GLUT4-Cre-driven insulin receptor knockout mice with a combined ablation of IR in Glut4-expressing tissues showed increased counterregulatory response to either 2-deoxyglucose-induced neuroglycopenia or systemic insulin-induced hypoglycemia.
Results suggest that, in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and that chronic infusion of insulin into the VMH is sufficient to normalize the sympathoadrenal response to hypoglycemia via restoration of GLUT4 expression in the VMH.
Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting.
The results showed that insulin induced hypoglycemia at 3h in 2 strains, and that this was coupled with increased expression of glucose transporters (GLUT2 in the liver and GLUT1, GLUT4 in the muscle) and glycolytic enzyme (HK2 in the muscle) in both strains.
A prolonged enhancement of GLUT-4 translocation and delayed counter-regulatory hormone responses may have contributed to the induction of hypoglycemia.
MCT2 and GLUT3 mRNA levels in the ORDX rat DVC did not differ among groups, but GLUT4 transcripts were progressively increased by acute and recurrent hypoglycemia.
In conclusion, (1) TG overexpressing GLUT4 exhibit greater muscle glycogen content at rest than WT; (2) during exercise, TG metabolize more carbohydrate, made possible by increased glycogenolysis in muscle and liver, and this predominates as a fuel source despite hypoglycemia and increased availability of FFA; (3) increased carbohydrate metabolism is linked to a decrease in lipid metabolism such that there is no change in overall energy expenditure; and (4) glycogen synthase I activity is inversely proportional to tissue glycogen content despite differences in circulating glucose, insulin, and FFA concentrations, indicating that glycogen content has an overriding regulatory influence on glycogen synthase.