Insights into Type 2 Diabetes Enzymes as Potential Drug Targets

Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.27 https://doi.org/10.5281/zenodo.17394107 Insights into Type 2 Diabetes Enzymes as Potential Drug Targets Anagha Balakrishnan1, Janvi Gajipara2, John J. Georrge1,2* 1 Department of Bioinformatics, University of North Bengal, District-Darjeeling, West Bengal-734013, India 2 Department of Bioinformatics, Christ College, Rajkot, Gujarat, India *Corresponding author: [email protected] Abstract: Type 2 diabetes (T2D) is a metabolic disorder caused by a deficiency in insulin release, function, or both. A rapid increase in the widespread presence of T2D is linked to environmental and lifestyle changes in addition to genetic susceptibility to diabetes. Present therapeutic options for T2D show reduced effectiveness, as they focus only on external factors like escalating insulin secretion or boosting insulin sensitivity. However, over time, these strategies led to progressive βcell dysfunction. Further, these strategies fail to address the underlying causes or complications associated with T2D, thus affecting all facets of the lives of diabetic patients. Hence, a comprehensive analysis of different proteins focusing on enzymes involved in the development of T2D is crucial. This study provides a deeper understanding of various enzymes by classifying them and examining the approved drugs used for treating T2D. In addition, the potentially druggable enzymes and their structural characteristics are also provided to identify more effective and novel therapeutic strategies for T2D than the conventional targets. Keywords: Type 2 diabetes, Metabolic disorder, βcell dysfunction, Enzymes, Therapy. 1. Introduction Type 2 diabetes (T2D) is a metabolic disorder identified by people with increased blood glucose levels attributable to deficiencies in insulin action or secretion. Diabetes happens when the pancreas cannot secrete sufficient insulin due to impairment in the incretin effect or insulin resistance (IR), where the insulin receptors are desensitised to insulin (Goldstein, 2002; Vilsbøll & Holst, 2004). These defects will eventually harm other organs or tissues in the body. The extent of people diagnosed with T2D has increased rapidly worldwide (Galicia-Garcia et al., 2020). The International Diabetes Federation (IDF) currently has 537 million people with diabetes. By 2045, this is expected to shoot to 783 million (Bergman et al., 2024; Sun et al., 2022). The prominent risk factors for developing T2D are age (Hillier & Pedula, 2003), sex (Kautzky-Willer et al., 2023), obesity (Chandrasekaran & Weiskirchen, 2024), low physical activity (Amanat et al., 2020), and heredity (Galicia-Garcia et al., 2020). It is also shown that environmental and lifestyle changes are major contributors to genetic susceptibility to diabetes (Franks et al., 2013). Diabetes is shown to be associated with developing severe complications, including cardiovascular diseases (Ma et al., 2022), diabetic neuropathy (Lu et al., 2020), diabetic nephropathy (Samsu, 2021), diabetic retinopathy (Bartoli et al., 2022; Lin et al., 2021), Diabetic Foot Disease (Edmonds et al., 2021), Hyperlipidemia (Stewart et al., 2020), NonAlcoholic Fatty Liver Disease (NAFLD) (Vetrano et al., 2023), and many more. The list of other complications of diabetes-associated diseases is depicted in Figure 1. This indicates the severity of the condition and the necessity of identifying novel therapeutic targets and treatments for the betterment of people's lives. Hence, in this chapter, we focus on the various enzymes as potent targets for curing type 2 diabetes. The current therapeutic strategies for T2D focus on escalating insulin secretion or boosting insulin sensitivity without addressing the underlying causes or complications associated with T2D. This has affected all facets of the lives of diabetic patients adversely. Furthermore, advanced medications targeting specific receptors involved in the root cause of Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.28 https://doi.org/10.5281/zenodo.17394107 the disease are often expensive, making them inaccessible for many patients in low-income settings (Butt, 2022; Nauck et al., 2021). These limitations emphasise the need for innovative approaches to treating T2D. Hence, in this study, we highlight the significance of enzymes from different classes and their structural features in contributing to the development of novel druggable targets in T2D. Figure 1: T2D-associated complications and comorbidities that underscore the importance of effective diabetes management. 2. Hormones are the cause of T2D. The insulin hormone is key in regulating blood glucose levels, which induces glucose absorption into the cells (Pfeifer et al., 1981). In T2D, the disease development is multifaceted, involving IR and a deficiency in insulin secretion. As the disease progresses, skeletal muscle and adipose tissues exhibit reduced insulin sensitivity (Goodpaster & Wolf, 2004). This means more insulin is required to increase glucose uptake and suppress hepatic glucose output. Factors such as obesity, chronic inflammation, and lipid accumulation in tissues commonly drive IR (Ahmed et al., 2021; Kahn & Flier, 2000; Turner et al., 2013; Wu & Ballantyne, 2020). To overcome this, the pancreas overproduces insulin, leading to hyperinsulinemia. This compensatory mechanism eventually fails because pancreatic beta cells are exhausted or dysfunctional, causing an insufficiency in insulin production (Kahn, 2003). This amalgamation of IR and βcell impairment is the hallmark of T2D. It contributes to persistent hyperglycemia, which may damage various organs or tissues if uncontrolled (Cantley & Ashcroft, 2015). In T2D, there is dysregulation of hormones such as glucagon, which promotes glucose production by the liver, further contributing to hyperglycemia and worsening the insulin-glucose imbalance (Hædersdal et al., 2023; Lundqvist et al., 2023). Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.29 https://doi.org/10.5281/zenodo.17394107 The incretin effect is key in maintaining postprandial glucose homeostasis through enhancing insulin release and modulating glucagon secretion. Dysfunction of the incretin effect contributes to T2D pathogenesis and progression (Nauck & Meier, 2016). Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the players involved in the incretin effect (Elahi et al., 1994; Seino & Yabe, 2013). By further inhibiting postprandial glucagon secretion, these hormones postpone stomach emptying and increase feelings of fullness (Holst et al., 2009; Phillips et al., 2015; Skytte et al., 2021). However, in the case of people with T2D, the incretin system is severely impaired. Scientific research suggests that secretion of GLP-1 is often decreased in T2D conditions. Whereas the secretion of GIP is maintained in T2D conditions, the β-cell responsiveness to GIP is grossly reduced, resulting in suboptimal insulin release and poor glycemic control (Kim & Lee, 2010; Nauck et al., 2004). Reduced incretin effect exacerbates hyperglycemia and contributes to progressive impairment of βcell (Fritsche et al., 2000). It creates a vicious cycle of chronic hyperglycemia, impairing the mechanism of incretin signalling over time and consequently contributing to this diabetic phenotype by intersecting with other metabolic derangements, such as increased hepatic glucose production and IR. Thus, incretin dysfunction contributes to T2D, with its pathophysiological contribution to disease onset, progression, and management (Drucker & Nauck, 2006). 3. Enzyme classification and approved drugs in T2D Enzymes play crucial roles in biological pathways, and their modulation can effectively alter disease progression. Classifying enzymes as novel drug targets is a key in drug discovery and development strategy. According to the International Union of Biochemistry and Molecular Biology (IUBMB), six classes are defined based on the chemical reactions the enzymes catalyse (McDonald & Tipton, 2023). These include oxidoreductases, which catalyse oxidation-reduction reactions by moving electrons or hydrogen atoms between molecules; transferases, which catalyse the movement of functional groups like methyl, glycosyl, or phosphate groups from one molecule to another; hydrolases, which catalyse the cleavage of bonds like ester, glycosidic, or peptide bonds by adding water; lyases, which break a variety of chemical bonds in ways other than hydrolysis or oxidation, frequently creating new double bonds or rings; isomerases, which catalyse intramolecular rearrangements, changing one isomer into another; and ligases, which join two molecules together using ATP or another highenergy molecule to drive the reaction. Enzymes catalysing the transport and separation of substances across membranes are included in the recently added class known as translocases (McDonald & Tipton, 2023). Each enzyme is given a specific classification number called the EC number, which indicates the type of enzyme based on its catalyzed reaction (McDonald et al., 2015). The systematic nomenclature thus helps one understand enzyme functions, research metabolic pathways, and create enzyme-based applications in biotechnology, medicine, and industry. Studies on enzymes have been implicated in developing inhibitors or drugs for treating various diseases (Nv et al., 2016; Patel et al., 2017). Enzymes are potential therapeutic targets in managing T2D. There are several approved drugs available targeting various enzymes involved in diabetes pathogenesis. These drugs can function by modulating pathways involved in glucose metabolism, insulin action, or hormone regulation. Below are some enzyme targets with their approved drugs to control hyperglycemia and other metabolic derangements in T2D. Dipeptidyl Peptidase-4 (DPP-4): This enzyme belongs to the hydrolases class in the peptidases (serine exopeptidases) subclass of enzymes. It catalyses the degradation of the incretin hormones required for the normal homeostasis of glucose (Mentlein, 2009). Approved drugs as DPP inhibitors include Sitagliptin, Saxagliptin, and Linagliptin, which inhibit the Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.30 https://doi.org/10.5281/zenodo.17394107 degradation of incretin hormones by DPP-4. This leads to a sustained incretin effect and aids in bringing the blood glucose level (Keller-Pintér et al., 2023; Soni et al., 2016). Alpha-Glucosidase: This enzyme also falls in the glycoside hydrolases class subclass. It is involved in the small intestine’s breakdown of carbohydrates into glucose. Thus, these are key enzymes in carbohydrate digestion and postprandial glucose spikes in the body (Lebovitz, 1997). Inhibitors such as acarbose and miglitol are designed to impede the action of the enzyme and aid in regulating the blood sugar spike after food intake (Ismail & Deshmukh, 2012). AMP-Activated Protein Kinase (AMPK): This enzyme belongs to the transferases class, kinase subclass. The activation of the AMPK enzyme enhances insulin sensitivity. It inhibits the skeletal muscle’s absorption and the liver’s synthesis of glucose by inhibiting gluconeogenesis (Fisher et al., 2002; Zhang et al., 2019). The most common drug in diabetes treatment, metformin, is also known to indirectly activate AMPK, contributing to its blood glucose homeostasis (Hasanvand, 2022). 4. Classification of Enzymes as Novel Drug Targets in T2D Enzymes are of prime importance in the pathophysiology of T2D and serve as novel drug targets for its treatment. They can be classified based on their functional involvement in glucose metabolism, insulin regulation, and associated pathways. Here, we provide some potential enzymes that can act as novel drug targets for treating diabetes, classified into different enzyme classes. 4.1 Hydrolases Lysophospholipase-like 1 (LYPLAL1): This enzyme is examined to have potential activity as a depalmitoylating enzyme, including its actions on substrates KCNMA1 (LargeConductance Calcium-Activated Potassium Channel Subunit Alpha-1, also known as BK or Maxi-K). KCNMA1 is a critical ion channel that regulates smooth muscle tone, neuronal excitability, and insulin secretion, among other physiological functions. Palmitoylation is a reversible addition of palmitic acid to cysteine residues. It is important for regulating KCNMA1 channel activity, trafficking, and membrane localisation (Chamberlain et al., 2021; Kim et al., 2014; Yeung et al., 2011). A distinctive α/β hydrolase fold of LYPLAL1 is shown in Figure 2a, which also contains the traditional catalytic triad of histidine, aspartate, and serine. A change in the loop and the nearby α-helix near Aspartin152 causes LYPLAL1 to block the hydrophobic tunnel required for accommodating the lipid part of acyl thioesterases. While this region has reduced conservation in the lysophospholipase subfamily, it is substantially conserved in the lysophospholipase-like subfamily. For this reason, LYPLAL1 does not have the structural framework required to degrade long-chain lipids in general and to delipidate big substrates such as palmitoylated proteins (Burger et al., 2012). Inositol Polyphosphate Phosphatase-like 1 (INPPL1): This is an enzyme involved in the hydrolysis of inositol phosphates, more especially the dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate (PIP3), an epochal component in insulin signalling (Eramo & Mitchell, 2016). Reduced insulin sensitivity and glucose metabolism brought on by overexpression or enhanced INPPL1 activity can result in IR and T2D. (Clément et al., 2001). The susceptibility to T2D increases with genetic variations in the INPPL1 gene (Marion et al., 2002). Targeting this enzyme is under investigation as a novel treatment approach to improve glucose homeostasis and insulin sensitivity in diabetes patients. Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.31 https://doi.org/10.5281/zenodo.17394107 The modular architecture of human INPPL1 contains an N-terminal SH2 domain, a catalytic inositol phosphatase domain, and a C-terminal proline-rich region. The 5-phosphate of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) is hydrolysed by the conserved catalytic core of the phosphatase domain, which transforms it into phosphatidylinositol (3,4)- bisphosphate (PIP2) (Prasad & Decker, 2005). The crystal structure of human INPPL1 is shown in Figure 2b. Figure 2: (a) Ribbon representation of the human Lysophospholipase-like 1 (LYPLAL1) structure (PDB ID: 3U0V) (b) Ribbon representation of the Inositol Polyphosphate Phosphatase-like 1 (INPPL1) structure (PDB ID: 3NR8) (c) Ribbon representation of the Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) structure (PDB ID: 7SH0) (d) Ribbon representation of the Prolidase structure (PDB ID: 2IW2). Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) is an enzyme involved in the peptide processing within the endoplasmic reticulum, specifically in regulating the antigen presentation pathway by MHC class I (López de Castro, 2018). Although its primary role is related to immunity, recent evidence has also shown that ERAP2 has a potential link to T2D through its involvement in inflammatory pathways. Variations in ERAP2 activity or expression may lead Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.32 https://doi.org/10.5281/zenodo.17394107 to increased inflammation and insulin signalling impairment, contributing to the advancement of T2D (Paldino & Fierabracci, 2023; Thomaidou et al., 2020). The structure of human ERAP2 reveals a zinc-dependent aminopeptidase with a typical four-domain architecture. It features a catalytic domain housing a zinc ion crucial for its enzymatic activity, supported by a metal coordination motif. ERAP2 adopts a closed conformation for processing the antigenic peptide substrates presented (Birtley et al., 2012). The structural image of ERAP2 is provided in Figure 2c. Prolidase, also known as peptidase D (PEPD), degrades proline-containing dipeptides, which play a crucial role in collagen turnover (Misiura & Miltyk, 2020). It is reported that PEPD serum levels are high in T2D conditions (Eren et al., 2013). Their role in the development of various health conditions in diabetic patients is well-recognized (Misiura & Miltyk, 2020). It can be considered a marker in osteoporosis in T2D (Erbağcı et al., 2002), diabetic neuropathy (Uzar et al., 2012), and diabetic nephropathy (Verma et al., 2014). The crystal structure of prolidase (Figure 2d) reveals a homodimeric enzyme with each monomer containing a manganese-dependent catalytic site essential for its activity. The active site comprises two manganese ions coordinated by conserved residues, enabling the hydrolysis of dipeptides with proline at the C-terminal. The enzyme adopts a TIM-barrel fold, optimising structural features for substrate binding and catalysis. It highlights its critical role in collagen metabolism and proline recycling (Wilk et al., 2017). ATPase Phospholipid Transporting 11A (ATP11A): This enzyme functions as a flippase and belongs to the P4-ATPase family. It facilitates the transfer of phosphatidylserine (PS) and phosphatidylethanolamine (PE), thus affecting the lipid composition of cellular membranes (Segawa et al., 2016). Thus, their activity can impact T2D since the lipid composition in insulin-responsive tissues causes the development of IR (Ansari et al., 2015; Baca et al., 2022; Pineau et al., 2021). Glucose-6-Phosphatase Catalytic Subunit 2 (G6PC2): It is an enzyme primarily expressed in the pancreas, regulating glucose homeostasis by controlling the conversion of glucose-6phosphate to glucose. This process is necessary to maintain blood glucose levels, particularly during fasting. G6PC2 regulates insulin secretion, modulating the glucose-sensing mechanism of pancreatic βcells (Hawes et al., 2024; van Schaftingen & Gerin, 2002). Variants of the G6PC2 gene have been associated with the progression of T2D (Bosma et al., 2020). Dysregulation of G6PC2 activity could lead to abnormal glucose production or inappropriate insulin secretion, impairing glucose tolerance and IR (Kumar et al., 2022; Zusi et al., 2021). Understanding the role of G6PC2 in glucose regulation may provide insight into how to manage T2D. 4.2 Lyases Adenylyl Cyclase 5 (ADCY5): This is an enzyme that converts ATP to cyclic AMP (cAMP), a critical second messenger involved in various cellular signalling processes (Pieroni et al., 1993). ADCY5 has been linked to insulin secretion and glucose metabolism (Sharp, 1979). Increased cAMP, resulting from increased ADCY5 activity, may increase insulin release from the pancreatic βcells (Wagner et al., 2011). However, the dysfunction of this pathway may cause β-cell dysfunction and contribute to IR. (Hodson et al., 2014). Genetic variants in ADCY5 predispose individuals to T2D, as alterations in the cAMP signalling pathway may lead to IR and glucose homeostasis (Guilherme et al., 2023; Khalid et al., 2021). Targeting Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.33 https://doi.org/10.5281/zenodo.17394107 ADCY5 or its downstream signalling pathways may be a therapeutic strategy to ameliorate IR and its sensitivity in patients with T2D. The ADCY5 comprises a membrane-bound architecture with two transmembrane domains, each containing six helices and two cytoplasmic catalytic domains. These catalytic domains form an active site where substrate binding and catalysis occur (Yen et al., 2024). The crystal structure of ADCY5 is shown in Figure 3. Oxidoreductase Ten-Eleven Translocation 2 (TET2): an oxidoreductase enzyme engaged in the regulation of DNA methylation through demethylation, converting 5-methylcytosine to 5-hydroxymethylcytosine (Ismail et al., 2020). TET2 has also been identified as a new candidate for regulating IR and βcell dysfunction in T2D. Altered DNA methylation patterns, primarily in genes encoding glucose metabolism and proinflammatory cytokines, appear to contribute to establishing IR, a key feature of T2D (Cai et al., 2024; Jaiswal et al., 2014). Impaired activity of TET2 could result in epigenetic alterations that would disrupt insulin signalling pathways or enhance chronic inflammation, both significant features of T2D pathogenesis (Davison et al., 2021). The catalytic domain of TET2 coordinates with Fe (II) and α-ketoglutarate for its reaction. The catalytic domain is formed by the double-stranded β helix (DSBH) and cysteine-rich domains brought together by two zinc fingers. These structural features aid TET2 in recognising the methylated cytosine and positioning it within the active site (Hu et al., 2013). Figure 4 displays the crystal structure of TET2. 4.3 Transferases B-lymphocyte kinase (BLK): A Protein tyrosine kinase implicated in signalling in immune cells, especially in B cells. It modulates B cell receptor signalling, impacting immunity and inflammation (Texido et al., 2000). It has been implicated that immune dysfunction and impaired inflammatory pathways lead to IR and βcell impairment (Donath et al., 2003; Szukiewicz, 2023). Hence, due to its function in inflammatory processes, BLK can be predicted to play a role in T2D pathogenesis (Kleinau, 2023; Samuelson et al., 2014). Investigation of BLK as a potential therapeutic target in T2D could offer new insights into managing inflammation and insulin sensitivity. Figure 3: Ribbon representation of Adenylyl Cyclase 5 (ADCY5) structure (PDB ID: 8SL4) Figure 4: Ribbon representation of Ten-Eleven Translocation 2 (TET2) structure. (PDB ID: 4NM6) Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.34 https://doi.org/10.5281/zenodo.17394107 Akt Serine/Threonine Kinase 2: This kinase enzyme is pivotal in the insulin transduction pathway. It balances glucose levels by mediating insulin-induced glucose absorption in tissues (Chen et al., 2020; Dummler et al., 2006; Khorami et al., 2015). Abnormalities of Akt2 are strongly associated with T2D (Elangeeb et al., 2023). Loss-of-function mutations impair insulin signalling, which leads to decreased glucose absorption and IR. On the other hand, hyperactivation of Akt2 may contribute to metabolic imbalances (Cimini et al., 2019; Miao et al., 2022). Hence, it is a chief player in glucose metabolism; it can be a promising therapeutic target for improving insulin sensitivity and managing T2D. The structural characteristics of an inactive Akt2 are shown in Figure 5. The kinase domain of Akt 2 is bilobal, with a gap in between. The smaller N-terminal lobe contains a twisted five-stranded antiparallel β sheet with one partially ordered α helix (αC). The larger C-terminal lobe is mostly α helical (Huang et al., 2003). These enzymes can thus act as potent drug targets in treating T2D. Developing drugs that can specifically modulate these enzymes can provide more precise, effective treatments with fewer side effects. Using advanced machine models and artificial intelligence in drug discovery can alleviate the time and cost of developing novel drugs. Natural products, including bioactive peptides, are an area of current interest due to their exceptional drug-like properties (Anagha et al., 2025). Several tools and databases are available for their identification and design processes. Hence, by integrating computational and structural biology, the drug discovery process can further advance the treatment of various diseases, including T2D. 5. Future Perspectives The classification of enzymes as drug targets in T2D has significant potential for advancing therapeutic strategies and addressing the multifaceted pathophysiology of the disease. Identification of enzymes as novel drug targets can have roles in major metabolic pathways, including glucose homeostasis, insulin signalling, lipid metabolism, and mitochondrial function (Tanvir et al., 2024; Zhao et al., 2023). Implementing high-throughput screening and computational approaches could be helpful in the discovery of novel peptide-based drugs or other biologics to modulate enzymatic activity with high specificity and low off-target effects (Balakrishnan et al., 2024; Son et al., 2024; Wu et al., 2023). Moreover, potential enzyme modulators could be more personalised for developing patient-specific treatment strategies (Singh et al., 2023). With the incorporation of different omics technologies, it may be possible to gain deeper insight into the dysregulation of enzymes in T2D and identify patient-specific therapeutic targets. Also, with advancements in artificial intelligence, the recognition of enzyme-drug interactions and the long-term outcomes of Figure 5: Ribbon representation of inactive Akt Serine/Threonine Kinase 2 structure (PDB ID: 1MRV) Recent Trends in Science and Technology-2024 Bioinformatics www.christcollegerajkot.edu.in, © Christ College, Rajkot, India ISBN: 9788197073274, Page No.35 https://doi.org/10.5281/zenodo.17394107 therapies can be predicted. Thus, knowledge about enzyme structure, function, and regulation will eventually lead not only to improved glycaemic control with enzyme-based therapies but also to addressing the actual causes of T2D, paving the way for more effective and durable therapies. 6. Conclusion The current therapeutic strategies for T2D possess several limitations, including reduced longterm efficacy, failure to address the underlying pathophysiology of the disease, and other complications developed due to prolonged diabetes conditions. These deficits point to an urgent need for new therapeutic approaches. Targeting enzymes that play important roles in metabolic regulation appears to be a promising approach to overcoming these challenges. Enzyme inhibitors such as DPP-4 and AMPK are crucial in the current treatment of T2D. Hence, by focusing on searching for other novel enzyme targets involved in T2D, it is possible to provide more precise, effective treatments with fewer side effects. This approach has the potential to be not only better for glycemic control. Still, it may also address broader metabolic dysfunctions associated with T2D. Studying enzyme-targeted therapies offers a pathway to more personalised treatments, which could improve patient outcomes. This could ultimately improve the quality of life of millions of individuals who have T2D. Such advances can revolutionise diabetes care, significantly contributing to public health and society. Funding None Data Availability Statement Not applicable. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethical approval Not applicable. References Ahmed, B., Sultana, R., & Greene, M. W. (2021). Adipose tissue and insulin resistance in obese. Biomedicine & Pharmacotherapy, 137, 111315. Amanat, S., Ghahri, S., Dianatinasab, A., Fararouei, M., & Dianatinasab, M. (2020). Exercise and type 2 diabetes. Physical Exercise for Human Health, 91-105. Anagha, B., Saurav Kumar, M., Kanchan, S., Chartha, G., & John, J. G. (2025). Intersecting Peptidomics and Bioactive Peptides in Drug Therapeutics. Current Bioinformatics, 20(2), 103-119. https://doi.org/http://dx.doi.org/10.2174/0115748936351054241010091822 Ansari, I.-u. H., Longacre, M. J., Paulusma, C. C., Stoker, S. W., Kendrick, M. A., & MacDonald, M. J. (2015). Characterisation of P4 ATPase Phospholipid Translocases (Flippases) in Human and Rat Pancreatic Beta Cells: THEIR GENE SILENCING INHIBITS INSULIN SECRETION *. Journal of Biological Chemistry, 290(38), 23110-23123. https://doi.org/10.1074/jbc.M115.655027 Baca, P., Barajas-Olmos, F., Mirzaeicheshmeh, E., Zerrweck, C., Guilbert, L., Sánchez, E. C., Flores-Huacuja, M., Villafán, R., Martínez-Hernández, A., & García-Ortiz, H. (2022). DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity. Nutrition & Diabetes, 12(1), 50. Balakrishnan, A., Mishra, S. K., & Georrge, J. J. (2024). Insight into Protein Engineering: From In silico Modelling to In vitro synthesis. Curr Pharm Des. https://doi.org/10.2174/0113816128349577240927071706 Bartoli, M., Abouhish, H., Jadeja, R., Martin, P. M., Elmasry, A., Georrge, J., Devkar, R., & Thounaojam, M. (2022). Anti-senescence properties of the flavone Silymarin in the diabetic retina involve direct inhibition