SEARCHNARRATIVE_REVIEWendocrinology, nutrition

narrative_review·endocrinology, nutrition, pharmacology, immunology, public health·PMC10821096

Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus

Life · 20 authors, 12 centres

AI SUMMARY

FIDELITY 100%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This narrative review summarizes novel therapeutic approaches for diabetes mellitus, including stem cell therapy, transdermal drug delivery, nanotechnology, and candidate drugs like fucoidan, SGLT-2 inhibitors, statins, quercetin, and immunological agents. The authors highlight that these interventions target multiple pathogenic pathways beyond glycemic control, but many are in early preclinical or clinical stages with limited safety data. The clinical significance lies in the potential to overcome limitations of conventional therapies, though further research is needed to establish efficacy and safety.

Full summary

6,927 CHARS

**Background:** Diabetes mellitus (DM) is a prevalent metabolic disorder characterized by hyperglycemia due to insulin deficiency, resistance, or excessive glucagon secretion. The disease is classified into type 1 (T1DM), type 2 (T2DM), gestational diabetes (GDM), and latent autoimmune diabetes in adults (LADA). Conventional treatments—lifestyle modifications, oral hypoglycemics (e.g., metformin, sulfonylureas, thiazolidinediones), and insulin—primarily target glycemic control but fail to address other pathogenic determinants (e.g., adipocyte insulin resistance, increased glucagon, renal glucose reabsorption, neurotransmitter dysfunction). Long-term use is associated with adverse effects such as hypoglycemia, hepatotoxicity, cardiovascular risks, and gastrointestinal issues. The recognition of the 'ominous octet' of pathogenic hotspots has spurred development of novel agents that target multiple pathways. This narrative review aims to provide comprehensive information on emerging therapeutic strategies for DM.

**Methods:** The authors conducted a narrative review of the literature, summarizing findings from various studies (preclinical, clinical trials, and observational) on novel therapeutic agents for DM. The review covers stem cell therapy, transdermal drug delivery systems (TDDS), nanotechnology, candidate drugs (fucoidan, SGLT-2 inhibitors, statins, quercetin), immunological approaches (cyclosporin A, rituximab, anti-TNF-α, GAD-65, TAK-875), ethnomedicine, and dietetics. The paper does not specify a systematic search strategy, inclusion/exclusion criteria, or quality assessment of included studies.

**Key Results:** - **Stem cell therapy:** Embryonic stem cells (ESc) can differentiate into insulin-secreting cells, improving glucose uptake in vitro and in vivo. Intravenous injection of very small embryonic-like stem cells (VSELs) in mice with pancreatic necrosis showed potential for pancreatic repair. Mesenchymal stem cells from Wharton's jelly restored β-cell population in T1DM patients. In six T2DM patients, implantation of umbilical cord mesenchymal stem cells significantly elevated C-peptide levels and improved postprandial glucose stability after 2 hours. Adiponectin controlled mobilization of bone marrow-derived mesenchymal stem cells (BMSCs), lowering glucose levels and encouraging bone regeneration in diet-induced obese mice. Autologous hematopoietic stem cell transplantation (AHSCT) with cyclophosphamide and anti-thymocyte globulin in 24 patients led to remission of T1DM with good glycemic control. Risk factors for AHSCT rejection included fasting C-peptide levels, age, and TNF-α levels. - **Transdermal drug delivery systems (TDDS):** A biosensor patch with a 3D microneedle array was designed for glucose monitoring; in vitro experiments showed stability and ability to detect extreme glucose levels, but sensitivity decreased at higher glucose levels due to bio-fouling. TDDS approaches include microneedle technology, nanoformulations, iontophoresis, and electroporation, offering non-invasiveness, prolonged release, and avoidance of first-pass metabolism. - **Nanotechnology:** Smart nanoparticles with glucose sensors enable glucose-responsive insulin release. Quantum dots and mesoporous silica nanoparticles have been used for sensitive glucose sensors. Challenges include biocompatibility, long-term safety, and scalability. - **Candidate drugs:** - **Fucoidan:** A sulfated polysaccharide from seaweeds (e.g., Fucus vesiculosus) acts as a glucosidase inhibitor and reduces diabetic retinopathy by inhibiting VEGF signaling. Fuc-Pg (from Pearsonothuria graeei, MW 310 kDa) reduced weight, hyperlipidemia, and liver steatosis in high-fat-diet-fed mice. - **SGLT-2 inhibitors:** Canagliflozin, dapagliflozin, and empagliflozin block renal tubular glucose reabsorption. Chronic outcomes still need evaluation. - **Statins:** A clinical trial on 6000 patients showed statin therapy maintains microvascular integrity and prevents angiopathy. However, the JUPITER trial and meta-analyses reported a modest increase in new-onset diabetes risk. Regular monitoring of blood glucose and HbA1c is recommended. - **Quercetin:** In streptozotocin (STZ) and alloxan-induced diabetic rat models, oral quercetin lowered blood glucose and HbA1c. In T2DM mice (C57BL/KsJ-db/db) and high-fat diet-induced insulin resistance models, quercetin reduced skeletal glucose uptake and influenced glucose-stimulated insulin secretion. The mechanism may involve GLUT expression or insulin signal transduction upregulation. - **Immunological approaches:** - **Cyclosporin A (CsA):** A calcineurin inhibitor that reduces IL-2 secretion by helper T cells. Disadvantages include cost and pancreatic β-cell toxicity. - **Regulatory T cells (Tregs):** CD4(+) CD25(high)CD127- Tregs showed positive outcomes for pancreatic islet survival. - **Rituximab:** In a phase II trial, 87 T1DM patients received 4 doses/week; after one year, average C-peptide AUC was elevated compared to placebo. - **Anti-TNF-α (etanercept):** A double-blinded experiment in children lowered required insulin dose and aided β-cell proliferation. - **GAD-65:** Intranasal administration in NOD mice induced Th2 response, inhibiting autoreactive Th1 responses and reducing β-cell autoimmunity. - **TAK-875 (GPR-40 agonist):** Increased insulinogenic index in diabetic patients but was stopped after week 10 of a 12-week phase 2 trial due to hepatotoxicity. - **Ethnomedicine:** Numerous herbs (e.g., Allium sativum, Gymnemasylvestre, Withania somnifera) contain bioactive compounds (terpenoids, flavonoids, phenolics) with anti-diabetic effects, though mechanisms are often unclear. - **Dietetics:** Medical nutrition therapy by ADA includes individualized diet plans. A low-carbohydrate, high-protein diet is effective for weight loss and blood sugar control. Vitamin D supplementation during early childhood (7–8 months) was associated with two-fold lower risk of T1DM, but other studies found no relationship. Vitamin D deficiency may affect insulin resistance and T2DM.

**Clinical Implications:** The review underscores the need for novel agents that target multiple pathogenic pathways beyond glycemic control. Stem cell therapy, TDDS, nanotechnology, and candidate drugs like fucoidan, SGLT-2 inhibitors, statins, quercetin, and immunological agents offer potential for improved efficacy and reduced side effects. However, most are in early stages; many have not been validated in large-scale clinical trials. Safety concerns (e.g., hepatotoxicity with TAK-875, new-onset diabetes with statins, β-cell toxicity with CsA) must be addressed. Ethnomedicine and dietetics provide affordable, low-side-effect options, but rigorous evidence is lacking. The review highlights the importance of individualized therapy and ongoing research to translate these novel approaches into clinical practice.

STUDY TYPE

narrative_review

SPECIALTY

endocrinology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10821096

Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus

Life

READ THE FULL PAPER

ABSTRACT

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

CITATION EXPORT

Ahmed M. E. Elkhalifa, Mehak Nazar, Sofi Imtiyaz Ali et al.. Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus. Life. (2024). https://doi.org/10.3390/life14010099

AUTHORS

20 · 12 CENTRES

Ahmed M. E. Elkhalifa, Mehak Nazar, Sofi Imtiyaz Ali, Ibraq Khursheed, Syed Taifa, Muzafar Ahmad Mir, Iqra Hussain Shah, Masood Malik, Zahid Ramzan, Shubeena Ahad, Nusrat Bashir, Elham Elamin, Elsharif A. Bazie, Elsadig Mohamed Ahmed, Majed Mowanes Alruwaili, Ammar W. Baltoyour, Abdullah Salah Alarfaj, Ibrahim Ali Al Bataj, Abdullah M. A. Arabe, Showkat Ul Nabi

1Department of Public Health, College of Health Sciences, Saudi Electronic University, Riyadh 11673, Saudi Arabia; [email protected]
2Department of Haematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti 1158, Sudan; [email protected]
3Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar 190006, India; [email protected] (M.N.); [email protected] (S.I.A.); [email protected] (S.T.); [email protected] (M.A.M.); [email protected] (I.H.S.); [email protected] (M.M.); [email protected] (Z.R.); [email protected] (S.A.); [email protected] (N.B.)
4Department of Zoology, Central University of Kashmir, Nunar, Ganderbal 191201, India; [email protected]
5Pediatric Department, Faculty of Medicine, University of El Imam El Mahdi, Kosti 1158, Sudan; [email protected]
6Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti 1158, Sudan
7Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
8Nursing Administration & Education Department, College of Nursing, Jouf University, Sakaka 72388, Saudi Arabia; [email protected]
9Dhahran Eye Specialist Hospital, Ministry of Health, Dhahran 39455, Saudi Arabia; [email protected]
10Dr. Suliman Al-Habib Hospital, Riyadh 11372, Saudi Arabia
11Najran General Hospital, Ministry of Health, Najran 66277, Saudi Arabia; [email protected]
12Diabetic Center and Unites, Ministry of Health, Riyadh 11176, Saudi Arabia

EDITOR / REVIEWER

Fabrizio Montecucco