Replicating human diabetes: insights from a novel animal model.

Abstract

Type 2 diabetes is considered the pandemic of the 21st century. The pathogenesis of diabetes is complex and multifactorial, and its understanding is crucial for its prevention and treatment. Nevertheless, the pathogenesis of β-cell dysfunction remains unclear. This gap in knowledge could be related to a lack of appropriate preclinical models of type 2 diabetes. Current animal models, mostly genotypic and monogenic, do not fully reflect the pathophysiology of type 2 diabetes or associated organ damage. Therefore, a new preclinical model is needed. In this study, we present a non-genotypic animal model of diabetes that combines obesity and the treatment with the diabetogenic immunosuppressor tacrolimus (TAC). Sprague-Dawley male rats were fed with a high-fat diet (HF) to establish obesity and metabolic syndrome. Then, TAC was administered for 6-9 mo to induce chronic hyperglycemia. These animals showed a decrease in Langerhans islets area and number, and development of islet fibrosis. There were also changes in pancreatic insulin and glucagon content, imbalance in the α/β-cell ratio and decrease in the expression of essential transcription factors V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), forkhead box protein O1 A (FOXO1A), pancreatic and duodenal homeobox 1 (PDX-1), and neuronal differentiation 1 (NEUROD1). Altogether, this could be a more appropriate animal model to study the pathophysiology of diabetes and, eventually, related organ damage. NEW & NOTEWORTHY After 6-9 mo of treatment, animals presented fasting and chronic hyperglycemia in intraperitoneal glucose tolerance test (IPGTT). Pancreas of obese-diabetic animals showed a decrease in Langerhans islets area and number, and development of islet fibrosis. Islets showed a decrease in insulin content and in β-cells proportion, and an increase in α cells proportion. There was also a decrease in the expression of transcriptional factors essential for β cells: V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), Forkhead box protein O1 A (FOXO1A), pancreatic and duodenal homeobox 1 (PDX-1), and Neuronal differentiation 1 (NEUROD1).

Keywords

Identifiers

DOI

10.1152/ajpendo.00226.2025

PubMed

40939012

Journal

American journal of physiology. Endocrinology and metabolism

Year

2025