摘要 :
Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in...
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Like other peptide hormones, glucose-dependent insulinotropic polypeptide (GIP) is rapidly cleared from the circulation. Dipeptidyl peptidase-4 (DPP-4) is known to be involved. Information on the overall pharmacokinetics of GIP in rodents is, however, lacking. We investigated the pharmacokinetics of exogenous GIP after intravenous, subcutaneous and intraperitoneal injection with and without DPP-4 inhibition in conscious female C57Bl/6 mice. Secondly, we compared total and intact GIP levels measured by an in-house RIA and commercially available ELISA kits to determine the suitability of these methods for in vivo and in vitro measurements. GIP half-life following intravenous injection amounted to 93 +/- 2 s, which was extended to 5 +/- 0.6 min by inhibition of DPP-4. Intact GIP levels following subcutaneous and intraperitoneal GIP administration were approximately 15 % of total GIP. The area under the curve of intact GIP (GIP exposure) following GIP injection was significantly increased by DPP-4 inhibition, whereas total GIP levels remained unchanged. We found significant variation between measurements of total, but not intact GIP performed with our in-house RIA and ELISAs in samples obtained after in vivo administration of GIP. Different preanalytical sample preparation (EDTA plasma, heparin plasma, assay buffer and PBS) significantly influenced results for all ELISA kits used. Thus, in experiments involving exogenous GIP(1-42) administration in mice, it is important to consider that this will result in a very low ratio of intact:total peptide but co-administration of a DPP-4 inhibitor greatly elevates this ratio. Furthermore, for comparison of GIP levels, it is essential to maintain uniformity concerning assay methodology and sample preparation.
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摘要 :
The increase in insulin response to oral glucose compared with glucose given by intravenous injection is termed the incretin effect and is mediated by two peptide hormones secreted from the gut in response to nutrient intake: gluc...
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The increase in insulin response to oral glucose compared with glucose given by intravenous injection is termed the incretin effect and is mediated by two peptide hormones secreted from the gut in response to nutrient intake: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic beta-cells. Both the GLP-1 receptor and the GIP receptor are members of the secretin family of G protein-coupled receptors and couple positively with adenylate cyclase, resulting in an increase in intracellular cAMP. In the present study, we investigated the activity of six previously reported peptide ligands at both the GLP-1 and GIP receptors expressed on HEK-293 cells using a highly sensitive reporter gene assay. GLP-1 and GIP demonstrated almost 100,000-fold selectivity for their respective receptors. Exendin 4 (Ex-4), a long-acting GLP-1 receptor agonist, displayed considerable activity at the GIP receptor. Exendin 9-39 (Ex 9-39) was able to block activity at both the GLP-1 and GIP receptors, and Pro3GIP, a previously-reported GIP receptor antagonist, was shown to act as a partial agonist at the GIP receptor. These data highlight the need for more selective antagonists to study these therapeutically important receptors.
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摘要 :
Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimu...
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Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30) NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TAG uptake. So far, there are no studies with a GIPR antagonist in patients with type 2 diabetes (T2D), but because the elevations in fasting plasma glucagon and paradoxical postprandial glucagon excursions, seen in patients with T2D, are aggravated by GIP, a GIPR antagonist could partly alleviate this and possibly improve the fasting and postprandial glycemia. Since the majority of patients with T2D are overweight, inhibition of GIP-induced fat deposition may be beneficial as well. Here we summarize the studies of GIPR antagonists and discuss the therapeutic potential of the GIP system in humans.
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Glucose-dependent insulinotropic polypeptide (GIP) is absolutely crucial in order to obtain optimal bone strength and collagen quality. However, as the GIPR is expressed in several tissues other than bone, it is difficult to ascer...
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Glucose-dependent insulinotropic polypeptide (GIP) is absolutely crucial in order to obtain optimal bone strength and collagen quality. However, as the GIPR is expressed in several tissues other than bone, it is difficult to ascertain whether the observed modifications of collagen maturity, reported in animal studies, were due to direct effects on osteoblasts or indirect through regulation of signals originating from other tissues. The aims of the present study were to investigate whether GIP can directly affect collagen biosynthesis and processing in osteoblast cultures and to decipher which molecular pathways were necessary for such effects.
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摘要 :
Glucose-dependent insulinotropic polypeptide (GIP), a peptide released from the intestines after meals, is thought to stimulate insulin secretion. GIP receptor cDNA has recently been cloned and its mRNA has been recognized in seve...
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Glucose-dependent insulinotropic polypeptide (GIP), a peptide released from the intestines after meals, is thought to stimulate insulin secretion. GIP receptor cDNA has recently been cloned and its mRNA has been recognized in several organs including the pituitary, but the physiological roles of GIP receptors of the pituitary have yet to be determined. We have demonstrated the possibility that GIP stimulates GH secretions from the pituitary adenoma cells of acromegalics. GIP-stimulated GH responses were studied in four acromegalics. In two acromegalics whose GH showed paradoxical secretion to oral glucose tolerance test (OGTT), GIP infusion (0.6μg/kg/h) drove GH secretion (13.7 to 68.1, 22.5 to 76.2 ng/ml, respectively). However, in the other two acromegalics whose GH showed no paradoxical response to OGTT, GIP infusion did not induce GH secretion. One of the patients who was studied extensively had a GH that responded to OGTT. This patient's serum GH levels increased after meals while adenomectomy abolished both the paradoxical GH secretions by OGTT and GH responses to the GIP infusion. These data suggested that some somatotroph adenoma cells have an aberrant response to GIP which may go toward explaining paradoxical GH secretions to OGTT in acromegalics.
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