The Characteristics of Hepatic Gsα-cAMP Axis in HSHF Diet-Fed Obese Insulin Resistance Rats and Genetic Diabetic Mice

Abstract

Stimulatory G protein α-subunit (Gsα) mediated cAMP signal is required for elevated hepatic glucose production (HGP) in diabetic patients. However, it remains obscure of the exact characteristics of hepatic Gsα-cAMP signal axis (including Gsα, glucagon receptor, β 2 -adrenergic receptor, cAMP, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) in insulin resistance (IR) and type 2 diabetes mellitus (T2DM). In current study, we investigated the changing characteristics of hepatic Gsα-cAMP signal axis and blood glucose in high-sugar-high-fat (HSHF)-diet-induced IR Wistar rats and db/db diabetic mice. As expected, the HSHF-diet rats were characterized by hyperinsulinemia, hyperglycemia and impaired glucose tolerance. According to a threshold (1.7) of homeostasis model assessment ratio (HOMA-R), the process of IR in HSHF-diet rats could be divided into slight and high IR stages, with the week-23 as the cut-off point. In early slight IR stage, key molecules expressions of hepatic Gsα-cAMP signal axis in HSHF-diet rats were up-regulated with significantly elevated fasting blood glucose (FBG) from 18 to 23 weeks. Unexpectedly, in high IR stage, hepatic Gsα-cAMP signal axis was recovered comparatively to that of normal chow-diet rats, and no significant differences in FBG levels were found. However, in diabetic db/db mice, up-regulation of hepatic Gsα-cAMP signal axis was responsible for its severely increased fasting hyperglycaemia. Our data revealed a positive correlation between hepatic Gsα-cAMP signal axis and FBG in slight IR stage of HSHFdiet rats and diabetic db/db mice. The current finding thus suggested hepatic Gsα-cAMP signal axis plays a central role in regulating of FBG during the developing and development of T2DM.

Glucagon, cyclic AMP, and hepatic glucose mobilization: A half‐century of uncertainty

“…The last is identical to the value of 12 pM reported for the ELISA-based estimates obtained from peripheral venous plasma reported by Miyachi and coworkers. Peripheral venous plasma values of around 6 pM in the rat were reported by Xue, Cei, et al (2017) using the Millipore RENDOI-85K rat endocrine Linco-plex assay, and in humans by Kobayashi (Kobayashi et al, 2020) using a sandwich ELISA assay. Based on the hepatic portal/peripheral venous concentration ratio of 1.5 depicted in Figure 2b, mean peripheral venous concentrations of 6-19 pM would translate to 9-29 pM in the hepatic portal circulation.…”

“…Constitutive hepatic cAMP levels were lower in the diabetics, but glucagon receptor binding affinities and capacities and cAMP‐phosphodiesterase activities were normal (Portha et al, 1983). In a diet‐induced insulin‐resistant rat model (Xue, Wei, et al, 2017), the animals were hyperglycemic and displayed elevated expressions of PEPCK and G6Pase but normal plasma glucagon levels and basal hepatic tissue cAMP levels. Expressions of Gαs and beta adrenoceptors were elevated, but glucagon receptor expressions or densities were not reported.…”