期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 303, 期 6, 页码 E740-E751出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00328.2011
关键词
insulin; protein kinase B; glycogen synthase kinase-3; extracellular signal-regulated kinase; beta-catenin; adenosine 3', 5'-cyclic monophosphate response element-binding protein; Wnt; proglucagon; gut; L cells
资金
- Novo Nordisk (LIBRA)
- Canadian Institute for Health Research (CIHR)
- Canadian Diabetes Association (CDA)
- Juvenile Diabetes Research Foundation
- CIHR New Investigator Program
- CIHR
- CDA
Liu S, Liu R, Chiang Y, Song L, Li X, Jin T, Wang Q. Insulin detemir enhances proglucagon gene expression in the intestinal L cells via stimulating beta-catenin and CREB activities. Am J Physiol Endocrinol Metab 303: E740-E751, 2012. First published July 17, 2012; doi:10.1152/ajpendo.00328.2011.-Insulin therapy using insulin detemir (d-INS) has demonstrated weight-sparing effects compared with other insulin formulations. Mechanisms underlying these effects, however, remain largely unknown. Here we postulate that the intestinal tissues' selective preference allows d-INS to exert enhanced action on proglucagon (Gcg) expression and the production of glucagon-like peptide (GLP)-1, an incretin hormone possessing both glycemia-lowering and weight loss effects. To test this hypothesis, we used obese type 2 diabetic db/db mice and conducted a 14-day intervention with daily injection of a therapeutic dose of d-INS or human insulin (h-INS) in these mice. The body weight of the mice after 14-day daily injection of d-INS (5 IU/kg) was decreased significantly compared with those injected with the same dose of h-INS or saline. The weight-sparing effect of d-INS was associated with significantly elevated circulating levels of total GLP-1 and reduced food intake. Histochemistry analysis demonstrated that d-INS induced rapid phosphorylation of protein kinase B (Akt) in the gut L cells of normal mice. Western blotting showed that d-INS stimulated Akt activation in a more rapid and enhanced fashion in the mouse distal ileum compared with those by h-INS. In vitro investigation in primary fetal rat intestinal cell (FRIC) cultures showed that d-INS increased Gcg mRNA expression as determined by Northern blotting and real-time RT-PCR. Consistent with these in vivo investigations, d-INS significantly increased GLP-1 secretion in FRIC cultures. Consistently, d-INS was also shown to induce rapid phosphorylation of Akt in the clonal gut cell line GLUTag. Furthermore, d-INS increased beta-catenin phosphorylation, its nuclear translocation, and enhanced cAMP response element-binding protein (CREB) phosphorylation in a phosphatidylinositol 3-kinase and/or mitogen-activated protein kinase kinase/extracellular signal-regulated kinase-sensitive manner. We suggest that the weight-sparing benefit of d-INS in mice is related to its intestinal tissues preference that leads to profound stimulation of Gcg expression and enhanced GLP-1 secretion in intestinal L cells, potentially involving the activation of insulin/beta-catenin/CREB signaling pathways.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据