Anti-Diabetic Drugs
Anti-Diabetic Drugs
Anti-Diabetic Drugs
Related terms:
Thiazolidinedione drugs
These anti-diabetic drugs are used to ameliorate hyperglycemia predominantly by
increasing insulin–stimulated glucose disposal by skeletal muscle. However, these
drugs also inhibit mitochondrial complex I which inhibits gluconeogenesis that
could contribute to antidiabetic action. The effectiveness of thiazolidinediones found
for inhibiting complex I or causing lactate release in skeletal muscle or rat liver ho-
mogenates was rosiglitazone > troglitazone > > metformin (Brunmair et al., 2004a,
b). Troglitazone incubated with HepG2 cells also decreased cellular ATP levels and
mitochondrial membrane potential (Tirmenstein et al., 2002). However, the order of
effectiveness for thiazolidinediones (50 μM) opening the mitochondrial permeability
transition pore of mouse liver mitochondria was troglitazone > ciglitazone whereas
rosiglitazone or pioglitazone were much less effective and correlated with their
hepatotoxicity (Masubuchi et al., 2006).
Troglitazone was introduced in 1997 but was withdrawn in 2000 after 90 severe
hepatotoxicity cases that had been reported in the 1.9 million patients taking the
drug. Earlier a black box warning was issued. Unlike the other thiazolidinediones,
troglitazone contains a vitamin E phenolic moiety and is thus also a potent antioxi-
dant. However, vitamin E at higher doses is a prooxidant that can be readily oxidized
to a cytotoxic phenoxyl radical metabolite which is also an intermediate formed
during CYP3A catalyzed quinone metabolite formation (Tafazoli and O’Brien, 2005).
Further evidence for this was that multiparameter flow cytometry showed that rat
hepatoma cells incubated with troglitazone underwent oxidative stress cytotoxicity
involving membrane peroxidation, a collapse in mitochondrial membrane potential
and superoxide radical formation. The superoxide radical formation was prevented
with cyclosporin, a mitochondrial permeability transition inhibitor (Narayanan et al.,
2003). Whether troglitazone induced idiosyncratic hepatotoxicity was a consequence
of mitochondrial damage and oxidative stress as hypothesized (Smith, 2003) is still
being investigated.
3.1.1 S-Ethyl-2-Ethoxy-3-(4-hydroxyphenyl)propanoate
Novo Nordisk A/S has developed a novel biocatalytic process for the
large-scale production of S-1 [S-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid],
a key intermediate in the synthesis of the new anti-diabetic drug Ragagli-
tazar [NNC61-0029((-)DRF2725)] from its racemic ethylester, rac-2 [rac-ethyl
2-ethoxy-3-(4-hydroxyphenyl)-propanoate], by enantioselective hydrolysis (Fig. 4).
This chemo-enzymic process was successfully run on a 44-kg pilot scale, with the
yield reaching 43–48% and the enantiomeric excess (ee) in the range of 98.4–99.6%
[28].
Forensic Science
Thomas Kraemer, Hans H. Maurer, in Handbook of Analytical Separations, 2008
Pancreatitis
To investigate the risk of pancreatitis associated with the use of incretin-based treat-
ments in patients with T2DM, a meta-analysis was conducted to compare treatment
with a glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4
(DPP-4) inhibitors with placebo, lifestyle modification, or active anti-diabetic drugs.
Fifty-five RCTs (n = 33 350) and five observational studies (three retrospective cohort
studies, two case–control studies; n = 320 289) were included in the analysis.
Pooled estimates of the RCTs did not suggest an increased risk of pancreatitis with
incretins versus control (placebo or active drug) (odds ratio 1.11, 95% confidence
interval 0.57–2.17). Additionally, the risk of pancreatitis was not increased in three
retrospective cohort studies; two associated with exenatide (adjusted odds ratios:
0.93 (0.63–1.36) or 0.9 (0.6–1.5)) and one associated with sitagliptin (adjusted hazard
ratio: 1.0 (0.7–1.3)). One case–control study suggested use of either exenatide or
sitagliptin was associated with significantly increased odds of acute pancreatitis
within two years of beginning therapy (adjusted odds ratio 2.07, 1.36–3.13). The
evidence from this meta-analysis suggests the incidence of pancreatitis among pa-
tients using incretins is low and that incretins do not increase the risk of pancreatitis
[42]. Similar results were observed comparing saxagliptin to placebo with the rates
of acute and chronic pancreatitis being similar in the two groups (acute pancreatitis,
0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis,
< 0.1% and 0.1% in the two groups, respectively) [36M].
Diabetes
Old World primates are good models for human type 2 diabetes mellitus (T2DM).
Like humans, the disease is naturally occurring, has similar onset and progression,
and occurs at an increased incidence with increased age and obesity (Cefalu, 2006;
Wagner et al., 2006). T2DM can also be induced with streptozotocin in Old World
primates; however, marmosets are a poor model as they require greater doses of
streptozotocin and develop complicating renal and hepatic toxicity. Type 2 diabetes
mellitus onset is characterized by obesity-associated peripheral insulin resistance
accompanied by a compensatory increase in insulin levels. During this pre-T2DM
phase, which is described as “metabolic syndrome,” fasting plasma glucose levels
remain normal and there is an onset of dyslipidemia and hypertension. This is
followed by decreased insulin secretion and corresponding increased fasting glu-
cose levels leading to T2DM. It may take years for the disease to fully progress.
Histopathological changes are also similar to those in humans with T2DM. As with
human disease, these consist of islet cell hyperplasia, increased islet amyloid with
loss of beta cells, and vascular (both micro and macro) and cardiovascular disease.
Nonhuman primates with T2DM are used for disease mechanism research and
studying the efficacy of potential drug candidates. Standard anti-diabetic treat-
ments have included insulin, a hormone which directly controls plasma glucose
levels, biguanides and sulfonylureas which stimulate insulin secretion, and thiazo-
lidinediones (peroxisome proliferator-activated receptor- [PPAR- ]) which regulate
genes controlling the expression and translocation of glucose receptors. New cat-
egories of antidiabetes drugs are being developed including dipeptidyl peptidase
inhibitor (DPP-IV – an oral hypoglycemic drug), glucagon-like peptide (GLP-1 – a
parenterally administered peptide receptor agonist), and a sodium-glucose cotrans-
porter inhibitor (SGLT-inhibitor – an oral inhibitor of gut and renal glucose uptake).
Nonclinical efficacy studies are done in disease models of multiple species.
Toxicity studies for the development of anti-diabetic drugs have been done in healthy
cynomolgus and rhesus monkeys. A class of structurally diverse small molecule
drugs being developed for T2DM is peroxisome proliferator-activated receptors
(PPAR) (Aleo et al., 2003; Schafer et al., 2004). There are three different forms of
PPARs: PPAR- , PPAR- , and PPAR- (also called PPAR- ). PPAR- is made primarily
in fat cells and affects the production of fat cells and the metabolism of lipids and
reduces insulin resistance. Insulin-resistant and diabetic monkeys have been found
responsive to PPAR- agonists, resulting in glycemic control. Nonclinical safety
studies with PPAR- in cynomolgus monkeys show a consistent set of drug-induced
effects. PPAR- causes fluid accumulation, weight gain, edema, proliferation of
white and brown fat, and an increased incidence of chronic heart failure (Aleo et al.,
2003). Bladder urothelial changes occur in monkey, as with rat, which cause concern
for neoplasia (Hardisty et al., 2008). Nonhuman primates have not predicted adverse
events of hepatic and cardiovascular toxicity that have occurred with marketed drugs
in humans. Given these are low incidence events in humans (Gale, 2001), it is not
unexpected that nonhuman primate and other animal species did not detect these
toxicities.
Dogs have been used to study the toxicity of DPP-IV inhibitors, which causes severe
toxicity. DPP-IV causes a skin lesion in nonhuman primates, prompting the FDA to
require testing all DPP-IV inhibitors in monkeys. Data from these studies should
clarify whether skin lesions are due to DPP-IV inhibition itself or to some other
mechanism of action (Chyan and Chuang, 2007).
Volume 2
D. Grahame Hardie, in Handbook of Cell Signaling (Second Edition), 2010
The discovery that the tumor suppressor LKB1 acted upstream of AMPK suggested
that AMPK-activating drugs might be of benefit in treatment of cancer as well
as diabetes. LKB1 is known to act upstream of 14 members of the AMPK-related
kinase family other than AMPK [75], and it remains possible that some of the
tumor-suppressing effects of LKB1 are mediated by these AMPK-related kinases.
However, there is now much evidence to support the idea that AMPK itself is a
tumor suppressor. Thus, activation of AMPK using the AMP mimetic 5-aminoim-
idazole-4-carboxamide riboside (AICAR) inhibits cell proliferation by a mechanism
involving p53 and the cyclin-dependent kinase inhibitor, p21 [76, 77]. Another mech-
anism by which AMPK restrains protein synthesis and cell growth is via inhibition
of the target-of-rapamycin complex-1 (TORC1), by a dual mechanism involving
phosphorylation of its upstream regulator TSC2 [78] and of its regulatory subunit
Raptor [57]. Correlative evidence supporting the idea that AMPK activators protect
against cancer came from studies showing that diabetics treated with the AMPK ac-
tivator metformin had a significantly lower incidence of cancer than those on other
medications [79, 80]. More direct evidence came from studies of a mouse model
that is cancer-prone due to hyperactivation of the phosphoinositide-3-kinase/Akt
pathway combined with reduced expression of LKB1. Treatment of these mice with
the AMPK activators metformin, phenformin, and A-769662 very significantly
delayed the onset of tumor formation [81]. Phenformin is a relative of metformin
that was withdrawn for use in diabetes treatment because in rare cases it caused
life-threatening lactic acidosis. However, it is a more effective activator of AMPK
than metformin, and rare side effects may be more acceptable in treatment of cancer
rather than diabetes.
Finally, mutations in AMPK genes can cause medical disorders. Mutations in the
2 gene cause hereditary cardiac arrhythmias (Wolf-Parkinson-White syndrome)
that are inherited in an autosomal dominant manner and that increase the risk of
sudden death because of a fatal arrhythmia [82]. In a few cases the effect of the
mutation is so severe that it causes death during the neonatal period [83, 84]: in these
cases neither parent has the mutation, which appears to have arisen de novo during
gametogenesis. The condition is usually associated with cardiac hypertrophy, but the
primary defect appears to be excessive storage of glycogen in cardiac myocytes [82].
The mutations occur at several positions within the CBS repeats of the 2 sub-unit,
and most affect residues that are conserved in the 1 subunit and that have been
shown by structural analysis of the latter to be directly involved in nucleotide binding
[14]. However, their effect is complicated because they reduce binding of both the
activator AMP (a potential loss-of-function effect) and the inhibitor ATP (a potential
gain-of-function effect). The gain-of-function effect may be what causes the clinical
condition: loss of binding of the inhibitor may cause an increase in the basal activity
of AMPK, in turn causing a persistent increase in glucose uptake and glycogen
synthesis. This interpretation is supported by recent work with a transgenic mouse
overexpressing one of the mutations in cardiac myocytes [85]. Exactly why excessive
glycogen content leads to arrhythmias is less well understood, but it appears to give
rise to anatomical defects in the heart during fetal development [82].
In conclusion, the AMPK system is now receiving increasing attention from medical
scientists researching various different conditions, from obesity, diabetes and cancer
to heart disease. This helps to explain the current strong interest in the system, with
an average of between one and two papers being published about the system per
day in 2008.
Culinary Herbs
Lamiaceae
The family of Lamiaceae or Labiatae includes several widely used culinary herbs,
such as sage, oregano, peppermint, marjoram, thyme, and basil. These herbs are
particularly rich in phenolic compounds (Table 9.1) which possess a high antioxidant
capacity [5,12], anti-glycant action (Table 9.2) and other beneficial properties, such
as anti-inflammatory and anticancer activities [13]. In addition, they can affect
glycemia by acting on several factors which influence glucose homeostasis (Table
9.3). Along with basic plant antioxidants, culinary herbs of Lamiaceae contain specific
characteristic antioxidants (Table 9.1), such as lamiatic acid, carnosic acid, carvacrol,
and various methyl and ethyl esters of these substances and derivatives of phenolic
acids, such as rosmarinic acid, one of the most effective antioxidant compounds in
these plants [4,14]. Both extracts and isolated antioxidant compounds from these
herbs have been shown to possess potential anti-diabetic properties.
Peppermint (Mentha x piperita )Family Lami- Ascorbic acid, beta carotene, narirutin, erio-
dictyol, eriodictyol 7-O- -glucoside, eriocitrin,
aceae hesperidin, isorhoifolin, luteolin 7-O- -gluco-
side, luteolin 7-O-rutinoside, diosmin, ros-
marinic acid, caffeic acid, piperitoside, mentho-
side, lithospermic acid [26]
Thyme (Thymus vulgaris)Family Lamiaceae Ascorbic acid, beta carotene, isochlorogenic acid,
labiatic acid, p-coumaric acid, rosmarinic acid [4]
Laurel or bay leaf (Laurus nobilis L.)Family Ascorbic acid, beta carotene, tocopherols,
eugenol, methyl eugenol, eudesmol [48]
Lauraceae
kaempferol, kaempferol-3-rhamnopyranoside,
kaempferol-3,7-dirhamnopyranoside, 8-cineole,
-terpinyl acetate, terpinen-4-ol, catechin, cin-
namtannin B1[47]
For more details see the text and the bibliographic references.
For more details see the text and the bibliographic references.
For more details see the text and the bibliographic references.
Sage (Salvia officinalis L) is a member of Salvia, the largest genus of the Lamiaceae’s
family which includes about 900 species, spread throughout the world. Many species
of Salvia have been used as traditional herbal medicines against several diseases,
but sage has been one of the most commonly used plants in folk medicine since
antiquity, as indicated by its Latin genus name Salvia, meaning ‘to cure’ and species
name officinalis, meaning ‘medicinal’. The plant is reported to have a wide range of
biological activities, including anti-oxidative properties [15], hypoglycemic [16] and
anti-inflammatory effects [11]. The beneficial effects of sage are the result of nu-
merous compounds from diverse chemical groups acting together, including many
phenolic compounds of which the main is rosmarinic acid [14]. Several studies have
demonstrated that sage has high in vitro antioxidant activity [3,6,11,14,15,17,18],
mainly due to its phenolic compounds. Moreover, sage tea has been shown to
improve liver glutathione levels in mice and rats [19]. In addition, Lima et al.
[20] demonstrated dose-dependent anti-diabetic activity of sage tea comparable
to the standard anti-diabetic drug glibenclamide (metformin) in rats [20]. This
study demonstrated that sage significantly reduced fasting plasma glucose by
increasing hepatocyte glucose consumption, decreasing fasting gluconeogenesis
and inhibiting the stimulation of hepatic glucose production by glucagon. Greek
sage (Salvia fruticosa) tea has been demonstrated to prevent the deterioration of
glucose homeostasis in streptozotocin diabetic rats (one of the most employed ani-
mal models for type 1 diabetes), by abrogating the streptozotocin-induced increase
in the intestinal Na+/glucose cotransporter-1 (SGLT-1). This anti-diabetic effect of
Greek sage appears to be due to the modulation of SGLT-1 trafficking caused by
rosmarinic acid [21].
Oregano (Origanum vulgare) and marjoram (Oregano majorana) are plants tradition-
ally used in diabetes control and treatment in North Africa and the Middle East;
however their anti-diabetic effects have not yet definitively been proven. In vitro
studies suggest a potential anti-diabetic effect of oregano due to its antioxidant
content [6,10,15,22], anti-glycant capacity [22,23], and inhibition of carbohydrate
digesting enzymes [10,24]. An aqueous extract of marjoram has been shown to have
anti-hyperglycemic activity similar to that of the hypoglycemic drug sodium-vana-
date in streptozotocin diabetic rats [25].
The genus Mentha L includes 18 species and about 11 hybrids, of which the most
used and cultivated are Mentha spicata (spearmint) and the hybrid Mentha x piperita
(peppermint). Mints are available in all five continents, are used in traditional medi-
cine for the prevention and therapy of several diseases, and are a well-known herbal
remedy used for their aromatic, stomachic, choleretic, carminative, and stimulant
properties. The most active compounds in mints are the essential oil and polyphe-
nols. The main phenolic compounds are phenolic acids and flavonoids [6,26,27].
Studies on the anti-diabetic effects of mint are scarce, despite their appreciable
total phenolic content. Water extracts of peppermint have been shown to improve
glycemia and lipidemia in offspring of streptozotocin-induced diabetic rats [28].
Nevertheless, Narendhirakannan et al. [29] have shown that peppermint ethanolic
extracts have no effect on insulin, C-peptide levels, and glucose tolerance in the
same animal model.
Studies on the anti-diabetic effects of Lamiaceae’s extracts have shown that basil,
sage, marjoram, oregano, and thyme significantly inhibit the activity of -amylase
and -glucosidase, two key enzymes of carbohydrate digestion, in vitro [3,10,30] and
in vivo [30]. Lamiaceae’s extracts have also been demonstrated to possess significant
anti-glycant capacity in vitro [3,22,23,31] and in vivo [23]. Büyükbalci et al. [18], have
investigated in vitro the antioxidant and anti-diabetic effects of herbal teas tradi-
tionally used in the treatment of diabetes in Turkey, and found that peppermint and
thyme have high antioxidant activity and inhibitory effects on glucose absorption,
whereas sage was less effective.
Garlic
Garlic (Allium sativum) and onion (Allium cepa) are two species widely used for
flavoring foods and in folk medicine. Onion, though not strictly an herb, is pre-
sented for comparison as it is used in flavoring food, albeit in large amounts.
Both these species of Allium are rich in sulfur-containing compounds that are
products of the transformation of S-alk(en)yl-l-cysteine sulfoxides (ACSOs) by the
enzyme alliinase and subsequent reactions. The ACSOs detected in intact onion are
S-1-propenyl-l-cysteine sulfoxide (1-PeCSO), S-methyl-l-cysteine sulfoxide (MCSO),
and S-propyl-l-cysteine sulfoxide. S-2-Propenyl-l-cysteine sulfoxide (2-PeCSO) is
the predominant ACSO in garlic, with smaller amounts of MCSO, 1-PeCSO and
S-Ethyl-l-cysteine sulfoxide [32]. In intact Allium tissues, ACSOs are located in the
cytosol, where they are protected from lysis by alliinase stored in vacuoles. Enzyme
and substrates react rapidly upon disruption of the tissue, and the sulfoxides are
converted into thiosulfinates, such as allicin [33]. These thiosulfinates and their
derivatives were found experimentally to have a wide variety of potential therapeutic
effects [32,34,35], including antioxidant and anti-inflammatory activities. Onion and
garlic are rich also in phenolic compounds (Table 9.1), and onions are among the
most important dietary sources of flavonoids. The main flavonoids in onions are
quercetin, kaempferol, myricetin, cyanidin, peonidin, and taxifolin and their deriv-
atives [36]. The main phenolic compounds of garlic are phenolic acids, in particular,
caffeic, vanillic, p-hydroxybenzoic, and p-coumaric acids [37]. Moreover, garlic and
onion are able to uptake and accumulate selenium from the soil readily, and use it
for the biosynthesis of selenocysteine, an amino acid required for the synthesis of
seleno-proteins, including the antioxidant enzymes glutathione peroxidase, thiore-
doxin reductase and iodothyronine deiodinases. Many studies have reported the role
of Allium species in the prevention and treatment of several human pathologies,
including diabetes [38–41], metabolic syndrome [42], and cardiovascular disease
[35,43]. An in vitro anti-glycant activity has been found both in garlic and onion [44].
Moreover, both garlic and onion have been shown to have hypoglycemic effects
in different animal models and in limited human trials [13,40,45,46]. However,
recently, a meta-analysis of their anti-diabetic effect in experimental diabetic rats
has shown that onion extracts and single components of both species (S-allylcys-
teine sulfoxide, S-methylcysteine sulfoxide, and diallyl trisulfide) have significant
positive effects on blood glucose concentration and body weight, while garlic has no
significant anti-diabetic effects [39].
Laurel (Bay Leaves)
Laurel (Laurus nobilis, Family Lauraceae) is used as a valuable flavoring agent in the
culinary and food industry. This plant is used in folk medicine, in stomachic and
carminative remedies, and for the treatment of digestive disease. Laurel contains
several compounds with antioxidant activity (Table 9.1). Both the water extract and
the non-polar fraction of leaves have been shown to possess high antioxidant activity,
the former mainly because of its polyphenol content [47], and the latter for its high
levels of terpenes [48]. A clinical trial showing that laurel improves glycemia and
lipid profiles in type 2 diabetes patients [49] makes this culinary herb a promising
anti-diabetic agent.