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Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat.


ABSTRACT:

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.

SUBMITTER: Zhou X 

PROVIDER: S-EPMC6329628 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat.

Zhou Xiaojun X   Zhang Rui R   Zou Zhiwei Z   Shen Xue X   Xie Tianyue T   Xu Chunmei C   Dong Jianjun J   Liao Lin L  

British journal of pharmacology 20181226 3


<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Sulfonylurea receptor 1 deficient (SUR1<sup>-/-</sup> ) rats were created by means of transcription activator-li  ...[more]

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