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Pharmaceuticals
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Antidiabetic Agents: New Drug Discovery Insights and Prospects
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Antidiabetic Agents: New Drug Discovery Insights and Prospects

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 May 2026 | Viewed by 2949

Special Issue Editor

Dr. Rosanna Maccari

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Guest Editor
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy
Interests: medicinal chemistry; drug design and discovery; structure–activity relationships; enzyme inhibitors; antidiabetic agents; anti-inflammatory agents; multitarget agents

Special Issue Information

Dear Colleagues,

Currently, about 10% of the world population suffers from diabetes mellitus (DM), and a dramatic increase in the number of diabetic patients is expected in the coming years. DM is a chronic disease characterized by hyperglycemia, due to tissue insulin resistance and/or insufficient insulin secretion. In the long term, hyperglycemia compromises various cellular functions and causes tissue damage, thus inducing the development of severe complications, such as retinopathy, nephropathy, neuropathies, and cardiovascular pathologies. Therefore, DM is one of the leading causes of death and disability worldwide, and growing attention is required to improve the treatment of this disease over a lifetime, considering the fact that currently available drugs can produce undesired side effects or limited efficacy in some patients. Novel insights into the molecular targets implicated in the complex pathogenesis of DM and its complications prompt drug discovery efforts aimed at the identification of new antidiabetic drugs. Moreover, multitarget agents could provide novel therapeutic options in place of antidiabetic drug combinations. This Special Issue aims to focus on recent advancements and prospects in the design and development of agents for treating DM and its complications. Original research papers, short communications, and review/perspective articles are welcome.

Dr. Rosanna Maccari
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diabetes mellitus
  • drug design
  • drug discovery
  • drug development
  • drug synthesis
  • computational-aided drug design
  • molecular targets
  • biological activity
  • structure–activity relationships

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Published Papers (3 papers)

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Research

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24 pages, 6691 KB  
Article
TAT-PBX1 Reverses Hyperglycemia Through β-Cell Regeneration and Functional Restoration in an STZ-Induced Diabetic Model
by Xiangyuan Meng, Zhenhu Zhao, Xin Zhang, Ruihan Guo, Shuran Yang, Shuhua Mao, Ziyu Zong and Jinyu Liu
Pharmaceuticals 2026, 19(1), 85; https://doi.org/10.3390/ph19010085 - 1 Jan 2026
Viewed by 891
Abstract
Objective: β-cell dysfunction and loss are major pathological determinants of impaired islet function and hyperglycemia in diabetes. Given the inability of current therapies to restore β-cell viability or glucose-responsive insulin secretion, this study aimed to investigate whether a cell-permeable PBX1 fusion protein (TAT-PBX1) [...] Read more.
Objective: β-cell dysfunction and loss are major pathological determinants of impaired islet function and hyperglycemia in diabetes. Given the inability of current therapies to restore β-cell viability or glucose-responsive insulin secretion, this study aimed to investigate whether a cell-permeable PBX1 fusion protein (TAT-PBX1) could rescue streptozotocin (STZ)-induced β-cell injury and restore β-cell functional integrity. Methods: A TAT-PBX1 recombinant fusion protein was produced using a prokaryotic expression system. Its protective effects were assessed in STZ-treated MIN6 β cells and in a mouse model of STZ-induced diabetes, with the glucokinase (GK) activator dorzagliatin included as a positive control. We evaluated β-cell apoptosis, DNA damage, ATP and NAD+/NADH levels, insulin signaling (IRS1/PI3K/Akt), and the expression of PDX1 and GK. Glucose-stimulated insulin secretion (GSIS), glucose tolerance, islet morphology, and β-cell proliferation were also examined in vivo. Results: TAT-PBX1 was detectable and significantly enriched in pancreatic tissue and mitigated STZ-induced cytotoxicity by reducing DNA damage, PARP1-associated energy depletion, and β-cell apoptosis. It restored intracellular ATP and NAD+/NADH ratios and reactivated IRS1/PI3K/Akt signaling. TAT-PBX1 further enhanced PDX1 protein levels and upregulated GK, resulting in improved glucose uptake and GSIS. In addition, it increased Ki67+ β-cell proliferation. In diabetic mice, TAT-PBX1 improved glucose tolerance, preserved islet morphology and number, and improved insulin signaling responsiveness. Conclusions: TAT-PBX1 restores β-cell function through coordinated protection of cellular metabolism and insulin signaling, leading to improved β-cell survival, glucose responsiveness, and regenerative capacity. These findings support TAT-PBX1 as a promising molecular strategy for β-cell-protective and β-cell-restorative diabetes therapy. Full article
(This article belongs to the Special Issue Antidiabetic Agents: New Drug Discovery Insights and Prospects)
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37 pages, 8927 KB  
Article
An Ongoing Search for Multitarget Ligands as Potential Agents for Diabetes Mellitus and Its Long-Term Complications: New Insights into (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic Acid Derivatives
by Rosanna Maccari, Rosaria Ottanà, Valerij Talagayev, Roberta Moschini, Francesco Balestri, Francesca Felice, Francesca Iannuccilli, Gemma Sardelli, Rebecca Sodano, Gerhard Wolber, Paolo Paoli and Antonella Del Corso
Pharmaceuticals 2025, 18(12), 1863; https://doi.org/10.3390/ph18121863 - 5 Dec 2025
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Abstract
Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed [...] Read more.
Background: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. Methods: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives 1a–g and 2a–g were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. Results: All compounds displayed excellent AKR1B1 inhibitory activity (IC50 0.03–0.46 μM 1a–g; IC50 0.48–6.30 μM 2a–g); 1g and 2e–g also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives 2e–g significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative 2e significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. Conclusions: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds 2e–g of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound 2e also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations. Full article
(This article belongs to the Special Issue Antidiabetic Agents: New Drug Discovery Insights and Prospects)
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Review

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24 pages, 2076 KB  
Review
Targeting the Ras–Ral Signaling Axis in Type 2 Diabetes Mellitus: A Dual-Modulation Approach to Correcting Insulin Resistance and β-Cell Dysfunction
by Narayanan Thulasi, Kannan Harithpriya, Kumar Ganesan and Kunka Mohanram Ramkumar
Pharmaceuticals 2026, 19(4), 648; https://doi.org/10.3390/ph19040648 - 21 Apr 2026
Viewed by 525
Abstract
Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. While Ras GTPases are known for oncogenic signaling, emerging evidence implicates the Ras–Ral axis as a critical regulator of glucose homeostasis. This review synthesizes the distinct roles of Ras and [...] Read more.
Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. While Ras GTPases are known for oncogenic signaling, emerging evidence implicates the Ras–Ral axis as a critical regulator of glucose homeostasis. This review synthesizes the distinct roles of Ras and Ral in metabolism. Ras hyperactivation promotes insulin resistance and inflammation via MAPK/PI3K pathways, whereas RalA supports GLUT4 translocation and insulin granule exocytosis. We propose a dual-pathway hypothesis: T2DM pathophysiology involves an imbalance characterized by excessive Ras signaling and insufficient Ral-mediated metabolic actions. Consequently, we explore the therapeutic potential of rebalancing this axis through combinatorial strategies, that selectively inhibit pathogenic Ras while enhancing protective Ral activity. We critically evaluate current Ras-targeted agents (e.g., farnesyltransferase inhibitors, allele-specific inhibitors) and discuss the emerging frontier of Ral-specific enhancers. Finally, we outline key translational challenges and future directions for validating this axis as a target for precision medicine in T2DM. Full article
(This article belongs to the Special Issue Antidiabetic Agents: New Drug Discovery Insights and Prospects)
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