INTRODUCTION

Nuclear receptors (NRs) have advanced remarkably in modern biomedical research and drug discovery (Mazaira et al., 2018). Hollenberg et al. (1985) first discovered NRs as the receptors of the most familiar hormones, including 17β-estradiol, and corticosteroids/thyroid hormone (TH) (Holzer et al., 2017). NRs play a significant role in physiological processes such as metabolism, osmoregulation, cell growth, immune response, enzymatic activities, development, and reproduction. The NRs superfamily comprises over 500 members and approximately 50 transcription factors (Alexander et al., 2017; Burris et al., 2013). NRs are an essential component of cellular physiology, which has attracted pharmaceutical interest. They serve as a target to treat diseases such as cancer, diabetes, inflammation, atherosclerosis, and endocrine disorders (Alexander et al., 2017; Burris et al., 2013). For example, estrogen receptors (ERs) antagonists treat breast cancer. Also, peroxisome proliferator-proliferator receptors (PPARs) agonists treat type 2 diabetes mellitus (T2DM) and hyperlipidemia. Furthermore, the role of NRs in the circadian rhythm, cholesterol transport, and autoimmune disorders has taken utmost significance in treating infectious diseases (Khorasanizadeh and Rastinejad, 2016; Leopold Wager et al., 2019).

NRs allow bone cells, such as osteoblasts, osteoclasts, and osteocytes, to sense their dynamic nature and respond to the development of bones and remodeling. Deficiency in specific NRs ligands can lead to bone loss; for example, estrogen loss in postmenopausal women can cause osteoporosis and increase the risk of bone fracture. On the other hand, glucocorticoids (GCs) could hamper one’s health (Zuo and Wan, 2017). NRs classically act in three steps, i) repression, ii) derepression, and iii) transcriptional activation (Robinson-Rechavi et al., 2003). The binding of NRs hormone to specific DNA sequences, termed hormone response elements (HRE), is responsible for the abovementioned functions (Escriva et al., 2000). A significant objective of ongoing medication advancement programs has been to deliver ligands that display agonist or antagonist activity in the tissue in a receptor-particular way. The point is to lessen adverse reactions and, on account of certain malignant growths (Robinson-Rechavi et al., 2003). NRs require multiple protein-protein interactions to regulate their target gene expression (Robinson-Rechavi et al., 2003). Hence, the engagement with co-regulators offers functional flexibility to NRs (McKenna and O’Malley, 2002).

NR CLASSIFICATION

NRs were grouped into three subfamilies based on their DNA-binding properties (Laudet et al., 1992). Later, in 2004, it was divided into four subfamilies based on their DNA-binding properties and heterodimer priorities (Novac and Heinzel, 2004; Porter et al., 2019). These are class I-steroid hormone receptors that primarily form ligand-induced homodimers. Receptors belonging to class I bind to DNA target sequences arranged in inverted repeats or palindromes. The second class (class II) is retinoid X receptors (RXRs) and thyroid receptors (TRs). The receptor belongs to class II heterodimerized and binds to symmetrical response elements. The third class (class III) is homodimerized and binds primarily to direct repeats. The fourth class (class IV) attaches to the core site of DNA as monomers (Novac and Heinzel, 2004; Porter et al., 2019). In addition to this, based on the amino acid and dipeptide composition, NR classification has also been further designed into TH (TR, RAR, ROR), HNF4-like (HNF4, RXR, TLL, Coup, USP), Fushi tarazu-F1 like (SFI, FTF, FTZ-F1), and estrogen-like [ER, ERR, GC receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR)] (Bhasin and Raghava, 2004). To date, the most acceptable one is the classification that classified NR into seven subfamilies. This classification numbered NR from zero to six based on the endogenous ligands that bind to specific receptors (Weikum et al., 2018).

OVERVIEW OF NR’S STRUCTURE

The general structure of NRs comprises five domains. These are the N-terminal domain (NTD), also known as the A/B domain, the DNA binding domain (DBD) or C domain, the hinge region (HRe) or D domain, the ligand-binding domain (LBD) or E domain, and the C-terminal domain (CTD) or F domain (Fig. 1) (Porter et al., 2019). These domains play a vital role in receptor biology. NRs mass might vary but generally between 66 and 100 kDa (Weikum et al., 2018). Unlike DBD, NTD is a highly variable region and least conserved in size and sequence. The NTD contains the activation function (AF) regions (Weikum et al., 2018). These AF regions are responsible for transcriptional activation. AF is transcriptionally active and mediates ligand-independent activation function-1 (AF-1). AF-1 is the term used to distinguish them from the well-known AF-2 domain found at the C terminus of LBD. The AF-1 region can initiate transcription independent of LBD or synergize with the AF-2 (ligand-dependent) region to produce maximal receptor function (Onate et al., 1998). AF-1 is a poorly structured activation domain that belongs to a broad category of intrinsically active compared to AF-2 (Almlöf et al., 1998, 1997). The NTD region completely lacks conservation within the NRs subfamilies: PPARs (PPARα, PPARβ, PPARγ), ERs (ERα and ERβ) / ERRs (ERRα, ERRβ, and ERRγ) suggesting the functional roles of the NTD is highly receptor-specific (Gadaleta and Magnani, 2013).

Figure 1. The general structure of NRs representing five domains. [Click here to view]

DBD is adjacent to NTD and is the central, most highly conserved domain of NRs (Gadaleta and Magnani, 2013). DBD also has conserved zinc fingers that are accountable for binding to cognate HRE (Zhang et al., 2004). Additionally, zinc fingers within the DBD are responsible for setting NRs apart from other DNA-binding proteins (Mangelsdorf et al., 1995) and interacting with histone deacetylases 3 and 4 (Franco et al., 2003). Zinc fingers contain a carboxy-terminal extension that provides DNA response elements and protein binding interfaces (Hart, 2002). Zinc finger motifs permit the specific recognition of short, imperfect inverted repeats of DNA (for steroid receptors) or direct repeats (for RXR-heterodimeric receptors) (Weatherman et al., 1999). According to nuclear magnetic resonance and crystallographic research, four invariable cysteines in each zinc finger organize tetrahedrally on zinc ions. Both zinc finger modules fold together to produce a compact and interdependent structure. Zinc fingers contain the “P box” and “D box.” These boxes are required to dimerize and discriminate core DNA recognition motifs. They are also responsible for direct interaction and binding specificity (Aranda and Pascual, 2001). The antiquated relationship between LBD and DBD has been demonstrated to be a profoundly influential association (Mangelsdorf et al., 1995). DBD is required for gene activation, while other molecular regions in the carboxyl and amino terminus enhance its AF (Carson-Jurica et al., 1990). DBD interacts with DNA sequences that are palindromic or direct repeats (six nucleotide segments in different configurations) or response elements (Fernandez, 2018).

LBD, the third region of NRs, was discovered in 1995 and contained -300 amino acids (Bain et al., 2007). This region shows diversity in sequence but exhibits certain similarities in its overall design. This region functions in a ligand-specific manner (Mahajan and Samuels, 2000). Generally, LBDs are 12α helices arranged in a three-layered antiparallel sandwich (van der Vaart and Schaaf, 2009). The “front” and “back” sheets are made up of helices that are parallel to one another. The middle sheet of helices runs across the two outer sheets and only takes up space in the domain’s upper half. The lower section of the domain is relatively devoid of protein, which forms an internal cavity for small-molecule ligands in most NR LBDs (Franco et al., 2003). This domain is required for efficient homo/heterodimerization and interaction with transcriptional co-factors and components of the general transcriptional machinery (Uppenberg et al., 1998). In this region, mutational investigation of ERs led to the identification of activation function-2 (AF-2). AF-2 is a highly conserved subregion inside the LBD’s distal carboxyl terminus and is required for transcriptional activation (AF-2) (Glass et al., 1997). Many pharmaceutical companies are developing LBD ligands to limit or modify hormone-dependent processes such as infertility, bone loss, tumor, and skin diseases (Egner, 2002).

HRe is also known as the DBD’s C-terminal extension. This region has about 25 amino acids and has a low similarity and resemblance to other NRs (Pawlak et al., 2012; Tetel et al., 1997). It is flexible, least conserved, and vulnerable to protease cleavage. It connects or hinges between the DBD and LBD for proper DNA binding and dimerization (Haelens et al., 2007). HRe also plays a role in harboring nuclear localization signals and comprises residues that abolish NRs interaction with the NR compressor when the mutation occurs (Aranda and Pascual, 2001). Though this domain is regarded as a passive polypeptide linker in the initial stage, it is a hotspot for post-translational modifications that exert translocation, DNA binding, and transactivation (Weikum et al., 2018).

F domain or CTD is present at the C-terminus of ER alpha and beta but not in all the NRs. It is one of the least conserved regions and varies in size (19–80 residues) (Skafar and Zhao, 2008). Though varying in length, the F domain plays a common function by affecting the transcriptional activation, dimerization, interactions with other proteins, and stabilizing agonist or antagonist-bound conformations in the NRs LBD (Patel and Skafar, 2015). The LBD was the least conserved region among other domains. Alternative mRNA splicing has been reported to occur in this region, resulting in complete or partial loss of LBD. The formation of these splice variants further influences the canonical receptors by functioning as dominant-negative inhibitors (van der Vaart and Schaaf, 2009).

NRS AS DRUG TARGETS

Drugs targeting NRs are explored as therapeutic targets and are among the most widely and commercially successful. Tamoxifen and raloxifene for ERs in breast cancer, thiazolidinediones for PPARs in type 2 diabetes, mifepristone for PRs in ovulation, and dexamethasone for GRs in inflammatory disorders are a few examples (Burris et al., 2013; Rastinejad et al., 2013). A few drugs targeting NRs are Cytosporone B, 6-mercaptopurine, Celastrol, and Amoitone B. These compounds have been reported to possess antitumor properties in-vitro and in-vivo (Zhang et al., 2018). In their study, Bertilsson et al. (1998)have shown that the search for other unknown/unexplored NR could be discovered using a few standard methods, viz., PCR or yeast two-hybrid interactions. Their findings demonstrated an hidden markov model (HMM) profile-based search strategy for identifying novel orphan NRs in expressed sequence tag databases. Using this technology, the authors discovered a previously unknown human NR called hPAR, which is effectively triggered by a group of pregnanes and a group of clinically used drugs known to stimulate the activation of human CYP3A enzymes selectively. As a result, it was concluded that hPAR would most likely intervene in a novel signal pathway important for CYP3A gene expression regulation, with possible implications for the therapeutic evaluation of drug reactions that are beneficial to humans (Bertilsson et al. 1998).

NRs play a significant role in the gut’s intestinal functions like absorption of nutrients and transport, water secretion/absorption, and gut-to-liver communication and regulation of the gut microbiome (Ning et al., 2019). Recently, several members of NRs have been validated as a therapeutic target in patients with IBD regulating gut physiology that is ERβ, GR, FXR, PPARγ, PXR, RARα, vitamin D receptor (VDR), HNF4α, or NR2F6 (Klepsch et al., 2019). In line with this, a study on mice deficient in NR2f6 was reported to be highly susceptible to dextran sodium sulfate-induced colitis characterized by the increased loss of weight, colonic tissue destruction, and immune cell infiltration. Taken together, NR2f6 alters intestinal permeability and decreases Muc2 expression (Klepsch et al., 2018). Similarly, the deletion of VDR in mice exaggerates colitis and colon tumorigenesis (Takada and Makishima, 2016). Interestingly, scientists have extended the role of AR from prostate cancer to T2DM. It has been demonstrated that AR deficiency in males is associated with T2DM and vice versa in females. The activation of AR in males has shown a beneficial effect in preventing T2DM. This is corroborated by preventing visceral fat accumulation and promoting insulin sensitivity in adipose tissue, skeletal muscle, and liver, regulating energy homeostasis in the liver and improving β-cell functions (Navarro et al., 2015).

DIABETES MELLITUS

According to WHO estimates from 2014, 422 million people worldwide have diabetes, with the majority living in low- and middle-income countries. According to WHO 2021, diabetes is accountable for 1.6 million mortality per year. Over the last 10 years, the number of incidents and the prevalence of diabetes has steadily increased. Type 1 diabetes mellitus (T1DM) affects 1.1 million children and adolescents aged 14–19 years, according to the International Diabetes Federation (IDF) report. Every year, over 4 million people die from chronic hyperglycemia. Additionally, it is expected that by 2025, India, China, and the United States will have the most significant percentage of diabetic patients (King et al., 1998). Diabetes is a group of metabolic diseases characterized by chronic hyperglycemia and glucose intolerance resulting from defects in insulin secretion, insulin action, or both (Kharroubi, 2015). Diabetes is a dangerous and potentially fatal disease marked by thirst, polyuria, blurred eyesight, and weight loss. The most severe clinical signs are ketoacidosis or a non-ketotic hyperosmolar condition, which can lead to dehydration and coma. Commonly, diabetes is categorized into T1DM, T2DM, gestational diabetes mellitus (GDM), prediabetes, and idiopathic diabetes. T1DM (due to autoimmune β-cell destruction, usually leading to total insulin deficiency) occurs at any age but most often happens in children and young adults. Family history plays a role, but only in about 10%–15% of people of this type (Gottlieb, 2004). T2DM is characterized by insulin resistance due to insulin secretory deficiency. GDM is diagnosed in the second or third trimester of pregnancy that is not overt diabetes before gestation. Prediabetes refers to blood glucose levels higher than usual but not yet high enough to be diagnosed as type 2 diabetes. In other words, prediabetes also refers to impaired fasting glucose, impaired glucose tolerance, or glycated hemoglobin (A1C) of 6.0%–6.4%. Although not everyone with prediabetes will develop type 2 diabetes, people are at a greater risk for developing diabetes and severe comorbidities (Gottlieb, 2004). Patients with idiopathic diabetes tend to have permanent insulinopenia and are also vulnerable to episodic ketoacidosis. A few cases with type 1 diabetes fall into this category (Zuo and Wan, 2017). Other types of diabetes, such as monogenic diabetes syndromes (like neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis, hemochromatosis), and drug-or chemical-induced diabetes (as with GCs, neuroleptics, HIV/AIDS treatment, or after organ transplantation) (Petersmann et al., 2018).

Of all the different forms of diabetes, T2DM is globally burdened and rapidly increasing, affecting people of all ages (Al-Rifai et al., 2019). It is reported that 90%–95% of patients suffer from T2DM (Galicia-Garcia et al., 2020). T2DM prevalence in the adult population has nearly doubled in the last decade, from 4.7% in 1980 to 8.5% in 2014. The global burden of T2DM in adults aged 20–79 is expected to go up to 629 million in 2045 (Al-Rifai et al., 2019). In the UK, the prevalence of T2DM was estimated at 4.5 million in 2016. According to audits, males are more likely to get T2DM than females, with men contributing to 56% of all adult diabetics. T2DM is linked with pancreatic, liver, and kidney cancer (Man Chu, 2018). According to the IDF, 415 million people worldwide have diabetes, with 91% suffering from T2DM. Those with diabetes have a greater cardiovascular disease (CVD) prevalence rate than adults without diabetes. T2DM can shorten life expectancy by up to 10 years. Other studies (Einarson et al., 2018) found that, along with rising T2DM incidence, the associated risk of CVD due to T2DM increased from 5.4% in 1952–1974 to 8.7% between 1975 and 1998 in the Framingham Heart Study (Einarson et al., 2018).

T2DM is also called non–insulin-dependent diabetes/type 2 diabetes/adult-onset diabetes. Patients suffering from this type are resistant to insulin, have relative (rather than absolute) insulin deficiency, and do not need insulin treatment to survive. There are probably several causes of this kind of diabetes (Galicia-Garcia et al., 2020). Although the specific etiology of T2DM is unknown, most people suffering from T2DM are obese. These patients develop insulin resistance in the peripheral tissues, hyperglycemia, and ketoacidosis (rarely occurring). In addition to obesity, other risk factors are age, women having a history of GDM, and also in people with hypertension and dyslipidemia. Patients suffering from T2DM are also associated with cognition and moderate cognitive impairment. Altogether, T2DM impairs cerebral health, structural rigidity, and brain activity (Tiwari and Kumar, 2018). T2DM undergoes undiagnosed for several years because the hyperglycemia develops slowly and, at the initial stages, is often not severe enough for the patient to observe any of the symptoms of diabetes.

Nonetheless, patients are at higher risk of macrovascular and microvascular complications. Macrovascular complications include cerebrovascular diseases (heart attacks, stroke, insufficient blood flow to legs) and peripheral vascular and cardiovascular disease. Microvascular complications include retinopathies (blindness), nephropathy, neuropathy with the incidence of ulcers in the foot, Charcot joints, amputation, and autonomic and sexual dysfunction. Insulin levels in individuals with this type of diabetes may appear normal or increased. As a result, insulin secretion in these people is impaired and is inadequate to counteract insulin sensitivity (Tiwari and Kumar, 2018).

Diabetes-related NRs

NRs are hormone-sensing transcription factors that convert changes in gene expression to nutritional or endocrine signals (Schupp and Lazar, 2010). Endogenous ligands for NRs include bile acids, phospholipids, steroid hormones, THs, retinoids, and vitamin D (Table 1) (Delerive et al., 2000; Schupp and Lazar, 2010).

The endogenous ligands of ERs are: estrone (E1), estradiol (E2), and estriol (E3) and have also been shown to bind diverse compounds with varying activity (Nelson and Habibi, 2013). ERα and ERβ are the most widely studied ERs. These receptors play a significant role in reproduction. They are expressed in other species, such as zebrafish and sea bream (Bardet et al., 2002). Both zebrafish (Menuet et al., 2002) and sea bream (Muñoz-Cueto et al., 1999) have receptors that are homologous to the human ERα (Green et al., 1986). AR endogenous ligands include testosterone and the more active form, dihydrotestosterone. Reproductive, immunologic, cardiovascular, musculoskeletal, neurological, and hemopoietic systems rely on AR for their development and maintenance (Davey and Grossmann, 2016). PRs are of two types: PRA and PRB. Both these receptors are activated in response to hormonal stimuli such as progesterone (Banner et al., 1992). Progesterone act on various tissues such as the uterus, mammary gland, brain, and bone and exerts diverse functions in these tissues (Graham and Clarke, 1997).

Bile acid is the endogenous ligand for FXR (Wang et al., 1999). FXR regulates bile acid and glucose metabolism, inflammatory reactions, barrier function, bacterial translocation prevention in the digestive organs (Ding et al., 2015), and cholesterol homeostasis (Wang et al., 1999). FXR also prevents cardiovascular risk factors such as central obesity, glucose intolerance, high cholesterol, and hypertension (Lefebvre et al., 2009). For VDRs, an endogenous ligand is 1,25-dihydroxy vitamin D₃ (1,25-(OH)₂D₃) (Teske et al., 2016). The activation of VDR initiates the autocrine and endocrine processes that are involved in gene expression and calcium absorption regulation (Heaney, 2008), the normal functioning of bones (Tanaka and Deluca, 1974), and the immune system (Haug et al., 1998).

Table 1. Few examples of NRs and their endogenous ligands. [Click here to view]

THR’s endogenous ligands include 3,5,3’,5’-tetraiodo-l-thyronine (T4) and 3,5,3’-triiodo-l-thyronine (T3). These hormones are vital for mammals’ average growth, development, and homeostasis. They also treat obesity, hyperlipidemia, depression, osteoporosis (Ye et al., 2003), cardiac diseases, and cancer. They also improve cognitive function (Brent, 2012), regulate skeletal growth (Kim and Mohan, 2013), and maintain adult brain function (Schroeder and Privalsky, 2014). While any dysfunction in this receptor, such as mutations, leads to resistance to THs, which further causes thyroid cancer, pituitary tumor, dwarfism, and metabolic abnormality (Cheng et al., 2010).

In mice, 9-cis-13,14-dihydroretinoic acid was reported to be the endogenous RXR ligand (Rühl et al., 2018). All-trans retinoic acid is the principal endogenous ligand for RAR. It is formed by the enzymatic oxidation of dietary vitamin A (di Martino and Welch, 2019). It is beneficial in treating osteoporosis, autoimmune disorders, asthma, cancer, diabetes, and obesity (Solt et al., 2010). From the experimental and clinical approach, it has been evidenced that vitamin A (retinol) and its active derivatives (i.e., the retinoids) exert various effects on vertebrate embryos. These effects include body shaping and organogenesis, tissue regeneration, cell growth, differentiation, apoptosis (Mark et al., 2009), visual functions (Kam et al., 2012), acute myeloid leukemia therapy (di Martino and Welch, 2019), and inflammation (Mihály et al., 2013). For REV-ERB, the endogenous ligand is haem/heme (Raghuram et al., 2007). Heme comprises an iron atom and a heterocyclic tetrapyrrole ring structure known as porphyrin. Several heme-containing proteins, such as hemoglobin, use this as a prosthetic group. Furthermore, the capacity of heme to organize an iron atom inside its structure and promote reduction-oxidation (redox) reactions is essential for the function of these proteins (Sawicki et al., 2015).

15d-PGJ2 appears to be a promising PPARγ endogenous ligand. Two linoleate derivatives, 9- and 13-HODEare possible PPARγ ligands among the oxidized lipids. OEA is an endogenous ligand with a higher affinity for PPARα (Lathion et al., 2006). Its primary role is discovered in many diseases such as adipogenesis and storage of fat and eventually obesity and associated metabolic diseases such as hypercholesterolemia, insulin sensitivity, T2DM; and cardiovascular disease including high blood pressure (Heikkinen et al., 2007), inflammation (Zieleniak et al., 2008), gastrointestinal cancer (Necela and Thompson, 2008), and suppress colon carcinogenesis (Thompson, 2007). LXR has two isoforms, LXRα and LXRβ. LXRα is predominantly found in the liver and gut, while LXRβ is found throughout the body. Endogenous ligands for LXR consist of cholesterol derivatives such as 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S)-25-epoxycholesterol. These ligands bind to both LXR isoforms and increase their transcriptional activity (Schulman, 2010). The involvement of NRs in diabetes has been studied since the discovery of PPAR agonists. Other NRs that act as potential targets for T2DM are discussed in Table 2.

Peroxisome proliferator-proliferator receptors

PPARs are the most widely studied NRs. PPAR subtypes, namely PPARα, γ, -β/δ, are members of the NR family that regulate glucose and lipid metabolism. PPARα agonist increases lipoprotein lipase activity and speeds up the process of β-oxidation (Wilding, 2012). Insulin sensitivity, blood pressure, and fatty acid (FA) uptake have all been demonstrated to improve when PPAR agonists are used (Ahmadian et al., 2013). When used alone, rosiglitazone, pioglitazone, and troglitazone have been found to cause obesity, bone resorption, heart failure, and bladder cancer (Ma et al., 2012). Troglitazone was also taken off the market due to its liver damage. However, using a dual PPAR agonist that activates PPARα and PPARγ has improved lipid profile and glycemic management. Remarkable, this dual activation displays fewer side effects. Such an approach has emerged as one of the most promising strategies for treating T2DM (Wei et al., 2013). Another approach includes a combination of PPAR agonists and dipeptidyl peptidase 4 (DPP4) inhibitors. This strategy improved glycemia by increasing the expression of insulin receptor substrate (IRS)-2 and protecting pancreatic β-cells (Hirukawa et al., 2015).

Table 2. NRs and potential ligands reported from preclinical studies for T2DM. [Click here to view]

Growing evidence shows that PPARγ activation in adipocytes makes a significant contribution to its insulin-sensitizing effects by repressing the release of insulin-desensitizing factors like non-esterified fatty acids (NEFAs), tumor necrosis factor-α, leptin, interleukin-6, and resistin, and stimulating the release of insulin-sensitizing factors like adiponectin and visfatin (Kanatani et al., 2007). Thiazolidinediones are progressively being demonstrated to reduce proteinuria and postpone the course of diabetic nephropathy, depending on or independent of glycemic management, in addition to their impact on insulin resistance and T2DM (Zheng and Guan, 2007). PPARγ has been linked to various renoprotective effects, including improved insulin resistance, reduced blood glucose, decreased rates of circulating NEFAs, and insulin-desensitizing cytokines, increased plasma adiponectin, lower blood pressure, and direct renal actions (Kollerits et al., 2007). Recently, intraperitoneal administration of sulfonylhydrazone derivative, LASSBio-1773, showed hypoglycemic efficacy in a streptozocin-induced diabetic pain model, lowering heat hyperalgesia and mechanical allodynia and demonstrating potential new targets in T2DM (Zapata-Sudo et al., 2016).

Estrogen receptors

ERs consist of mainly three isoforms, ERα, ERβ, and GPER1. Among these, ERβ has a crucial role in diabetes prevention. ERβ is involved in adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel blockade. This effect occurs through the induction of 17β-estradiol (E2) in ERα-/- and ERβ-/- mice. Similarly, agonist activation of ERβ by diarylpropionitrile (DPN) lowered the activity of K_ATP in a cGMP/PKG-dependent manner in β-cells of wild type (WT) but not in ERβ-/- mice. Consequently, this leads to increased glucose-induced intracellular calcium [Ca²⁺]_I signals and induced insulin release (Soriano et al., 2009). K_ATP channels are complexes formed by the hetero-octameric and co-assembly of four Kir6.2 subunits called pore-forming subunits and four sulfonylurea receptor1 (SUR1) subunits called regulatory subunits. KCNJ11 and ABCC8 are the genes that code for both these two subunits. K_ATP channels are crucial in physiological and pathophysiological states (Remedi and Nichols, 2016). K_ATP converts metabolic status into electrical activity and processes as a metabolic sensor by sensing the metabolic changes in the pancreatic β-cells. This event occurs due to K_ATP channel inhibition by ATP and activation by magnesium-ADP (Mg-ADP) (Szeto et al., 2018). In diabetes mellitus, where normal glucose oxidation and a rise in [ATP]:[ADP] ratio fails to take place, inhibition or reduction of K_ATP channels is necessary because this helps in membrane depolarization and is critical for voltage-dependent Ca²⁺ channels opening. This further allows calcium entry into the cells and increases [Ca²⁺] concentration. Consequently, this is essential for insulin vesicles-plasma membrane fusion and subsequent insulin release (Remedi and Nichols, 2016). Hence, selective ERβ agonists could help increase insulin release (Fig. 3). In contrast, in vivo study of postmenopausal (performed via bilateral ovariectomy) diabetes-induced vascular dysfunction (VD) in rats, selective ERβ agonists, and DPN did not show any improvement in impaired glycemia, VD, oxidative stress (OS), or inflammation (Bansal and Chopra, 2014).

Figure 2. Mechanism of action of LXRs in diabetes. [Click here to view]

Figure 3. Mechanism of action of ERs in diabetes. [Click here to view]

Vitamin D receptor

VDR is a nonsteroidal NR. VDR heterodimerized with retinoid X receptor to transcribe genes (Lei et al., 2020). Apart from immune cells, VDR is also found in the liver, muscle fibers, adipocytes, and islets of the pancreas and may improve insulin sensitivity upon activation. In both T1DM and T2DM models, it has been found that VDR expression is decreased, suggesting that a decrease in VDR expression is a potential risk for diabetes development (Morró et al., 2020). Recently, the potential role of VDR agonists and the bromodomain-containing protein 9 (BDCP9) inhibitor (iBDCP9) in partially restoring β-cell function and ameliorating hyperglycemia has been reported. The activation of VDR prevents the activities of inflammatory genes, while the use of iBDCP9 prolongs the activation and enhances the activity of VDR. In physiological condition and at the chromatin level, BDCP9 bind with acetylated lysine 91 residue of VDR and inhibit its activity (Wei et al., 2018). Further, mechanistic insight into the anti-inflammatory activity of VDR activation has been linked with the inhibition of inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) alpha (IκBα) kinase (IκK), a key signaling component of NF-κB. Consequently, this improves insulin sensitivity (Dong et al., 2020) and could be one of the mechanisms for preserving β-cells, reducing inflammation, and preventing Streptozotocin (STZ)-induced diabetes (Morró et al., 2020).

Figure 4. Mechanism of action of AR activation in diabetes. [Click here to view]

OTHER THERAPEUTIC TARGETS IN T2DM

Current T2DM treatments aim to increase pancreatic β-cell production and decrease insulin resistance. Other treatment includes lifestyle counseling, oral anti-hyperglycemic medications, and/or insulin secretion (Esther Chan et al., 2012). Currently approved therapies for T2DM are metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide1 (GLP-1) receptor agonists, DPP4 inhibitors, and sodium-glucose co-transporter-2 inhibitors. These therapies, in some cases, are ineffective in maintaining long-term glycemic control and display severe side effects. Problems related to sulfonylureas and meglitinides include loss of effectiveness, hypoglycemia, and weight gain. Also, metformin, alpha-glycosidase inhibitors, and GLP-1 receptor agonists have gastrointestinal side effects. At the same time, weight gain and heart failure are possible side effects of thiazolidinediones (Marín-Peñalver et al., 2016). A few examples of the targets for T2DM are discussed in Table 3.

G Protein-coupled receptors (GPCRs)

GPCRs are the most diverse and widely studied transmembrane receptors. These cell surface receptors are targeted for a wide range of diseases. In diabetes, these receptors may be divided into two main groups. One group increases insulin secretion and maintains β-cell mass; the other acts on adipose tissue and skeletal muscle. The second group contributes to glycogen storage and inhibiting glycogenolysis and gluconeogenesis in the liver. Other GPCRs are present in gastrointestinal enteroendocrine cells (GECs), the hypothalamus, and the gastrointestinal tract (GIT). These GPCRs are targeted to induce incretin secretion, decrease appetite, and reduce glucose after food intake (Atanes and Persaud, 2019). Of these, GPCRs that are targeting on induce incretin secretion have gained attention in recent times. A few examples of GPCRs targeting in diabetes are GLP1R, GIPR, GPR119, free FA receptor 1 (FFAR1) (GPR40), FFAR4 (GPR120), and the bile acid receptor GPBAR1 (TGR5). GLP1 analogs such as exenatide, lixisenatide, and liraglutide target GLP1 receptors, bromocriptine target dopamine D2 receptors, and pramlintide target calcitonin/RAMP receptors are at the forefront GPCRs that have been approved for the treatment of diabetes (Atanes and Persaud, 2019).

Table 3. Other molecular targets and potential ligands reported from preclinical studies for T2DM. [Click here to view]

CONCLUSION

T2DM is the most common type of diabetes, causing a global burden. Recently, it has been demonstrated that NRs deficiency, namely AR (in males), ERβ, LXR, VDR, REV-ERB A, PPAR, and NRs overexpression, PR, GR, and MR are associated with T2DM. Therefore, the activation of AR (in males), ERβ, and LXR and the inactivation of PR, GR, and MR could be a potential strategy for managing and treating T2DM. Several recent studies have shown great interest in AR activation for T2DM. These studies, however, focus on the uses of AR’s endogenous ligands, such as testosterone and Dihydrotestosterone (DHT). Particularly in men, the use of these agents is controversial because they are androgenic and could potentially promote prostate cancer development. Since AR activation is required in men with T2DM, the search for modulators that are cell-specific, non-steroidal, and non-androgenic is the need of the hour. For this reason, we are currently working on identifying selective AR modulators (SARMs) that are cell-specific. Importantly, we focus on plant-derived compounds because they offer fewer side effects. These compounds are currently under development for pancreatic β-cell regeneration since β-cell apoptosis has been reported in most cases of T2DM. Further, we are working on targeting pancreatic β-cell of the male population since clinical data on T2DM shows a positive correlation with androgen deficiency. The successful development of SARMs could revolutionize the harmful impact of T2DM on males.

ACKNOWLEDGEMENT

The authors would like to thank the Indian Council of Medical Research (ICMR), Department of Health Research-Ministry of Health and Family Welfare for supporting this project under the division “Senior Research Fellow” Award No- 2021-11508-F1. The authors would also like to thank the Department of Science and Technology—Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi, for their infrastructure support to our department.

AUTHOR CONTRIBUTION

Deepa initiated the conception, design, and data collection. Deepa also wrote and prepared the entire manuscript. Emdormi contributed to data collection, diagrammatic illustration, and manuscript preparation. Soumya contributed to data collection. Divakar contributed to manuscript suggestions and corrections. Divakar also contributed to proofreading the whole manuscript. All the authors approved the final manuscript for submission and publication.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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