Diabetes & Metabolism Journal

Original Article

Basic and Translational Research
Pancreatic Islet Transplantation in Extrahepatic Sites: Evaluation of the Venous Sac in Large Mammal Models: Giorgi Kenchadze, Ivane Abiatari, Antonello Pileggi, Norma S. Kenyon, Dora M Berman, R. Damaris Molano, Konstantine Gogichaishvili, Revaz Otarashvili, Anzor Tchavtchavadze, Teona Midelashvili, Mariam Motsikulashvili, Camillo Ricordi, Thierry Berney, Ekaterine Berishvili; Diabetes Metab J. 2026;50(3):495-505. Published online September 8, 2025; DOI: https://doi.org/10.4093/dmj.2024.0400

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Abstract PDF PubReader ePub: Background
The long-term clinical efficacy of intraportal islet transplantation is hampered by islet loss due to inflammation, oxidative stress, and insufficient vascularization. This study explores the venous sac as an alternative implantation site for islet transplantation in large animal models.
Methods
An immunosuppressed, diabetic cynomolgus monkey received allogeneic islet implants in its mesenteric venous sac, with metabolic assessments over 112 days. Dogs underwent islet autotransplantation into various venous sacs, with their glycemic control and other metabolic parameters monitored for 1 month.
Results
In a nonhuman primate, the mesenteric venous sac site improved glycemic control over a 3-month period, followed by destabilization of graft function. Histological studies revealed healthy islets. The lack of mononuclear cell infiltrate suggested no signs of graft rejection. Saphenous venous sacs in dogs showed superior glycemic control, reduced insulin requirements, and maintained C-peptide levels, comparable to intraportal transplantation. Histological analyses confirmed islet preservation and graft vascularization in saphenous venous sacs.
Conclusion
This study provides preclinical evidence in support of the venous sac as a valuable extrahepatic location for pancreatic islet implantation. We found that the saphenous vein is a more effective site for islet engraftment than the mesenteric vein. This study offers potential benefits for improving the success rates of clinical islet transplantation.

Reviews

Complications
Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions: Md Jakir Hossain, Michael D. Kendig, Meg E. Letton, Margaret J. Morris, Ria Arnold; Diabetes Metab J. 2022;46(2):198-221. Published online March 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0347

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Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the ‘Neurodiab’ criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

Citations

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Animal Models and Experimental Medicine.2026; 9(3): 442. CrossRef
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Samea Khan, Maria Markoulli, Lamia Nureen, Nick Di Girolamo, Mark Willcox
Nutrients.2026; 18(14): 2243. CrossRef
Mechanistic Insights into Diabetic Neuropathy: Oxidative Stress, Mitochondrial Injury, and Translational Therapeutics
Muzafar Ahmad Mir, Showkat ul Nabi, Rakeeb Ahmad Mir, Sofi Imtiyaz Ali, Irfan Ahmed Noorani, Shabista Muzaffar, Ibraq Khurshid
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Journal of Neuroimmune Pharmacology.2025;[Epub] CrossRef
Ameliorating Effect of Red Fruit (Pandanus conoides Lamk) Oil in Streptozotosin-Induced Diabetic Peripheral Neuropathy Rat Model: role of oxidative and neuroinflammatory pathways
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Journal of Pharmacopuncture.2025; 28(1): 11. CrossRef
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Varsha Motilal Shende, Deepti Dinesh Bandawane
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Zahra Bahadoran, Asghar Ghasemi
Nitric Oxide.2025; 159: 147. CrossRef
Chitosan Protects Peripheral Nerves Against Damage Induced by Diabetes Mellitus
Anca-Maria Țucă, Carmen Albu, Alexandra Nicoleta Preda, Alexandra Oltea Dan, Elena-Anca Târtea, Andrei Greșiță, Denisa Floriana Vasilica Pîrșcoveanu, Veronica Sfredel, Smaranda Ioana Mitran, Georgică Târtea
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International Journal of Oral Biology.2025; 50(4): 179. CrossRef
SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy
Jing Yang, Zhuoying Yu, Ye Jiang, Zixian Zhang, Yue Tian, Jie Cai, Min Wei, Yanhan Lyu, Dongsheng Yang, Shixiong Shen, Guo‐Gang Xing, Min Li
CNS Neuroscience & Therapeutics.2024;[Epub] CrossRef
Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes
Susanna C. Byram, Krista M. Lotesto, Michael Volyanyuk, Jacob E. Exline, Elizabeth A. Sager, Eileen M. Foecking
Frontiers in Anesthesiology.2024;[Epub] CrossRef
The impact of gut microbial dysbiosis on the atrophy of the hippocampus and abnormal metabolism of N-acetyl aspartate in type 2 diabetic rats
Zhenyang Zhu, Qingqing Chen, Gege Jiang, Yuan Liang, Jing Shen, Jianlin Wu
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Advances in the treatment of diabetic peripheral neuropathy by modulating gut microbiota with traditional Chinese medicine
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Painful Diabetic Neuropathy: Sex-Specific Mechanisms and Differences from Animal Models to Clinical Outcomes
Emma Merlin, Chiara Salio, Francesco Ferrini
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Compound Qiying Granules alleviates diabetic peripheral neuropathy by inhibiting endoplasmic reticulum stress and apoptosis
Yan Hu, Chen Chen, Zhengting Liang, Tao Liu, Xiaoling Hu, Guanying Wang, Jinxia Hu, Xiaolin Xie, Zhiyan Liu
Molecular Medicine.2023;[Epub] CrossRef
HCV affects KATP channels through GnT-IVa-mediated N-glycosylation of GLUT2 on the surface of pancreatic β-cells leading to impaired insulin secretion
Ben Niu, Lijing Ma, Lixuan Yao, Yating Zhang, Heng Su
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Multimodal Comparison of Diabetic Neuropathy in Aged Streptozotocin-Treated Sprague–Dawley and Zucker Diabetic Fatty Rats
Annalisa Canta, Valentina A. Carozzi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Virginia Rodriguez-Menendez, Barbara Sala, Roberto Cosimo Melcangi, Silvia Giatti, Raffaella Lombardi, Roberto Bianchi, Paola Marmiroli, Guido Cavaletti
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Basic Research
Application of Animal Models in Diabetic Cardiomyopathy: Wang-Soo Lee, Jaetaek Kim; Diabetes Metab J. 2021;45(2):129-145. Published online March 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0285

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Graphical Abstract Abstract PDF PubReader ePub

Diabetic heart disease is a growing and important public health risk. Apart from the risk of coronary artery disease or hypertension, diabetes mellitus (DM) is a well-known risk factor for heart failure in the form of diabetic cardiomyopathy (DiaCM). Currently, DiaCM is defined as myocardial dysfunction in patients with DM in the absence of coronary artery disease and hypertension. The underlying pathomechanism of DiaCM is partially understood, but accumulating evidence suggests that metabolic derangements, oxidative stress, increased myocardial fibrosis and hypertrophy, inflammation, enhanced apoptosis, impaired intracellular calcium handling, activation of the renin-angiotensin-aldosterone system, mitochondrial dysfunction, and dysregulation of microRNAs, among other factors, are involved. Numerous animal models have been used to investigate the pathomechanisms of DiaCM. Despite some limitations, animal models for DiaCM have greatly advanced our understanding of pathomechanisms and have helped in the development of successful disease management strategies. In this review, we summarize the current pathomechanisms of DiaCM and provide animal models for DiaCM according to its pathomechanisms, which may contribute to broadening our understanding of the underlying mechanisms and facilitating the identification of possible new therapeutic targets.

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Complications
Lost in Translation? Measuring Diabetic Neuropathy in Humans and Animals: Heung Yong Jin, Seong-Su Moon, Nigel A. Calcutt; Diabetes Metab J. 2021;45(1):27-42. Published online December 15, 2020; DOI: https://doi.org/10.4093/dmj.2020.0216

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The worldwide diabetes epidemic is estimated to currently afflict almost 500 million persons. Long-term diabetes damages multiple organ systems with the blood vessels, eyes, kidneys and nervous systems being particularly vulnerable. These complications of diabetes reduce lifespan, impede quality of life and impose a huge social and economic burden on both the individual and society. Peripheral neuropathy is a debilitating complication that will impact over half of all persons with diabetes. There is no treatment for diabetic neuropathy and a disturbingly long history of therapeutic approaches showing promise in preclinical studies but failing to translate to the clinic. These failures have prompted re-examination of both the animal models and clinical trial design. This review focuses on the functional and structural parameters used as indices of peripheral neuropathy in preclinical and clinical studies and the extent to which they share a common pathogenesis and presentation. Nerve conduction studies in large myelinated fibers have long been the mainstay of preclinical efficacy screening programs and clinical trials, supplemented by quantitative sensory tests. However, a more refined approach is emerging that incorporates measures of small fiber density in the skin and cornea alongside these traditional assays at both preclinical and clinical phases.

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Lost in Translation? Measuring Diabetic Neuropathy in Humans and Animals (Diabetes Metab J 2021;45:27-42)
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Original Article

Pattern of Stress-Induced Hyperglycemia according to Type of Diabetes: A Predator Stress Model: Jin-Sun Chang, Young-Hye You, Shin-Young Park, Ji-Won Kim, Hun-Sung Kim, Kun-Ho Yoon, Jae-Hyoung Cho; Diabetes Metab J. 2013;37(6):475-483. Published online December 12, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.6.475

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Background

We aimed to quantify stress-induced hyperglycemia and differentiate the glucose response between normal animals and those with diabetes. We also examined the pattern in glucose fluctuation induced by stress according to type of diabetes.

Methods

To load psychological stress on animal models, we used a predator stress model by exposing rats to a cat for 60 minutes and measured glucose level from the beginning to the end of the test to monitor glucose fluctuation. We induced type 1 diabetes model (T1D) for ten Sprague-Dawley rats using streptozotocin and used five Otsuka Long-Evans Tokushima Fatty rats as obese type 2 diabetes model (OT2D) and 10 Goto-Kakizaki rats as nonobese type 2 diabetes model (NOT2D). We performed the stress loading test in both the normal and diabetic states and compared patterns of glucose fluctuation among the three models. We classified the pattern of glucose fluctuation into A, B, and C types according to speed of change in glucose level.

Results

Increase in glucose, total amount of hyperglycemic exposure, time of stress-induced hyperglycemia, and speed of glucose increase were significantly increased in all models compared to the normal state. While the early increase in glucose after exposure to stress was higher in T1D and NOT2D, it was slower in OT2D. The rate of speed of the decrease in glucose level was highest in NOT2D and lowest in OT2D.

Conclusion

The diabetic state was more vulnerable to stress compared to the normal state in all models, and the pattern of glucose fluctuation differed among the three types of diabetes. The study provides basic evidence for stress-induced hyperglycemia patterns and characteristics used for the management of diabetes patients.

Citations

Citations to this article as recorded by

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B Sivaprakash
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