Augmented glucagon-induced gluconeogenesis in primary hepatocytes from Otsuka Long-Evans Tokushima Fatty rats.

Glucagon dysregulation is a hallmark of type 2 diabetes mellitus (T2DM), yet its early hepatic effects remain unclear. Here, we demonstrate that glucagon-induced gluconeogenesis is markedly enhanced in primary hepatocytes from prediabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a well-established model of human T2DM. Compared to control LETO rats, OLETF hepatocytes showed significantly higher glucagon-stimulated expression of gluconeogenic genes (Pepck, G6pase, and Fbp1) at both mRNA and protein levels, along with elevated glucose production. Notably, mRNA decay analysis revealed prolonged half-lives of gluconeogenic transcripts in OLETF hepatocytes, indicating enhanced mRNA stability as a novel mechanism contributing to increased hepatic glucose output. These findings highlight aberrant glucagon responsiveness and posttranscriptional regulation as potential predisposing factors in genetically susceptible models prior to the onset of overt metabolic abnormality, which may be of interest for preventive or therapeutic strategies for controlling fasting hyperglycemia.