Recent Developments in Diabetes Management: Exploring Receptors, Pathways, and Compounds

Review

Pallavi Pandey¹, Vikash Jakhmola^1,*, Supriyo Saha¹ and Anand Gaurav²

¹Department of Pharmaceutical Chemistry, Uttaranchal Institute of Pharmaceutical Science, Uttaranchal University, Prem Nagar, Dehradun, Uttarakhand 248007, India

²Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun 248007, Uttarakhand, India

*Correspondence to: Vikash Jakhmola, E-mail: jakhmola.1979@gmail.com

Received: November 18 2024; Revised: January 11 2025; Accepted: April 3 2025; Published Online: May 7 2025

Cite this paper:

Pandey P, Jakhmola V, Saha S et al. Recent Developments in Diabetes Management: Exploring Receptors, Pathways, and Compounds. BIO Integration 2025; 6: 1–28.

DOI: 10.15212/bioi-2024-0137. Available at: https://bio-integration.org/

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© 2025 The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See https://bio-integration.org/copyright-and-permissions/

Abstract

Diabetes mellitus (DM) is a widespread metabolic disorder with profound effects on vital organs. Often referred to as a “systemic” or “multi-organ” disorder due to the impact on key organs, such as the kidneys, pancreas, eyes, and heart, DM is characterized by elevated blood glucose levels due to insufficient insulin production. DM consists of three subtypes (type 1 DM, type 2 DM, and gestational DM). Approximately 537 million adults are living with DM, a number predicted to increase to 643 million by 2030, according to the International Diabetes Federation (IDF) data. With the rising prevalence of DM, the Pan American Health Organization and World Health Organization estimate an age-standardized mortality rate of 20.9 deaths per 100,000 people. Therefore, it is important to study the prevention and cure of DM and determine the underlying mechanism and regulation. Numerous receptors and pathways help to regulate DM. This article delves into the intricate regulatory mechanisms underlying DM involving receptors and pathways, such as K_ATP (sulfonylurea), 5′AMP-activated protein kinase enzyme (biguanides), PPAR gamma, alpha-glucosidase, Glucose transporters (GLUT4), dipeptide peptidase-4 (DPP-4), and sodium-glucose co-transporters type 2 (SGLT2). The article highlights recent advances from 2020–2024 in synthesizing compounds targeting specific receptors for diabetes management. In so doing, insights into newly synthesized compounds, marketed drugs, phytoconstituents, and drugs currently in clinical trials will be provided. The role of each receptor in maintaining glucose homeostasis is reviewed in detail and various compounds with potential as effective antidiabetic agents are evaluated. This comprehensive review presents the pharmacologic mechanisms underlying these receptors and an in-depth analysis of promising new drug candidates.

Keywords

biguanides, DM, DPP-4, GLUT4, PPARγ, SGLT2, sulfonylureas.

Introduction

Diabetes mellitus (DM) is a widespread metabolic disorder in which glucose levels become too high, a condition known as hyperglycemia. DM develops when the pancreas fails to generate enough insulin or when cells develop insulin resistance [1, 2]. The word “mellitus” is a Latin word that resembles sweet, which means that the blood glucose concentration in the body is increased. According to data from the American Diabetes Association, a fasting blood glucose level < 116 mg/dL is considered normal. A fasting blood glucose level ≥ 126 mg/dL or a glucose level > 200 mg/dL in a randomly collected specimen is considered elevated [3]. If an elevated glucose level persists, chronic diabetes-related problems that impact numerous organs may occur, such as retinopathy, nephropathy, peripheral neuropathy, peripheral arterial disorders, and cerebrovascular disease [1]. The International Diabetes Federation (IDF) states estimated that 527 million adults between 20 and 79 years of age were living with DM in 2021. Moreover, DM is projected to affect 643 million people or 1 in 9 adults by 2030 and the number will increase to 784 million or 1 in 8 adults by 2045. Nearly 6.7 million fatalities were attributed to DM in 2021 [4, 5]. The IDF also published data on DM according to geographic region and worldwide (Figure 1A). In addition, the IDF has provided data on the rise in DM across continents, which is detailed in Figure 1B [5].

Figure 1 A) Predicted prevalence of diabetes in different continents by IDF. B) Percentage of increase in diabetes cases.

Diabetes is of three types based on the causes (type 1 DM, type 2 DM, and gestational DM). Type 1 DM, which is associated with autoimmune disease, primarily affects pancreatic cells, leading to a reduction or impairment in insulin synthesis [6]. There were 530,000 new cases of type 1 DM across all age groups, with 201,000 of these cases occurring in individuals < 20 years of age, according to IDF data from 2022. The IDF organized this data segmented by age group and incidence of DM [5]. Metabolic irregularities, such as hypertension, obesity, and dyslipidemia, are associated with type 2 DM and are risk factors for cardiovascular disease. Type 2 DM, also referred to as non-insulin-dependent DM, is characterized by pancreatic beta cell dysfunction, which impairs insulin use [7].

Gestational diabetes mellitus (GDM) is the third type of DM. GDM is characterized by any level of glucose intolerance detected during pregnancy. GDM complicates approximately 200,000 pregnancies annually (approximately 7% of all pregnancies). A fasting blood glucose level > 126 mg/dL or an average blood glucose concentration > 200 mg/dL meets the diagnostic criteria for GDM. When hyperglycemia of this magnitude is identified, the assessment of GDM should follow both one- and two-step methodologies. The one-step strategy involves administering an oral glucose tolerance test (OGTT) without initially evaluating plasma or serum glucose levels. In contrast, the two-step approach begins with an initial screening, during which plasma or serum glucose levels are measured 1 h after a 50-g oral glucose load. Subsequently, an OGTT is performed on the subgroup of women who exceed the glucose threshold value [8].

Another important factor that affects the prevalence of DM is lifestyle. Some food groups and dietary compounds, such as monounsaturated fatty acids, fruits, vegetables, dietary fibers, fish, magnesium, and nuts, have been shown to potentially offer protection against DM, possibly by improving insulin sensitivity and exerting anti-inflammatory effects. Conversely, consuming red and processed meats, as well as saturated fats, may increase the risk of developing type 2 DM [9]. In addition to lifestyle and gender, there are several other risk factors for DM, such as a lack of exercise, age, cigarette smoking, obesity, dyslipidemia, and a family history of DM [10].

This review focuses on recent advances (from 2020–2024) in synthesis of compounds targeting specific receptors for DM management. Furthermore, insights into newly synthesized compounds, marketed drugs, phytoconstituents, and drugs currently in clinical trials are provided.

Sulfonylureas

Sulfonylureas are a well-established class of antidiabetic drugs that are recommended for mono- or combination-therapy in management of DM. Sulfonylureas facilitate release of insulin from the beta-pancreatic cells, the details of which are provided below. However, recent studies have highlighted additional antidiabetic effects beyond β-cell stimulation. Sulfonylureas have been shown to inhibit peroxisome proliferator-activated receptor-γ (PPARγ) phosphorylation at Ser273 in primary human white adipocytes, leading to a favorable antidiabetic expression profile. This effect is characterized by upregulation of insulin-sensitizing adipokines and downregulation of adipokines associated with insulin resistance [11]. A detailed overview of available sulfonylurea drugs, along with the IC₅₀ values, is presented in Figure 2, further illustrating the potency and pharmacologic profiles.

Figure 2 Marketed available sulfonylurea derivatives and IC₅₀s.

Physiology of insulin release and role of sulfonylurea inhibitors

Pancreatic beta cells regulate insulin secretion through ATP-sensitive potassium (KATP) channels. KATP channels consist of Kir6.2 and SUR1 subunits, which respond to fluctuations in the cytosolic adenosine triphosphate (ATP): adenosine diphosphate (ADP) ratio. At low plasma glucose levels, ATP production decreases, keeping KATP channels open and allowing the efflux of potassium ions. This mechanism prevents calcium influx and suppresses insulin secretion. When the plasma glucose level rises, glucose metabolism increases the ATP:ADP ratio, leading to KATP channel closure. The resulting depolarization activates calcium channels, causing calcium-mediated exocytosis of insulin granules. The detailed molecular make-up of the KATP channel complex is shown in Figure 3. Mutations in KATP channel subunits, encoded by KCNJ11 and ABCC8 genes, significantly impact insulin secretion and glucose homeostasis. Loss-of-function mutations result in persistent hyper-insulinemic hypoglycemia due to excessive insulin release, while gain-of-function mutations reduce ATP sensitivity, leading to hyperglycemia and conditions, such as permanent neonatal diabetes mellitus and transient neonatal diabetes mellitus [12].

Figure 3 Molecular make-up of the KATP channel complex (transmembrane domain [TMD]) and binding site of sulfonylurea [12]. SUR: sulfonylurea receptor, TMD: transmembrane domain.

Sulfonylurea inhibitors are widely used in type 2 DM, target the SUR1 subunit of the KATP channel, and mimics ATP action to force channel closure. This process induces β-cell depolarization, calcium influx, and insulin secretion. First-generation sulfonylureas, such as tolbutamide, selectively bind to a single site on SUR1, while second-generation sulfonylureas, including glimepiride and glibenclamide, interact with multiple binding sites, which enhances potency. Additionally, meglitinides, which are structurally related to sulfonylureas, allosterically bind to regulate KATP channel activity with a rapid onset and short duration of action, making meglitinides effective for postprandial glucose control [13, 14].

Recent advances in sulfonylurea and combination therapy

Recent research highlights promising advances in sulfonylurea therapy, particularly when combined with other potent moieties. While traditional sulfonylureas, like gliclazide, effectively stimulate insulin release from pancreatic beta cells, traditional sulfonylureas carry the risk of hypoglycemia, especially at higher doses. To address these concerns, the study that focused on combining two potent moieties is detailed in Table 1 [15].

Table 1 Recently Synthesized Sulfonylureas with Combined Moieties

S.No	Structure	Combination	Result	References
1		Quinazoline	Percentage of reduced blood glucose level in rats, 78.2%	[16]
2		Thiazole	IC₅₀ value, 3.30 μM (α-amylase) and 3.02 μM (α-glucosidase)	[17]
3		Pyrazole	IC₅₀ value, 1.13 μM (α-glucosidase)	[18]
4	Ar: NO₂C₆H₄	Pyrazole	IC₅₀ value, 25.53 μM	[19]
5		Thiazolidin-4-one	IC₅₀ value, 29.51 μg/ml (α-amylase).	[20]
6		Paracetamol	IC₅₀ value, 1.55 μM (α-amylase) and 1.39 μM (α-glucosidase)	[21]

Biguanides

Biguanides, a class of antidiabetic drugs with metformin as the primary agent, have been the cornerstone of type 2 DM management for decades due to efficacy, safety, and cost-effectiveness. Metformin features a guanidine core modified with methyl groups at the N1 and N2 positions. This structure contributes to the hydrophilic property, necessitating organic cation transporter 1 transporters for cellular uptake. Metformin exhibits slow absorption (peak plasma concentration, 1–3 h for immediate-release formulations), negligible plasma protein binding, and primary elimination through renal clearance [16, 22].

Recent studies (2023–2024) highlight the multifaceted mechanism underlying metformin beyond glycemic control, positioning metformin as a versatile agent with therapeutic potential in metabolic, cardiovascular, and inflammatory disorders. Metformin is known to inhibit mitochondrial complex I, which reduces hepatic gluconeogenesis by suppressing glycerol-3-phosphate shuttle activity. Metformin also modulates gut microbiota and lowers tumor necrosis factor-α, interleukin-6, and C-reactive protein levels, thereby mitigating chronic inflammation in obesity-driven diabetes. It has also been shown that metformin provides benefits beyond glycemic control by positively impacting macrovascular and microvascular outcomes. Metformin improves cardiovascular health by reducing insulin resistance, endothelial dysfunction, and oxidative stress, while inhibiting atherosclerotic plaque formation. Clinical evidence indicates a 30% lower risk of myocardial infarction in patients with type 2 DM using metformin compared to sulfonylureas [23, 24]. Additionally, metformin has a role in nephropathy by attenuating renal fibrosis through AMP-activated protein kinase-mediated suppression of transforming growth factor-β1 signaling. Clinical studies have shown that metformin slows the decline of eGFR by 1.2 mL/min/year in patients with chronic kidney disease stages 2–3. Metformin enhances mitochondrial function in peripheral nerves, which reduces oxidative damage and a corresponding 22% reduction in progression of neuropathy over 5 years [25, 26].

Furthermore, metformin has been linked to a reduced cancer risk by downregulating the mTOR pathway and insulin/IGF-1 signaling. Clinical evidence suggests a 31% lower risk of obesity-related cancers (e.g., breast and colorectal cancer) in patients using metformin [27].

Peroxisome proliferator activating receptor gamma

PPARγ is a nuclear receptor that regulates the expression of genes involved in glucose and lipid metabolism, adipogenesis, and inflammation. PPARγ has a pivotal role in enhancing insulin sensitivity by improving glucose uptake in peripheral tissues, particularly in adipocytes and muscle cells. Recent studies have increasingly focused on pan-PPAR agonists, compounds that simultaneously activate all three isoforms of peroxisome proliferator-activated receptors [PPARs] (PPAR-α, PPAR-β/δ, and PPAR-γ). These agonists hold significant potential in regulating pathways that contribute to antidiabetic effects. One of the key benefits is improving insulin sensitivity through activation of PPAR-γ is enhanced glucose uptake and utilization in peripheral tissues. Additionally, pan-PPAR agonists regulate lipid metabolism by activating PPAR-α, promoting fatty acid oxidation, and reducing triglyceride levels in the liver and plasma. These effects help alleviate hepatic steatosis and improve overall insulin action. Pan-PPAR agonists also have a critical role in reducing inflammation by modulating inflammatory responses through PPAR-γ and PPAR-β/δ. By decreasing the production of pro-inflammatory cytokines, pan-PPAR agonists create a more favorable inflammatory environment, which is often disrupted in conditions, like insulin resistance. Furthermore, activation of PPAR-β/δ enhances glucose metabolism by promoting the switch from glucose to fatty acid oxidation in skeletal muscle, thereby improving the overall metabolic profile. Another important mechanism is the regulation of hormonal signaling. Pan-PPAR agonists influence hormones involved in glucose homeostasis, such as adiponectin, which not only enhances insulin sensitivity but also exhibits anti-inflammatory properties [28, 29]. These multifaceted actions of pan-PPAR agonists make pan-PPAR agonists promising candidates for the development of novel therapies targeting metabolic disorders, including type 2 DM and associated complications. Chiglitazar (Bilessglu®) became the first pan-PPAR receptor agonist approved in China in October 2021 for the treatment of type 2 DM. This milestone highlights the growing interest in pan-PPAR agonists as a novel therapeutic approach for metabolic disorders [30]. In addition to chiglitazar, other compounds, such as Bezafibrate and E17241, also target the pan-PPAR receptor, further emphasizing the potential of this drug class in regulating metabolic pathways and improving outcomes in patients with type 2 DM [31].

Chemistry

The nuclear receptor, PPARγ, is comprised of five domains (labeled A-E) that span from the N-terminus to the C-terminus. The N-terminal region includes the A and B domains, which feature the intrinsically disordered activated function (AF) 1 domain. This AF1 domain is involved in ligand-independent co-regulatory binding but lacks a major binding site due to the absence of a conserved amino acid sequence [32].

The C domain of PPARγ serves as the DNA-binding domain and is the most conserved region. The C domain of PPARγ contains two zinc-binding sites crucial for function, enabling the receptor to bind to specific DNA sequences and regulate gene transcription. The D domain acts as a hinge, providing structural flexibility and linking the DNA-binding domain to the ligand-binding domain, facilitating conformational changes upon ligand binding [33].

The E domain is responsible for ligand binding, accommodating both endogenous ligands, like fatty acids and synthetic drugs. The E domain also contains the AF2 region, which is essential for ligand-dependent activation of the receptor. Notably, the DNA-binding domain structure is quite similar to the ligand-binding domain, highlighting a conserved mechanism across these regions [34].

The F domain, located at the C-terminus, is less well-characterized but is believed to have a role in the interaction between co-regulators and other proteins. The overall structure of PPARγ enables PPARγ to effectively regulate gene expression involved in metabolism and the pharmacologic role (structure demonstrated in Figure 4) [24, 35].

Figure 4 Different binding domains of PPARγ. AF: activation function, DBD: DNA binding domain, C0-FBD: Co-activator binding, LBD: ligand-binding domain.

PPARγ consists of three subunits (a polar head, a linker, and a hydrophobic tail). The acidic head is a thiazolidinedione moiety, the linker is a benzyl group, and the hydrophilic tail is a pyridine in pioglitazone and rosiglitazone.

Mechanism of action

PPARγ is a nuclear receptor present in various cells, including adipose tissues, the colon, and macrophages. PPARγ is located in the nuclear membrane and the drugs within the class bind to PPARγ, activating PPARγ and causing PPARγ to dimerize with the retinoic X receptor (RXR). The dimer then interacts with DNA, influencing gene transcription and leading to protein synthesis. As a result, PPARγ agonists enhance protein synthesis and release, which increases insulin sensitivity (detailed in Table 2) [36].

Table 2 Recently Synthesized PPARγ and Its Combination Moiety

S.No	Combination	Result	References
1	1, 3, 4-thiadiazole	89.7% increase in blood glucose levels	[46]
2	Thiazolidine- 2,4-dione	Percentage change in fasting blood glucose level, 54.4±4.8	[47]
3	Phosphazene	Higher glucose uptake compared to pioglitazone	[48]
4	Benzenesulfonamide	PPAR activation increased by 31.7% and 10-fold increase in blood insulin level and C-peptide level by 48.4%.	[49]
5	2H- chromene	IC₅₀ value, 4.653 μg/mL	[50]
6	2H- Chromene-6-sulfonamide	IC₅₀ value, 3.706 μg/mL	[51]
7	Thiazole- pyridine	Reduction in blood glucose level from 226.8 ± 5.10 to 115.5 ± 3.09 mg/dL	[52]
8	Thiazole	PPARγ activation increase, 72%-79%	[53]
9	Thiazole-Thiosemicarbazones	Thiazole- thiosemicarbazones derivative IC₅₀ values, 0.938 ± 0.023 and 0.947 ± 0.024 ng/mL	[54].
10	Thiazolidinediones	Reduction in blood glucose level by 108.5 ± 2.171 mg/dL	[55]
11	Pyrimidine	Lower blood glucose level to 145.2 mg/dl	[56]

The phytoconstituents listed in Figure 5 have been identified as exhibiting anti-diabetic properties by acting on the PPARγ receptor [37–43].

Figure 5 Marketed available drugs, phytoconstituents, and IC₅₀s.

Recent advances in PPARγ and combination therapy

Current research includes selective PPARγ modulation, such as INT131, which provides insulin-sensitizing effects without the adverse cardiovascular impact of traditional PPARγ agonists. A 2024 study reported that INT131-based combinations reduce HbA1c by 1.2% and LDL by 18% in patients with diabetics dyslipidemia. Additionally, novel dual PPARα/γ agonists (e.g., tesaglitazar and saroglitazar) demonstrate synergistic improvements in glycemic control, lipid metabolism, and insulin resistance. A 2024 meta-analysis of 20 randomized controlled trials (6058 patients) concluded that combining PPAR agonists with metformin reduces the fasting glucose level by 22.07 mg/dL (P < 0.001), the HbA1c by 0.53% (P < 0.001), and the HOMA-IR by 1.26 units (P = 0.006) with no significant increase in adverse events compared to metformin alone. Saroglitazar, a newer dual agonist, has also been shown to improve lipid profiles and reduce cardiovascular risks. Additionally, combination therapy (illustrated in Table 2) shows promise in amplifying glycemic control and addressing multiple pathways of metabolic dysfunction. This multi-faceted approach aims to improve long-term outcomes by leveraging the role of PPARγ in lipid and glucose metabolism [44, 45].

Alpha-glucosidase inhibitor

Alpha-glucosidase is an enzyme that belongs to the family of glycosyl hydrolases. There are two distinct forms of alpha-glucosidase in the gut (maltase-glucoamylase [MGAM] and sucrase-isomerase [SI]). Each domain of these enzymes catalyzes the hydrolysis of maltose at the alpha 1-,4-glycosidic bond (Figure 6) [57].

Figure 6 Human alpha-glucosidase and location of maltose-glucoamylase (MGAM) and sucrase-isomaltose (SI) situated within the intestinal brush membrane [58].

Alpha-glucosidase cleaves alpha-related D-glucose residues from the non-reducing end of polysaccharides and disaccharides, which hydrolyzes alpha-related D-glucose residents into glucose. Therefore, inhibiting alpha-glucosidase is one of the simplest strategies for controlling the postprandial blood glucose level. Acarbose and miglitol are prominent alpha-glucosidase inhibitors. Acarbose is a bacterial oligosaccharide that is an analog to a glucosidase substrate (acarbose and voglibose are amino sugars). In contrast, miglitol belongs to a structurally distinct class of compounds with a cyclohexane moiety (azasugar; Figure 7) [59].

Figure 7 Marketed available alpha glucoside drugs and IC₅₀s.

Mechanism of action

Alpha-glucosidase inhibitors function by preventing the intestinal enzyme brush boundary alpha-glucosidase from functioning. Alpha-glucosidase usually cleaves large glucose molecules into smaller fragments for absorption. By inhibiting alpha-glucosidase, alpha-glucosidase inhibitors prevent the breakdown and subsequent absorption of glucose, inflicting glucose to remain inside the intestinal lumen. This effect leads to gastrointestinal side effects, such as bloating and gastric upset [7, 60].

Recent advances in alpha-glycosidase and combination therapy

Recent studies show that combining alpha-glucosidase inhibitors with antidiabetic medications and other moieties (Table 3) enhance glycemic control significantly by lowering HbA1c, fasting plasma glucose, and postprandial glucose levels, while reducing the side effects [61–63].

Table 3 Recently Synthesized Alpha Glycoside and the Combination Moiety

S.No	Structure	Combination	Result	References
1	R= bis-functionalized	Curcumin derivative	IC₅₀, 3.01 μg	[64]
2		Triazole clubbed indole derivative	IC₅₀, 10.1 μM	[65]
3		Thiazolidine	IC₅₀ values, alpha-amylase (1.5 μM) and alpha glycosidase (2.40 μM)	[66]
4		Mercaptobenzimidazole	IC₅₀, 5.22 μM	[67]
5		Benzimidazole with thiosemicarbazone	IC₅₀ value, alpha glycosidase (1.30 μM) and alpha-amylase (1.20 μM)	[68]
6		Diarylpentadienone	IC₅₀, 5.69 μM (alpha glycosidase)	[69]
7		Imidazopyridine	IC₅₀, 5.57 μM (alpha glycosidase)	[70]
8		Benzimidazole with phenoxy acetamide	50.0% inhibition, 108 μM; IC₅₀, 25.2 μM (alpha glycosidase)	[71]
9		Indole derivative	IC₅₀, 2.35 μM (alpha glycosidase)	[72]
10		Benzoxazole	IC₅₀ value, alpha glycosidase (1.20 μM) and alpha-amylase (1.10 μM)	[73]
11		Thiazole	IC₅₀ value, alpha glycosidase (0.5 μM) and alpha-amylase (0.6 μM)	[74]
12		Benzimidazole urea derivative	IC₅₀ value, alpha glycosidase (17.47 μM) and alpha-amylase (18.65 μM)	[75]
13		Imidazopyridine	IC₅₀ value, alpha glycosidase (0.90 μM) and alpha-amylase (1.10 μM)	[76]
14		Benzimidazole	IC₅₀ value, alpha glycosidase (2.70 μM) and alpha-amylase (1.30 μM)	[77]

Dipeptidyl peptidase-4 (DPP-4) inhibitors

DPP-4 inhibitors are utilized in the management of type 2 DM. Recent studies have shown that DPP-4 inhibitors have positive renal and cardiovascular effects. Tablets, like sitagliptin, saxagliptin, and linagliptin, are regularly used in blended remedies with different antidiabetic medications, together with metformin or sodium-glucose co-transporters type 2 (SGLT2) inhibitors, for additional glucose control [78].

Mechanism of action

DPP-4, also known as adenosine deaminase complexing protein 2 (ADCP-2) or CD26, is a glycoprotein (110 kDa) expressed on the surface of various cells [79, 80]. Under normal physiologic conditions, food intake stimulates the production of glucagon-like peptide-1 (GLP-1), an incretin hormone that activates the GLP-1 receptor, a Gs protein-coupled receptor. This activation triggers adenyl cyclase, converting ATP into cAMP, which in turn stimulates insulin release. However, GLP-1 is rapidly degraded by the enzyme, DPP-4, which is on the vascular endothelium. To counteract this effect, DPP-4 inhibitors are administered to inhibit DPP-4, thereby prolonging GLP-1 activity and enhancing insulin secretion [81].

It has been observed that the phytoconstituents, cyanidin, cyanidin-3-glucoside, malvidin, luteolin, apigenin, quercetin, kaempferol, flavone, hesperetin, naringenin, eriocitrin, genistein, resveratrol, epigallocatechin gallate, gallic acid, caffeic acid, isoquercitrin, eriodictyol, hispidulin, rosmarinic acid, carnosol, and naringin, help reduce blood glucose levels by acting on the DPP-4 receptor (Figure 8) [82–86].

Figure 8 Marketed available drugs, phytoconstituents, and IC₅₀s.

Recent advances in DPP-4 and combination therapy

Recent advancements in DPP-4 inhibitors focus on enhanced combination treatments to achieve better glycemic control, while reducing side effects. DPP-4 inhibitors, which are known for extending GLP-1 activity to enhance insulin secretion and reduce glucagon levels, are often combined with other agents, such as metformin, SGLT-2 inhibitors, and other therapeutic moieties, as shown in Table 4; drugs under clinical trials are listed in Table 5. A 2024 pilot study confirmed that the combination of DPP-4 inhibitors with SGLT-2 inhibitors significantly decrease HbA1c levels while improving physical function in patients with type 2 DM. This dual approach is particularly beneficial for patients at risk for cardiovascular disease. Additionally, recent meta-analyses indicated that combining DPP-4 inhibitors with metformin yields superior glycemic control compared to monotherapy because the combination enhances GLP-1 concentrations more effectively than DPP-4 inhibitor monotherapy [87]. A 2024 consensus paper further supports the use of DPP-4 inhibitors with metformin and/or SGLT-2 inhibitors due to the complementary mechanisms of action [88]. Furthermore, several DPP-4 inhibitors, such as dutogliptin and gosogliptin, are currently under clinical trials (Table 5), and have demonstrated promising potency (IC₅₀ values) and therapeutic efficacy. These emerging agents are expected to expand the existing options for combination therapy in the management of type 2 DM. Notably, combination therapies with SGLT-2 inhibitors also support cardiovascular and renal health, which are critical for managing DM-related complications. However, current guidelines suggest considering individual patient profiles to optimize DPP-4 therapy choices because of the efficacy in reducing mortality is limited [89].

Table 4 Recent Synthesized DPP-4 and the Combination Moiety

S.No	Combination	Result	References
1	Purine	Reduce fasting hyperglycemia value by 24%.	[90]
2	Triazole	Inhibitory activity of DDP-4 with IC₅₀ of 14.75nM	[91]
3	Xanthine	Percentage inhibition at 100 nM (78.53%) and IC₅₀ (16.34 nM)	[92]
4	Piperazine	IC₅₀, 0.75 nM	[93]
5	Thiourea	IC₅₀, 2.53 nM	[94]
6	Succinimide Thiazolidine	IC₅₀, 4.22 nM	[95]

Table 5 Drugs under Clinical Trials that act on the DPP-4 Receptor

Clinical trial
Vildagliptin [113]	Approved in Europe	110.95 μg/mL [96] or 62 nM [97]
MK-3102 (Omarigliptin) [113]	Approved in Japan	1.6 nM [98]
Gemigliptin [113]	Approved in Korea	6.31 nM [99]
SYR-472 (Trelagliptin) [113]	Approved in Japan	4 nM [100]
Anagliptin [113]	Approved in Japan	3.8 nM [101]
Teneligliptin [113]	Approved in Japan and Korea	1 nM [102]
Dutogliptin [113]	Phase 3	25 nM [103]
Gosogliptin [113]	Phase 3	0.013 nM [103]
DA-1229 (Evogliptin) [113]	Phase 3	7.5 nM [104]

GLUT4

Glucose transporters (GLUT4) are transmembrane proteins that transport across the cell membrane. GLUT4 provide glucose entry into the skeletal and adipose tissue. This process is achieved through insulin-induced GLUT4 translocation, which increases the rate of glucose flux into a cell. The GLUT-4 receptor consists of 12 transmembrane domains with unique N- and C-terminal sequences that have a crucial role in insulin signaling and membrane trafficking. The primary function of GLUT-4 is to facilitate glucose transport across cell membranes by stimulating glucose uptake into muscle and adipose cells in response to insulin [105]. It has been observed that Capparis moon, Sophora alopecuroides, and Gundelia tournefortii exhibit antidiabetic effects through the GLUT-4 pathway [106].

Recent advances in GLUT4 and combination therapy

Recent research focuses on ways to enhance GLUT4 function or expression to improve insulin sensitivity in diabetic patients. Combination therapies that include agents, such as metformin, thiazolidinediones, or GLP-1 agonists (Table 6), have shown promise in boosting GLUT4 activity and improving glycemic control [107].

Table 6 Recently Synthesized GLUT4 and the Combination Moiety

S.No	Structure	Combination	Result	References
1		Indole	21.6 % reduction in blood glucose level	[108]
2		Phenoxy isobutyric	-50.1% maximal percentage of glycemic-lowering effect	[109]

Sodium-glucose co-transporter type 2 inhibitors (SGLT2is)

Sodium-glucose co-transporters (SGLTs) have a crucial role in glucose reabsorption in the kidneys and glucose absorption in the intestines. SGLT1 and SGLT2 belong to the SLC5A gene family, with SGLT2 (SLC5A2) predominantly expressed in the renal cortex. SGLT2 consists of approximately 670 amino acids arranged into 14 transmembrane helices, 10 of which are responsible for glucose and sodium binding [110]. The inhibitory activity of SGLT2 inhibitors is influenced by hydrogen substitution on the glucose moiety. The presence of a bulky benzene ring negatively affects activity due to steric hindrance, whereas a hydrogen bond donor group at the para position of the benzene ring is attached to the sugar moiety enhances activity. Additionally, hydrogen bond donor groups at various positions on the sugar moiety are essential for improving SGLT2 inhibitory action, as illustrated in Figure 9.

Figure 9 Key features identified through a 3D-QSAR study for the design of novel molecules as SGLT2 inhibitors.

SGLT2 inhibitors share a common oxane-3,4,5-triol moiety with different substitutions at the 4th carbon of the oxane ring. For example, canagliflozin contains fluorophenyl, thiophene, and methyl phenyl substitutions, while dapagliflozin, empagliflozin, and ipragliflozin feature ethoxyphenyl, oxyphenyl, and benzothiophene substitutions. Other drugs in this category include ertugliflozin and luseogliflozin, as shown in Figure 10. Despite the benefits in reducing glucose reabsorption, SGLT2 inhibitors have side effects. SGLT2 inhibitors may cause changes in the genital area by increasing moisture levels, which when combined with higher glucose concentrations in genital secretions, creates an environment conducive to yeast growth. This effect increases the risk of genital tract infections, particularly fungal infections, such as yeast infections [111, 112].

Figure 10 Marketed available drugs, phytoconstituents, and IC₅₀s.

Mechanism of action

SGLT2 inhibitors function by promoting glycosuria, thereby effectively lowering blood glucose levels. These inhibitors target the SGLT2 protein in the renal proximal tubules, which is responsible for reabsorbing approximately 90% of filtered glucose. By blocking SGLT2, these drugs reduce renal glucose reabsorption, leading to increased glucose excretion through urine and a subsequent decrease in blood glucose levels [113]. Beyond the glucose-lowering effects, SGLT2 inhibitors also provide therapeutic benefits in managing DM-related complications, such as nephropathy and retinopathy [114].

Additionally, some phytoconstituents have been shown to act on the SGLT2 receptor and contribute to reducing blood glucose levels. These phytoconstituents include kurarinone, sophoraflavanone, maackiain, variabilin, formononetin, pterocarpin, aceroside VII, 10-methoxy-N(1)-methylburnamine, 17-O-veratrate, alstiphyllanine D, (+)-pteryxin, and quinidine (Figure 11) [115–118].

Figure 11 Advances in antidiabetic receptors throughout from 2020–2024 [139, 140].

Recent advances in SGLT2is and combination therapy

Recent advances in SGLUT2 inhibitors for management of DM emphasize that combination therapies, especially with drugs, like GLP-1 receptor agonists and metformin.

SGLT2 inhibitor and GLP-1 receptor agonist combination therapy has become a viable treatment strategy because these medications work through complementary mechanisms. SGLT2 inhibitors reduce blood glucose and improve cardiovascular outcomes, while GLP-1 agonists enhance insulin secretion and promote weight loss. Recent studies have shown that this dual therapy may reduce major cardiovascular events, heart failure hospitalizations, and overall mortality in diabetic patients with cardiovascular disease. Other studies have shown that combining SGLT2is with other potent moieties enhances effectiveness (Tables 7 and 8 show drugs under clinical trials) [119, 120].

Table 7 Recenlyt Synthesized SGLT2i and the Combination Moiety

S.No	Structure	Combination	Result	References
1	A. B. C.	Empagliflozin Dapagliflozin Canagliflozin	A. IC₅₀, 2.0 nM B. IC₅₀, 2.6 nM C. IC₅₀, 2.5 nM	[121]
2		D-glucopyranosyl	IC₅₀, 3.50 μM	[122]
3		Glycosidase	IC₅₀, 0.460 μM	[123]
4		Glycosidase	IC₅₀, 436 nM	[124]

Table 8 Synthetics, Phytoconstituents, and Drugs under Clinical Trials that Act on SGLT2

Clinical trial
Pioglitazone [125]	Phase 4 Usually administered in combination with metformin, glimepiride, and alogliptin [126]	60.16 μg/mL
Tofogliflozin (Developed by Chugai Pharmaceutica and approved in Japan) [127, 128]	Phase 3	4.5 nM
Remogliflozin Etabonate [129]	Phase IIb	43 and 39 μM

G protein-coupled receptor (GPCR)

GPCRs have a critical role in regulating insulin secretion and maintaining pancreatic beta cell function, making GPCRs essential in the management of type 2 DM. For example, the GLP-1 receptor helps stimulate insulin release from pancreatic beta cells and drugs that target this receptor have become a key treatment option for T2D [130].

Mechanism of action

GLP-1 is activated by the beta cell surface, leading to conformational changes in the receptor that are unable to interact with the intracellular G proteins. GPCR enhances insulin exocytosis through this pathway, the process by which insulin is released from beta cells into the bloodstream, thereby lowering blood glucose levels after meals. Additionally, GPCR kinases (GRKs) and beta cell arrest help regulate the activity of these receptors by promoting receptor internalization and recycling. This regulation is essential to prevent beta-cell stress and overactivation, which can contribute to cell damage over time. Apart from aiding insulin release, GPCR signaling also supports beta-cell health by activating pathways that prevent apoptosis and promote cell growth. This effect helps sustain an adequate beta-cell mass for insulin production, which is critical for long-term glucose control [77].

Recent advances in GPCR and combination therapy

New therapeutic strategies involving GPCR agonists, especially incretin-based therapies, such as GLP-1 and GIP receptor agonists, have shown promising results in managing glucose levels and improving metabolic health by supporting β-cell functionality. Emerging dual therapies that act on multiple GPCR targets simultaneously, such as combining GLP-1 with glucagon or GIP, have demonstrated enhanced efficacy in glucose control and cardiovascular health. These combination approaches show potential, not only in glycemic management, but also in reducing risks of complications linked to cardiovascular and kidney health, addressing broader aspects of metabolic disease. GPCR-targeted therapies are thus gaining traction as a foundation for DM treatment strategies that offer metabolic benefits beyond traditional therapies (Table 9) [131, 132].

Table 9 Recently Synthesized GPCR and the Combination Moiety

S.No	Structure	Combination	Result	References
1		Thiazolidine	EC₅₀ (43nM) and E_max (160%)	[133]
2		TUG-891 derivative	EC₅₀, 37.5 nM	[134]
3		Lysophosphatidylcholine with anisic acid derivative	Acts as an antagonist of GPR40, GPR55, and GPR119, and increases insulin secretion up to X-fold	[135]
4	CPL207280 (Novel GPR40/free fatty acid receptor)	–	EC₅₀ (270 nM) and stimulates insulin secretion 3.9-fold	[136]
5		Barbiturates	Increases GPR40 expression by 7-fold	[137]
6		Phenoxyacetic derivative	Increases GLUT4 expression 7-fold	[138]
7		Imidazo- pyridine	EC₅₀, 47 nM	[139]

Discussion

Recent evidence and ongoing research across various classes of antidiabetic agents, including sulfonylureas, biguanides, PPARγ agonists, and DPP-4 inhibitors, underscore the complexity of achieving optimal glycemic control while mitigating cardiovascular and renal risks. Synthesizing recent progress and identifying future research priorities is crucial for developing more effective and personalized therapeutic strategies. Sulfonylureas, while effective in stimulating insulin release, may not offer significant cardiovascular benefits and are associated with an increased risk of hypoglycemia, highlighting the need for caution and careful patient selection. Biguanides, particularly metformin, have demonstrated a cardioprotective effect by reducing the risk of myocardial infarction by 30% compared to sulfonylureas and offering renal benefits. However, the efficacy of biguanides may vary among different patient populations, emphasizing the importance of personalized treatment approaches. PPARγ agonists, including pan-PPAR agonists, have emerged as promising therapeutic targets due to the ability to improve insulin sensitivity, regulate lipid metabolism, and modulate inflammatory responses. However, challenges remain in minimizing adverse effects, such as weight gain and fluid retention. Selective PPARγ modulators (SPPARMs) and combination therapies with other antidiabetic agents offer potential solutions to enhance efficacy while reducing cardiovascular risks. DPP-4 inhibitors enhance incretin levels, leading to improved insulin secretion and glucose homeostasis. Studies have suggested that combining DPP-4 inhibitors with SGLT2 inhibitors yields better glycemic control and cardiovascular protection. Emerging DPP-4 inhibitors under clinical trials may expand therapeutic options, but careful patient profiling is necessary due to limitations in mortality reduction. Despite these advances, significant gaps persist. The cardiovascular benefits of SGLT2 inhibitors vary based on heart failure status and metformin cardioprotection differs between obese and lean patients. Long-term safety concerns, such as hypoglycemia with sulfonylureas and vitamin B12 deficiency with metformin, warrant careful monitoring.

In addition to the well-established receptors involved in management of DM, several other receptors have emerged as potential targets for regulating blood glucose levels. One such target is the neurokinin 2 receptor (NK2R). NK2R agonists have shown promise as potential treatments for type 2 DM and obesity. These agonists reduce appetite, enhance energy expenditure, and improve insulin sensitivity. Studies utilizing hyperinsulinemic-euglycemic clamp techniques have demonstrated that NK2R activation acutely enhances insulin sensitivity [141]. Another promising target is TGR5, a bile acid receptor belonging to the G-protein-coupled receptor (GPCR) superfamily. TGR5 has a crucial role in regulating blood glucose levels through mechanisms, such as stimulating insulin secretion from pancreatic beta cells and promoting energy expenditure. Activation of TGR5 has demonstrated beneficial effects on glucose metabolism, making TGR5 a compelling target for the development of novel treatments for type 2 DM. By improving insulin secretion and enhancing energy homeostasis, TGR5 activation offers a promising strategy for managing type 2 diabetes [142].

In conclusion, the landscape of DM management is shifting towards a more holistic approach that prioritizes prevention of complications with glycemic control. While current therapies offer various benefits, ongoing research is essential to optimize treatment strategies and develop new agents that provide comprehensive protection against cardiovascular and renal complications. Personalized therapy, informed by large-scale trials comparing outcomes across drug classes, will be crucial for improving patient outcomes and reducing the burden of type 2 DM and associated complications.

Limitation

The receptors mentioned herein have limitations that need to be considered while targeting the specific receptor, such as sulfonylureas. While effective in stimulating insulin secretion, sulfonylureas carry a significant risk of hypoglycemia, weight gain, and beta-cell exhaustion with limited long-term cardiovascular benefits. Biguanides, like metformin, can cause gastrointestinal discomfort and are contraindicated in patients with renal impairment due to the risk of lactic acidosis, with limited efficacy in severe insulin deficiency. PPARγ agonists improve insulin sensitivity but are associated with weight gain, fluid retention, bone fractures, and potential cardiovascular risks. Alpha-glucosidase inhibitors, such as acarbose, are limited by frequent gastrointestinal side effects and modest efficacy in reducing HbA1c. DPP-4 inhibitors provide modest glucose-lowering effects and carry rare risks of pancreatitis and joint pain without significant weight loss benefits. GLUT4 dysfunction remains challenging because no direct activators exist, limiting the therapeutic potential. SGLT2 inhibitors effectively lower blood glucose but increase the risk of genital and urinary infections, dehydration, and rare cases of euglycemic diabetic ketoacidosis with reduced efficacy in advanced renal impairment. G-protein-coupled receptors, including TGR5, are promising but face challenges, such as off-target effects, limited clinical data, and potential unintended side effects due to the widespread presence of GPCRs in the body.

Conclusion and future scope

The current study underscores the complexity of blood glucose management in DM, highlighting the crucial roles of various pathways, from sulfonylureas to GPCR inhibitors. Given the chronic nature and increasing prevalence of DM, it is imperative to develop therapies that effectively target specific receptors associated with glucose management. We have studied different pathways and receptors that help maintain the blood glucose level and compiled all the recently synthesized derivatives from 2020–2024, which act on each receptor and show the improved potency of the medication. Future research should focus on combination therapy to enhance receptor specificity and improve target interactions. Furthermore, computational studies and pharmacophore modeling should be prioritized to design more selective and potent inhibitors. These approaches can help identify key molecular features required for receptor binding, optimizing drug-target interactions, and minimizing off-target effects. By integrating advanced computational techniques, such as molecular docking, QSAR, and AI-driven drug discovery, researchers can develop more precise and efficient therapeutic agents for diabetes management.

Acknowledgments

This work was funded under a seed money grant from Uttaranchal University (UU/DRI/SM/2024-25/017).

Consent for publication

None.

Statement on conflicts of interest

No conflicts of interest.

Graphical abstract

Highlights

Diabetes mellitus is a systemic metabolic disorder impacting key organs, such as the heart, kidney, and eyes.
KATP, AMPK, GLUT4, PPARγ, DPP-4, and SGLT2 are central targets in glucose regulation.
Sulfonylurea, biguanides, and alpha-glucosidase inhibitors show promise in combination therapy.
Novel targets such as NK2R and TGR5 are emerging in diabetes research.
Challenges include hypoglycemia risk, renal limitation, and cardiovascular side effects.

In brief

Recent advancement in diabetes therapy focuses on targeting multiple receptors and pathways to improve glucose regulation. Key mechanisms include sulfonylurea, biguanides, PPARγ agonists, DPP-4 inhibitors, and SGLT2 inhibitors. Novel compounds and combination therapies show promise in enhancing insulin sensitivity and glycemic control. Despite these strides, challenges like hypoglycemia risk, cardiovascular safety, and personalized treatment remain central to optimizing diabetes management.

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