Recent Progress of Antidiabetic Agents for The Treatment of Type 2 Diabetes; A Mini-Review

Abstract

Diabetes mellitus is a group of metabolic disorders that involve hyperglycemia caused by defects in the production of insulin, its action, or both. Diabetes mellitus is primarily divided into type 1 diabetes and type 2 diabetes. Type 1 diabetes is typically treated with insulin therapy and is also known as Insulin-dependent Diabetes mellitus (IDDM), but type 2 diabetes is commonly treated with oral antidiabetic agents. Sulphonylureas, biguanides, insulin sensitizers, glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors (DPP-4), and sodium-glucose co-transporter-2 (SGLT2) inhibitors are the main drugs used to treat type 2 diabetes. The overall work of these drugs is to reduce blood glucose levels by increasing levels of incretin hormones and pancreatic beta cell function. Patients who are unable to accomplish treatment goals with first-line oral antidiabetic agents as monotherapy frequently receive prescriptions for dual medication therapy. In the proposed review article, we have made an effort to study the pathophysiology of diabetes, treatment, herbal drugs, mode of action of drugs, adverse effects as well as current work on antidiabetic agents.

Keywords

Introduction

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Figure 1. Pathophysiology of diabetes mellitus

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Figure 2. Symptoms of diabetes mellitus.

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Figure 3. Targets for diabetes mellitus

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Figure 4. Site of action for oral antidiabetic medications.

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Biguanides: They reduce blood glucose levels by lowering the amount of glucose that in liver produces and then releases into your bloodstream. Additionally, they help with lowering blood glucose levels by increasing the skeletal muscle tissue's tolerance to insulin, helping it to better absorb glucose for energy. Insulin resistance is decreased and insulin sensitivity is raised as a result. As they improve insulin resistance, they're also known as insulin sensitizers. Metformin, which is formed from 2-cyanoguanidine and dimethyl ammonium chloride, contains two methyl substituents in position 1. The phenethyl biguanide derivative of metformin known as Phenformin is described by the replacement of one terminal nitrogen atom with a 2-phenylethyl group. E.g. Phenformin, Metformin, Butformin [53].

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Meglitinides: It assists the pancreas in producing insulin. They bind at different locations, but they have the same effect on potassium channels as sulfonylureas. They bind directly to the pancreatic β-cells’ receptors. It depolarizes the β-cell membrane and causes ATP-sensitive K+ channels to close. After that, it causes voltage-gated Ca+2 channels to open, which increases insulin secretion from β-cells. We call these compounds insulin secretagogues. E.g. Repaglinide, Nateglinide [54].

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Thiazolidinediones: They are also known as PPAR-γ agonists because they bind to the receptor and activate peroxisome proliferator activated receptor-γ (PPAR-γ). To improve glucose uptake, they overexpress GLUT-1 and GLUT-4 receptors on their cell surface. They also decrease hepatic gluconeogenesis and insulin resistance. They reduce the HbA1c level as well as the postprandial glucose level [55]. E.g. Pioglitazone, rosiglitazone are two drugs approved by the FDA as monotherapy or combined with metformin or sulfonylureas for the treatment of type 2 diabetes.

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Glucosidase inhibitors: They inhibit the α-glucosidase enzyme present in the intestinal brush border epithelium, and also delaying the absorption and metabolism of carbohydrates. The enzyme α-glucosidase facilitates the breakdown of poly- and oligosaccharides into monosaccharides and helps in their digestion. Among this drug class's most common side effects are loose motion and flatulence. These medications have an anti-hyperglycaemic action; hypoglycemia is not produced by them [56, 57]. E.g. Acarbose, Miglitol, Voglibose.

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DPP-4 inhibitors

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Figure 5. DPP-4 inhibitors mode of action.

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GLP-1 receptor agonist: The glucose-dependent and glucagon-like peptide incretins, or peptides originating from the gut, are also referred to as insulinotropic polypeptides. It is a group of endogenous metabolic hormones known as incretins, they reduce blood glucose levels. GLP-1 agonists are the new group of injectable for treatment of type 2 diabetes mellitus. Although GLP-1 has an alanine residue at the N terminus, DPP-4 is capable of breaking down it. Thus, other amino acids such as threonine, serine, and glycine were substituted for the alanine group to derive the novel GLP-1 analogues. In vitro, such derivatives exhibited greater stability than DPP-4. Not only, certain GLP-1 derivatives are twice as effective as GLP-1, but they were also stable. The first GLP-1 agonist medication to be released as an anti-diabetic was Exenatide. Due to the medication's fast clearance, it was given twice daily. Tirzepatide is the first dual GIP/GLP-1 receptor agonist approved for the treatment of type 2 diabetes [64-66].

Recent update on antidiabetic agents

Here we added recent work on all antidiabetic agents like sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, thiazolidinedione’s, α-glucosidase inhibitors, GLP agonists, PTP1B inhibitory etc. after the review work, we found that there is no recent work on antidiabetic class like biguanides, meglitinides and sulphonylureas and recent work on only few classes like GLP agonists, α-glucosidase, thiazolidinedione, and DPP-4 inhibitors. Tiziano et. al., in their mini-review, explored various methods that have appeared in the literature to synthesize sulfonylureas placing significance on the reaction mechanisms of vital synthetic steps [69]. Sroor et. al., synthesized sulfonylurea derivatives having alkyl substituents such as isopropyl or n-butyl and also evaluated the anti-diabetic activities of compounds 4, 5, 7, and 10. Ghadeer et. al., in this study, evaluated the insulin signalling pathway via L6 skeletal muscle cell in vitro and in vivo study of glycosylated sulfonylureas [70]. Temel et al., synthesized 2-pyrazoline analogues and investigated DPP-4 inhibitory activity and cytotoxicity MTT assay on the L929 mouse fibroblast cell line [71]. Nidhar et. al., reported ourself, the design, synthesis, and evaluation of some pyrazole triazole persulfonimide and aryl triazole persulfonimide as potent antidiabetic agents [72]. Gupta et. al. (2023), synthesized new imeglimin-inspired 1,3,5-triazine derivatives, tested against DPP enzymes and revealed the selective and potent DPP-4 inhibitor activity of compound 8c by in-vivo antidiabetic activity test in Wistar rats. They also performed docking studies [73]. Guang-Jing Feng et. al., designed and synthesized novel thioglucoside gliflozins as potent gliflozin drugs and they were biologically Evaluated, where they studied two series of thioglucoside gliflozins, First series substitution of S-atoms at meta positions and another with substitution of S-atom at ortho position. These drugs showed greater stability and inhibitory activity against SGLT2 inhibitors [74]. Masahiko Seki et. al. synthesized dapagliflozin and canagliflozin as advanced SGLT2 inhibitors for the treatment of diabetes [75]. Yoshiaki Kitamura et. al., synthesized carbasugar analogues as SGLT2 inhibitors via click reaction Cu catalysed azide-alkyne cycloaddition, and compounds 7b and 7c were found as potent SGLT2 inhibitors [7]. CenJun et. al., worked on synthesized, physicochemical properties, crystal studies, and DFT calculation of empagliflozin. [77] Najmi, et. al., reported the design and synthesis of 5 novel benzylidene-thiazolidine-2,4-diones (5a–e) as PPAR-γ agonists and they were characterized using analytical methods. As revealed by the in vivo antidiabetic study, the compounds 5d and 5e have comparable activity with standard rosiglitazone. It is found to have no significant impact on body mass after 21 days of animal administration [78]. Amin et. al., synthesized novel pyrimidine thiazolidinedione derivatives, characterized them using spectroscopic analytical techniques and evaluated their anti-diabetic property. The best compounds 6e and 6m were evaluated for activity in STZ-induced rats and neither show an increase in body weight nor any toxicity [79]. Srinivasa et. al., synthesized and characterized a group of new 3-((5-phenyl-1,3,4-oxadiazol-2-yl) methyl) thiazolidine-2,5-dione derivatives (5a–5j) based on the prediction that thiazolidinediones and 1,3,4-oxadiazoles could improve the inhibition of α-amylase and α-glucosidase. They found that compounds 5a, 5b, and 5j could be a lead for the development of a new class of antidiabetic agents that might be potent against both enzymes [80].  Huneif et. al., designed and created five novel succinimide-thiazolidinedione hybrid derivatives (10a–e) in a multistep reaction. Following in vitro tests on multiple targets, the compound 10d was found to be the most active antidiabetic agent. Its activity is further investigated in experimental animals and a molecular docking study was also performed for compound 10d [81]. Shakour et. al., designed and synthesized new series of imidazolyl-methyl- l-2,4-thiazolidinediones 9a-9m, and carried out in silico studies. The studies revealed that compounds 9e and 9b are more active compared to pioglitazone and compound 9e was weight neutral or had no major side effects following its administration [82]. Singh et. al., synthesized and evaluated the α-amylase and α-glucosidase inhibition of nineteen thiazolidine-2,4-diones (TZDs)-hybrids. From the results, it was clear that the best dual inhibitors were the compounds 7i, 7k, and 7p and the derivatives were found to be good anti-oxidants. They are non-toxic and possess good GI absorption. The most effective molecule, according to the in vivo study, was 7p, whose activity was lower than that of the standard drug pioglitazone [83].  Mengyue et. al. synthesized a set of thiazolidine-2,4-dione derivatives (C1-C36) and all compounds demonstrated better α-glucosidase inhibition in comparison with standard drug acarbose. The reversible mixed-type inhibitor C23 was found to be the most active out of the compounds synthesized and did not possess cytotoxicity against LO2 and 293 cells. It showed binding interaction with α-glucosidase in the molecular docking study and reduced the glucose level in mice on oral administration [84]. Ghomi et. al., synthesized and spectroscopically analysed a group of twenty novel quinoline-linked benzothiazole hybrids (8a–t) as potential α-glucosidase inhibitors and the compounds 8b, 8h, 8n, and 8o demonstrated better α-glucosidase inhibitory activity compared with standard acarbose. A non-competitive inhibition was shown by the most active molecule (8h) on enzyme kinetic studies. The key interactions of the most active compound 8h are further identified by homology modelling, molecular docking, and molecular dynamics simulation studies, and the drug ability of the novel derivatives are predicted [85].  Ali et. al., designed, synthesized, and the structure confirmed by spectroscopic analysis, of a new class of 1,3,4-thiadiazole containing Schiff base analogues (1–12) and compounds 4, 8, and 9 exhibited excellent inhibition of α-glucosidase enzymes by using standard acarbose. Molecular docking, pharmacokinetics, cytotoxic evaluation, and density functional theory study were also conducted [86].   Yousefnejad et. al., synthesized and evaluated benzo[d]imidazole-amide containing 1,2,3-triazole-N-arylacetamide derivatives 8a–n, and the N-2-methylphenylacetamide derivative 8c was found to be the most promising inhibitor of α-glucosidase. As revealed by the kinetic study compound 8c is a competitive inhibitor and the ADMET study predicted the oral activity of compound 8c. Furthermore, the compounds 8c, 8e, and 8g did not show cytotoxic effects against the cancer and normal cell lines [87].  Emadi et. al., designed a new group of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides (11a-11n) and synthesized them. They were screened for in-vitro inhibitory activity against the α-glucosidase enzyme. Compounds 11j and 11i were most active with positive control acarbose. Kinetic analysis, molecular docking, molecular dynamics, and in silico pharmacokinetic study were also performed [88]. Tariq et. al., through facile chemical reactions, synthesized, and characterized coumarin–hydrazone hybrids (7a-7i), and the in vitro α-glucosidase inhibitory activity of the synthesized compounds were carried out and compound 7c was found to be the most potent α-glucosidase inhibitor among the synthesized compounds [89] Dong et. al. (2024), designed and synthesized a novel better acting long-acting dual GLP-1/GIP RA that compared to standard tirzepatide which exhibited beneficial impact on blood sugar and body weight when evaluated in diet-induced and db/db obese (DIO) mice [90] Zhang et. al. (2023), designed, and synthesized by liquid-phase synthesis, Sixteen GLP-1 receptor agonists (13-28) with dual fatty acid side chains and they were biologically evaluated. Their structures were confirmed and evaluated for receptor affinity, activity, and plasma stability. It was discovered that conjugate 19 was superior to Semaglutide [91]. Ehsasatvatan and Kohnehrouz (2023) designed and computationally analysed chimeric long-lasting GLP-1 receptor agonists including stability, and solubility and they predicted the secondary and tertiary structures and validated them. The structures were stable throughout the molecular dynamic simulation studies [92]. Girdhar et. al. (2022), Designed, synthesized, and biologically evaluated a set of small molecule oral glucagon-like-peptide-1 receptor agonists. They found that the small molecule PK2 (6-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl) methyl)-6H-indolo[2,3-b] quinoxaline) which showed solid binding with GLP1R ectodomain is orally active nonpeptidic able to maintain or replenish viable β-cell mass. [93]. Thareja et. al. (2023), designed and synthesized novel biphenyl thiazolidinedione conjugates (8a-n), and their in-vitro PTP1B inhibitory potency and in-vivo anti-hyperglycaemic efficacy were assessed with Suramin and Pioglitazone as standard respectively. Additionally, the effect on weight, pancreatic safety, and in-silico ADMET investigations of drug-likeness were also performed. The conjugate 8j showed the best result in which all the molecules 8a-n exhibited good activity [94]. Sroor et. al. (2022) designed, synthesized, characterized, and evaluated novel series of sulfonylurea analogues (3–11) and most of the analogues showed significant In-vivo anti-diabetic activity. The most active (compared with Diamicron) analogues 4, 5, and 10 were further evaluated for liver enzyme activities, antioxidant, and oxidative stress biomarkers, and a histological examination was also carried out. As it is clear from SAR, the anti-diabetic property was increased by the alkyl substituents such as isopropyl or n-butyl [95]. Shah et. al. (2023) based on their previous work, optimized, synthesized, and evaluated new potent multitarget antidiabetic compounds 47–49 and 55–57 with central 5-benzylidine thiazolidine-2,4-dione moiety as inhibitors of α-amylase, α-glucosidase, PTP-1B and DPP-4. It resulted in compounds with an in-vitro potency that is many times higher than the lead (Z)-5-(4-hydroxy-3-methoxybenzylidene)-3-(2-morpholinoacetyl) thiazolidine-2,4-dione (Z-HMMTD) in which compound 56 showed remarkable results as the glucose-uptake promoter [96-98].

Recent update on Herbal antidiabetic agents

Hibiscus sabdariffa: Hibiscus sabdariffa also known as roselle or red sorrel, is a flowering shrub. The study investigates the possible use of Roselle Extracts to manage diabetes mellitus. Previous studies have demonstrated the extracts' effects on blood glucose levels and insulin sensitivity in diabetic mice. The study also discovers chemicals in Roselle Calyces that could be used to treat type 2 diabetes by inhibiting Phosphoenolpyruvate carboxykinase (PEPCK). The extracts block pancreatic enzymes and modulate gene expression related to glucose regulation, hence improving insulin sensitivity. [99]

Catharanthus roseus: A systematic evaluation of research papers on the antihyperglycemic activities of Catharanthus roseus Linn., a plant used in Ayurveda to treat diabetes, discovered that the herb appeared to reduce blood sugar levels in test subjects. This possible antidiabetic advantage could be attributed to the plant's ability to stimulate insulin secretion from damaged beta cells in response to glucose and boost the activity of genes involved in sugar uptake (GLUT-2 and GLUT-4).  [100]

Ficus racemose: Ficus racemosa fruit methanolic extract, a medicinal plant used to treat various diseases. The presence of secondary metabolites such as bioflavonoids, glycosides, alkaloids, tannins in the crude methanolic extract may contribute to its antidiabetic and antimicrobial properties. Ayurvedic medicine extensively uses the herb F. racemosa Linn. (Moraceae) to treat various ailments, including kidney stones, biliary disorders, jaundice, diarrhoea, inflammatory conditions, liver disorders, haemorrhoids, respiratory and urinary diseases. [101]

Coriandrum sativum: Coriander contains a variety of phytochemicals, including polyphenols, reducing sugars, terpenoids, carotenoids, glycosides, sterols, isocoumarins, flavonoids, tannins, alkaloids, fatty acids, and coumarins. Consuming coriander has been shown to be an effective strategy of keeping blood glucose levels stable in pre-diabetic patients. A study of 10 individuals with type 2 diabetes found that coriander seed consumption reduced fasting blood sugar, serum insulin, and Homeostasis Model Assessment of Insulin Resistance. Coriander oil contains antioxidant properties and helps treat renal and pancreatic pathological problems caused by diabetes. Phenols and flavonoids have antioxidant properties that reduce oxidative damage and boost glucose metabolism. It improves α amylase enzyme inhibition, which contributes to their anti-diabetic properties. Linalool and petroselinic acid have been linked to anti-inflammatory qualities that aid in blood sugar regulation. [102]

Cinnamomum verum: The anti-diabetic properties of an ethanolic extract of C. verum bark utilising in vitro and in silico models. C. verum inhibits carbohydrate digestion enzymes α-glucosidase and α-amylase, and affects glucose uptake in 3T3 adipocytes. HPLC-quantified molecules were docked with the GLUT 4 glucose transporter and PPAR-γ. It inhibits α-glucosidase and α-amylase enzymes and promotes adipocyte glucose uptake. [103]

Azadirachta indica: Azadirachta indica, a medicinal plant used in Ayurveda to treat diabetes, was investigated for its effects on insulin signal transduction and glucose homeostasis in high-fat, fructose-induced type 2 diabetic male rats. According to the study, the extract restored normal levels of blood glucose, serum insulin, lipid profile, insulin signalling molecules, glycogen concentration, and glucose oxidation in skeletal muscle. This shows that Azadirachta indica might help manage type 2 diabetes by enhancing insulin signalling molecules and glucose utilization in the skeletal muscle. [104]

Trigonella foenum-graecum: Fenugreek, a popular Asian dietary herb, has been traditionally used for diabetes treatment due to its hyperglycaemic-regulating components. Fenugreek's antidiabetic impact was linked to increased glucose transporter type-4 activity, lowered glucose-6-phosphatase and fructose-1,6 bisphosphatase activities, inhibited α-amylase and maltase activities, protected β cells, and raised insulin release. Further clinical studies revealed better blood glucose levels and lipid profiles. [105]

Caesalpinia bonducella: The study found that phytochemicals from Caesalpinia bonducella seeds have antioxidant and anti-diabetic activities. The seed extract was found to inhibit the enzyme responsible for glucose metabolism, with maximum inhibition at 0.25 mg/mL, and the chemical was discovered to be highly reactive to free radicals. In the DPPH assay, the plant seed extract had the highest inhibitory activity of 92.04% at high concentrations. Additionally, the plant seed extract inhibited H2O2 scavenging by 88.3% at a dosage of 0.75 g/mL. These findings suggest therapeutic benefits for diabetes and oxidative stress disorders. [106]

Gynura procumbens: The GLUT-4 expression levels in Alloxan-induced diabetic rats were compared with untreated healthy rats and rats treated with different doses of G. procumbens extract using enzyme-linked immunosorbent assay (ELISA) specified for rat GLUT-4. The researchers found that all test groups, including the metformin control group, showed elevated GLUT-4 expression in liver tissue compared to the diabetic control group. Result shows that the ethanolic extract of G. procumbens facilitated serum-glucose modulatory antidiabetic activity by upregulating GLUT-4 expression and increasing glucose uptake. [107] G. procumbens was found to have a higher hypoglycaemic impact when combined with Azadirachta indica or Andrographis paniculata. [108-109] Add herbal drug table

CONCLUSION

In this article, we have included an overview of diabetes, and the management of type-2 diabetes. After a careful survey of target enzymes, antidiabetic drugs, herbal drugs and their mode of action, we can conclude that there are many antidiabetic drugs available in the market to manage diabetic conditions but the following are showing efficacy Metformin, Glipizide, Glimepiride, Invokana, Jardiance, Pioglitazone, Januvia, toward lowering blood sugar level but long-term treatment is limited due to their side effects. The ultimate role of these drugs is to reduce the blood sugar level by increasing the level of insulin and decreasing the level of glucagon in pancreatic beta cells. After the review, we found that available drugs have good potency but need to be focused on to reduce adverse effects, and we can also use these drugs for the long term. Currently, it is imperative to develop more effective antidiabetic medications to counteract the adverse effects associated with antidiabetic treatments.

ACKNOWLEDGEMENTS

Manisha Nidhar, Ashish Kumar Tewari and authors would like to express their gratitude to Banaras Hindu University's and Amrita Vishwa Vidyapeetham, Amrita School of Pharmacy, Kochi, Kerala for Financial support.

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