
acting analogues can be used just before meals or immediately after
meals [159]. Short acting insulin analogues possess lower propen-
sity to form hexamers than regular insulin, being absorbed more
quickly. Thus, short acting insulin analogues achieve peak plasma
concentrations about twice as high and within approximately half
the time compared to regular insulin [160]. These analogues should
be administrated 20 to 30 minutes before meals to cover the insulin
needs [159]. Intermediate acting insulin analogues have a reduced
absorption rate compared to regular insulin due to the addition of
protamine or zinc to the insulin preparation, hindering the hexamers
dissociation [159]. These analogues cover insulin needs for about
half the day or overnight [161] and are often combined with rapid
or short acting insulin [162]. Long acting insulin analogues have the
longest duration of action of all insulin analogues, once they have
an activity duration of up to 36 hours [159]. The basic principle of
these preparations is shifting the isoelectric point of human insulin
from pH 5.4 toward more neutral to make insulin less soluble on the
administration site. This is achieved by adding positively charged
amino acids to the regular insulin [163].
CELLULAR METABOLISM: GENERAL CONCEPTS AND
RELEVANT PATHWAYS TO ANTIDIABETIC DRUG AC-
TION
Glycolysis
Foods containing carbohydrates are digested to glucose, which
is then absorbed into the bloodstream. Then, glucose enters the cells
through GLUTs by facilitated diffusion [166, 167]. But there are
other ways for attaining this sugar. When glucose is not available in
plasma, it can also be obtained through glycogenolysis (Fig. 1).
Once a glucose molecule has passed from blood into a cell, it is
gradually transformed in a controlled sequence of biochemical
steps. These steps, commonly known as metabolic pathways, are
supported by enzymes, which may or may not need cofactors de-
rived from vitamins to function properly. There are three main
Meneses et al.
metabolic pathways involved in processes related to conservation of
energy from glucose to ATP. First, the glucose is oxidized through
glycolysis, resulting in two molecules of pyruvate [168] (Fig. 1).
The first limiting step of glycolysis is usually described as being
mediated by the irreversible conversion of fructose-6-phosphate to
fructose-1,6-biphosphate [169]. This reaction is catalysed by phos-
phofructokinase 1, whose activity is also known to be related with
the energy status of the cell [168, 170]. Pyruvate may then follow
one of three pathways [171]. One of those is the Krebs cycle, being
necessary for the entry of pyruvate into the mitochondria [172]. In
the Krebs cycle, which originates six molecules of carbon dioxide,
NAD+ and FAD+ become reduced and carry electrons to the respira-
tory chain [173]. Here, energy is conserved in ATP and GTP mole-
cules. Another pathway is the conversion of pyruvate to lactate by
lactate dehydrogenase [171] and the last one is the conversion of
the end product of glycolysis into alanine by alanine aminotrans-
ferase [173]. Lactate was, for several times, considered a dead-end
waste product of glycolysis [174]. Nowadays, it is known that lac-
tate is the main energy source of several cells, including for the
developing male germ cells [175]. Lactate has also been reported to
act in wound healing processes through its effect on down-
regulation of ADP-ribosylation. In cases of injury and sepsis, lac-
tate accumulation may relate to an adrenaline surge and a resulting
stimulation of the sodium-potassium ATPase pump [174]. Another
metabolite that has been suggested to play crucial roles beyond the
classic relevance in glycolysis, is alanine. Indeed, alanine is a major
gluconeogenic substrate constituting the glucose-alanine cycle and
a transporter of nitrogen generated by protein breakdown back to
the liver for excretion as urea [176].
Krebs Cycle
Krebs cycle, also known as citric acid cycle or tricarboxylic
acid cycle, is composed by a series of biochemical reactions where
the components form essential connections with crucial pathways
such as gluconeogenesis, lipogenesis and amino acid metabolism.
Krebs cycle is essential in all oxidative organisms and provides
precursors for anabolic processes and reducing factors that drive the
generation of energy [177]. This cycle oxidizes the pyruvate de-
rived from glycolysis and acetyl-CoA to produce NADH and
FADH2 for ATP synthesis in the respiratory chain [173] (Fig. 1).
The activity of Krebs cycle is mainly controlled by the regulation of
two enzymes: pyruvate dehydrogenase, which mediates the trans-
formation of pyruvate into acetyl-CoA [178], and isocitrate dehy-
drogenase, which catalyzes the third step of the cycle (oxidative
decarboxylation of isocitrate, producing alpha-ketoglutarate), while
converting NAD+ to NADH in the mitochondria [179].
Lipogenesis
Lipogenesis is the pathway in which acetyl-CoA is converted
into fatty acids (Fig. 1). It is through lipogenesis that simple sugars
are converted into fatty acids, which are combined with glycerol
and stored as triglycerides. One source of acetyl-CoA is the citrate
produced during the Krebs cycle. It may be then exported from
mitochondria to cytosol by citrate carrier and converted into acetyl-
CoA through ATP citrate lyase [180].
Fatty acid synthesis is catalysed by the fatty acid synthase com-
plex [181]. This complex requires malonyl-CoA, a coenzyme A that
is formed by irreversible carboxylation of acetyl-CoA, which com-
bines with the acyl carrier protein to form malonyl acyl carrier pro-
tein [182]. The fatty acid synthesis continues in a cyclical serie of
reactions to form palmitate. Then, three fatty acid molecules are
combined with glycerol 3-phosphate to be stored as triglycerides.
Lipogenesis is very responsive to either hormonal or nutritional
changes. One of the major nutrients responsible for stimulating
lipogenesis is glucose. It is a substrate for lipogenesis by being
converted to acetyl-CoA and increases lipogenesis by stimulating
the release of insulin and inhibiting the release of glucagon from the
Antidiabetic Drugs Current Pharmaceutical Design, 2015, Vol. 21, No. 25 3611

Table 1. Summary of some antidiabetic drugs, its mechanism of action, main advantages and disadvantages.

Antidiabetic class Antidiabetic Drug Mechanism of action Advantages Disadvantages References

-glucosidase Acarbose Inhibit carbohydrates degradation Weight neutral Gastrointestinal side-effects [23-25]
inhibitors Miglitol in intestinal villi Negligible effect on cholesterol
Voglibose Potential elevations in liver
function tests

Biguanides Metformin Block liver gluconeogenesis Long-term safety Adverse gastrointestinal effects [49, 50, 164]
 skeletal muscle uptake of glucose Weight neutral or Probability of lactic acidosis
 the absorption of glucose in the loss Contraindicated for patients
intestinal mucosa Low risk of with liver or heart failure
 plasma levels of GLP-1 hypoglycemia

Sulfonylureas Glicazide  insulin secretion by activating
- Long-term safety Risk of hypoglycemia [65-67, 69]
Glibenclamide cell SUR 1 Risk of weight gain
Glimepiride

Meglitinides Nateglinide Binds to
-cell SUR 1 Faster insulin Risk of weight gain [59, 61, 77,
Repaglinide response Risk of hypoglycemia 87]

Mitiglinide Complex dosing schedule

GLP-1 receptor Exenatide Binds to GLP-1 receptor, causing: Weight loss Gastrointestinal side-effects [102, 103,
agonists Liraglutide  insulin secretion, delayed gastric Low risk of Administration by subcutane- 105, 112]
emptying, and satiety. hypoglycemia ous injection

DPP-4 inhibitors Sitagliptin  incretin (GIP and GLP-1) con- Weight neutral Gastrointestinal side-effects [109, 110,
Saxagliptin centrations 112, 114]
Alogliptin  insulin secretion
 glucagon secretion

Thiazolidinedi- Pioglitazone Activators of the PPAR Low risk of Risk of weight gain [122, 123,
ones Rosiglitazone  differentiation of pre-adipocytes hypoglycemia Risk of oedema 126]

 insulin sensitivity in muscle, Risk of heart failure

hepatic and adipose tissue
 glucose uptake in peripheral
tissues

SGLT2 inhibitors Dapagliflozin Limits renal glucose reabsorption Weight loss Risk of genitourinary tract [145, 150]
Canagliflozin Low risk of infections
hypoglycemia

Exogenous insulin Rapid acting Activates the insulin receptor Numerous for- Risk of weight gain [159, 165]
Short acting  hepatic glucose output mulations and Risk of hypoglycemia
delivery systems
Intermediate acting Administration by subcutane-
Long acting ous injection

, increase; , decrease; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon like peptide 1; GIP, glucose-dependent insulinotropic polypeptide; PPAR
, peroxisome proliferator-
activated receptor
; SGLT2, sodium dependent glucose co-transporter 2; SUR 1, sulfonylurea receptor 1

pancreas [183]. On the other hand, insulin is perhaps the most im-
portant hormone influencing lipogenesis [180, 183]. One of the
several mechanisms is the recruitment of glucose transporters to the
plasma membrane, increasing the uptake of glucose to the cell
[183].

-oxidation

-oxidation is the process by which fatty acids are oxidized,
thus providing a source of energy [184]. Although studies on
-
oxidation have begun in the first 1900s, a complete elucidation of
this pathway was not accomplished until the discovery of coenzyme
A and the recognition that acetyl-CoA is the product of
-oxidation
[185].
Fatty acids are activated to acyl-CoA after transport across the
plasma membrane. Subsequently, acyl-CoA is transported across
the mitochondrial membrane [186] (Fig. 1). Once inside the mito-
chondria, it is dehydrogenated by acyl-CoA dehydrogenase to yield
a 2,3-enoyl-CoA. The latter enters then in a series of steps catalysed
by mitochondrial trifunctional protein (MTP). MTP is an enzyme
complex composed of four alpha-subunits (harboring enoyl-CoA
3612 Current Pharmaceutical Design, 2015, Vol. 21, No. 25
Glucose
GLUT
Lactate
LDH
Glucose Glycolysis
Glucose-6-P Pyruvate
PFK
Glucose-1-P ALT
Glycogenolysis Alanine
Glycogen
Pyruvate
PDH
Nucleus
Fig. (1). Representative diagram of some pathways of cellular metabolism: glycogenolysis, glycolysis, Krebs cycle, lipogenesis and -oxidation. Abbreviation:
GLUT, glucose transporter; -P, -phosphate; PFK, phosphofructokinase; LDH, lactate dehydrogenase; ALT, alanine aminotransferase; PDH, pyruvate dehydro-
genase; ACAD, acyl-coenzyme A dehydrogenase; MTP, mitochondrial trifunctional protein.
hydratase and 3-hydroxyacyl-CoA dehydrogenase) and four beta-
subunits (harboring long-chain 3-ketoacyl-CoA thiolase) [185,
186]. The final product of these steps is a shortened acyl-CoA and
acetyl-CoA (Fig. 1).
MECHANISMS OF ACTION OF ANTIDIABETIC DRUGS
AND POTENTIAL IMPLICATIONS ON CELLULAR ME-
TABOLISM

-glucosidase Inhibitors
Voglibose not only inhibits
-glucosidase enzymes, but also
increases total GLP-1 plasma levels, both by stimulating the secre-
tion of GLP-1 from gut L-cells, and by decreasing plasma DPP-4
activity. As a result, a 1.8-fold increase in plasma active GLP-1
levels after voglibose treatment has been reported in db/db mice, an
animal model of T2DM [187]. Moreover, voglibose (1-4mM) is
reported to possess a strong inhibitory effect on melanin production
in melanoma cells by blocking the proper N-glycan processing of
tyrosinase, a glycoprotein involved in melanogenesis, resulting in a
dramatic reduction of this protein [188]. Notably, voglibose has
also been used in a case of nonalcoholic steatohepatitis, improving
patient’s hepatitis. The real mechanisms remain unclear but it may
be related with a decreased production of free radicals, thereby
causing a reduction in the mRNA and protein expression of the
hepatic inflammatory cytokine, TNF-
[189].
Shimabukuro and collaborators have demonstrated that a single
administration of acarbose [190] or nateglinide [191] improves
postprandial endothelial dysfunction, the initial stage of atheroscle-
rosis, in T2DM. However, they neither assessed nor compared the
long-term effects of both agents on postprandial endothelial func-
tion. These effects were later investigated in a comparative study by
Meneses et al.
Mitochondrion
PDH Fatty Acids
Lipogenesis
Citrate Acetyl-CoA Fatty Acids
Fatty Acyl-CoA
Acetyl-CoA Citrate
-oxidation ACAD
Krebs MTP
Acetyl-CoA + 2,3 Enoyl CoA
cycle
Shortened Acyl-CoA
Kato and collaborators. After 12 weeks of treatment with acarbose
or nateglinide, the postprandial endothelial dysfunction in newly
diagnosed T2DM patients was improved and acarbose was more
effective than nateglinide [192]. It was then hypothesized that acar-
bose may improve endothelial function by inhibiting postprandial
hyperglycemia, without increasing postprandial insulin secretion,
while nateglinide may improve endothelial function less signifi-
cantly by inhibiting postprandial hyperglycemia with an increase in
postprandial insulin secretion [192]. More studies are needed to
consolidate these assumptions and unveil the relevance of these
mechanisms to cellular metabolism in the several systems through-
out the body.
Biguanides
One of the most prescribed and used antidiabetic drugs is met-
formin, however its exact mechanism of action remains unknown.
Interestingly, some studies discuss possible pathways of action for
this drug and a common point in the majority of them is AMPK
[51, 164, 193]. Studies showed data consistent with a model where
increased phosphorylation and activation of AMPK lead to the ef-
fects on glucose and lipid metabolism observed after treatment with
metformin [194, 195]. It has been suggested that activation of
AMPK leads to phosphorylation and inactivation of acetyl-CoA
carboxylase, inhibiting the rate-limiting step of lipogenesis [194,
196] (Fig. 2). Reduced synthesis of malonyl-CoA, the acetyl-CoA
carboxylase product, is also predicted to relieve inhibition of car-
nitine palmitoyltransferase 1, resulting in increased fatty acid oxida-
tion [195, 197] (Fig. 2). These effects may contribute to the met-
formin’s in vivo ability to lower triglycerides [197]. It was also
demonstrated, using an AMPK inhibitor, that AMPK activation is
required for inhibition of hepatocyte glucose production by met-
Antidiabetic Drugs
formin [193]. Moreover, an association between increased glucose
uptake and AMPK activation was observed in isolated skeletal
muscles, and it was suggested that metformin’s effect in augment-
ing muscle insulin action in vivo may be attributed to AMPK as
well [193].
Another study showed that AMPK activation is required for the
glucose-lowering action of metformin in vivo but with genetic evi-
dence. The genetic deletion of liver kinase B1, one of the upstream
activators of AMPK, did not impair AMPK activation in muscle,
yet it eliminated the effect of metformin on serum glucose levels.
This led the authors to hypothesize that in mice, metformin primar-
ily decreases blood glucose concentrations by decreasing hepatic
gluconeogenesis [198]. Interestingly, it was recently reported that
metformin could be considered as a suitable antidiabetic drug for
male patients of reproductive age with T2DM. The authors showed
that besides not having deleterious effects on human Sertoli cells,
the cells that support spermatogenesis [49, 173, 199], metformin
presented a possible antioxidant activity. Moreover, metformin
stimulated lactate production by those testicular cells [49], which
provides nutritional support [199] and has an anti-apoptotic effect
in developing germ cells [200].
Besides T2DM, metformin is also considered a therapeutic
option for other diseases related with insulin resistance, such as
polycystic ovary syndrome (PCOS) [53], an endocrinopathy charac-
terized by hyperandrogenism, menstrual irregularity/anovulation,
and polycystic-appearing ovaries on ultrasound [201, 202]. How-
ever, the specific molecular pathways where metformin acts on the
ovary remain elusive [164]. As in the case of T2DM, it is thought
that AMPK is involved in metfomin’s mechanism of action in
PCOS. AMPK is present in all cell compartments of the ovary and
its expression could be different depending on the maturation stage.
In vitro studies with primary cells of theca interna from the rat
showed that the addition of metformin was associated with in-
creased activity of AMPK and inhibition of insulin stimulated pro-
liferation [203].
In addition, there are several studies associating metformin to
reduced cancer development and progression [164]. The different
mechanisms associated to this metformin action are fundamentally
focused on inhibition of growth stimuli and alterations of metabolic
processes, which control cancer cell growth. This characteristic
began to be observed in epidemiological studies, but was later con-
firmed by in vitro and in vivo studies. In fact, it has been demon-
strated that metformin has an antiproliferative action in various cell
lines and animal models [50]. After its uptake into the cells, met-
formin seems to cause a reduction in ATP via inhibition of the mi-
tochondrial respiratory chain complex 1 leading to activation of
AMPK [204] (Fig. 2). AMPK activation then disrupts the expres-
sion of genes involved in gluconeogenesis, protein synthesis, lipo-
genesis and possibly angiogenesis [205] (Fig. 2). Moreover, treat-
ment with metformin may decrease serum levels of insulin and
insulin-like growth factor, therefore reducing the stimulus for cell
growth. In fact, a decrease in insulin and insulin-like growth factor,
whose receptors are expressed on many cancer cells, induced by
caloric restriction has been shown to reduce the incidence of cancer
in in vivo animal models [206]. Numerous studies have revealed
growth-inhibiting effects of metformin in breast, endometrial, lung,
liver, gastric, and medullary thyroid cancer cell lines [207]. More-
over, studies of the effects of some chemotherapeutics (cisplatin,
carboplatin and paclitaxel) on endometrial [208] and ovarian [209]
cancer cell lines have suggested a role for metformin as adjuvant
therapy. On endometrial cancer cells, it has been described that
metformin acted by a downregulation of glyoxalase I, an enzyme
that is related with glycometabolism. Moreover, glyoxalase I is
overexpressed in endometrial cancer cells and its gene silencing
enhances the sensitivity of endometrial cancer cells to chemothera-
peutic drugs [208].
Current Pharmaceutical Design, 2015, Vol. 21, No. 25 3613
Thiazolidinediones
Pioglitazone, an agonist of PPAR, increased the expression of
glucose transporters GLUT1 and GLUT4 in 3T3-F442A preadipo-
cyte cultures treated with pioglitazone (1
mol/L) and insulin (1
mg/L). This increase was mainly due to the stabilization of GLUT1
and GLUT4 transporter messenger RNA transcripts [210]. The
increase on GLUT4 expression was also observed in epididymal fat
cells in an animal model of insulin-resistant T2DM (KKAy mice).
This augment was registered after a treatment with pioglitazone 20
mg/kg/day for 4 days. Besides, treatment with pioglitazone partially
corrected the reduction on mRNA encoding hexokinase II levels in
epididymal fat and muscle in this animal model [211]. In addition,
pioglitazone also increases protein phosphatase-1, the enzyme that
activates glycogen synthase, activity in hepatocytes from streptozo-
tocin-induced diabetic Sprague Dawley rats treated with insulin 0.1

M and pioglitazone 5
M [212]. An induction of adipose tissue
secretion was also observed after treatment with 3
M pioglitazone,
particularly of the high molecular weight adiponectin [213]. Fur-
thermore, pioglitazone decreased angiotensin II-induced connective
tissue growth factor expression and proliferation in atrial fibro-
blasts. This effect might be at least in part related with its inhibitory
effect on transforming growth factor-
1 / Smad2/3, as well as on
transforming growth factor-
1 / tumor necrosis factor receptor as-
sociated factor 6 / transforming growth factor-
-associated kinase 1
signaling pathway [214].
Concerning the female reproductive system, pioglitazone is
reported to counterbalance the inhibition of FSH-induced follicular
development and steroidogenesis by TNF-. These results suggest
that, in patients with PCOS, pioglitazone may directly act on ovar-
ian functions through PPAR activation [215]. Pioglitazone can
also suppress hepatic fetuin-A expression, a hepatokine that induces
insulin resistance [216], in vitro and in vivo. This seems to be a
characteristic restricted to thiazolidinedione derivatives compared
to other antidiabetic drugs, such as metformin [217]. Thiazolidin-
ediones were also found to have a renoprotective effect. This effect
may be related to a decreased albuminuria and proteinuria [218].
Since functional PPAR has been identified in renal glomerular and
tubular segments [219], thiazolidinediones can also protect against
renal injury through these receptors at the kidney. The action of
pioglitazone in cell metabolism remains completely unknown and
further studies are needed to unveil how these mechanisms alter
cells and organs metabolic phenotype.
Meglitinides
Meglitinides are also known for their action in glucose metabo-
lism. Interestingly, it was found that repaglinide is more effective in
lowering glucose levels when there is a greater concentration of this
sugar [220]. Furthermore, in the absence of glucose, repaglinide
had no effect on insulin secretion in isolated mouse [221] or rat
[222] pancreatic islet cells. Another study showed that repaglinide
(10 uM) has no significant effect on basal insulin release. However,
in the presence of glucose (>5 mmol/L) repaglinide was reported to
stimulate insulin release in a concentration-dependent manner. In
contrast to nateglinide, which mainly stimulates first phase insulin
release, repaglinide does not clearly induce biphasic insulin secre-
tion in perfused islets [223, 224]. Unlike sulfonylureas, repaglinide
did not inhibit glucose-stimulated proinsulin biosynthesis in iso-
lated rat
-cells [225]. Notably, the insulinotropic action of repa-
glinide was not attributable to any significant increase in the me-
tabolism of exogenous or endogenous nutrients [223]. Regarding
glucagon release, neither repaglinide nor nateglinide had significant
effects in studies using isolated perfused rat pancreas. On the other
hand, somatostatin release, which is a regulatory peptide that inhib-
its glucagon secretion [226], was augmented by both meglitinide
analogues [227].
3614 Current Pharmaceutical Design, 2015, Vol. 21, No. 25 Meneses et al.

Metformin
OCT

Metformin
Lipogenesis
ACAC
Acetyl-CoA Malonyl-CoA Fatty Acids

Fatty Acids
CPTI

Citrate Fatty Acyl-CoA

ATP I
-oxidation ACAD
Krebs MTP
AMPK Acetyl-CoA +
cycle 2,3 Enoyl CoA
Shortened Acyl-CoA

Gluconeogenesis,
protein synthesis and
lipogenesis related genes
Nucleus

Fig. (2). Possible metformin mechanism of action in cells. Metformin enters the cell through organic cation transporter (OCT) and may lead to the phosphory-
lation and inactivation of acetyl-CoA carboxylase (ACAC), which is responsible for the rate-limiting step of lipogenesis. The reduced synthesis of malonyl-
CoA is also predicted to relieve inhibition of carnitine palmitoyltransferase 1 (CPTI), resulting in increased
-oxidation. Moreover, metformin seems to cause
a reduction in ATP via inhibition of the mitochondrial respiratory chain complex 1 (I) leading to activation of AMP-activated protein kinase (AMPK). AMPK
activation then disrupts the expression of genes involved in gluconeogenesis, protein synthesis and lipogenesis.

fects on human adipose cell precursors, inhibiting proliferation and

GLP-1 Receptor Agonists and DPP-4 Inhibitors
Exenatide, a GLP-1 receptor agonist, induced an increase in a
series of vasodilators in patients with T2DM on treatment with oral
hypoglycemic agents and insulin. These patients were started on
exenatide 5
g twice a day and the dose was increased to 10
g
twice daily a week later for a period of 12 weeks [228]. The in-
crease in vasodilators may contribute to the anti-hypertensive ac-
tions of exenatide in patients with T2DM on treatment with oral
hypoglycemic agents and insulin. Exenatide has also been studied
for the treatment of Parkinson’s disease [229, 230]. A 12-month
treatment with exenatide improved motor and cognitive measures
compared with the control group [230]. After 12 months of cessa-
tion of this treatment, treated patients maintained the advantage in
comparison with the placebo group [229]. However, more studies
are necessary to assure these neuroprotective effects, and the over-
all effect of exenatide on organs and systems. However, these stud-
ies provide clear evidence that exenatide may exert its protective
effects by modulating crucial metabolic pathways though the
mechanisms remain unknown.
Liraglutide, another GLP-1 receptor agonist, increased insulin
sensitivity and attenuated high fat diet-induced insulin resistance
after a treatment of 6 weeks (0.1 mg/kg, twice daily). A reduction in

-cell mass was observed in liraglutide-treated control and high fat
diet-fed mice at 6 weeks, and was associated with a lower
-cell
proliferation rate after 1 week of treatment [231]. An in vitro study
showed that liraglutide (10–100nM) significantly inhibited adipose
stem cells proliferation and viability. Moreover, the glucose uptake
was significantly reduced in a dose dependent manner and the
treatment with liraglutide reduced intracellular lipid accumulation
in differentiating adipose stem cells. Thus, liraglutide exerted ef-
differentiation. Furthermore, it stimulated the expression of insulin-
sensitizing adipokines. These effects could contribute to the actions
of GLP-1 receptor agonists on body weight and insulin sensitivity
[232]. However, there is a lack of studies focused on the effects of
liraglutide in other cellular systems.
The effects of DPP-4 inhibitors, more specifically saxagliptin,
in cardiovascular system are controversial. An in vivo study with
CETP-ApoB100 transgenic mice, a transgenic mouse model of
human atherosclerosis, treated with saxagliptin (10 mg/kg/day)
showed that saxagliptin treatment reversed endothelial dysfunction
and reduced atherosclerotic lesion area [233]. However, a study
involving 16.492 patients with T2DM showed that although DPP-4
inhibition with saxagliptin did not increase or decrease the rate of
ischemic events but the rate of hospitalization for heart failure was
increased [234]. Thus, even though saxagliptin improves glycemic
control, other approaches are necessary to reduce cardiovascular
risk in patients with T2DM. However, saxagliptin was found to be a
suitable antidiabetic for T2DM patients with renal failure. These
patients were treated with saxagliptin 2.5 mg once daily and the
extent of adverse events and hypoglycemic events were similar
between placebo and treated groups [235]. More studies are needed
to consolidate these findings and expose the mode of action of
DPP-4 inhibitors in cells and organs.
SGLT2 Inhibitors
In vivo studies showed that dapagliflozin acutely induces renal
glucose excretion in normal and diabetic rats, improves glucose
tolerance in normal rats, and reduces hyperglycemia in Zucker dia-
betic fatty rats after single oral doses ranging from 0.1 to 1.0 mg/kg.
Moreover, dapagliflozin treatment once a day over 2 weeks signifi-
Antidiabetic Drugs Current Pharmaceutical Design, 2015, Vol. 21, No. 25 3615

cantly lowered fasting and fed glucose levels at doses ranging from cardiovascular diseases, which are the leading cause of death
0.1 to 1.0 mg/kg and resulted in a significant increase in glucose worldwide.
utilization rate accompanied by a significant reduction in glucose
production [236]. In a randomized, double-blind, placebo- ABBREVIATIONS
controlled, parallel-group, 28-day study, in 29 subjects with T2DM DM = Diabetes Mellitus
not optimally controlled, canagliflozin (100 mg once daily or 300 T2DM = Type 2 Diabetes Mellitus
mg twice a day) was well tolerated without evidence for glucose
malabsorption, and the patients presented improved glycemic con- T1DM = Type 1 Diabetes Mellitus
trol [237]. In fact, after the 28 days of treatment with canagliflozin, GLP-1 = Glucagon-like peptide-1
the renal threshold for glucose excretion was reduced; urinary glu- AMPK = AMP-activated protein kinase
cose excretion was increased [237]. However, canagliflozin was
reported to increase the risk of genital mycotic infections [238]. PPAR
= Peroxisome proliferator-activated receptor

This is one of the newest classes of antidiabetics and thus the out- SUR 1 = Sulfonylurea receptor 1
comes on cellular metabolism remain unknown. It is a field of re- GIP = Glucose dependent insulinotropic polypeptide
search that will be on the spotlight for the next years.
DPP-4 = Dipeptidyl peptidase-4
CONCLUSION AND FUTURE PERSPECTIVES PPAR = Peroxisome proliferator-activated receptor 
The development of an effective and safe antidiabetic involves SGLT = Sodium dependent glucose co-transporters
a large investment. Every year new advances are made and new GLUT = Glucose transporters
compounds are presented as a gold standard to maintain glycemic
control in diabetic individuals. The newer classes and the high de- MTP = Mitochondrial trifunctional protein
mand for therapy lead to an increase in the sales of antidiabetics. PCOS = Polycystic ovary syndrome
Besides the obvious safety issue, the side effects are also on the TNF-
= Tumor necrosis factor

spotlight. There are several problems that may arise from the use of
antidiabetics, namely the higher risk of hypoglycemias with some CONFLICT OF INTEREST
drugs. This is a delicate situation since severe hypoglycemias lead The authors confirm that this article content has no conflict of
to serious complications, such as myocardial infarction or demen- interest.
tias. Moreover, transient deprivation of insulin may induce several
health problems, as for instance in the reproductive potential of ACKNOWLEDGEMENTS
males [239, 240] or in the muscular system [241, 242]. This work was supported by the “Fundação para a Ciência e a
There are several potential new targets to develop a safe and Tecnologia”–FCT co-funded by Fundo Europeu de Desen-
effective antidiabetic drug. One of the most relevant topics in this volvimento Regional - FEDER via Programa Operacional Factores
subject is focused on genetic studies. Indeed, many authors suggest de Competitividade - COMPETE/QREN to UMIB (PEst-
that there is an urgent need for gene expression analyses to unveil OE/SAU/UI0215/2014); CICS-UBI (Pest-C/SAU/UI0709/2014);
specific molecular signatures associated with the development and PF Oliveira (PTDC/QUI-BIQ/121446/2010 and Programa Ciência
establishment of DM. In fact, in the recent years, large investments 2008) and MG Alves (SFRH/BPD/80451/2011).
have been made in genome-wide association studies with the expec-
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