Effect of Sitagliptin and Glimepiride on Glucose Homeostasis and cAMP Levels in Peripheral Tissues of HFD/STZ Diabetic Rats

Abstract

Introduction: T2DM is a group of metabolic disorders manifested by hyperglycemia as a result of insulin insufficiency and/or resistance. The main goal of antidiabetic therapies is to lower glucose levels, and therefore prevent development of diabetes complications. DPP-4 inhibitors (e.g. sitagliptin) are relatively new antidiabetic drugs which inhibit the activity of DPP-4 enzyme and therefore prevent rapid degradation of incretin hormones. Objective: We investigated effects of sitagliptin on glucose homeostasis, lipid profile, and insulin signaling by determination of cAMP levels in peripheral tissues of HFD/STZ diabetic rats, compared to glimepiride. Methods: The experimental rats were divided into five groups, each group comprising 10 rats. Group (1) served as the normal control rats and administered DMSO (without treatments) as the vehicle. The rest of the groups were rendered diabetic by feeding HFD containing 40% fats for 4 weeks, followed by a single I.P. injection of STZ (45 mg/kg of body weight). One week after STZ injection, the rats with FBG level of ≥ 200 mg/dl were considered diabetic. Group (2) served as the diabetic untreated rats and administered DMSO (without treatments) as the vehicle. Group (3) served as diabetic rats treated with glimepiride (0.1 mg/kg of body weight). Group (4) and group (5) served as diabetic rats treated with sitagliptin (10 and 30 mg/kg of body weight, respectively). Treatments were dissolved in DMSO and were given orally for 4 weeks. At the end of the treatment period, the blood, liver and adipose tissues (White and brown) were collected for biochemical analysis. Results: In normal control rats, the highest content of cAMP was observed in BAT. Diabetic rats showed an elevation in cAMP levels of liver and WAT to be 1.3 and 3.9 fold control values, respectively, while in BAT, cAMP level decreased to be 0.4 fold control value. Sitagliptin and glimepiride significantly decreased cAMP levels in liver and WAT. Conclusion: We conclude that sitagliptin and glimepiride have comparable effects on glucose homeostasis. Both drugs have cAMP-lowering effect which may suggest their potential protecting effect against vascular complications of diabetes.

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

“…Parallel to the changes in blood glucose level in the different studied groups, serum insulin showed significant reduction in untreated diabetic group compared to control rats, in accordance with [37][38][39], who reported a reduced serum insulin level in HFD/STZ rat model of type 2DM, and in controversy with the study of Saad et al [40] in which the diabetic rats exhibited significantly high serum insulin in the same rat model. The suggested explanation for this controversy may be the duration of HFD feeding in the aforementioned study.…”

Similar and Additive Effects of Ovariectomy and Diabetes on Insulin Resistance and Lipid Metabolism

“…In lipolytically active adipocytes, elevated intracellular cyclic adenosine monophosphate (cAMP) levels following hormonal stimulation result in phosphorylation of perilipin which rapidly initiates lipolysis of triglycerides to glycerol and fatty acids by phosphorylated HSL. Previously, our lab demonstrated that the diabetic state differentially affects cAMP levels according to the type of adipose tissue; WAT showed increased cAMP level, while BAT showed a decline in cAMP level [ 22 ]. Moreover, unrestrained lipolysis increases circulating levels of NEFA in the absorptive state, the driving force of insulin resistance.…”

“…On the other hand, BAT of diabetic rats showed elevated perilipin which could be explained by the fact that BAT is more insulin sensitive than WAT [ 24 ] and may retain insulin sensitivity even under insulin resistance. This declined cAMP and elevated perilipin levels in BAT may result in shifting in its metabolic capacity from lipolytic and catabolic into lipogenic and anabolic pathways which could change cells phenotype from BAT (metabolically active) into WAT (storage) phenotype [ 22 ].…”

Modulation of Adipocytokines Production and Serum NEFA Level by Metformin, Glimepiride, and Sitagliptin in HFD/STZ Diabetic Rats

“…One week after injection, fasting blood glucose (FBG) levels were determined from tail blood using an Accu-Chek Active glucometer (Roche Diagnostics, Manheim, Germany). The rats with FBG levels above 200 mg/dL were considered as diabetic [ 10 ]. Group (2) served as the diabetic untreated rats and were administered DMSO as a vehicle without any treatments.…”

“…At the end of the treatment period, the rats were fasted overnight, anaesthetized with diethyl ether, and sacrificed by cervical decapitation. The blood was collected for serum separation and biochemical analysis [ 10 ].…”