High-Throughput Luminescent Reporter of Insulin Secretion for Discovering Regulators of Pancreatic Beta-Cell Function

Esters of succinic acid are potent insulin secretagogues, and have been proposed as novel antidiabetic agents for type 2 diabetes. This study examines the effects of acute and chronic exposure to succinic acid monomethyl ester (SAM) on insulin secretion, glucose metabolism and pancreatic beta cell function using the BRIN-BD11 cell line. SAM stimulated insulin release in a dose-dependent manner at both non-stimulatory (1.1mM) and stimulatory (16.7mM) glucose. The depolarizing actions of arginine also stimulated a significant increase in SAM-induced insulin release but 2-ketoisocaproic acid (KIC) inhibited SAM induced insulin secretion indicating a possible competition between the preferential oxidative metabolism of these two agents. Prolonged (18hour) exposure to SAM revealed decreases in the insulin-secretory responses to glucose, KIC, glyceraldehyde and alanine. Furthermore, SAM diminished the effects of nonmetabolized secretagogues arginine and 3-isobutyl-1-methylxanthine (IBMX). While the ability of BRIN-BD11 cells to oxidise glucose was unaffected by SAM culture, glucose utilization was substantially reduced. Collectively, these data suggest that while SAM may enhance the secretory potential of non-metabolized secretagogues, it may also serve as a preferential metabolic fuel in preference to other important physiological nutrients and compromise pancreatic beta cell function following prolonged exposure.

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Pancreatic beta-cell function evaluated by intravenous glucose and glucagon stimulation. A comparison between insulin and C-peptide to measure insulin secretion

Scandinavian Journal of Clinical and Laboratory Investigation ◽

10.3109/00365519209115506 ◽

1992 ◽

Vol 52 (7) ◽

pp. 631-639 ◽

Cited By ~ 24

Author(s):

A. Gottsäter ◽

M. Landin-Olsson ◽

P. Fernlund ◽

B. Gullberg ◽

Å. Lernmark ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Intravenous Glucose ◽

C Peptide ◽

Pancreatic Beta Cell Function

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Effects of 2 Novel PYY(1-36) Analogues, (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL), on Pancreatic Beta-Cell Function, Growth, and Survival

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.1177/1179551419855626 ◽

2019 ◽

Vol 12 ◽

pp. 117955141985562 ◽

Cited By ~ 7

Author(s):

Ryan A Lafferty ◽

Victor A Gault ◽

Peter R Flatt ◽

Nigel Irwin

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Protective Effects ◽

Dipeptidyl Peptidase 4 ◽

Induced Apoptosis ◽

Pancreatic Beta Cell Function

Recent studies have identified a beneficial role for peptide tyrosine tyrosine (PYY) on pancreatic beta-cell function and survival. These effects are linked to the activation of neuropeptide Y1 receptors (NPYR1s) by PYY(1-36). However, PYY(1-36) is subject to rapid degradation by dipeptidyl peptidase-4 (DPP-4), resulting is the loss of NPYR1 activity. Therefore, the aim of this study was to develop 2 enzymatically stable PYY(1-36) analogues, namely, (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL), with further structural modifications to enhance NPYR1 specificity. As expected, (P3L31P34)PYY(1-36) was fully resistant to DPP-4-mediated degradation in vitro, whereas PYY(1-36) and PYY(1-36)(Lys12PAL) were both liable to DPP-4 breakdown. PYY(1-36) and (P3L31P34)PYY(1-36) induced significant reductions in glucose-stimulated insulin secretion (GSIS) from BRIN BD11 cells, but only PYY(1-36) diminished alanine-stimulated insulin secretion. In contrast, PYY(1-36)(Lys12PAL) had no impact on GSIS or alanine-induced insulin release. All 3 PYY peptides significantly enhanced proliferation in BRIN BD11 and 1.1B4 beta-cell lines, albeit only at the highest concentration examined, 10-6 M, for (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL) in BRIN BD11 cells. Regarding the protection of beta-cells against cytokine-induced apoptosis, PYY(1-36) induced clear protective effects. Both (P3L31P34)PYY(1-36) and PYY(1-36)(Lys12PAL) offered some protection against apoptosis in BRIN BD11 cells, but were significantly less efficacious than PYY(1-36). Similarly, in 1.1B4 cells, both PYY analogues (10-6 M) protected against cytokine-induced apoptosis, but (P3L31P34)PYY(1-36) was significantly less effective than PYY(1-36). All 3 PYY peptides had no impact on refeeding in overnight fasted mice. These data underline the beta-cell benefits of PYY(1-36) and highlight the challenges of synthesising stable, bioactive, NPYR1-specific, PYY(1-36) analogues.

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