The VGF-Derived Neuropeptide TLQP-21 Shows No Impact on Hormone Secretion in the Isolated Perfused Rat Pancreas

Svendsen, Berit; Holst, Jens J.

doi:10.1055/s-0034-1395615

Cited by 10 publications

(12 citation statements)

References 28 publications

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“…We used the physiologically relevant isolated perfused rat pancreas model [7] and found that SGLT2 activity had no effect on glucagon secretion whether transporter activity was inhibited by dapagliflozin or phloridzin or whether it was activated by the SGLT-specific substrate α-MGP. Of note, the dapagliflozin concentration used (0.5 μmol/l) matches peak plasma concentration in humans after intake of therapeutic doses (5-10 mg/day) [24] and, in all experiments, secretion was tightly regulated by the glucose concentration so glucagon secretion was high at low glucose.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. As glucagon secretion is tightly regulated by blood glucose, which is lowered by SGLT2 inhibitors, we chose the isolated perfused rat pancreas as experimental model [6,7], where perfusate glucose is kept constant. We studied the effects of the SLGT2 inhibitor dapagliflozin, the SGLT1/2 inhibitor phloridzin and the metabolically inert SGLT-specific substrate methyl-α-D-glucopyranoside (α-MGP) on glucagon secretion in this model.…”

Section: Introductionmentioning

confidence: 99%

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No direct effect of SGLT2 activity on glucagon secretion

et al. 2019

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Aims/hypothesis Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. Methods We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Results Glucagon output decreased three-to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Conclusions/interpretation Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucoselowering effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

No direct effect of SGLT2 activity on glucagon secretion

et al. 2019

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“…Abscisic acid appears to behave similarly to linoleic acid in its ability to induce GLP‐1 release from the vascular, but not from the luminal side. Linoleic acid is an essential fatty acid, introduced with the diet and capable of stimulating GLP‐1 release from the isolated rat small intestine from the vascular side only . Nevertheless, it should also be noted that ABA administration in the intestinal perfusion system gave similar results to taurodeoxycholate (TDCA).…”

Section: Discussionmentioning

confidence: 99%

“…Linoleic acid is an essential fatty acid, introduced with the diet and capable of stimulating GLP-1 release from the isolated rat small intestine from the vascular side only. 28 Nevertheless, it should also be noted that ABA administration in the intestinal perfusion system gave similar results to taurodeoxycholate (TDCA). Application of 100 μmol/L TDCA, via the vasculature, in perfused rat small intestine, robustly increased GLP-1 release, whereas luminal application of TDCA at the same concentration was significantly less effective, 29 presumably because TDCA stimulates GLP-1 secretion by postabsorptive activation of basolateral located Taconic-G-proteincoupled receptors (TGR5).…”

Section: Aba Stimulates Glp-1 Secretion From the Proximal Small Intmentioning

confidence: 92%

Abscisic acid stimulates the release of insulin and of GLP‐1 in the rat perfused pancreas and intestine

Booz

Kuhre

Saltiel

et al. 2018

Diabetes Metabolism Res

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Aims Previous results indicate that nanomolar concentrations of abscisic acid (ABA) stimulate insulin release from β‐pancreatic cells in vitro and that oral ABA at 50 mg/kg increases plasma GLP‐1 in the fasted rat. The aim of this study was to test the effect of ABA on the perfused rat pancreas and intestine, to verify the insulin‐ and incretin‐releasing actions of ABA in controlled physiological models. Materials and methods Rat pancreas and small intestine were perfused with solutions containing ABA at high‐micromolar concentrations, or control secretagogues. Insulin and GLP‐1 concentrations in the venous effluent were analysed by radioimmunoassay, and ABA levels were determined by ELISA. Results High micromolar concentrations of ABA induced GLP‐1 secretion from the proximal half of the small intestine and insulin secretion from pancreas. GLP‐1 stimulated ABA secretion from pancreas in a biphasic manner. Notably, a positive correlation was found between the ABA area under the curve (AUC) and the insulin AUC upon GLP‐1 administration. Conclusion Our results indicate the existence of a cross talk between GLP‐1 and ABA, whereby ABA stimulates GLP‐1 secretion, and vice versa. Release of ABA could be considered as a new promising molecule in the strategy of type 2 diabetes treatment and as a new endogenous hormone in the regulation of glycaemia.

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“…Indeed, chronic icv administration of the VGF-derived peptide TLQP-21 increased energy expenditure and body temperature and limited diet-induced obesity in mice (Bartolomucci et al, 2006), and decreased food intake, body weight and adiposity in Siberian hamsters (Jethwa et al., 2007). Peripheral ip administration of TLQP-21 increased lipolysis (Possenti et al, 2012), and enhanced glucose-stimulated insulin secretion in human and rat islets and improved glycemic control in vivo (Stephens et al, 2012), but had no effect on hormone secretion in perfused rat pancreas (Christiansen et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight

et al. 2017

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Germline ablation of VGF, a secreted neuronal, neuroendocrine, and endocrine peptide precursor, results in lean, hypermetabolic, and infertile adult mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes (Hahm et al., 1999, 2002). To assess whether this phenotype is predominantly driven by reduced VGF expression in developing and/or adult neurons, or in peripheral endocrine and neuroendocrine tissues, we generated and analyzed conditional VGF knockout mice, obtained by mating loxP-flanked (floxed) Vgf mice with either pan-neuronal Synapsin-Cre- or forebrain alpha-CaMKII-Cre-recombinase-expressing transgenic mice. Adult male and female mice, with conditional ablation of the Vgf gene in embryonic neurons had significantly reduced body weight, increased energy expenditure, and were resistant to diet-induced obesity. Conditional forebrain postnatal ablation of VGF in male mice, primarily in adult excitatory neurons, had no measurable effect on body weight nor on energy expenditure, but led to a modest increase in adiposity, partially overlapping the effect of AAV-Cre-mediated targeted ablation of VGF in the adult ventromedial hypothalamus and arcuate nucleus of floxed Vgf mice (Foglesong et al., 2016), and also consistent with results of icv delivery of the VGF-derived peptide TLQP-21 to adult mice, which resulted in increased energy expenditure and reduced adiposity (Bartolomucci et al., 2006). Because the lean, hypermetabolic phenotype of germline VGF knockout mice is to a great extent recapitulated in Syn-Cre+/−,Vgfflpflox/flpflox mice, we conclude that the metabolic profile of germline VGF knockout mice is largely the result of VGF ablation in embryonic CNS neurons, rather than peripheral endocrine and/or neuroendocrine cells, and that in forebrain structures such as hypothalamus, VGF and/or VGF-derived peptides play uniquely different roles in the developing and adult nervous system.

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The VGF-Derived Neuropeptide TLQP-21 Shows No Impact on Hormone Secretion in the Isolated Perfused Rat Pancreas

Cited by 10 publications

References 28 publications

No direct effect of SGLT2 activity on glucagon secretion

No direct effect of SGLT2 activity on glucagon secretion

Abscisic acid stimulates the release of insulin and of GLP‐1 in the rat perfused pancreas and intestine

Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight

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