The Enteroinsular Axis
Emmanuel Opara in NUTRITION and DIABETES, 2005
GIP was isolated from porcine intestine in 1969, and, initially characterized for its ability to inhibit gastric-acid secretion, was named gastric-inhibitory polypeptide. However, it was quickly found to be a potent insulin secretogogue [4, 5] and was renamed glucose-dependent insulinotropic polypeptide (retaining the acronym GIP) to reflect the biological role which was perceived to be the more relevant. GIP alone does not account for the entire incretin effect, as was demonstrated initially by the retention of an incretin effect following GIP immunoneutralization [6] and, subsequently, in studies with GIP receptor antagonists [7]. A second biologically active incretin, GLP 1, was later identified. GLP 1, the product of differential processing of the preproglucagon gene in the gut, is a powerful insulinotropic factor, more powerful, on a molar basis, than GIP [8]. The relative importance of these two hormones in the enteroinsular axis, particularly in diabetes, is a source of continuing debate, [9, 10] but together they account for most, if not the entire, incretin effect.
Regulation of Food Intake
Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss in Nutrition and Cardiometabolic Health, 2017
The enteroendocrine L cells form an important part of the gut–brain axis. They express the preproglucagon gene, which undergoes tissue-specific posttranslational processing, that is, it generates different hormonal products when processed in different organs, such as the pancreas or intestine. The prohormone convertase 1 is responsible for the production of GLP-1, glucagon-like peptide-2 (GLP-2), and OXM from proglucagon in the intestine [80]. L cells in the intestine co-secrete different gut peptides depending on their location. The upper small intestinal cells secrete gastric inhibitory polypeptide (GIP). The lower small intestinal cells co-secrete GLP-1 and PYY, and these are important for energy homeostasis. Both GLP-1 and PYY are secreted in a biphasic manner with a first phase of release on arrival of food in the proximal small intestine, which is neurally mediated, and a second phase when food reaches the distal intestine through a nutrient receptor–mediated process [81].
Biocatalyzed Synthesis of Antidiabetic Drugs
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Incretins are gut hormones that potentiate insulin secretion after meal ingestion in a glucose-dependent manner (Campbell and Drucker, 2013). The incretin effect, a term that refers to the observation that orally administered glucose results in a larger increase in plasma insulin levels and insulin-dependent decrease in blood glucose concentration when compared to the same amount of glucose given intravenously (Rondas et al., 2013), is responsible for 50%-70% insulin production. The two best studied incretins are glucose-dependent insulinotropic polypeptide (also named gastric inhibitory polypeptide, GIP), a 42 amino acid peptide synthesized in and secreted from enteroendocrine K cells located primarily in the duodenum and proximal jejunum, although CNS production of GIP has also been described);glucagon-like peptide-1 (GLP-1) a 30 amino acid residue peptide, originated from preproglucagon, synthesized in the l-cells in the distal ileum, in the pancreas and in the brain.
Design of novel therapeutics targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) to aid weight loss
Published in Expert Opinion on Drug Discovery, 2023
The remainder of the review will focus on how GLP-1R-based therapies are being improved by the addition of drugs targeting GIPR. GIP is a 42 amino acid peptide derived from the pre-pro-GIP gene, found in the enteroendocrine K cells present in the duodenum and the upper jejunum. It was discovered prior to GLP-1 in the early 1970s by Brown and Pederson working at the University of British Columbia [16]. GIP was initially believed to be an enterogastrone, an acid inhibitory factor that is released from the small intestinal mucosa by fat. Thus, it was given the name gastric inhibitory polypeptide. However, shortly after its initial discovery, Dupre, in collaboration with Brown, showed that an intravenous infusion of GIP in humans during a glucose tolerance test potentiated insulin secretion [17]. This finding was mirrored ex vivo, as Pederson showed that GIP could increase insulin secretion in a perfused rat pancreas in a glucose-dependent manner [18]. It quickly became apparent that its incretin action was a more important function of the peptide, and thus GIP became known as glucose-dependent insulinotropic polypeptide. In fact, in normal physiology, GIP is overall a more important contributor to the incretin effect than GLP-1, although in type 2 diabetes, GIP becomes less effective due to GIP resistance, whereas GLP-1 retains its incretin activity.
The safety of lanreotide for neuroendocrine tumor
Published in Expert Opinion on Drug Safety, 2019
Amandeep Godara, Nauman S. Siddiqui, Margaret M. Byrne, Muhammad Wasif Saif
In summary, most of the biological effects of somatostatin are inhibitory. It inhibits gastric, pancreatic, biliary, and even salivary secretions, in addition to inhibiting the release of a broad variety of GI hormones, such as gastrin, cholecystokinin, secretin, pancreatic polypeptide, gastric inhibitory polypeptide (GIP), motilin, glucagon, and insulin. Somatostatin also inhibits motor events along the GI tract, including lowering the rate of gastric emptying, decreasing the splanchnic and portal blood flow. As an analog of somatostatin, lanreotide is a long-acting cyclic agonist peptide that has shown benefit in the treatment of GI hormone-secreting tumors, diarrheal disorders, and carcinoid syndrome. Health-care providers should be aware of the potential AEs associated with lanreotide and closely monitor for these toxicities as well as drug–drug interactions. However, these issues are quite manageable but increased awareness of these adverse effects can markedly reduce these incapacitating side effects and subsequently, could increase quality of life for patients.
Applications of multiple reaction monitoring targeted proteomics assays in human plasma
Published in Expert Review of Molecular Diagnostics, 2019
Georgia Kontostathi, Manousos Makridakis, Jerome Zoidakis, Antonia Vlahou
Miyachi et al. [93] established an MRM assay for the quantification of the active (GIP1 − 42) and inactive (GIP3 − 42) forms of the gastric inhibitory polypeptide (GIP). The latter is a peptide hormone secreted by duodenal cells after absorption of glucose or fat, of relevance especially to diabetic patients, since antidiabetic drugs (such as α-glucosidase inhibitors (α-GI) or dipeptidyl peptidase-4 (DPP-4) inhibitors) affect GIP levels. Sample processing included protein precipitation and digestion with Aspartase N for the generation of the targeted surrogate peptides (GIP1-8 and GIP 3–8). A detailed analytical evaluation of the presented MRM method was conducted, including interestingly, MRM3 (fragmentation of product ion) which increased specificity and sensitivity in the quantification of the active GIP. As a proof of principle, the plasma levels of the two GIP forms were measured in 96 plasma samples from 32 type-2 diabetic patients treated with sitagliptin or α-GI miglitol (Table S1). The ratio of active GIP1-42 to total GIP was significantly higher in patients treated with the former (sitagliptin) compared to miglitol, suggesting a potential higher efficacy of sitagliptin in diabetes treatment. This study is one of very few that evaluate drug effects in human plasma, but these initial findings must be validated in larger patient cohorts [93].
Related Knowledge Centers
- Gastric Acid
- Incretin
- Mucous Membrane
- Jejunum
- Insulin
- Releasing & Inhibiting Hormones
- Secretin Family
- Hormone
- Glucagon-Like Peptide-1
- Duodenum