Evaluation of type 2 diabetic mellitus animal models via interactions between insulin and mitogen‑activated protein kinase signaling pathways induced by a high fat and sugar diet and streptozotocin

Abstract

Type 2 diabetic mellitus (T2DM), which is characterized by insulin resistance (IR), hyperglycemia and hyperlipidemia, is a comprehensive dysfunction of metabolism. The insulin receptor (INSR)/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is well acknowledged as a predominant pathway associated with glucose uptake; however, the effect of streptozotocin (STZ) plus a high fat and sugar diet (HFSD) on the proteins associated with this pathway requires further elucidation. In order to explore this effect, a T2DM rat model was constructed to investigate T2DM pathogenesis and potential therapeutic advantages. Rats were randomly divided into control and model groups, including normal diet (ND) and HFSD types. ND types were administered intraperitoneal (IP) injections of STZ (35 mg/kg) or a combination of STZ and alloxan monohydrate (AON) (40 mg/kg), whereas HFSD types were composed of HFSD pre-given, post-given and simul-given groups, and were modeled as follows: IP or intramuscular (IM) injection of STZ (35 mg/kg) or a combination of STZ and AON (40 mg/kg). Results indicated that, compared with controls, blood glucose, insulin, homeostatic model assessment-insulin resistance and total triglyceride were significantly elevated in groups with HFSD and modeling agents (P<0.05 or P<0.01), whereas total cholesterol and low-density lipoprotein levels were significantly elevated in groups simultaneously administered HFSD and modeling agents (P<0.05 or P<0.01), in addition to downregulation of the expression of insulin signaling pathway proteins in the liver, including INSR, PI3K, AKT1, phosphatidylinositol-5-phosphate 4-kinase type-2α (PIP5Kα) and glucose transporter (GLUT)2, and increased expression of inflammatory factors, including p38, tumor necrosis factor (TNF)α and interleukin (IL)6. Furthermore, compared with other two HFSD types including pre-given and post-given group, the simul-given group that received IM injection with STZ exhibited decreased expression levels of major insulin signal pathway proteins INSR, PI3K, AKT1, PIP5Kα, GLUT2 or GLUT4 in the liver and pancreas (P<0.05 or P<0.01), whereas the opposite was observed in the skeletal muscle. In addition, the protein expression levels of phosphorylated-p38, p38, IL6 and TNFα in the simul-given group that received IM injection with STZ were increased (P<0.05 or P<0.01), and histopathology also indicated inflammation in pancreas and liver. The present findings suggest that a low dose of STZ may partially impair the β cells of the pancreas, whereas long-term excess intake of HFSD may increase lipid metabolites, inhibit the insulin signaling pathway and activate the mitogen-activated protein kinase p38 signaling pathway. The combined action of STZ and AON may result in insulin resistance, which ultimately results in abnormalities in glucose and lipid metabolism. The present model, analogue to T2DM onset of humans, evaluated the medical effect on metabolic dysfunction and provides an insight into the underlining mechanism of IR.

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

“…In regards to the pancreatic weight and pancreas/body weight ratio, both parameters were significantly reduced in untreated diabetic animals compared to their control rats, in accordance with previous works [33,34]. Oral administration of sitagliptin alone significantly increased both parameters when compared to the untreated diabetic rats.…”

MicroRNA-17-92 Regulates Beta-Cell Restoration After Streptozotocin Treatment

“…In addition, Crem has also been reported to directly repress the insulin gene promoter activation in beta-cell (66). In the present study, the expression of MafA and Glut2 in islets of RIP-Cre-STZ and miR-17-92βKO-STZ group was down-regulated, which reduced insulin gene transcription as previous studies (57)(58)(59)67). Meanwhile, the upregulation of Sox6 and Crem resulted in the decrease of insulin transcription.…”

“…Diabetes mellitus shows features of hyperglycemia because of absolutely or relatively insufficient serum insulin secretion. Pancreatic beta-cells have fundamental functions to modulate insulin synthesis and secretion, which is regulated by various transcriptional activators such as Pdx-1 (pancreas/duodenum homeobox factor-1) (54), MafA (55,56), and Glut2 (57)(58)(59) and transcriptional repressors including Sox6 (60) and Crem (61). Pdx-1 plays pivotal roles in the early differentiation, maturation and regeneration of pancreatic islet cells (57).…”

Shorea roxburghii Leaf Extract Ameliorates Hyperglycemia Induced Abnormalities in High Fat/Fructose and Streptozotocin Induced Diabetic Rats

“…The combination of high fat diet/high sugar with STZ has been extensively used for establishing T2DM animal models. This model has been reported to represent the pathogenesis of T2DM in humans . Typical symptoms experienced in T2DM animal models including increase in FGB, polyphagia, polydipsia and body weight reduction were evidently observed in all the diabetic rat groups.…”

“…This model has been reported to represent the pathogenesis of T2DM in humans. [22,23] Typical symptoms experienced in T2DM animal models including increase in FGB, polyphagia, polydipsia and body weight reduction were evidently observed in all the diabetic rat groups. Our study showed that SRL treatment improved these conditions by suppressing hyperglycemia, polyphagia and improving the body weight gain in treated diabetic rats.…”