Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39.

Edwards, C. M. B.; Todd, Jeannie F; Mahmoudi, Maryam; Wang, Zhili; Wang, Ren Ming; Ghatei, Mohammed A.; Bloom, Stephen R.

doi:10.2337/diabetes.48.1.86

Cited by 325 publications

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“…It is strongly insulinotropic in mimicry experiments [38], and animal experiments involving an antagonist of the GLP-1 receptor have shown that GLP-1 is responsible for a substantial part of the insulin response to oral glucose [39,40]. Furthermore, experiments with the same antagonist in humans have suggested that GLP-1 might be essential for normal glucose tolerance [41]. In agreement with these observations, mice with a targeted deletion of the GLP-1 receptor become glucose intolerant and might develop fasting hyperglycaemia [42].…”

Section: Glucagon-like Peptide-1 (Glp-1)mentioning

confidence: 99%

Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging. The incretin effectThe incretin effect seems to play a major role in the regulation of glucose metabolism in healthy subjects. "The incretin effect" implies that ingestion of carbohydrates (glucose) causes the release from the intestinal mucosa of substances that enhance insulin secretion beyond the release caused by the absorbed glucose itself [1]. The effect can be quantified by comparing insulin or C-peptide responses to oral or intravenous glucose loads, adjusted to cause identical increases of plasma glucose concentrations. The much higher responses observed after oral administration

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Section: Glucagon-like Peptide-1 (Glp-1)mentioning

confidence: 99%

Incretins, insulin secretion and Type 2 diabetes mellitus

2004

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“…Moreover, the GLP-1 receptor antagonist exendin [9 -39] blocked the insulin secretory response after intraduodenal administration of glucose in rats (7). Later, Edwards et al (8) demonstrated a marked deterioration of oral glucose tolerance in healthy subjects during the administration of exendin [9 -39]. However, when GLP-1 was administered during meal ingestion, a dose-dependent deceleration of gastric emptying as well as a reduction in postprandial insulin secretion was found in healthy volunteers as well as in patients with type 2 diabetes (9,10).…”

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Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

et al. 2005

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Glucagon-like peptide 1 (GLP-1) has been proposed to act as an incretin hormone due to its ability to enhance glucose-stimulated insulin secretion. Because GLP-1 also decelerates gastric emptying, it physiologically reduces rather than augments postprandial insulin secretory responses. Therefore, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 ؎ 4 years, BMI 25.0 ؎ 4.9 kg/m 2 ) were studied with an infusion of GLP-1 (0.8 pmol ⅐ kg ؊1 ⅐ min ؊1 from ؊30 to 240 min) or placebo. On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at ؊30 min per oral), or erythromycin (200 mg intravenously from ؊30 to ؊15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml) was administered at 0 min. Capillary and venous blood samples were drawn for the determination of glucose (glucose oxidase), insulin, C-peptide, GLP-1, glucagon, gastric inhibitory polypeptide (GIP), and pancreatic polypeptide (specific immunoassays). Gastric emptying was assessed by the phenol red dilution technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P < 0.001). This was completely counterbalanced by erythromycin, whereas the other prokinetic drugs used had no effect. Postprandial glucose concentrations were lowered by GLP-1 (P < 0.001 vs. placebo), but this effect was partially reversed by erythromycin (P < 0.05). Insulin secretory responses to the meal were lower during GLP-1 administration (P < 0.05 vs. placebo). However, when erythromycin was added to GLP-1, insulin concentrations were similar to those in placebo experiments. The suppression of meal-related increments in glucagon secretion by GLP-1 was reversed by erythromycin (P < 0.001). The time course of GIP secretion was delayed during GLP-1 administration (P < 0.05), but when erythromycin was added, the pattern was similar to placebo experiments. GLP-1 administration led to a reduction in pancreatic polypeptide plasma concentrations (P < 0.05). In contrast, pancreatic polypeptide levels were markedly increased by erythromycin (P < 0.001). Intravenous erythromycin counteracts the deceleration of gastric emptying caused by GLP-1, probably by interacting with the parasympathetic nervous system (pancreatic polypeptide responses). Despite augmented rises in insulin secretion, the glucose-lowering effect of GLP-1 is markedly reduced when the deceleration of gastric emptying is antagonized, illustrating the importance of this facet of the multiple antidiabetic actions of GLP-1. Diabetes 54: 2212-2218, 2005 I nsulin secretion after meal ingestion is stimulated not only by the rise in glycemia, but also by the secretion of peptide hormones ("incretins") from the gut (1,2). The postprandial enhancement of insulin secretion by gut-derived factors is called the ...

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“…We reasoned that, if glucose sensing is involved, the BOLD response to either stimulus is expected to be similar (or even more pronounced in response to iv administration, depending on ensuing plasma glucose levels). If, on the other hand, insulin and/or gut peptides are involved, iv glucose administration should evoke a considerably less pronounced BOLD response, since infusion of glucose stimulates gut peptide and insulin release to a lesser extent than oral intake (14,18,20,24,41). …”

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Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion

Smeets¹,

Vidarsdottir²,

Graaf³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Smeets PA, Vidarsdottir S, de Graaf C, Stafleu A, van Osch MJ, Viergever MA, Pijl H, van der Grond J. Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion. Am J Physiol Endocrinol Metab 293: E754-E758, 2007. First published June 12, 2007; doi:10.1152/ajpendo.00231.2007.-We previously showed that hypothalamic neuronal activity, as measured by the blood oxygen level-dependent (BOLD) functional MRI signal, declines in response to oral glucose intake. To further explore the mechanism driving changes in hypothalamic neuronal activity in response to an oral glucose load, we here compare hypothalamic BOLD signal changes subsequent to an oral vs. an intravenous (iv) glucose challenge in healthy humans. Seven healthy, normal-weight men received four interventions in random order after an overnight fast: 1) ingestion of glucose solution (75 g in 300 ml) or 2) water (300 ml), and 3) iv infusion of 40% glucose solution (0.5 g/kg body wt, maximum 35 g) or 4) infusion of saline (0.9% NaCl, equal volume). The BOLD signal was recorded as of 8 min prior to intervention (baseline) until 30 min after. Glucose infusion was associated with a modest and transient signal decline in the hypothalamus. In contrast, glucose ingestion was followed by a profound and persistent signal decrease despite the fact that plasma glucose levels were almost threefold lower than in response to iv administration. Accordingly, glucose ingestion tended to suppress hunger more than iv infusion (P Ͻ 0.1). We infer that neural and endocrine signals emanating from the gastrointestinal tract are critical for the hypothalamic response to nutrient ingestion. functional magnetic resonance imaging; glucose homeostasis; insulin; incretins THE BLOOD OXYGEN LEVEL-DEPENDENT (BOLD) signal, produced by functional magnetic resonance imaging (fMRI), is a noninvasive measure of neuronal activity (19, 30,35). We (36, 37) have recently shown that the BOLD signal in the upper part of the hypothalamus of healthy, normal-weight humans consistently declines in response to an oral glucose load, which strongly suggests that glucose ingestion blunts hypothalamic neuronal activity in these subjects. The hypothalamus plays a critical role in the control of energy balance. Neural circuits in hypothalamic nuclei perceive and integrate endocrine and metabolic cues reflecting bodily energy content to coordinate behavior and fuel flux so as to maintain energy homeostasis (28, 34). Thus, adaptations of hypothalamic neuronal activity driven by nutrient ingestion may serve to guard energy equilibrium in the face of an environmental challenge.The mechanism linking glucose intake and changes in hypothalamic neuronal activity in humans is currently unknown. Various metabolic and endocrine cues are worthwhile to consider. Circulating levels of glucose can be sensed by specialized neurons in the arcuate and ventromedial nuclei of the hypothalamus, and these neurons project to other key nuclei (21). Alternatively, insulin inhibits NPY neuronal activit...

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Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39.

Cited by 325 publications

References 0 publications

Incretins, insulin secretion and Type 2 diabetes mellitus

Incretins, insulin secretion and Type 2 diabetes mellitus

Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects

Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion

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