Abstract
SUMMARYThe Goto-Kakizaki (GK) rat is an inbred model of type 2 diabetes (T2D); GK rats are lean but have hyperglycemia and increased gluconeogenesis. However, fasting hyperglycemia in other commonly used rodent models of T2D is associated with increased corticosterone, and thus the underlying mechanism for hyperglycemia differs significantly from T2D in humans. Information regarding corticosterone in the GK rat is not readily available. We studied 14- to 16-week-old GK rats in comparison with age-matched control Wistar-Kyoto (WK) rats. GK rats had lower body weights (WK: 343±10 g vs GK: 286±9 g, P<0.01), but higher plasma glucose concentrations (WK: 132±1.5 mg/dl vs GK: 210±11.7 mg/dl, P<0.01). This was associated with an ∼twofold increase in PEPCK1 expression (P<0.05). However, these findings were also associated with elevations in plasma corticosterone and urinary corticosterone excretion. Ketoconazole (KTZ) treatment in GK rats reduced plasma corticosterone, fasting glucose (GK: 218±15 mg/dl vs GK-KTZ: 135±19 mg/dl, P<0.01) and rates of glucose production [GK: 16.5±0.6 mg/(kg-minute) vs GK-KTZ: 12.2±0.9 mg/(kg-minute), P<0.01]. This was associated with an ∼40% reduction in hepatic PEPCK1 expression as well as a 20% reduction in alanine turnover. Thus, hypercorticosteronemia might contribute to the diabetic phenotype of GK rats and should be considered as a potential confounder in rodent models of T2D.
Highlights
Animal models are indispensable in studying the mechanisms responsible for the pathogenesis and complications of type 2 diabetes (T2D), as well as preclinical testing for novel therapeutic agents
Hyperglycemia was associated with an ~twofold increase in fasting plasma insulin concentrations, Corticosterone in Goto-Kakizaki rats
We found an increased rate of glucose production in GK rats compared with WK rats, and this was associated with increased expression of PEPCK1 mRNA
Summary
Animal models are indispensable in studying the mechanisms responsible for the pathogenesis and complications of type 2 diabetes (T2D), as well as preclinical testing for novel therapeutic agents. Attempts to establish a hyperglycemic phenotype utilized experimental destruction of the pancreas, accomplished either surgically or chemically (e.g. streptozotocin, alloxan). Both methods continue to be used, they are often criticized as not accurately reflecting the human T2D phenotype. Many investigators rely on specific rodent strains that model key features of T2D. These genetic models have been widely used to explore the pathophysiology of obesity and T2D, as well as in preclinical drug development
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