Study on a network of gut signals and development of diabetes

胃抑制多肽（GIP）是一种十二指肠激素，主要由摄入的脂肪吸收诱导分泌。我们的研究显示，GIP受体敲除小鼠在口服葡萄糖负荷后具有较高的血糖水平，并且初始胰岛素反应受损。喂食高脂饮食的GIP受体敲除小鼠明显地免受肥胖和胰岛素抵抗的影响，Kir6.2和GIP受体双敲除小鼠中胰岛素应答几乎完全丧失，并且GIP受体敲除小鼠中的骨形成参数显著较低，并且GIP受体敲除小鼠具有较薄的骨小梁。这些结果以及GIP不仅直接作用于胰腺B细胞而且还作用于脂肪细胞和成骨细胞的体外研究表明，由GIP介导的早期胰岛素分泌决定了口服葡萄糖负荷后的葡萄糖耐量，GIP直接将营养过剩与肥胖联系起来，GIP是KATP通道缺陷小鼠中响应于葡萄糖负荷的胰岛素分泌中的主要促胰岛素因子，因此，在胰岛素分泌受损的糖尿病中，如在日本主要观察到的，GIP信号传导应当被GIP受体激动剂或DPPIV抑制剂激活，并且在胰岛素抵抗的糖尿病中应当被GIP受体拮抗剂抑制，如在西方国家主要观察到的。

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat.. Our studies revealed that GIP receptor knockout mice have higher blood glucose levels with impaired initial insulin response after oral glucose load., that GIP receptor knockout mice fed a high-fat diet were clearly protected from both the obesity and the insulin resistance, that the insulin response was almost completely lost in Kir6.2 and GIP receptor double knockout mice, and that bone formation parameters in the GIP receptor knockout mice were significantly lower and the GIP receptor knockout mice had thinner trabeculae. These results and the in vitro studies that GIP directly acts not onlypancreatic b-cells but also adipocytes and osteoblasts indicated that early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load, that GIP directly links overnutrition to obesity, that GIP is the major insulinotropic factor in the secretion of insulin in response to glucose load in KATP channel-deficient mice, and that GIP directly links calcium contained in meal to calcium deposition on bone.Therefore, GIP signaling should be activated by GIP receptor agonists or DPPIV inhibitors in diabetes with impaired insulin secretion, such as predominantly observed in Japan, and should be inhibited by GIP receptor antagonists in diabetes with insulin resistance, such as predominantly observed in western countries.