Glucagon-like peptide-1 (GLP-1): A gut hormone of potential interest in the treatment of diabetes

Åhrén, Bo

doi:10.1002/(sici)1521-1878(199808)20:8<642::aid-bies7>3.0.co;2-k

Cited by 119 publications

(88 citation statements)

References 73 publications

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“…This suggests that 1) it is unlikely that epinephrine contributes to the early insulin response after meal ingestion in humans, and 2) there is a difference between our present human study versus the previous studies in dogs (39,40) and rats (41) with regard to epinephrine response to food intake. Both GIP and GLP-1 are of importance for the insulin response to meal ingestion (18,20,21); their physiological relevance is illustrated by findings that mice in which the GIP or GLP-1 receptor has been deleted are glucose intolerant, with impaired insulin response to oral glucose (42,43). However, whether the two hormones contribute to the neurally mediated early insulin response has not been established.…”

Section: Discussioncontrasting

confidence: 57%

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Åhrén

Holst²

2001

Diabetes

259

177

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We studied the mechanisms and physiological relevance of the cephalic insulin response to meal ingestion in 12 healthy women (age 63 ؎ 0.4 years; BMI 27.7 ؎ 1.7 kg/m 2 ). The ganglionic antagonist, trimethaphan, which impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia, or atropine or saline was given intravenously during the first 15 min after ingestion of a standard meal (350 kcal). During saline infusion, insulin levels increased during the first 10 min after meal ingestion, whereas the first increase in glucose was evident at 15 min. The preabsorptive 10-min insulin response was reduced by 73 ؎ 11% by trimethaphan (P ‫؍‬ 0.009), accompanied by impaired reduction of glucose levels from 25 to 60 min after meal ingestion (⌬glucose ‫؍‬ -1.27 ؎ 0.5 [with saline] vs. 0.1 ؎ 0.4 mmol/l [with trimethaphan]; P ‫؍‬ 0.008). This reduction at 25-60 min in glucose levels correlated significantly to the 10-min insulin response (r ‫؍‬ 0.65, P ‫؍‬ 0.024). The 10-min insulin response to meal ingestion was also reduced by atropine, but only by 20 ؎ 9% (P ‫؍‬ 0.045), which was lower than the reduction with trimethaphan (P ‫؍‬ 0.004). The preabsorptive insulin response was not accompanied by any increase in circulating levels of gastric inhibitory polypeptide (GIP) or glucagon-like peptide 1 (GLP-1). In conclusion, 1) the early preabsorptive insulin response to meal ingestion in humans can be largely attributed to autonomic activation mediated by noncholinergic and cholinergic mechanisms, 2) this cephalic insulin response is required for a normal postprandial glucose tolerance, and 3) GIP and GLP-1 do not contribute to the preabsorptive cephalic phase insulin response to meal ingestion.

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Section: Discussioncontrasting

confidence: 57%

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Åhrén

Holst²

2001

Diabetes

259

177

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“…An example of particular interest is glucagon-like peptide-1 (GLP-1), 1 one of the most potent enhancers of glucose-stimulated insulin secretion and in current focus for treatment of type 2 diabetes (3). The GLP-1 effect is seen in the presence of stimulatory concentrations of glucose and is exerted through cAMP-induced activation of protein kinase A (PKA) (3,4). Although this classic concept of cAMP/PKA signaling, leading to phosphorylation of protein substrates that regulate insulin release, still holds as the principal mechanism by which cAMP exerts its effects, apparent PKA-independent stimulation of ␤-cell exocytosis mediated by cAMP has also been observed (5).…”

mentioning

confidence: 65%

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

Härndahl¹,

Jing²,

Ivarsson³

et al. 2002

Journal of Biological Chemistry

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Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic ␤-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on ␤-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6 -8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly lowered in transduced cells (INS-1(832/13)), and insulin secretion in response to stimulation with high glucose (11.1 mM) was reduced by 40% (islets) and 50% (INS-1). Further, the ability of GLP-1 (100 nM) to augment glucose-stimulated insulin secretion was inhibited by ϳ30% (islets) and 70% (INS-1). Accordingly, when stimulating with cAMP, a substantial decrease (65%) in exocytotic capacity was demonstrated in patch-clamped single ␤-cells. In untransduced insulinoma cells, application of the PDE3-selective inhibitor OPC3911 (10 M) was shown to increase glucose-stimulated insulin release as well as cAMP-enhanced exocytosis. The findings suggest a significant role of PDE3B as an important regulator of insulin secretory processes.

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“…In fact, decreased expression of PDE3B has been observed in adipose tissue from patients with diabetes (43) and recently, a sibling study suggests a coupling of a polymorphism in exon 4 of the human PDE3B gene to hyperinsulinemia. 2 Treatment of obesity and diabetes by use of PDE3 inhibitors has been discussed (44). Based on the findings of the present study, it seems reasonable to further suggest that development of PDE3 inhibitors specifically targeting ␤-cell PDE3B would be beneficial.…”

Section: ␤-Cell-targeted Overexpression Of Pde3b In Micementioning

confidence: 99%

“…In particular, several physiological enhancers of glucose-stimulated insulin release, such as pituitary adenylate cyclase-activating polypeptide and glucagon-like peptide (GLP) 1 1, act mainly through increased formation of cAMP (1)(2)(3) and, at least in part, its subsequent activation of protein kinase A (PKA). However, the exact mechanisms by which cAMP mediates the potentiating effect on insulin secretion remain to be established.…”

mentioning

confidence: 99%

β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

Härndahl

Wierup

Enerbäck

et al. 2004

Journal of Biological Chemistry

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The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic ␤-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagonlike peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucosestimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.

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Glucagon-like peptide-1 (GLP-1): A gut hormone of potential interest in the treatment of diabetes

Cited by 119 publications

References 73 publications

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

The Cephalic Insulin Response to Meal Ingestion in Humans Is Dependent on Both Cholinergic and Noncholinergic Mechanisms and Is Important for Postprandial Glycemia

Important Role of Phosphodiesterase 3B for the Stimulatory Action of cAMP on Pancreatic β-Cell Exocytosis and Release of Insulin

β-Cell-targeted Overexpression of Phosphodiesterase 3B in Mice Causes Impaired Insulin Secretion, Glucose Intolerance, and Deranged Islet Morphology

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