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22 Frontiers in Clinical Drug Research-Diabetes & Obesity, 2023, Vol. 7, 22-47
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CHAPTER 2
Current Strategies of New Drugs for Diabetes
Management
Maliha Sarfraz
1,*
, Rahman M. Hafizur2, Hayat Ullah
3,*
, Sanaullah Sajid4,
Rana Waseem Akhtar5, Mamoona Noreen1, Shazia Perveen1 and Misbah
Ullah Khan
1
Department of Zoology, Wildlife and Fisheries University of Agriculture Faisalabad Sub
Campus, Toba Tek Singh 36050, Pakistan
2
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for
Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi 75270, Pakistan
3
Department of Chemistry, University of Okara, Okara 56300, Punjab, Pakistan
4
Institute of Microbiology, University of Agriculture Faisalabad, Pakistan
5
Faculty of Veterinary and Animal Sciences, Muhammad Nawaz Shareef University of
Agriculture, Multan, Pakistan
6
Center for Nano-Sciences, University of Okara, Okara 56300, Punjab, Pakistan
Abstract: Several aspects need to be explored in drug therapy for diabetes patients.
Some specific glucose-reducing medicines are present, while other medicines are
associated with unintentional changes in hyperglycemia. Diabetes is a developing
epidemic that has caused significant socioeconomic problems in several countries
throughout the world. Despite scientific discoveries, greater healthcare services, and
higher literacy rates, the disease continues to plague many industries, particularly
developing countries. The current trends show an increase in premature mortality,
which threatens world prosperity. Experimental and technical improvements have been
made in sulphonylureas, alpha-glucosidase inhibitors, biguanides, and
thiazolidinediones, all of which are beneficial in lowering glucose levels. The latest
drug research techniques have led to the development of novel therapeutic groups such
as amylin analogs, incretin mimetics, GIP analogs, active peroxisome proliferator
receptors, and dipeptidyl peptidase-4 inhibitors as targets for future diabetes therapy
medications. Furthermore, drug development and detection for diabetes treatment have
been revolutionized by identifying and investigating bioactive compounds from herbs.
This chapter discusses vital fields of clinical diabetology regarding opportunities for
stem cells and nanotechnology as next-generation therapies, with an emphasis on
evolving developments and reviews why plant-derived products are reliably common
for treating and managing diabetes.
6
*
Corresponding authors Maliha Sarfraz and Hayat Ullah: Department of zoology wildlife and
fisheries university of agriculture Faisalabad sub campus Toba tek Singh 36050, Pakistan;
E-mails: maliha.sarfraz@yahoo.com, hayatullah@uo.edu.pk
All rights reserved-© 2023 Bentham Science Publishers
Shazia Anjum (Ed.)
Drugs for Diabetes Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 23
Keywords: Diabetes, Emerging Trends, Herbal Formulations, Glucose-lowering
Drugs.
INTRODUCTION
Diabetes mellitus (DM) is a complicated metabolic condition identical to elevated
blood glucose levels or hyperglycemia, resulting from insulin secretion
deficiencies, intervention, or both, as displayed in Fig. (1). The persistent
metabolic disproportion related to this condition places the patient at increased
danger of long-standing macro and microvascular problems, leading to repeated
hospitalization and complications, including an elevated danger of cardiovascular
disease, unless high-quality treatment is provided [1].
Fig. (1). Diabetes mellitus and its types.
Diabetes is a common and significant global public health concern. According to
the International Association of Diabetes (IDF), around 463 million adult diabetes
patients were documented worldwide in 2019, which is around 9.3 percent of
adults aged 20-79 years, and the number of diabetes patients is still rising [2]. The
selection and implementation of glucose control therapy rely on a variety of
factors, such as the condition of hyperglycemia, the underlying liver and kidney
functions, hypoglycemic risk, the body mass index, capacity to regulate blood
24 Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 Sarfraz et al.
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glucose, and drug cost. Type 2 diabetes therapeutics include stimulus for insulin
release by GLP analogs such as liraglutide and exenatide [3, 4], insulin injection
to balance β-cell defects, inhibition of dipeptidyl peptidase-4 (DPP-4) by
sitagliptin, and improved islets survival [5, 6] and islet cell regeneration through
islet neogenesis associated protein (INGAP) peptide therapy aiming at islet cell
regeneration [7].
Diabetes has become a threat to people’s health and is a significant global
problem for health and society. A timely clinical concern is diabetes care. Along
with diet variety and appropriate workouts, antidiabetic medications are important
approaches in the treatment of diabetes. Several hypoglycemic agents, like insulin
and insulin analogs, biguanides, sulfonylureas, thiazolidinediones, glinides, alphaglucosidase inhibitors, dipeptidyl peptidase 4 (DPP4), glucagon-like peptide 1
(GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2)
inhibitors, are currently used in the treatment of diabetes [8]. However, almost
half of patients with diabetes cannot achieve treatment goals, including glycemic
control, even over 10 years [9 - 11]. A big confusion about the suitable choice and
screening of antidiabetic drugs because of the various hypoglycemic drugs is the
accessibility and the possibility that the same hypoglycemic agent may contribute
to different beneficial responses in each individual. The American Diabetes
Association (ADA) and the European Association for the Study of Diabetes
(EASD) also propose individualized diabetes attention and precision medicine
applications [12, 13]. Providing medication that relates to the genetic knowledge
of individuals through pharmacogenomics is one way to achieve precision
medicine and direct the proper use of antidiabetic agents [14, 15].
Strategies for the treatment of pharmacologic agents (leptin, β-3-agonists) can
increase the resistance of glucose uptake by effectively reducing visceral fat. A
function for macrophage fatty-inhibitors (thiazolidinediones, CCR2 antagonists)
in treating insulin resistance and vascular disease is also strengthened in different
reported studies. Thus, two research lines worth exploring include (i) the
interpretation of the visceral fat secretory biology to determine key mediators of
the Mets and (ii) drug production for modulative delivery of body fat [16]. Some
new kinds of hypoglycemic medicines, such as GLP-1, DPP-IV inhibitors, amylin
inhibitors, peroxisome proliferators, and activated receivers, have also been
developed and recorded. Any active molecules and bioactive compounds purified
from herbs and seeds add to the war on diabetes. These plant components have
overturned the production of medicines and led to the discovery of diabetes drugs.
Several recent studies have been conducted on important fields of diabetes,
focusing more on the statin-based method of diabetes treatment and nextgeneration antidiabetic stem cell therapy [17].
Drugs for Diabetes Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 25
Also, potential novel diabetes medications have begun to emerge; new targets are
projected to provide more reliable care for diabetes. This article would also
outline the hypoglycemic drugs and nearly future new goals for diabetes patients'
care and discuss some additional successful diabetes therapies. The rising trend in
diabetes occurrence and prevalence is alarming and puts a heavy burden on
medical expenditure and our modern healthcare system.
CURRENT TREATMENTS FOR TYPE-2 DIABETES MELLITUS
T2D can not be healed permanently, but medications, herbs, and dietary changes
can be used to control the severity and symptoms. Drugs of various types, such as
biguanides (metformin), sulfonylureas (glyburide and glipizide), meglitinides
(repaglinide and nateglinides), and thiazolidinediones, are some of the most
commonly employed pharmacological agents for the treatment of T2D.
Pioglitazone is the first line of protection, the medications belonging to these
groups are prescribed to avoid deterioration of the diabetic disease (Fig. 2).
Fig. (2). Common therapeutic approaches for type-2 diabetes mellitus.
Thiazolidinediones
Thiazolidinediones (TZDs) are insulin sensitizers that primarily operate on target
organs such as the liver and muscles by improving insulin sensitivity. The
mechanism by which TZDs exert their anti-diabetic effect includes stimulation of
the peroxisome proliferator-activated receptor (PPAR γ) transcription factor. This
element modifies the transcription, namely fatty acyl-CoA synthase, glucokinase,
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malic enzyme, and glucose transporter 4 (GLUT4), of many genes intricated in
lipid metabolism and glucose for energy balance. In this way, insulin tolerance in
adipose tissue, liver, and muscle is decreased by TZDs (Fig. 3) [18]. The
increased proliferation of peripheral adipocytes to increase the absorption of free
fatty acids is one of the key side effects of PPAR γ receptor activation. This effect
can adversely result in weight gain and increased mass of peripheral fat [19]. The
possible effect of TZD on coronary events in diabetes patients has been revealed
in many recent research and reviews. In this sense, meta-analyses of adverse
effect evidence from randomized clinical trials have found that thiazolidinedione
usage can be linked with increased myocardial ischemic risk events in the diabetic
patient role [20]. Fluid accumulation is another detrimental effect associated with
the use of TZDs. It has been indicated that the stimulation of sodium-coupled
bicarbonate absorption from the renal proximal tubule may result in the
development of TZD-induced edema in the kidney. The increase in sodium and
fluid absorption from the renal tubule contributes to an increase in the volume of
the kidneys [21]. The findings of this research have sparked controversy and
instilled doubt about the application of TZDs in care plans for diabetes.
Biguanide
Biguanides are another insulin sensitizer, and metformin belongs to this family of
widely used anti-diabetic medicines. The hypoglycemic activity of metformin, by
its action on insulin receptors and glucose transporters presents on target cells,
such as the skeletal muscle and liver cells, involves an increase in the use of
glucose [22]. It is understood that metformin inhibits the activity of pyruvate
dehydrogenase and thus contributes to lactic acidosis, an uncommon but possibly
lethal complication linked with metformin usage shown in Fig. (3). The elevated
risk of lactic acidosis caused by metformin normally occurs in patients with renal,
pulmonary, or cardiac insufficiency or a history of liver failure [23].
Sulfonylureas
Sulfonylureas are secretagogues and are meant to enhance the release of insulin
from pancreatic beta-cells. The ATP-sensitive potassium (KATP) channels, which
regulate the pancreatic β-cell membrane potential, are the primary targets of drugs
belonging to the sulfonylurea class. The binding of the drug to the subunit of the
sulfonylurea receptor (SUR) of the KATP channel allows the cell membrane to
depolarize, leading to calcium ion influx. This results in insulin granule
exocytosis from the pancreatic β-cell [24]. For those people who have been taking
sulfonylureas (like glyburide) for a longer time, diabetic hypoglycemia is a big
concern. Elderly patients and patients who also skip meals are more vulnerable to
the risk of sulfonylurea-associated hypoglycemia. Increased cardiovascular risk is
Drugs for Diabetes Frontiers in Clinical Drug Research-Diabetes & Obesity, Vol. 7 27
also associated with sulfonylurea. Studies suggest that, while inducing the closing
of the pancreas β-cell KATP channels to promote insulin secretion, this treatment
can also contribute to the closure of the myocardial KATP channels, contributing
to a higher frequency of coronary activity in these patients [25]. Sulfonylureas are
usually an alternative for hyperglycemia following a biguanide treatment or
patients with metformin intolerance. Hypoglycemia is a known side effect of the
drug type, and the blood sugar level of patients should be monitored regularly
while on a sulphonylurea regimen. These patients should also monitor their body
weight and renal function regularly [26].
Fig. (3). Site of action of Biguanides, Thiazolidinediones, Sulfonylureas, and alpha glucoside inhibitors.
Meglitinides
The mode of action of meglitinides is like that of sulfonylureas; but, when
contrasted with sulfonylureas, its action is regulated by a separate binding site on
the SUR of the β-cell [27]. To treat the different co-morbidities involved with
T2D, a variety of other medications are also prescribed, along with the antidiabetic drugs discussed above. Some anti-diabetic drugs are vulnerable to drugdrug reactions, resulting in adverse events and side effects that lead to the diabetic
patient's complications. For instance, a known structural analog of sulphonylurea,
sulphonamides, replaces it with plasma protein and makes it more freely available
for its activity. This potentiates the risk of sulfonylurea-caused hypoglycemia
[28]. Some sulfonylureas are metabolized by liver metabolic enzymes, and thus
inducers of hepatic drug metabolism, such as rifampicin, increase the clearance of
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sulfonylureas and hence decrease the plasma concentrations of sulfonylurea and
its efficacy [26]. For the optimal care of T2D patients, knowledge of the benefits,
as well as the dangers of the large variety of medications available today, is
therefore important.
SGLT2 Inhibitors
SGLT2 inhibitors are a new class of drugs for the treatment of type-2 diabetes that
act by inhibiting renal glucose reabsorption. They have been adopted rapidly into
clinical practice guidelines due to a combination of glucose-lowering with weight
reduction [29 - 31]. The difficulty in matching the normal physiology of insulin
secretion with exogenous insulin use is a constant challenge when managing type1 diabetes. As weight gain is a frequent consequence of intensive glucose control
[32], the use of adjunctive treatments that promote weight loss is sometimes
considered. In addition, there is preliminary evidence that SGLT2 inhibitors may
attenuate the progression of kidney disease in type-1 diabetes by decreasing
glomerular hyperfiltration [33, 34]. As a result of these preliminary data, some
clinicians have considered SGLT2 inhibitors to represent an attractive option in
type-1 diabetes, resulting in off-label use in this population. Case reports of
diabetic ketoacidosis (DKA) associated with SGLT2 inhibitors started to appear
earlier this year [35 - 37]. The US Food and Drug Administration (FDA)
published a formal warning regarding this potential complication in May 2015,
reporting cases in type-2 diabetes [38]. This has been followed by a similar
warning from the European Medicines Evaluation Agency (EMEA) and the
manufacturers of the three currently approved SGLT2 inhibitors, dapagliflozin,
canagliflozin, and empagliflozin [39] (Fig. 4).
Insulin
Insulin is a hormone produced by pancreatic beta cells, regulates sugar levels in
the bloodstream of the body, and allows excess glucose to be stored mainly in the
liver. Although T2D patients produce their insulin, either the quantity of insulin
produced is insufficient, or there is a further low insulin response in these patients'
target cells as the disease progresses shown in Fig. (5). Hence, in most cases,
insulin therapy is chosen as the final step for glucose-lowering therapies [40]. The
major disadvantages linked with long-term insulin therapy usage are
hypoglycemia and weight gain. These symptoms are well-justified because there
is a decrease in glycosuria and decreases in energy consumption in these patients
as this therapy improves the glycemic level [41]. Additionally, its indirect effect
on cell proliferation is a serious problem known to be associated with
hyperinsulinemic hypoglycemia. Specific cell proliferation and survival pathways
may be improved by hyperinsulinemia (due to its growth-promoting properties),
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