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 was originally isolated from
crude extracts of porcine small intestine. Based on its ability to inhibit gastric acid
secretion in dogs, it was initially named gastric inhibitory polypeptide (GIP),. Using more purified GIP, Dupre et al. showed that GIP could also stimulate insulin secretion in animals and human. Subsequently, it was found that GIP can act directly on pancreatic islets to stimulate insulin secretion. Since the effect of GIP on stimulation of insulin secretion was seen at physiologic levels while inhibitory effect of GIP on gastric acid secretion occurred at pharmacologic doses, GIP was then renamed glucose-dependent insulinotropic polypeptide in order to reflect its physiologic action. Secreted from K cell of the proximal small intestine, GIP is stimulated by enteral glucose, lipids, and products of meal digestion in a dose-dependent manner. Further studies showed that GIP only contributes to the partial incretin effect in vivo, because immunological depletion of GIP reduced but did not abolish all insulin-stimulating activity of gut extracts.

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

Regulation of GLP-1 and GIP secretion

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

Many agents that can directly stimulate GLP-1 secretion have been identified in various 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 peptide, 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 (by up to 250% of the control) from fetal rat intestinal cells, a mouse L cell line (GLUTag), and a human L cell line (NCI-H716) in a dose-dependent manner. Moreover, leptin also stimulated GLP-1 secretion in rat and ob/ob mouse models. However, high fat diet induced obese and diabetic mice showed decreased GLP-1 secretion in response to oral glucose administration. It was reported that autonomic nervous system plays an important role in the regulation of nutrient-induced GLP-1 secretion. Study in an in situ model of the rat gastrointestinal system showed that both corn oil and electrical stimulation of the celiac branches of the vagus can significantly increase GLP-1 secretion, whereas bilateral subdiaphragmatic vagotomy completely inhibited fat-induced GLP-1 secretion. Recently, studies using murine GLP-1-producing enteroendocrine cell lines showed that, at the cellular level, sodium-dependent glucose co-transporters and sweet taste receptor T1R3 mediate glucose-induced GLP-1 secretion. It also reported that fatty 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 of intracellular signaling pathways including PKA, PKC, calcium, and MAPK.

GIP secretion is triggered by the ingestion of carbohydrate or fatty acids in intestinal K cells, which are located in the duodenal and jejunal epithelia. GIP is secreted 10 to 20 minutes after oral nutrients. Because the GIP-containing K cells are predominantly located in the duodenum and proximal jejunum and have apical surfaces opening into the gut lumen, GIP secretion is believed to be triggered by a direct nutrient contact with K cells. Studies on isolated perfused rodent intestine have suggested that carbohydrate detection by K cells involves the sodium-dependent sugar uptake pathway, which is consistent with the structural requirements for activation of the intestinal Na+-coupled glucose transporters. In contrast, the inhibitor of sodium-dependent glucose transporter 1 phloridzin inhibited glucose-stimulated GIP secretion in rodent intestine. Because there is a lack of validated cell models for studying GIP release in vitro, little is known about how K cells respond to glucose and other stimuli at the cellular and molecular levels. Several studies in cultured canine endocrine cells suggested that activation of adenylyl cyclase, increases in intracellular calcium ion levels, K+-mediated depolarization, glucose, GRP, and beta-adrenergic stimulation can increase GIP secretion.

 

Reference:

Zhangfang,Kang. Impaired Incretin Effects in Type 2 Diabetes: Mechanism and Therapeutic Implication. The Chinese University of Hong Kong, 2012