Miranda-Alves, L. | bioRxiv Science

bioRxiv2025

Interplay between Hyperglycemia and Chikungunya Virus Infection: Pathophysiological Insights from Murine Model

Chikungunya fever (CHIKF) is a re-emerging viral disease characterized by acute systemic manifestations and debilitating musculoskeletal symptoms that can persist after viral clearance. Although typically self-limiting in healthy individuals, clinical outcomes are significantly worsened in patients with pre-existing comorbidities, particularly diabetes mellitus (DM). Epidemiological data links DM to heightened CHIKF severity and a greater risk of developing chronic arthropathy, yet the mechanism underpinning this association remains poorly understood. In this study, we established an in vivo streptozotocin (STZ)-induced diabetic C57BL/6 mice as a model to investigate the impact of DM on CHIKV pathogenesis. STZ induces selective pancreatic {beta}-cell destruction and persistent hyperglycemia. Diabetic animals infected with CHIKV exhibited aggravated joint inflammation, increased nociceptive sensitivity, and elevated serum markers of muscle and hepatic injury, including creatine kinase (CK) and alanine aminotransferase (ALT). Histopathological analyses revealed that CHIKV infection alone disrupted joint architecture. However, in the diabetic context, these alterations were significantly exacerbated, with enhanced inflammatory infiltrates, chondrocyte loss, osteocyte necrosis, and fibrotic remodeling. These results demonstrate that the diabetic metabolic environment profoundly amplifies CHIKV-induced tissue damage and impairs resolution of inflammation, offering a plausible mechanistic explanation for the poorest CHIKF outcomes observed in diabetic patients. Thus, this model provides a valuable platform for exploring the molecular drivers of CHIKF severity and chronicity, especially among DM patients, as well as for development of pharmacological tools to mitigate CHIKV-associated complications in metabolically vulnerable populations. ImportanceChikungunya virus is responsible for a re-emerging disease that causes intense joint pain and long-lasting inflammation, especially in vulnerable individuals. People with diabetes are known to suffer more severe and persistent symptoms, but the biological reasons behind this have remained unclear. In this study, we used a diabetic mouse model to investigate how a high-glucose environment influences the course of Chikungunya virus infection. We found that diabetic mice experienced more intense joint damage, increased pain sensitivity, and signs of broader organ injury compared to non-diabetic animals. Microscopic analyses of tissues showed greater inflammation and structural damage in the joints of diabetic animals. These findings suggest that diabetes directly worsens the effects of Chikungunya virus infection by amplifying inflammation and delaying healing. This model helps explain why diabetic patients have worse outcomes and may assist in developing new treatments to protect high-risk populations from long-term complications of this infection.

immunology↗

bioRxiv2025

Dietary zinc restriction induces irreversible allodynia in adult mice

IntroductionNeuropathic pain is a debilitating condition highly prevalent worldwide. One of the main factors related to its development is poor nutrition and micronutrient deficiency in the diet. Essential metals, especially divalent ions as zinc, play crucial roles in the neurobiology of the nervous system, including pain signaling and transmission mechanisms, and metabolism control. The present study aimed to understand the impact of zinc in neuropathic pain, evaluating whether restriction and direct repletion of a dietary zinc could change nociceptive behavior and metabolic parameters in adult mice. MethodsAdult male Swiss mice received a zinc-restricted diet for eight weeks. The repletion group received the restricted diet for four weeks followed by normal zinc diet for another four weeks. Mechanical and heat thermal pain sensitivity were assessed using the von Frey filaments and Hargreaves tests, respectively. ResultsZinc restriction resulted in decreased body weight gain and led to an increased mechanical and thermal sensitivity to heat. Dietary zinc repletion reversed the thermal allodynia and increased weight gain, abdominal adipose tissue, and liver weight compared to a normal zinc diet. No changes were observed concerning food and water intake, glycemic profile, pancreatic morphology and plasma amylin, ConclusionsThe reduction in the bioavailability of dietary zinc promotes metabolic and nociceptive changes in adult mice, inducing allodynia characteristic of neuropathic pain.

biochemistry↗

bioRxiv2019

Zinc restriction promotes β-cell hyper-hormonemia and endocrine pancreas degeneration in mice

Zinc is a key component of proteins, including interaction with varying pancreatic hormones, including insulin and amylin. Zinc is key in insulin crystallinity in ZnT8 knock-out mice models, although the dietary role of zinc restriction over both energetic metabolism and {beta}-pancreatic hormonemia and morphology remained unexplored. We aimed to test whether dietary zinc restriction on swiss male mice would impact over endocrine pancreas and metabolic phenotype. We evaluated the role of dietary zinc restriction on {beta}-pancreatic hormonemia on non-transgenic Swiss male mice weaned onto a control or low-zinc diet for 4 weeks. Growth, glycemia, insulinemia, amylinemia and pancreatic islet were smaller in intervention group despite insulin crystallinity in secretory granules. We have found overlabelling for insulin, amylin and toxic oligomers in apoptotic pancreatic islet. High production of {beta}-pancreatic hormones in zinc-restricted animals counteract the decreasing islet size due to their apoptotic cells. We conclude that zinc deficiency is sufficient to promote islet {beta}-cell hormonal disruption and degeneration.

biochemistry↗