{"id":449,"date":"2017-04-10T22:30:57","date_gmt":"2017-04-11T03:30:57","guid":{"rendered":"http:\/\/www.creative-peptides.com\/blog\/?p=449"},"modified":"2017-04-10T22:32:13","modified_gmt":"2017-04-11T03:32:13","slug":"the-incretin-hormones-glp-1-and-gip","status":"publish","type":"post","link":"https:\/\/www.creative-peptides.com\/blog\/the-incretin-hormones-glp-1-and-gip\/","title":{"rendered":"The incretin hormones: GLP-1 and GIP"},"content":{"rendered":"

Glucagon-like peptide-1(GLP-1)<\/a> and glucose-depended insulinotropic polypeptide<\/a>
\n(GIP)<\/a> are the two peptides that have been confirmed to act as incretin hormones to
\ndate. GIP was the first incretin hormone identified. It was originally isolated from
\ncrude extracts of porcine small intestine. Based on its ability to inhibit gastric acid
\nsecretion in dogs, it was initially named gastric inhibitory polypeptide <\/em>(GIP),.\u00a0Using more purified GIP, Dupre et al. <\/em>showed that GIP could also stimulate\u00a0insulin secretion in animals and human. Subsequently, it was found that GIP can act\u00a0directly on pancreatic islets to stimulate insulin secretion. Since the effect of\u00a0GIP on stimulation of insulin secretion was seen at physiologic levels while inhibitory\u00a0effect of GIP on gastric acid secretion occurred at pharmacologic doses, GIP was then\u00a0renamed glucose-dependent insulinotropic polypeptide in order to reflect its\u00a0physiologic action. Secreted from K cell of the proximal small intestine, GIP is\u00a0stimulated by enteral glucose, lipids, and products of meal digestion in a\u00a0dose-dependent manner. Further studies showed that GIP only contributes to the\u00a0partial incretin effect in vivo<\/em>, because immunological depletion of GIP reduced but\u00a0did not abolish all insulin-stimulating activity of gut extracts.<\/p>\n

GLP-1, another incretin hormone, was identified after the cloning and sequencing\u00a0of the cDNA and genes encoding human proglucagon. The proglucagon gene\u00a0encodes two peptides that share about 50% sequence homology to glucagon. The two\u00a0peptides were named glucagon-like peptide-1 (GLP-1) and glucogan-like peptide-2\u00a0(GLP-2). After tissue-specific proteolytically posttranslational processing, GLP-1 is\u00a0released from L cell of lower intestine and colon in response to nutrient ingestion.\u00a0GLP-1 stimulates glucose-dependent insulin secretion in isolated islets as well as in\u00a0human, whereas GLP-2 was unable to stimulate insulin secretion and is not\u00a0an incretin hormone.<\/p>\n

Regulation of GLP-1\u00a0and GIP secretion<\/p>\n

GLP-1<\/a> is secreted from enteroendocrine L cells in the distal intestine in response\u00a0to food ingestion. Glucose and fatty acids in food are the primary physiologic\u00a0stimuli for GLP-1 secretion. Administration of mixed meals or individual\u00a0nutrients such as glucose or other sugars, fatty acids, essential amino acids, and\u00a0dietary fiber all can stimulate GLP-1 secretion. In humans, oral but not intravenous\u00a0glucose administration stimulates GLP-1 secretion. It was also reported that\u00a0zein hydrolysate (a hydrolysate prepared from zein: a major corn protein) stimulated\u00a0GLP-1 secretion directly in the ileum and indirectly in the duodenum in rat. It\u00a0was found that nutrients stimulated GLP-1 secretion through two alternative pathways:\u00a0one is via direct contact with L cells and the other is through indirect information\u00a0transfer. GLP-1 secretion generally includes two phases: an early phase occurred at 10\u00a0to 15 minutes and the second phase occurred at 30 to 60 minutes after oral nutrient\u00a0ingestion. It seems that the second phase of GLP-1 secretion is caused by direct\u00a0contact of nutrients with L cells in the distal small intestine, while it is unlikely that\u00a0the early phase of GLP-1 secretion is caused by the same mechanism since it takes\u00a0more than 15 minutes for nutrients to get to the distal small intestine after oral meal\u00a0uptake. This suggests that the existence of a proximal gut signal regulating GLP-1\u00a0release from the L cells of the distal small intestine.<\/p>\n

Many agents that can directly stimulate GLP-1 secretion have been identified in\u00a0various models of the intestinal L cell, including a perfused model of the rat ileum, a murine intestinal endocrine cell line, and a primary cell culture of fetal rat intestinal cells. It was found that GIP, gastrin-releasing peptide (GRP), calcitonin gene-related\u00a0peptide, and agonists of acetylcholine all can contribute to the rapid GLP-1 secretion (40-42). It has also been shown that leptin significantly stimulated GLP-1 secretion\u00a0(by up to 250% of the control) from fetal rat intestinal cells, a mouse L cell line\u00a0(GLUTag), and a human L cell line (NCI-H716) in a dose-dependent manner.\u00a0Moreover, leptin also stimulated GLP-1 secretion in rat and ob\/ob <\/em>mouse models.\u00a0However, high fat diet induced obese and diabetic mice showed decreased GLP-1\u00a0secretion in response to oral glucose administration. It was reported that\u00a0autonomic nervous system plays an important role in the regulation of\u00a0nutrient-induced GLP-1 secretion. Study in an in situ <\/em>model of the rat gastrointestinal\u00a0system showed that both corn oil and electrical stimulation of the celiac branches of\u00a0the vagus can significantly increase GLP-1 secretion, whereas bilateral\u00a0subdiaphragmatic vagotomy completely inhibited fat-induced GLP-1 secretion.\u00a0Recently, studies using murine GLP-1-producing enteroendocrine cell lines showed\u00a0that, at the cellular level, sodium-dependent glucose co-transporters and sweet taste\u00a0receptor T1R3 mediate glucose-induced GLP-1 secretion. It also reported that\u00a0fatty acid receptors GPR40 and GPR120 mediate fatty acids-induced GLP-1 secretion. In addition, GLP-1 secretion is also associated with activation of a number\u00a0of intracellular signaling pathways including PKA, PKC, calcium, and MAPK.<\/p>\n

GIP<\/a> secretion is triggered by the ingestion of carbohydrate or fatty acids in\u00a0intestinal K cells, which are located in the duodenal and jejunal epithelia. GIP\u00a0is secreted 10 to 20 minutes after oral nutrients. Because the GIP-containing\u00a0K cells are predominantly located in the duodenum and proximal jejunum and have\u00a0apical surfaces opening into the gut lumen, GIP secretion is believed to be\u00a0triggered by a direct nutrient contact with K cells. Studies on isolated perfused rodent\u00a0intestine have suggested that carbohydrate detection by K cells involves the\u00a0sodium-dependent sugar uptake pathway, which is consistent with the structural\u00a0requirements for activation of the intestinal Na+<\/sup>-coupled glucose transporters.\u00a0In contrast, the inhibitor of sodium-dependent glucose transporter 1 phloridzin\u00a0inhibited glucose-stimulated GIP secretion in rodent intestine. Because there is a\u00a0lack of validated cell models for studying GIP release in vitro, little is known about\u00a0how K cells respond to glucose and other stimuli at the cellular and molecular levels.\u00a0Several studies in cultured canine endocrine cells suggested that activation of\u00a0adenylyl cyclase, increases in intracellular calcium ion levels, K+<\/sup>-mediated\u00a0depolarization, glucose, GRP, and beta-adrenergic stimulation can increase GIP\u00a0secretion.<\/p>\n

 <\/p>\n

Reference:<\/h4>\n

Zhangfang,Kang.\u00a0Impaired Incretin Effects in Type 2 Diabetes:\u00a0Mechanism and Therapeutic Implication. The Chinese University of Hong Kong, 2012<\/p>\n","protected":false},"excerpt":{"rendered":"

Glucagon-like peptide-1(GLP-1) and glucose-depended insulinotropic polypeptide (GIP) are the two peptides that have been confirmed to act as incretin hormones to date. GIP was the first incretin hormone identified. It …<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[5],"tags":[88,87],"_links":{"self":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/449"}],"collection":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/comments?post=449"}],"version-history":[{"count":2,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/449\/revisions"}],"predecessor-version":[{"id":451,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/posts\/449\/revisions\/451"}],"wp:attachment":[{"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/media?parent=449"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/categories?post=449"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.creative-peptides.com\/blog\/wp-json\/wp\/v2\/tags?post=449"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}