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GIP (human) Sale

(Synonyms: 抑胃肽; Gastric Inhibitory Peptide (GIP), human) 目录号 : GC17838

GIP(人)是一种由42个氨基酸组成的肽激素,是葡萄糖依赖性胰岛素分泌的刺激剂和胃酸分泌的弱抑制剂。

GIP (human) Chemical Structure

Cas No.:100040-31-1

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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Kinase experiment [1]:

Preparation Method

The cells were grown and transfected as described in GIP Receptor Signaling.125I labeled GIP was used as radioligand, and the competition binding analysis was performed on intact cells, seeded at a concentration of 50,000 cells/well, on the second day after transfection, the cells were incubated for 16 h at 4°C in 0.25 ml of buffer consisting of 25 mM Tris HCl, pH 7.4, and 5 mM MgCl2, using 15 pM 125I-GIP as radioligand. Increasing concentrations of unlabeled GIP, ranging from 10-11 to 10-6 M, were used as competitors. The competition binding was terminated by washing the cells once with 1 ml of binding buffer, and subsequently, the cells were lysed by the addition of 1 ml of lysis buffer (8 M carbamide, 3 M acetic acid, 2% Nonidet-P 40). The binding data were analyzed and IC50 values determined using nonlinear regression analysis.

Reaction Conditions

16 h at 4°C

Applications

For the homologous competition binding, IC50 value of GIP was observed to be 5.2 nM.

Cell experiment [2]:

Cell lines

3T3-L1 cells

Preparation Method

Following incubation of 3T3-L1 cells, for the time periods indicated in figure legends, GIP in the incubation medium were precipitated with 1/10 vol. of 7% (wt/vol) ZnSO4, incubated on ice for 10 min, and 1/5 vol. 0.1 m NaOH added at room temp. The mixture was centrifuged and the supernatant assayed for glycerol with an enzymatic assay.

Reaction Conditions

10 min

Applications

GIP stimulated glycerol release with an EC50 of 3.28 +/- 0.63 Nm.

Animal experiment [1]:

Animal models

Male Wistar rats (390–440 g, 12 wk old)

Preparation Method

GIP was dissolved in 0.9% NaCl containing 1% HSA and infused into the arterial line with the use of a syringe pump to give final perfusate concentrations of 1 nM GIP. After a basal period, peptides were infused alone for 10-min periods separated by 15-min rest periods, during which time endocrine secretion returned to basal levels.

Dosage form

1 nM GIP

Applications

Perfusion of the pancreas with 1 nM GIP increased insulin secretion significantly (P<0.001) relative to basal secretion during perfusion with 10 mM glucose alone.

References:

[1]. Deacon CF, Plamboeck A, Rosenkilde MM, de Heer J, Holst JJ. GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations. Am J Physiol Endocrinol Metab. 2006 Sep;291(3):E468-75.

[2]. McIntosh CH, Bremsak I, Lynn FC, Gill R, Hinke SA, Gelling R, Nian C, McKnight G, Jaspers S, Pederson RA. Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin. Endocrinology. 1999 Jan;140(1):398-404.

产品描述

Gastric inhibitory polypeptide, also known as glucose-dependent insulinotropic polypeptide (GIP), is a 42-amino acid peptide that plays an important role in maintaining glucose and lipid homeostasis. Although originally discovered as an inhibitor of gastric acid secretion, its principal physiological property is its role as an incretin peptide, in which it mediates the enteroinsular axis. GIP is synthesized by enteroendocrine K-cells of the duodenum/proximal jejunum, and its secretion is stimulated postprandially. GIP signaling stimulates glucose absorption in enterocytes, potentiates endogenous glucose-dependent insulin release from islet beta-cells, increases glucose uptake while inhibiting lipolysis in adipocytes, increases nutrient uptake into bone, and inhibits bone resorption [1].

The competition binding experiments were carried out in transiently transfected COS-7 cells using 125I GIP as radioligand. For the homologous competition binding, an IC50 value of 5.2 nM was observed [2]. GIP receptor messenger RNA was detected by RT-PCR and RNase protection assay. Receptors were detected in binding studies (IC50 26.7 +/- 0.7 nM). GIP stimulated glycerol release with an EC50 of 3.28 +/- 0.63 nM [3].

Perfusion of the pancreas with 1 nM GIP increased insulin secretion significantly (P[2]. The effects of GIP on fat metabolism in vivo may depend upon the circulating insulin level, and that meal-released GIP may elevate circulating fatty acids, thus optimizing pancreatic β-cell responsiveness to stimulation by glucose and GIP [3].

References:
[1].Zhang CY, Boylan MO, Arakawa H, Wolfe MM. Effects of gastric inhibitory polypeptide (GIP) immunoneutralization on mouse motor coordination and memory. Peptides. 2020 Mar;125:170227.
[2].Deacon CF, Plamboeck A, Rosenkilde MM, de Heer J, Holst JJ. GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations. Am J Physiol Endocrinol Metab. 2006 Sep;291(3):E468-75.
[3].McIntosh CH, Bremsak I, Lynn FC, Gill R, Hinke SA, Gelling R, Nian C, McKnight G, Jaspers S, Pederson RA. Glucose-dependent insulinotropic polypeptide stimulation of lipolysis in differentiated 3T3-L1 cells: wortmannin-sensitive inhibition by insulin. Endocrinology. 1999 Jan;140(1):398-404.

胃抑制多肽,也称为葡萄糖依赖性促胰岛素多肽 (GIP),是一种由 42 个氨基酸组成的肽,在维持葡萄糖和脂质稳态方面发挥着重要作用。虽然最初被发现是胃酸分泌的抑制剂,但其主要生理特性是其作为肠促胰岛素肽的作用,在该肽中它介导肠岛叶轴。 GIP 由十二指肠/近端空肠的肠内分泌 K 细胞合成,其分泌在餐后受到刺激。 GIP 信号刺激肠细胞对葡萄糖的吸收,增强胰岛 β 细胞释放内源性葡萄糖依赖性胰岛素,增加葡萄糖摄取,同时抑制脂肪细胞的脂肪分解,增加骨骼对营养的摄取,并抑制骨吸收[1] .

竞争结合实验是在瞬时转染的 COS-7 细胞中进行的,使用 125I GIP 作为放射配体。对于同源竞争结合,观察到 IC50 值为 5.2 nM [2]。通过RT-PCR和RNase保护试验检测GIP受体信使RNA。在结合研究中检测到受体 (IC50 26.7 +/- 0.7 nM)。 GIP 刺激甘油释放,EC50 为 3.28 +/- 0.63 nM [3]

用 1 nM GIP 灌注胰腺可显着增加胰岛素分泌(P[2]。GIP 对体内脂肪代谢的影响可能取决于循环中的胰岛素水平,而膳食释放的GIP 可能会增加循环脂肪酸,从而优化胰腺 β 细胞对葡萄糖和 GIP 刺激的反应性[3]

Chemical Properties

Cas No. 100040-31-1 SDF
别名 抑胃肽; Gastric Inhibitory Peptide (GIP), human
Canonical SMILES CC[C@]([C@@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/C/N=C(O)/[C@](/N=C(O)/[C@](/N=C(O)/[C@](N)([H])CC1=CC=C(O)C=C1)([H])C)([H])CCC(O)=O)([H])[C@@](O)([H])C)([H])CC2=CC=CC=C2)([H])[C@@](CC)([H])C)
分子式 C226H338N60O66S 分子量 4983.58
溶解度 Soluble to 1 mg/ml in water 储存条件 Desiccate at -20°C
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Research Update

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.

Biology of incretins: GLP-1 and GIP

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.

GIP_HUMAN[22-51] is a new proatherogenic peptide identified by native plasma peptidomics

We recently established a new plasma peptidomic technique and comprehensively identified a large number of low-molecular weight and low-abundance native peptides using a single drop of human plasma. To discover a novel polypeptide that potently modulates the cardiovascular system, we performed a bioinformatics analysis of the large-scale identification results, sequentially synthesized the selected peptide sequences, tested their biological activities, and identified a 30-amino-acid proatherogenic peptide, GIP_HUMAN[22-51], as a potent proatherosclerotic peptide hormone. GIP_HUMAN[22-51] has a common precursor with the glucose-dependent insulinotropic polypeptide (GIP) and is located immediately N-terminal to GIP. Chronic infusion of GIP_HUMAN[22-51] into ApoE-/- mice accelerated the development of aortic atherosclerotic lesions, which were inhibited by co-infusions with an anti-GIP_HUMAN[22-51] antibody. GIP_HUMAN[22-51] increased the serum concentrations of many inflammatory and proatherogenic proteins, whereas neutralising antibodies reduced their levels. GIP_HUMAN[22-51] induced IκB-α degradation and nuclear translocation of NF-κB in human vascular endothelial cells and macrophages. Immunoreactive GIP_HUMAN[22-51] was detected in human tissues but there was no colocalization with the GIP. The plasma GIP_HUMAN[22-51] concentration in healthy humans determined using a stable-isotope tagged peptide was approximately 0.6 nM. This study discovered a novel endogenous proatherogenic peptide by using a human plasma native peptidomic resource.

Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice

Objective: Pharmacological strategies that engage multiple mechanisms-of-action have demonstrated synergistic benefits for metabolic disease in preclinical models. One approach, concurrent activation of the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptors (i.e. triagonism), combines the anorectic and insulinotropic activities of GLP-1 and GIP with the energy expenditure effect of glucagon. While the efficacy of triagonism in preclinical models is known, the relative contribution of GcgR activation remains unassessed. This work aims to addresses that central question.
Methods: Herein, we detail the design of unimolecular peptide triagonists with an empirically optimized receptor potency ratio. These optimized peptide triagonists employ a protraction strategy permitting once-weekly human dosing. Additionally, we assess the effects of these peptides on weight-reduction, food intake, glucose control, and energy expenditure in an established DIO mouse model compared to clinically relevant GLP-1R agonists (e.g. semaglutide) and dual GLP-1R/GIPR agonists (e.g. tirzepatide).
Results: Optimized triagonists normalize body weight in DIO mice and enhance energy expenditure in a manner superior to that of GLP-1R mono-agonists and GLP-1R/GIPR co-agonists.
Conclusions: These pre-clinical data suggest unimolecular poly-pharmacology as an effective means to target multiple mechanisms contributing to obesity and further implicate GcgR activation as the differentiating factor between incretin receptor mono- or dual-agonists and triagonists.

The pathogenic role of the GIP/GIPR axis in human endocrine tumors: emerging clinical mechanisms beyond diabetes

The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic β-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet β-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.