Gut-pancreas axis in the control of insulin secretion in streptozotocin-resistant rats

The Spontaneously Running Tokushima Shikoku (SPORTS) rat is characterized by hyperactive behavior but is also a potential model for studies of the role of the gut-pancreas axis in the regulation of insulin secretion. We here explored the role of ghrelin, a hormone associated with appetite regulation, in insulin dynamics within the context of streptozotocin (STZ) resistance in SPORTS rats. Comprehensive analyses-including histological examinations, gene expression profiling, and assessment of metabolic parameters-revealed that SPORTS rats are resistant to STZ-induced pancreatic injury and that, in addition to low circulating ghrelin levels, they manifest increased circulating levels of active glucagon-like peptide-1 (GLP-1) and upregulated expression of Pdx1 in the pancreas. Ghrelin administration attenuated the STZ resistance of these rats, with suppression of GLP-1 and downregulation of Pdx1 expression being implicated in this effect. Our results highlight the complex interplay among ghrelin, GLP-1, and insulin dynamics, and they suggest potential new therapeutic targets for diabetes.