scholarly journals Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice

2019 ◽  
Vol 12 ◽  
pp. 117955141987545 ◽  
Author(s):  
RA Perry ◽  
SL Craig ◽  
MT Ng ◽  
VA Gault ◽  
PR Flatt ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Receptor Activation ◽  
Contributing Factors ◽  
Glucose Lowering ◽  
Incretin Hormone ◽  
Glucose Levels ◽  
First Time ◽  
Gip Receptor

Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weight-reducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial in vitro studies revealed that the GIPR agonists, human (h) GIP(1-42), hGIP(1-30) and mouse (m) GIP(1-30), stimulated ( P < 0.01 to P < 0.001) insulin secretion from rat BRIN-BD11 cells. Analysis of insulin secretory effects of the N- and C-terminally cleaved GIP peptides, including hGIP(3-30), mGIP(3-30), h(Pro3)GIP(3-30), hGIP(5-30), hGIP(3-42) and hGIP(5-42), revealed that these peptides did not modulate insulin secretion. More pertinently, only hGIP(3-30), mGIP(3-30) and h(Pro3)GIP(3-30) were able to significantly ( P < 0.01 to P < 0.001) inhibit hGIP(1-42)-stimulated insulin secretion. The human-derived GIPR agonist sequences, hGIP(1-42) and hGIP(1-30), reduced ( P < 0.05) glucose levels in mice following conjoint injection with glucose, but mGIP(1-30) was ineffective. None of the N- and C-terminally cleaved GIP peptides affected glucose homeostasis when injected alone with glucose. However, hGIP(5-30) and mGIP(3-30) significantly ( P < 0.05 to P < 0.01) impaired the glucose-lowering action of hGIP(1-42). Further evaluation of these most effective sequences demonstrated that mGIP(3-30), but not hGIP(5-30), effectively prevented GIP-induced elevations of plasma insulin concentrations. These data highlight, for the first time, that mGIP(3-30) represents an effective molecule to inhibit GIPR activity in mice.

scholarly journals Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

2015 ◽  
Vol 225 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Astrid C Hauge-Evans ◽  
James Bowe ◽  
Zara J Franklin ◽  
Zoheb Hassan ◽  
Peter M Jones
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Beta Cells ◽  
Plasma Insulin ◽  
Inhibitory Effect ◽  
Isolated Islets ◽  
Glucose Levels ◽  
Blood Glucose Levels

The inhibitory effect of somatostatin (SST) on insulin secretionin vivois attributed to a direct effect on pancreatic beta cells, but this is inconsistent with somein vitroresults in which exogenous SST is ineffective in inhibiting secretion from isolated islets. We therefore investigated whether insulin secretion from the pancreatic islets may partly be regulated by an indirect effect of SST mediated via the CNS. Islet hormone secretion was assessedin vitroby perifusion and static incubations of isolated islets andin vivoby i.v. or i.c.v. administration of the SST analogue BIM23014C with an i.v. glucose challenge to conscious, chronically catheterised rats. Hormone content of samples was assessed by ELISA or RIA and blood glucose levels using a glucose meter. Exogenous SST14/SST28 or BIM23014C did not inhibit the release of insulin from isolated rodent isletsin vitro, whereas peripheral i.v. administration of BIM23014C (7.5 μg) with glucose (1 g/kg) led to decreased plasma insulin content (2.3±0.5 ng insulin/ml versus 4.5±0.5 ng/ml att=5 min,P<0.001) and elevated blood glucose levels compared with those of the controls (29.19±1.3 mmol/l versus 23.5±1.7 mmol/l,P<0.05). In contrast, central i.c.v. injection of BIM23014C (0.75 μg) had no significant effect on either plasma insulin (3.3±0.4 ng/ml,P>0.05) or blood glucose levels (23.5±1.7 mmol/l,P>0.05) although i.v. administration of this dose increased blood glucose concentrations (32.3±0.7 mmol/l,P<0.01). BIM23014C did not measurably alter plasma glucagon, SST, GLP1 or catecholamine levels whether injected i.v. or i.c.v. These results indicate that SST does not suppress insulin secretion by a centrally mediated effect but acts peripherally on islet cells.

scholarly journals Cephalic phase insulin secretion is KATP channel independent

2013 ◽  
Vol 218 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Yusuke Seino ◽  
Takashi Miki ◽  
Wakako Fujimoto ◽  
Eun Young Lee ◽  
Yoshihisa Takahashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Critical Role ◽  
Pancreas Perfusion ◽  
Glucose Levels ◽  
Cephalic Phase ◽  
Plasma Insulin Levels ◽  
Atropine Methyl Nitrate ◽  
Nutrient Injection

Glucose-induced insulin secretion from pancreatic β-cells critically depends on the activity of ATP-sensitive K+channels (KATPchannel). We previously generated mice lackingKir6.2, the pore subunit of the β-cell KATPchannel (Kir6.2−/−), that show almost no insulin secretion in response to glucosein vitro. In this study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) andKir6.2−/−mice. Underad libitumfeeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar inKir6.2+/+andKir6.2−/−mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly inKir6.2−/−mice but was markedly attenuated compared with that inKir6.2+/+mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent inKir6.2−/−mice. Pretreatment with a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood–brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate inKir6.2−/−mice. Substantial glucose-induced insulin secretion was induced in the pancreas perfusion study ofKir6.2−/−mice only in the presence of carbamylcholine. These results suggest that a KATPchannel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrientsin vivo.

scholarly journals Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Yaser Albadr ◽  
Andrew Crowe ◽  
Rima Caccetta
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

Development of hyperinsulinemia and insulin resistance during the early stage of weight gain

2008 ◽  
Vol 294 (3) ◽  
pp. E568-E575 ◽  
Author(s):  
Johannes Erdmann ◽  
Bianca Kallabis ◽  
Ulrich Oppel ◽  
Oleg Sypchenko ◽  
Stefan Wagenpfeil ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Early Stage ◽  
Normal Range ◽  
Intravenous Glucose ◽  
C Peptide ◽  
Glucose Levels ◽  
Hyperglycemic Clamp ◽  
First Time

Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m2 BMI within 41/2 mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.

scholarly journals Determining the Effect of Pterostilbene on Insulin Secretion Using Chemoproteomics

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2885
Author(s):  
Chiara Cassiano ◽  
Daniela Eletto ◽  
Alessandra Tosco ◽  
Raffaele Riccio ◽  
Maria Chiara Monti ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Metabolic Disorders ◽  
Therapeutic Potential ◽  
Pharmacological Profile ◽  
Biological Targets ◽  
Cell Assays ◽  
Potential Applications ◽  
Insulin Dependent

Pterostilbene, the 3,5-dimethoxy derivative of resveratrol, is a well-known polyphenolic compound, mainly found in blueberries, grapevines, and Pterocarpus marsupium heartwood, which has recently attracted a great deal of attention due to its wide bio-pharmacological profile. Moreover, pterostilbene is more lipophilic than resveratrol, with a consequently better bioavailability and a more interesting therapeutic potential. In this work, a chemoproteomic approach, based on affinity chromatography, was applied on pterostilbene in the attempt to identify the biological targets responsible for its bioactivity. On this basis, syntaxins, a group of proteins involved in the formation of SNARE complexes mediating vesicles exocytosis, were selected among the most interesting pterostilbene interactors. In vitro and in cell assays gave evidence of the pterostilbene ability to reduce insulin secretion on glucose-stimulated pancreatic beta cells, opening the way to potential applications of pterostilbene as a supplement in the care of insulin-dependent metabolic disorders.

scholarly journals Murine macrophages and pancreatic beta cells. Chemotactic properties of insulin and beta-cytostatic action of interleukin 1.

1987 ◽  
Vol 166 (4) ◽  
pp. 1174-1179 ◽  
Author(s):  
E H Leiter
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Islet Cells ◽  
Interleukin 1 ◽  
Inhibitory Effect ◽  
Secretory Product ◽  
In Vitro Techniques ◽  
Mouse Pancreatic Islet ◽  
Potential Interactions

This study has used in vitro techniques to investigate the potential interactions between mouse pancreatic islet cells and syngeneic macrophages (M phi). Islets strongly stimulated M phi migration from agarose microdroplets; insulin was the only one of four islet cell hormones tested that was effective individually. Chronic exposure of islet monolayers to recombinant mouse IL-1, an M phi secretory product, was not cytolytic, but inhibited insulin secretion, reduced intracellular insulin content, and produced beta cell-specific degranulation. These effects were unique to IL-1; another monokine, tumor necrosis factor, as well as the lymphokine IL-2, and lymphotoxin were all without effect on insulin secretion or monolayer viability at the concentrations tested. The potential pathological consequences of the chemoattractive action of insulin on M phi, and the inhibitory effect of IL-1 on insulin secretion, are discussed.

Cell-wide analysis of secretory granule dynamics in three dimensions in living pancreatic β-cells: evidence against a role for AMPK-dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin granule movement

2010 ◽  
Vol 38 (1) ◽  
pp. 205-208 ◽  
Author(s):  
Angela McDonald ◽  
Sarah Fogarty ◽  
Isabelle Leclerc ◽  
Elaine V. Hill ◽  
D. Grahame Hardie ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glutathione Transferase ◽  
Three Dimensions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Levels ◽  
Insulin Granules ◽  
Elevated Glucose ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells requires the kinesin-1/Kif5B-mediated transport of insulin granules along microtubules. 5′-AMPK (5′-AMP-activated protein kinase) is a heterotrimeric serine/threonine kinase which is activated in β-cells at low glucose concentrations, but inhibited as glucose levels increase. Active AMPK blocks glucose-stimulated insulin secretion and the recruitment of insulin granules to the cell surface, suggesting motor proteins may be targets for this kinase. While both kinesin-1/Kif5B and KLC1 (kinesin light chain-1) contain consensus AMPK phosphorylation sites (Thr693 and Ser520, respectively) only recombinant GST (glutathione transferase)–KLC1 was phosphorylated by purified AMPK in vitro. To test the hypothesis that phosphorylation at this site may modulate kinesin-1-mediated granule movement, we developed an approach to study the dynamics of all the resolvable granules within a cell in three dimensions. This cell-wide approach revealed that the number of longer excursions (>10 μm) increased significantly in response to elevated glucose concentration (30 versus 3 mM) in control MIN6 β-cells. However, similar changes were seen in cells overexpressing wild-type KLC1, phosphomimetic (S517D/S520D) or non-phosphorylatable (S517A/S520A) mutants of KLC1. Thus, changes in the phosphorylation state of KLC1 at Ser517/Ser520 seem unlikely to affect motor function.

scholarly journals Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

2021 ◽  
Author(s):  
Han Yan ◽  
Zhenzhen Chen ◽  
Haizeng Zhang ◽  
Weili Yang ◽  
Xiangyang Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Mitochondrial Protein ◽  
Extracellular Atp ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Intracellular Atp ◽  
Pdx1 Expression ◽  
Ca2 Channels

AbstractFAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet β cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic β cells was further examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice. In vitro, FAM3A overexpression elevated both intracellular and extracellular ATP contents and promoted PDX1 expression and insulin secretion. FAM3A-induced increase in cellular calcium (Ca2+) levels, PDX1 expression, and insulin secretion, while these were significantly repressed by inhibitors of P2 receptors or the L-type Ca2+ channels. FAM3A-induced PDX1 expression was abolished by a calmodulin inhibitor. Likewise, FAM3A-induced β-cell proliferation was also inhibited by a P2 receptor inhibitor and an L-type Ca2+ channels inhibitor. Both intracellular and extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin secretion, and proliferation of pancreatic β cells.

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