Effects of Glucagon-Like Peptide 1 (7–36 Amide) on Glucose Kinetics during Somatostatin-Induced Suppression of Insulin Secretion in Healthy Men

Shalev, Anath; Ninnis, Ronald; Keller, Ulrich

doi:10.1159/000023175

Cited by 22 publications

(20 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that maximal insulin suppression during the oGTT was achieved by the direct octreotide effect alone, which is in accordance with the reported insulin suppression by even lower octreotide doses than ours (17,23). However, GLP-1 has additional effects, including glucagon suppression, stimulation of pancreatic somatostatin release (8,11,24) and possibly a peripheral effect on glucose uptake/insulin sensitivity (13), although the latter remains controversial (12,14). While a mouse model with disrupted GLP-1 receptor signaling (25) suggests that only its incretin effect is essential for glucose homeostasis, disruption of other GLP-1 actions may still be important for the fine tuning of the metabolic response to oral nutrients.…”

Section: European Journal Of Endocrinology (1999) 140supporting

confidence: 85%

See 1 more Smart Citation

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects

et al. 1999

View full text Add to dashboard Cite

Objective: To study the effect of octreotide on glucagon-like peptide (7-36) amide (GLP-1) and insulin secretion in patients with pituitary tumors during preoperative treatment and in healthy subjects. Design: Open design prospective clinical study. Methods: Eighteen patients with pituitary macroadenomas (13 clinically nonfunctioning (NFA; 11/13 had GH insufficiency), 5 GH secreting (GHA)) received preoperative octreotide treatment: 3×100 mg/day s.c. for 3 months, and 3×500 mg/day s.c. for an additional 3 months. Seven healthy subjects received (for ethical reasons) only 3×100 mg/day for 10 days. A standardized meal (St-M) test, oral glucose test (oGTT) and i.v. glucose test (ivGTT) were done before octreotide therapy, on days 1, 2 and 3 (D1,2,3), after 3 months (M3) and 6 months (M6) of octreotide treatment in the patients, and before treatment, on D1,2,3 and on D8,9,10 of octreotide treatment in the healthy subjects. Serum GLP-1, insulin and GH as well as plasma glucose were determined for 180 min (oGTT, St-M) or 120 min (ivGTT).Results: Pretreatment fasting GLP-1 concentrations as well as integrated responses (area under the curve 0-180 min) to oGTT and St-M were not significantly different between NFA, GHA and healthy subjects. During the oGTT, octreotide initially almost abolished the early (0-60 min) and diminished the late (60-180 min) GLP-1 and insulin responses in patients and healthy subjects. At M6 integrated insulin responses had significantly recovered, while the increase in GLP-1 response failed to reach significance (GLP-1: 56.5% of pretreatment at D2 versus 93.5% at M6 and 41.2 versus 63.1% in NFA and GHA respectively; insulin: 50.2 versus 71.2% and 35.5 versus 70.4%). An escape of GLP-1 and insulin in healthy subjects (D2 versus D9) was not significant. Intestinal glucose absorption was apparently not reduced, since the early glucose rise was similar before and during octreotide treatment. During the St-M the GLP-1 and insulin responses were similarly suppressed by octreotide and recovered during ongoing treatment (GLP-1: 49.6% of pretreatment at D1 versus 79.0% at M6 in NFA and 46.9 versus 52.9% in GHA. Insulin: 27.6 versus 83.9% and 23.5 versus 54.4%). The escape was significant in NFA but not in GHA. In the healthy subjects the escape was already significant on D8 (GLP-1: 39.5% of pretreatment at D1 versus 68.3% at D8; insulin: 36.6 versus 53.8%). During the ivGTT GLP-1 did not increase. The early insulin response (0-30 min) was abolished by octreotide, followed by a reduced peak at 60 min. The reduction of the integrated insulin response during ivGTT was similar to that during oGTT. An insulin escape reached significance only for NFA (52.6% of pretreatment at D3 versus 66.7% at M6). Glucose tolerance (K G value) deteriorated and did not improve during ongoing treatment. Octreotide suppressed the median GH concentration (8 h profile) of the GHA patients from 10.3 mg/l (pretreatment) to 5.8, 6.3 and 3.7 mg/l at D4, M3 and M6 with no escape. GH was 1.5 mg/l postoperatively. Conclusions:...

show abstract

Section: European Journal Of Endocrinology (1999) 140supporting

confidence: 85%

“…These include glucagon suppression and slowing of gastric motility (8,11). A peripheral effect on glucose uptake and metabolism is controversial (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects

et al. 1999

View full text Add to dashboard Cite

show abstract

“…The presence of these in vivo extrapancreatic effects of GLP-1, when intravenously administered, has been suggested in man, normal and diabetic (Gutniak et al 1992, D'Alessio et al 1994, Shalev et al 1998, and also in depancreatized dogs (Sandhu et al 1999) and diabetic rats (Mizuno et al 1997), but its relevance is questioned by other studies on healthy humans (Toft-Nielson et al 1996, Orskov et al 1996, Ryan et al 1998, type 2 diabetic patients , Vella et al 2000 and insulin-dependent diabetic dogs (Freyse et al 1999). Still, a recent work (Vella et al 2001) performed in type 1 diabetic subjects has demonstrated that in the presence of hyperglycemia, hyperinsulinemia and enterally delivered glucose, GLP-1 does not modify splanchnic but increases total body glucose uptake, the skeletal muscle being, most probably, responsible for it.…”

Section: Discussionmentioning

confidence: 96%

Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes

Luque¹,

González²,

Márquez³

et al. 2002

Journal of Endocrinology

116

View full text Add to dashboard Cite

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not -at least in liver and muscle -cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10 13 mol/l, a doserelated increase of the -[U-14 C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10 11 mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.

show abstract

“…Subsequently, several groups noted effects of GLP-1 to promote glucose uptake in skeletal muscle, adipocyte, or hepatocyte preparations in vitro (16,21,27,45). Although the initial in vivo study by Gutniak et al was consistent with the in vitro results, subsequent studies in humans have been divergent, with some studies favoring extrapancreatic effects of 12,15,29,30,39,43) and others showing no effect (2,34,38,44). Furthermore, even among the studies that demonstrated an extrapancreatic effect, there has been a disparity in the apparent site of action of the GLP-1, with some investigators suggesting an effect on peripheral tissues (15,29,30,43), whereas others suggested an effect on endogenous glucose production (EGP; see Ref.…”

mentioning

confidence: 78%

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Prigeon

Quddusi²,

Paty³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

182

129

View full text Add to dashboard Cite

. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 285: E701-E707, 2003. First published May 28, 2003 10.1152/ ajpendo.00024.2003.-Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release. It has been hypothesized that GLP-1 also reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has independent actions on endogenous glucose production, we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on glucose appearance (R a) and glucose disposal (Rd) was measured in eight men during a pancreatic clamp that was performed by infusing octreotide to suppress secretion of islet hormones, while insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. After stabilization of plasma glucose and equilibration of [ 3 H]glucose tracer, GLP-1 was given intravenously for 60 min. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 Ϯ 14 vs. 113 Ϯ 11 pM; 0.153 Ϯ 0.029 vs. 0.156 Ϯ 0.026 nM; and 64.7 Ϯ 11.5 vs. 65.8 Ϯ 13.8 ng/l, respectively). With the initiation of GLP-1, plasma glucose decreased in all eight subjects from steadystate levels of 4.8 Ϯ 0.2 to a nadir of 4.1 Ϯ 0.2 mM. This decrease in plasma glucose was accounted for by a significant 17% decrease in R a, from 22.6 Ϯ 2.8 to 19.1 Ϯ 2.8 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.04), with no significant change in Rd. These findings indicate that, under fasting conditions, GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion.incretin; glucose production; pancreatic clamp; gastrointestinal hormone; glucose tolerance GLUCAGON-LIKE PEPTIDE-1 (GLP-1; 7-36 amide) is an intestinal hormone that plays an important role in glucose homeostasis. GLP-1 is a potent insulinotropin that is secreted after meal ingestion, thereby contributing to the incretin effect (the greater insulin release occurring after oral compared with intravenous glucose administration; see Refs. 9, 28, and 35). GLP-1 also decreases glucagon release, either through direct interaction with the ␣-cell or indirectly via stimulation of insulin and somatostatin secretion (10, 47). Thus the overall effect of GLP-1 on pancreatic islet secretion is to decrease circulating glucose concentrations. In addition to the regulation of islet hormones, GLP-1 slows gastric emptying (49), another action that attenuates the rise in plasma glucose after meal ingestion. This broad range of acute effects on processes governing circulating levels of glucose has stimulated interest in using GLP-1 or GLP-1 analogs for the treatment of diabetes.Many investigators have also suggested that GLP-1 has effects on glucose metabolism beyond the regulation of pancreatic islet hormone secretion, e.g., extrapancreatic effects. The first report was from Gutniak and colleagues (20)...

show abstract

Effects of Glucagon-Like Peptide 1 (7–36 Amide) on Glucose Kinetics during Somatostatin-Induced Suppression of Insulin Secretion in Healthy Men

Cited by 22 publications

References 18 publications

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects

Octreotide suppresses the incretin glucagon-like peptide (7-36) amide in patients with acromegaly or clinically nonfunctioning pituitary tumors and in healthy subjects

Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes

Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect

Contact Info

Product

Resources

About