Diabetes mellitus (DM) is an endocrine disorder that is characterized by high level of blood glucose due to either insulin deficiency or defectiveness or both. DM has been associated with both micro- and macro- vascular complications, and these are arguably the principal actors in its morbidity and mortality. Over the years, several classes of Oral Antidiabetic Drugs (OADs) ranging from the sulfonylureases to the dipeptidyl peptidase IV inhibitors have been introduced besides insulin therapy. Diabetes management has no doubt been improved with the use of these therapies. Nonetheless, obvious limitations associated with these drugs have made DM a long standing and increasing global health challenge. It is therefore imperative that in search for perfect antidiabetic agents, the limitations of the existing remedies should be noted and taken into cognizance as vital pointers in the direction to go.
Keywords: Diabetes mellitus; health challenge; oral antidiabetic drugs
Diabetes mellitus (DM) remains a global health challenge due to lack of curative therapy. Most available therapies are for management of the diseases and are associated with various side effects. The incidence of the disease is alarming and threatens a worldwide epidemic, particularly among the upper age cadre [1,2]. Its prevalence as at 2010 was 5.2 % of the global populace, affecting over 285 million people worldwide. As at 2015, this number has increased to 415 million people, with over 5.0 million deaths attributable to diabetes, and the total global health expenditure due to diabetes estimated at 673 billion US dollars . Diabetes obviously has a great economic impact on individuals, healthcare systems and economies of nations . The number of people affected by diabetes is still on the rise, with the number rising to 422 million in 2016, and expected to escalate to over 642 million by 2040 [3,5]. Global estimates predict that the proportion of adult population with diabetes will increase by 69% by the year 2030 .
The morbidity and mortality associated with diabetes mellitus often occur as a result of the complications of the disease . These complications which are usually termed diabetic complications are categorized into micro-vascular and macro- vascular complications, and they are arguably the principal actors in the pathogenesis and mortality of the disease .
Management of diabetes without any side effect is still a challenge for the medical system. Home et al., (2007) reported that
despite many oral hypoglycemic agents available to manage type 2 diabetes, 5 to 10 % of the population with diabetes experience secondary failure . This bottleneck can be arrested if the limitations of some therapies currently in use are acknowledged and improved upon. The currently used antidiabetic drugs are associated with multiple undesirable side effects which include haematological, cutaneous and gastrointestinal reactions, hypoglycemic coma and impairment of liver and kidney functions. This scenario has greatly encouraged a fast-growing interest in search of perfect antidiabetic drugs.
The prevalence of diabetes mellitus is increasing with ageing of the population and lifestyle changes associated with rapid urbanization and westernization. The disease is found in all parts of the world and is rapidly increasing in its scope, affecting both the old and the young . Globally, the prevalence of diabetes, without type distinction, is on the increase. According to the World Health Organization, it was estimated in 2010 that 6.4 % (285 million adults) of the world’s population have diabetes and the prevalence is expected to double by the year 2030 to rise to7.7%, with 439 million adults affected [2,10]. This scary prevalence is to escalate to 14.19 % by the year 2040 .
Diabetes Mellitus has a great economic burden on the individual as well as the health care systems and economies of nation . It is documented by the American Diabetes
Association (ADA) that individuals with diabetes have about 2.3
times higher medical expenditures compared to those without
diabetes in USA . Diabetes mellitus is a disproportionately
expensive disease and has profound implications on global
economy [12,13]. According to Kirigia et al. (2009) diabetes
mellitus poses a big economic burden with regards to direct
health care costs, indirect costs engendered by patient
disability and premature mortality as well as intangible costs of
psychological and emotional trauma experienced by the family
and loved ones of the diabetics . Studies have shown that the
annual national costs of managing diabetes are severely biting
deep into the fabric of budgets of nations with high prevalence
of the disease. As at 2003; Barceló et al. reported US $65.2 billion
as the total annual cost for diabetes care in Latin America and
the Caribbean . As at 2007, the total annual costs (direct
and indirect) for diabetes care in the United States of America
(USA) was pegged at $174 billion . India with a prevalence
of 200,000 type 1 diabetics in 2002 reported the cost of diabetes
treatment to be as high as US $50 million. AS at 1994, there were
over 1.4 million known diabetics in Spain and the total direct
cost of the disease was reported to be over US$650 million. The
list goes on and on for countries with adequate and up to data
Several studies have shown that oxidative stress is a key
element in the development and progression of diabetes and its
associated complications [16-18] had earlier proposed oxidative
stress as a major participant in the pathophysiology of diabetic
complications . Although, oxidative stress is not the primary
cause of diabetes, it nonetheless facilitates the induction of
multiple cellular pathways which ultimately lead to both the
onset and complications of diabetes [20-22]. Moreover, oxidative
stress has been shown to affect the two major mechanisms failing
during diabetes: insulin action and insulin secretion [22-24].
Life style management is apparently the cornerstone of
management of diabetes mellitus. It is recognized as being an
essential part of diabetes and cardiovascular disease prevention.
Meta-analyses demonstrate that lifestyle interventions,
including diet and physical activity, led to a 63% reduction in
diabetes incidence in those at high risk . In spite of the
underscored importance of lifestyle measures in diabetes
management, the importance of drug therapy in achieving
glycemic control and homeostasis in the diabetics cannot
be undermined. Sequel to the limitation of insulin therapy,
different oral antihyperglycemic drugs (OADs) with distinct
mechanisms have been in use till date. They include the
sulphonylureas (e.g., glimepiride), α-glucosidase inhibitors (e.g.,
acarbose), meglitinides (e.g., repaglinide), thiazolidinediones
(e.g., pioglitazone), biguanides (e.g., metformin) and dipeptidyl
peptidase IV inhibitors (e.g., sitagliptin). Sulfonylureases and
the non-sulfonylurea secretagogues establish normoglycemia by
up regulating endogenous insulin secretion. Alpha-glucosidase
inhibitors work by delaying intestinal carbohydrate absorption.
Thiazolidinediones (TZDs) maintain normoglycemia by
enhancing insulin sensitivity primarily by increasing peripheral
glucose disposal and suppressing hepatic glucose production.
Biguanides such as metformin function by decreasing hepatic
gluconeogenesis while at times also increasing peripheral
glucose mobilization and disposal  (Figure 1).
Sulfonylureases (SUs) are the oldest and most widely
used medications for the treatment of type 2 diabetes
mellitus. Although SU therapy effectively lowers blood glucose
concentrations by stimulating insulin secretion from β-cells,
treatment with SUs is associated with a progressive linear decline
in β-cell function [27-28]. Hypoglycemia and weight gain are the
common adverse effect associated with SUs therapy. Weight gain
is thought to result from an anabolic effect of increased insulin
Alpha glucosidase inhibitors, such as acarbose, are competitive
inhibitors of membrane-bound intestinal α-glucosidases that
hydrolyze oligosaccharides, trisaccharides and disaccharides to
glucose and other monosaccharides in the small intestine and
thereby delay postprandial glucose absorption . These agents
are available as a first-line treatment in patients with slightly
raised basal glucose concentrations and marked postprandial
hyperglycaemia . AGIs have an average decrease capacity
in HbA1c of 0.5–1%. Derosa et al., (2009) demonstrated that
both repaglinide and acarbose had a similar effect in reducing
postprandial glucose levels (-14.9%, p < 0.05; -16.2%, p < 0.05;
compared to baseline, respectively . Treatment of diabetes
with AGIs has been associated with significant risk reduction
of cardiovascular disease via suppression of oxidative stress
induced by postprandial hyperglycemia . Despite their
good safety record, limited gastrointestinal tolerability has
substantially restricted their use.
Meglitinides such as repaglinide and nateglinide are
prandial insulin releasers that stimulate rapid insulin secretion
. Repaglinide (NovoNorm®, Prandin®, GlucoNorm®) is
the first clinically available insulin secretagog that specifically
enhances early-phase prandial insulin response by increasing
the sensitivity of β-cells to elevated glucose levels, producing a
greater insulin release under hyperglycemic conditions [35,36].
In this regard, it has been shown in vitro that repaglinide is fivetimes
more potent than glibenclamide in stimulating insulin
secretion, with half-maximal stimulation observed at 40 and
200 nmol/L, respectively . Lower risk of hypoglycemia
makes these agents attractive option for some elderly patients,
in particular when other agents may be contraindicated.
The thiazolidinediones are insulin-sensitizing drugs
that improve whole-body insulin sensitivity through gene
regulation . These agents increase glucose uptake via
glucose transporter-4 in skeletal muscle and reduce rates of
gluconeogenesis in the liver. Reductions in plasma insulin
concentration and lowering of circulating triglycerides are
additional indirect mechanisms that may help improve wholebody
insulin sensitivity. Thiazolidinediones have also been
known to improve β-cell function and reduce insulin resistance;
however, they are associated with weight gain and can cause
peripheral edema .
The biguanides such as Metformin, which act directly
against insulin resistance, are regarded as insulin sensitizing
drugs and are considered to be a cornerstone in the treatment
of type 2 diabetes mellitus . Metformin acts on the liver
to produce a hypoglycemic effect. Available formulations
include Glucophage®, Glucophage XR®, Riomet®, Fortamet®,
Glumetza®, Obimet®, Dianben®, Diabex® and Diaformin®.
Metformin lowers blood glucose levels without causing overt
hypoglycemia or stimulating insulin secretion. In a study of
the metformin mechanism of action, it was postulated that
metformin decreases endogenous glucose production in type
2diabetes patients. Treatment with the drug decreases fasting
plasma glucose concentrations by 25% and reduced hepatic
gluconeogenesis by interfering with respiratory oxidation
in mitochondria. Despite being the most widely used oral
antidiabetic drug (OAD) in the world, metformin can reach a
plateau of effectiveness due to progressive β-cell failure [40,41].
Metformin is only effective when there is sufficient endogenous
or exogenous insulin and, because of this, patients are unable to
maintain tight glycemic control as their disease progresses .
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are compounds
which suppress the degradation of a variety of bioactive
peptides, including DPP-IV and subsequently increasing the
endogenous concentration of incretins, such as GLP-1glucagonlike
peptide-1 [43,44]. Bioavailability of GLP-1 evidently
improves glycemic control . DPP-IV inhibitors are orally
administered drugs with a significant effect on glucose tolerance
and lasting improvement of HbA1c . Several agents are in
different stages of clinical development. Sitagliptin is a good
example of selective DPP-IV inhibitor, it was approved by the
Food and Drug Agency in 2006 in United States as an adjunct to
diet and exercise in patients with type 2 diabetes. In 2009, 2011
and 2013, Saxagliptin, Linagliptin, Alogliptin (other selective
DPP-IV inhibitors) were respectively approved in the US .
The effective roles of some plants in the management of
diabetes mellitus are well documented. According to Piero et al.
(2012), plant derived medications have in recent times found
immense use in the management of diabetes mellitus . To
date, the catalogue of antidiabetic medicinal plants is growing at
a pleasantly high rate particularly in the African continent. The
antidiabetic potential of some medicinal plants extracts has been
demonstrated in human and animal models of type 2 diabetes.
The increasing reliance on antidiabetic medicinal plants is a major motivation for scientists to investigate more plants in a
bid to elucidate more hypoglycemic agents of natural origin.
Diabetic conditions have no doubt been improved by existing
therapies. However, their associated limitations have made DM
a long standing and increasing global health challenge. In search
for perfect antidiabetic agents, it is therefore important for
scientists to continuously ride on the strength and weaknesses
of the available therapeutic options.