Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat

Background and Purpose Sulfonylureas (SUs) have been suggested to have an insulin‐independent blood glucose‐decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrap...

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Bibliographic Details
Published in:British journal of pharmacology 2019-02, Vol.176 (3), p.478-490
Main Authors: Zhou, Xiaojun, Zhang, Rui, Zou, Zhiwei, Shen, Xue, Xie, Tianyue, Xu, Chunmei, Dong, Jianjun, Liao, Lin
Format: Article
Language:English
Subjects:
Activation
AKT protein
Animal models
Animals
Blood glucose
Blood Glucose - drug effects
Diabetes mellitus
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - pathology
Gene targeting
Gluconeogenesis
Glucose
Glucose transporter
Glycogen
High fat diet
Hypoglycemia
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - pharmacology
Insulin
Liver
Low fat diet
Metformin
Muscles
Nuclease
Nutrient deficiency
Rats
Research Paper
Research Papers
Streptozocin
Sulfonylurea
Sulfonylurea Compounds - administration & dosage
Sulfonylurea Compounds - pharmacology
Sulfonylurea Receptors - antagonists & inhibitors
Sulfonylurea Receptors - deficiency
Sulfonylurea Receptors - metabolism
Transcription
Transcription activator-like effector nucleases
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Summary:Background and Purpose Sulfonylureas (SUs) have been suggested to have an insulin‐independent blood glucose‐decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrapancreatic blood glucose‐lowering activity in vivo. Experimental Approach Sulfonylurea receptor 1 deficient (SUR1−/−) rats were created by means of transcription activator‐like effector nucleases (TALEN)‐mediated gene targeting technology. Type 2 diabetic models were established by feeding a high‐fat diet and administering a low‐dose of streptozotocin. These rats were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2 weeks. Key Results Glimepiride decreased blood glucose levels and increased insulin sensitivity without elevating insulin levels. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied by the activation of Akt in the liver. Moreover, glimepiride increased both total and membrane glucose transporter 4 (GLUT4) levels in muscle and fat, which might be attributed to insulin receptor‐independent IRS1/Akt activation. Conclusion and Implications Glimepiride possesses an extrapancreatic blood glucose‐lowering effect in vivo, which might be attributed to its direct effect on insulin‐sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injections should not be excluded per se.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.14553