Experimental evidence for the use of CCR2 antagonists in the treatment of type 2 diabetes

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• 作者：Timothy J. Sullivan ; Zhenhua Miao ; Bin N. Zhao ; Linda S. Ertl ; Yu Wang ; Antoni Krasinski ; Matthew J. Walters ; Jay P. Powers ; Daniel J. Dairaghi ; Trageen Baumgart ; Lisa C. Seitz ; Robert D. Berahovich ; Thomas J. Schall ; Juan C. Jaen
• 关键词：T2D ; type 2 diabetes ; DIO ; diet-induced obese ; AT ; adipose tissue ; HFD ; high-fat diet ; REI ; receptor engagement index ; G-6-Pase ; glucose-6-phosphatase)
• 刊名：Metabolism
• 出版年：November, 2013
• 年：2013
• 卷：62
• 期：11
• 页码：1623-1632
• 全文大小：1973 K

文摘

Objective

CCR2 inhibition has produced promising experimental and clinical anti-hyperglycemic effects. These results support the thesis that insulin resistance and Type 2 diabetes (T2D) are associated with chronic unresolved inflammation. The aim of this study was to provide a broad analysis of the various physiological changes occurring in mouse models of T2D in connection with pharmacological CCR2 inhibition.

Materials/Methods

A mouse-active chemical analogue of the clinical candidate CCX140-B was tested in diet-induced obese (DIO) mice and db/db mice. Measurements included: adipose tissue inflammatory macrophage counts; peripheral blood glucose levels at steady-state and after glucose and insulin challenges; peripheral blood insulin and adiponectin levels; 24-h urine output and urinary glucose levels; pancreatic islet number and size; hepatic triglyceride and glycogen content; and hepatic glucose-6-phosphatase levels.

Results

In DIO mice, the CCR2 antagonist completely blocked the recruitment of inflammatory macrophages to visceral adipose tissue. The mice exhibited reduced hyperglycemia and insulinemia, improved insulin sensitivity, increased circulating adiponectin levels, decreased pancreatic islet size and increased islet number. It also reduced urine output, glucose excretion, hepatic glycogen and triglyceride content and glucose 6-phosphatase levels. Similar effects were observed in the db/db diabetic mice.

Conclusions

These data indicate that pharmacological inhibition of CCR2 in models of T2D can reduce inflammation in adipose tissue, alter hepatic metabolism and ameliorate multiple diabetic parameters. These mechanisms may contribute to the promising anti-diabetic effects seen in humans with at least one CCR2 antagonist.