Why is it so difficult to measure glucagon-like peptide-1 in a mouse?

Windeløv, Johanne Agerlin; Albrechtsen, Nicolai J. Wewer; Kuhre, Rune Ehrenreich; Jepsen, Sara L.; Hornburg, Daniel; Pedersen, Jens; Jensen, Elisa P.; Galsgaard, Katrine D.; Winther-Sørensen, Marie; Ørgaard, Anne; Deacon, Carolyn F.; Mann, Matthias; Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens J.

doi:10.1007/s00125-017-4347-7

Cited by 45 publications

(38 citation statements)

References 47 publications

(72 reference statements)

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“…However, we have not measured the active isoform of GLP-1 in these study samples. Furthermore, recent work reveals differences in the GLP-1 isoform profile between humans and rodents ( Windeløv et al, 2017 ). However, consistent with active GLP-1 primarily being secreted in the postprandial state, previous studies in rodents and humans show that fasting plasma active GLP-1 levels do not change after bariatric surgery ( Cummings et al, 2010 ; Laferrère et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice

et al. 2018

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SUMMARYBariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible β cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the β cell GLP-1R in islet function. Our data show that loss of β cell GLP-1R signaling decreases α cell GLP-1 expression after VSG. Furthermore, we find a β cell GLP-1R-dependent increase in α cell expression of the prohormone convertase required for the production of GLP-1 after VSG. Together, the findings herein reveal two concepts. First, our data support a paracrine role for α cell-derived GLP-1 in the metabolic benefits observed after VSG. Second, we have identified a role for the β cell GLP-1R as a regulator of α cell proglucagon processing.

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Section: Discussionmentioning

confidence: 99%

β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice

et al. 2018

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“…Moreover, by using a C‐terminal assay, all molecular forms carrying the amidation would be detected, including any extended or degraded molecular forms (Windeløv et al. ). In addition, using the isolated perfused mouse intestine allowed us to determine any effect on secretion with much greater sensitivity compared to what would have been possible in in vivo studies in mice (Windeløv et al.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, using the isolated perfused mouse intestine allowed us to determine any effect on secretion with much greater sensitivity compared to what would have been possible in in vivo studies in mice (Windeløv et al. ).…”

Section: Discussionmentioning

confidence: 99%

Acute administration of interleukin-6 does not increase secretion of glucagon-like peptide-1 in mice

et al. 2018

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Interleukin 6 (IL‐6) is a cytokine secreted from skeletal muscle in response to exercise which, based on animal and cell studies, has been suggested to contribute to glucose metabolism by increasing secretion of the incretin hormone glucagon‐like peptide‐1 (GLP‐1) and affecting secretion of insulin and glucagon from the pancreatic islets. We investigated the effect of IL‐6 on GLP‐1 secretion in GLP‐1 producing cells (GLUTag) and using the perfused mouse small intestine (harboring GLP‐1 producing cells). Furthermore, the direct effect of IL‐6 on insulin and glucagon secretion was studied using isolated perfused mouse pancreas. Incubating GLUTag cells with 1000 ng/mL of IL‐6 for 2 h did not significantly increase secretion of GLP‐1 whereas 10 mmol/L glucose (positive control) did. Similarly, IL‐6 (100 ng/mL) had no effect on GLP‐1 secretion from perfused mouse small intestine whereas bombesin (positive control) increased secretion. Finally, administering IL‐6 (100 ng/mL) to perfused mouse pancreases did not significantly increase insulin or glucagon secretion regardless of perfusate glucose levels (3.5 vs. 12 mmol/L glucose). Acute effects of IL‐6 therefore do not seem to include a stimulatory effect on GLP‐1 secretion in mice.

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“…Insulin sensitivity Hepatic glucose production Food intake and body weight [2,40] Natriuretic peptides (ANP, BNP)…”

Section: Positive Effectsmentioning

confidence: 99%

“…In fact, a study in pigs demonstrated that dual neprilysin and DPP-4 inhibition may have additive effects and therapeutic potential for type 2 diabetes, as combined neprilysin and DPP-4 inhibition was more effective at maintaining active GLP-1 levels and enhancing insulin secretion than inhibition of either alone [3]. Unlike DPP-4, which cleaves active GLP-1 at a single site to yield truncated GLP-1(9-36)amide, neprilysin degrades both active and truncated GLP-1 at multiple sites [2,40] (Fig. 2), limiting both GLP-1 receptor binding and activation.…”

Section: Considerations For Clinical Use Of Neprilysin Inhibitors In mentioning

confidence: 99%

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

Esser

Zraika

2019

Diabetologia

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Neprilysin is a widely expressed peptidase with broad substrate specificity that preferentially hydrolyses oligopeptide substrates, many of which regulate the cardiovascular, nervous and immune systems. Emerging evidence suggests that neprilysin also hydrolyses peptides that play an important role in glucose metabolism. In recent studies in humans, a dual angiotensin receptor-neprilysin inhibitor (ARNi) improved glycaemic control and insulin sensitivity in individuals with type 2 diabetes and/or obesity. Moreover, preclinical studies have also reported that neprilysin inhibition, alone or in combination with renin-angiotensin system blockers, elicits beneficial effects on glucose homeostasis. Since neprilysin inhibitors have been approved for the treatment of heart failure, their repurposing for treating type 2 diabetes would provide a novel therapeutic strategy. In this review, we evaluate existing evidence from preclinical and clinical studies in which neprilysin is deleted/inhibited, we highlight potential mechanisms underlying the beneficial glycaemic effects of neprilysin inhibition, and discuss possible deleterious effects that may limit the efficacy and safety of neprilysin inhibitors in the clinic. We also review the favourable impact neprilysin inhibition can have on diabetic complications, in addition to glucose control. Finally, we conclude that neprilysin inhibitors may be a useful therapeutic option for treating type 2 diabetes; however, their combination with angiotensin II receptor blockers is needed to circumvent deleterious consequences of neprilysin inhibition alone.

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Why is it so difficult to measure glucagon-like peptide-1 in a mouse?

Cited by 45 publications

References 47 publications

β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice

β Cell GLP-1R Signaling Alters α Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice

Acute administration of interleukin-6 does not increase secretion of glucagon-like peptide-1 in mice

Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

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