Secretion of the Incretin Hormones Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide Correlates with Insulin Secretion in Normal Man Throughout the Day

Ørskov, Cathrine; Wettergren, André; Holst, Jens J.

doi:10.3109/00365529609009147

Cited by 237 publications

(154 citation statements)

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“…Additional time series analyses also disclosed no trend towards altered regularity or coordination, indicating that this finding is independent of the mathematical approach applied. Different results might have been obtained following long-term infusion of GLP-1 but short-term stimulation as carried out in this study would seem to best resemble the postprandial situation with a rather steep increase of GLP-1 concentration to a maximum of 50±60 pmol/l [26].…”

Section: Discussionmentioning

confidence: 76%

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

et al. 2000

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Type II (non-insulin-dependent) diabetes mellitus is among a vast number of abnormalities characterised by disturbed beta-cell function. This includes defects in first-phase and second-phase insulin secretion as well as a deterioration of the highly coordinated pulsatile release pattern seen in healthy subjects [1,2]. The full impact on glucose control of the latter alterations in Type II diabetic patients is not established, but in vivo experiments suggest that pulsatile insulin delivery is important for insulin actions [3±5].Stimulation of insulin secretion has been the principal goal in the treatment of Type II diabetic patients for decades. The impact of pharmacological beta-cell stimulation on insulin pulsatility has not been examined in Type II diabetes, although the nature of the insulin response could be important to shortterm and long-term glucose control. In non-diabetic Diabetologia (2000) 43: 583±588 Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness Abstract Aims/hypothesis. The enteric incretin hormone, glucagon-like peptide-1 (GLP-1), is a potent insulin secretagogue in healthy humans and patients with Type II (non-insulin-dependent) diabetes mellitus. In this study we assessed the impact of short-term GLP-1 infusion on pulsatile insulin secretion in Type II diabetic patients. Methods. Type II diabetic patients (n = 8) were studied in a randomised cross-over design. Plasma insulin concentration time series were obtained during basal conditions and during infusion with saline or GLP-1 (1.2 pmol/l × kg ±1 × min ±1 ) on 2 separate days. Plasma glucose was clamped at the initial concentration by a variable glucose infusion. Serum insulin concentration time series were evaluated by deconvolution analysis, autocorrelation analysis, spectral analysis and approximate entropy. Results. Serum insulin concentrations increased by approximately 100 % during GLP-1 infusion. Pulsatile insulin secretion was increased as measured by secretory burst mass (19.3 ± 3.8 vs 53.0 ± 10.7 pmol/l/ pulse, p = 0.02) and secretory burst amplitude (7.7 ± 1.5 vs 21.1 ± 4.3 pmol/l/min, p = 0.02). A similar increase in basal insulin secretion was observed (3.6 ± 0.9 vs 10.2 ± 2.2 pmol/l/min, p = 0.004) with no changes in the fraction of insulin delivered in pulses (0.50 ± 0.06 vs 0.49 ± 0.02, p = 0.84). Regularity of secretion was unchanged as measured by spectral analysis (normalised spectral power: 5.9 ± 0.6 vs 6.3 ± 0.8, p = 0.86), autocorrelation analysis (autocorrelation coefficient: 0.19 ± 0.04 vs 0.18 ± 0.05, p = 0.66) and the approximate entropy statistic (1.48 ± 0.02 vs 1.51 ± 0.02, p = 0.86). Conclusion/interpretation. Short-term stimulation with GLP-1 jointly increases pulsatile and basal insulin secretion, maintaining but not improving system regularity in Type II diabetic patients. [Diabetologia (2000) 43: 583±588]Keywords GLP-1, Insulin, pulsatility, insulin secretion, time series, Type II diabetes, human.Received: 11 November 1999 and in revise...

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Section: Discussionmentioning

confidence: 76%

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

et al. 2000

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“…This could be explained by the fact that both GLP-1 and GIP producing cells are found throughout the small intestine and, perhaps, also by the recent finding that a significant number of gut endocrine cells in several mammals, including humans, produce both GIP and GLP-1 [45]. In agreement with this, a mixed meal will normally cause a release of both peptides, but whereas the GIP concentrations might increase to several hundred picomoles per litre, GLP-1 concentrations rarely exceed 50 pmol/l [37].…”

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

confidence: 85%

“…However, as a circulating hormone in humans, its concentration is probably too low to influence insulin secretion under physiological circumstances [35]. GLP-1 secretion is stimulated by the presence of nutrients in the lumen of the gut (but additional neural or endocrine mechanisms could also operate) [36], and the secretion of GLP-1 throughout the day is highly correlated to the release of insulin [37]. GLP-1 is one of the most potent insulin-releasing substances known.…”

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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“…This study demonstrates that peripherally administered GLP-1 in slightly supraphysiological concentrations, 24 decreased hunger and reduced energy intake in Figure 1 Mean AE s.e.m. appetite ratings (hunger, fullness, desire to eat, and prospective consumption) during glucagon-like peptide-1 (GLP-1, ®lled circles) and saline (®lled squares) infusion in eight obese male subjects.…”

Section: Discussionmentioning

confidence: 99%

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.

et al. 1999

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BACKGROUND: Peripheral administration of glucagon-like peptide-1 (GLP-1) for four hours, to normal weight and obese humans, decreases food intake and suppresses appetite. OBJECTIVE: The aim of this study was to assess the effect of an eight hour infusion of GLP-1 on appetite and energy intake at lunch and dinner in obese subjects. DESIGN: Randomised, blinded cross-over design with intravenous infusion of GLP-1 (0.75 pmol Á kg 71 Á min 71 ) or saline. SUBJECTS: Eight obese (body mass index, BMI, 45.5 AE 2.3 kgam 2 ) male subjects. MEASUREMENTS: Ad libitum energy intake at lunch (12.00 h) and dinner (16.00 h) after an energy ®xed breakfast (2.4 MJ) at 08.00 h. Appetite sensations using visual analogue scales, (VAS) immediately before and after meals and hourly in-between. Blood samples for the analysis of glucose, insulin, C-peptide, GLP-1 and peptide YY. Gastric emptying after breakfast and lunch using a paracetamol absorption technique. RESULTS: Hunger ratings were signi®cantly lower with GLP-1 infusion. The summed ad libitum energy intake at lunch and dinner was reduced by 1.7 AE 0.5 MJ (21 AE 6%) by GLP-1 infusion (P 0.01). Gastric emptying was delayed by GLP-1 infusion, and plasma glucose concentrations decreased (baseline: 6.6 AE 0.35 mmolaL; nadir: 5.3 AE 0.15 mmolaL). No nausea was recorded during GLP-1 infusion. CONCLUSIONS: Our results demonstrate that GLP-1 decreases feelings of hunger and reduces energy intake in obese humans. One possible mechanism for this ®nding might be an increased satiety primarily mediated by gastric vagal afferent signals.

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Secretion of the Incretin Hormones Glucagon-Like Peptide-1 and Gastric Inhibitory Polypeptide Correlates with Insulin Secretion in Normal Man Throughout the Day

Abstract: These results support the notion that GLP-1 and GIP are important incretin hormones.

Cited by 237 publications

References 39 publications

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

Short-term treatment with GLP-1 increases pulsatile insulin secretion in Type II diabetes with no effect on orderliness

Incretins, insulin secretion and Type 2 diabetes mellitus

Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.

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