Insulin Sensitivity is Modified by a Glycogen Phosphorylase Inhibitor: Glucopyranosylidene-Spiro-Thiohydantoin in Streptozotocin-Induced Diabetic Rats

Abstract

The major role of liver glycogen is to supply glucose to the circulation maintaining the normal blood glucose level. In muscle and liver the accumulation and breakdown of glycogen are regulated by the reciprocal activities of glycogen phosphorylase and glycogen synthase. Glycogen phosphorylase catalyses the key step of glycogen degradation and its activity can be inhibited by glucose and its analogues. Obviously, any readily accessible inhibitor of glycogen phosphorylase can be used as a potential therapy of non-insulin-dependent or type 2 diabetes. Hepatic glycogen phosphorylase has been identified as a new target for drugs that control blood glucose concentration. In our experiments glucopyranosylidene-spirothiohydantoin (TH) was tested on the insulin sensitivity and blood glucose level of control and streptozotocin-treated rats. The streptozotocin-treated rats failed to gain weight and exhibited stable hyperglycemia (4.7 ± 0.5 mmol/L glucose in control vs. 7.8 ± 0.5 mmol/L) and low plasma insulin levels (9.6 ± 1.9 µIU/mL in control vs. 3.2 ± 2.2 µIU/mL). When insulin supplementation with slow-release implants (2 IU/day) was started 8 weeks after streptozotocin injection, blood glucose concentration remained suppressed, plasma insulin level dramatically increased and the insulin sensitivity restored. TH administration significantly reduced the high blood glucose concentration and restored the insulin sensitivity of STZtreated rats.

The effect of swimming exercise and powdered-Salicornia herbacea L. ingestion on glucose metabolism in STZ-induced diabetic rats

“…The main role of the liver glycogen is to circulating glucose to maintain normal blood glucose levels. The accumulation and degradation of glycogen in the muscles and in the liver is regulated by the interaction of glycogen-phosphorylase and glycogen-synthase [ 34 ], and the Glut-2 and 4 are increased and absorb glucose for glycogen synthesis [ 35 ]. Insulin resistance and type 2 diabetes suggest that diabetes mellitus reduces the protein expression of Glut-4, a glucose transporter chain in skeletal muscles which is led to inhibition of glycogen synthesis [ 36 ].…”

The effect of swimming exercise and powdered-Salicornia herbacea L. ingestion on glucose metabolism in STZ-induced diabetic rats

“…The accumulation and degradation of glycogen in the muscles and in the liver is regulated by the interaction of glycogen-phosphorylase and glycogen-synthase [34], and the Glut-2 and 4 are increased and absorb glucose for glycogen synthesis [35]. Insulin resistance and type 2 diabetes suggest that diabetes mellitus reduces the protein expression of Glut-4, a glucose transporter chain in skeletal muscles which is led to inhibition of glycogen synthesis [36].…”

A multidisciplinary study of 3-(β- d -glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors: Computation, synthesis, crystallography and kinetics reveal new potent inhibitors

“…A large number of synthetic and natural product GP inhibitors targeting the different binding sites have been identified in recent years and solved structures of inhibitor bound GP complexes have facilitated further structure based inhibitor design efforts [4,5,9]. GP inhibitors have demonstrated considerable potential for T2D treatment in cellular models [10][11][12] and in vivo [13][14][15][16], as well as promise against other conditions such as myocardial and cerebral ischemias, and tumors [17][18][19].…”