Neuropeptide Y and somatostatin inhibit insulin secretion through different mechanisms

Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to glucose elevation and G protein-coupled receptor (GPCR) activation. Neuropeptide Y (NPY) and somatostatin (SST) attenuate insulin secretion through Gi activation of Y1 and SSTR1&5 receptors, respectively. The downstream pathways altered by NPY and SST are poorly understood. Thus, we investigated these underlying mechanisms. NPY and SST increase cellular redox potential, suggesting that their inhibitory effect may not be mediated through metabolic inhibition. NPY does not affect intracellular calcium ([Ca2+]i) activity upon glucose stimulation, whereas SST alters this response. Gβγ-subunit inhibition by gallein attenuates insulin secretion but does not alter metabolism or [Ca2+]i. mSIRK-induced Gβγ activation does not modulate glucose metabolism but increases [Ca2+]i activity and potentiates insulin release. Cotreatment with gallein and NPY or SST reduces insulin secretion to levels similar to that of gallein alone. mSIRK and NPY cotreatment potentiates insulin secretion similarly to mSIRK alone, whereas mSIRK and SST treatment decreases insulin release. The data support a model where SST attenuates secretion through Gβγ inhibition of Ca2+ activity, while NPY activates a Ca2+-independent pathway mediated by Gα. GPCR ligands signal through multiple pathways to inhibit insulin secretion, and determining these mechanisms could lead to novel diabetic therapies.

Download Full-text

Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet β-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00035.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. E670-E677 ◽

Cited By ~ 167

Author(s):

Ken Fujiwara ◽

Fumihiko Maekawa ◽

Toshihiko Yada

Keyword(s):

Insulin Secretion ◽

Oleic Acid ◽

Insulin Release ◽

Β Cells ◽

Pancreatic Β Cells ◽

Insulinoma Cell ◽

Transduction Mechanisms ◽

Glucose Stimulated Insulin Secretion ◽

Interfering Rna ◽

G Protein Coupled

It has long been thought that long-chain free fatty acids (FFAs) stimulate insulin secretion via mechanisms involving their metabolism in pancreatic β-cells. Recently, it was reported that FFAs function as endogenous ligands for GPR40, a G protein-coupled receptor, to amplify glucose-stimulated insulin secretion in an insulinoma cell line and rat islets. However, signal transduction mechanisms for GPR40 in β-cells are little known. The present study was aimed at elucidating GPR40-linked Ca2+ signaling mechanisms in rat pancreatic β-cells. We employed oleic acid (OA), an FFA that has a high affinity for the rat GPR40, and examined its effect on cytosolic Ca2+ concentration ([Ca2+]i) in single β-cells by fura 2 fluorescence imaging. OA at 1–10 μM concentration-dependently increased [Ca2+]i in the presence of 5.6, 8.3, and 11.2 mM, but not 2.8 mM, glucose. OA-induced [Ca2+]i increases at 11.2 mM glucose were inhibited in β-cells transfected with small interfering RNA targeted to rat GPR40 mRNA. OA-induced [Ca2+]i increases were also inhibited by phospholipase C (PLC) inhibitors, U73122 and neomycin, Ca2+-free conditions, and an L-type Ca2+ channel blocker, nitrendipine. Furthermore, OA increased insulin release from isolated islets at 8.3 mM glucose, and it was markedly attenuated by PLC and L-type Ca2+ channel inhibitors. These results demonstrate that OA interacts with GPR40 to increase [Ca2+]i via PLC- and L-type Ca2+ channel-mediated pathway in rat islet β-cells, which may be link to insulin release.

Download Full-text

GW9508 inhibits insulin secretion by activating ATP-sensitive potassium channels in rat pancreatic β-cells

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0019 ◽

2013 ◽

Vol 51 (1) ◽

pp. 69-77 ◽

Cited By ~ 7

Author(s):

Yu-Feng Zhao ◽

Li Wang ◽

Dingjun Zha ◽

Li Qiao ◽

Lianjun Lu ◽

...

Keyword(s):

Insulin Secretion ◽

Membrane Potential ◽

Primary Culture ◽

Acute Effects ◽

Β Cells ◽

Pancreatic Β Cells ◽

Intracellular Ca ◽

Glucose Stimulated Insulin Secretion ◽

G Protein Coupled ◽

Inhibit Insulin Secretion

GW9508 is an agonist of G protein-coupled receptor 40 (GPR40) that is expressed in pancreatic β-cells and is reported to regulate insulin secretion. However, the effects of GW9508 on pancreatic β-cells in primary culture have not been well investigated. This study measured the acute effects of GW9508 on insulin secretion from rat pancreatic islets in primary culture, and the insulin secretion-related events such as the changes in membrane potential, ATP-sensitive potassium currents (KATP currents), and intracellular Ca2+ concentrations ([Ca2+]i) of rat islet β-cells were also recorded. GW9508 (10–40 μM) did not influence basal insulin levels at 2 mM glucose, but it (above 20 μM) significantly inhibited 5 and 15 mM glucose-stimulated insulin secretion (GSIS). GW9508 did not inhibit insulin secretion stimulated by tolbutamide, the closer of KATP channels. GW9508 activated KATP channels and blocked the membrane depolarization and the increase in [Ca2+]i that were stimulated by glucose. GW9508 itself stimulated a transient increase in [Ca2+]i, which was fully blocked by depletion of intracellular Ca2+ stores with thapsigargin or by inhibition of phospholipase C (PLC) activity with U73122. GW9508-induced activation of KATP channels was only partly inhibited by U73122 treatment. In conclusion, although it stimulates a transient release of Ca2+ from intracellular Ca2+ stores via activation of PLC, GW9508 inhibits GSIS by activating KATP channels probably in a distal step to GPR40 activation in rat β-cells.

Download Full-text

PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Nature Communications ◽

10.1038/s41467-020-20632-z ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Daniela Nasteska ◽

Nicholas H. F. Fine ◽

Fiona B. Ashford ◽

Federica Cuozzo ◽

Katrina Viloria ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Metabolic Stress ◽

Human Islets ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Ionic Fluxes ◽

Transcriptomic Level ◽

Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

Download Full-text

Insulin secretion in health and disease: nutrients dictate the pace

Proceedings of The Nutrition Society ◽

10.1017/s0029665115004152 ◽

2015 ◽

Vol 75 (1) ◽

pp. 19-29 ◽

Cited By ~ 9

Author(s):

Romano Regazzi ◽

Adriana Rodriguez-Trejo ◽

Cécile Jacovetti

Keyword(s):

Fatty Acids ◽

Insulin Secretion ◽

Cell Mass ◽

Insulin Biosynthesis ◽

Β Cells ◽

Β Cell ◽

Altered Expression ◽

Cell Dysfunction ◽

Dietary Nutrients ◽

Underlying Mechanisms

Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

Download Full-text

Regulation of glucokinase in pancreatic islets by prolactin: a mechanism for increasing glucose-stimulated insulin secretion during pregnancy

Journal of Endocrinology ◽

10.1677/joe-07-0043 ◽

2007 ◽

Vol 193 (3) ◽

pp. 367-381 ◽

Cited By ~ 55

Author(s):

Anthony J Weinhaus ◽

Laurence E Stout ◽

Nicholas V Bhagroo ◽

T Clark Brelje ◽

Robert L Sorenson

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Pancreatic Islets ◽

Glucose Transporter ◽

Β Cells ◽

Glucose Transporter 2 ◽

Underlying Mechanisms ◽

Glucose Stimulated Insulin Secretion ◽

Induced Changes

Glucokinase activity is increased in pancreatic islets during pregnancy and in vitro by prolactin (PRL). The underlying mechanisms that lead to increased glucokinase have not been resolved. Since glucose itself regulates glucokinase activity in β-cells, it was unclear whether the lactogen effects are direct or occur through changes in glucose metabolism. To clarify the roles of glucose metabolism in this process, we examined the interactions between glucose and PRL on glucose metabolism, insulin secretion, and glucokinase expression in insulin 1 (INS-1) cells and rat islets. Although the PRL-induced changes were more pronounced after culture at higher glucose concentrations, an increase in glucose metabolism, insulin secretion, and glucokinase expression occurred even in the absence of glucose. The presence of comparable levels of insulin secretion at similar rates of glucose metabolism from both control and PRL-treated INS-1 cells suggests the PRL-induced increase in glucose metabolism is responsible for the increase in insulin secretion. Similarly, increases in other known PRL responsive genes (e.g. the PRL receptor, glucose transporter-2, and insulin) were also detected after culture without glucose. We show that the upstream glucokinase promoter contains multiple STAT5 binding sequences with increased binding in response to PRL. Corresponding increases in glucokinase mRNA and protein synthesis were also detected. This suggests the PRL-induced increase in glucokinase mRNA and its translation are sufficient to account for the elevated glucokinase activity in β-cells with lactogens. Importantly, the increase in islet glucokinase observed with PRL is in line with that observed in islets during pregnancy.

Download Full-text

L-leucine methyl ester stimulates insulin secretion and islet glutamate dehydrogenase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.4.e338 ◽

1983 ◽

Vol 245 (4) ◽

pp. E338-E346 ◽

Cited By ~ 2

Author(s):

P. Knudsen ◽

H. Kofod ◽

A. Lernmark ◽

C. J. Hedeskov

Keyword(s):

Insulin Secretion ◽

Methyl Ester ◽

Glutamate Dehydrogenase ◽

Insulin Release ◽

Methyl Esters ◽

Tumor Cell Line ◽

Fold Increase ◽

Inhibitory Effect ◽

Amino Acid Derivative ◽

Mouse Pancreatic Islets

Column perifusion of collagenase-isolated mouse pancreatic islets was used to study the dynamics of insulin release in experiments lasting for several hours. The methyl esters of L-leucine and L-arginine were synthesized. Whereas L-arginine methyl ester (L-arginine OMe) had no effect, L-leucine OMe stimulated the release of insulin. The effect of L-leucine OMe was maximal at 5 mmol/liter. Whereas the Km for glucose-stimulated insulin release was unaffected by 1 mmol/liter L-leucine OMe, the maximal release of D-glucose was increased by the amino acid derivative that appeared more effective than L-leucine. L-Leucine OMe was also a potent stimulus of insulin release from the perfused mouse pancreas. In the presence of 10 mmol/liter L-glutamine, 1 mmol/liter L-leucine OMe induced a 50- to 75-fold increase in insulin release. A similar stimulatory effect was also observed in column-perifused RIN 5F cells, a cloned rat islet tumor cell line. A twofold increase in islet glutamate dehydrogenase activity was induced by 5 mmol/liter L-leucine OMe, a larger effect than that of L-leucine (P less than 0.02), whereas L-arginine OMe had a small inhibitory effect. We conclude that L-leucine OMe is a potent stimulus of insulin secretion and that its effect on the beta-cells may be exerted by activating islet glutamate dehydrogenase.

Download Full-text

Tolbutamide and diazoxide modulate phospholipase C-linked Ca2+ signaling and insulin secretion in β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.4.e639 ◽

2000 ◽

Vol 278 (4) ◽

pp. E639-E647 ◽

Cited By ~ 6

Author(s):

Christof Schöfl ◽

Julia Börger ◽

Thilo Mader ◽

Mark Waring ◽

Alexander von zur Mühlen ◽

...

Keyword(s):

Insulin Secretion ◽

Phospholipase C ◽

Insulin Release ◽

Arginine Vasopressin ◽

Bay K 8644 ◽

Free Medium ◽

Β Cells ◽

Pancreatic Β Cells ◽

Activating Receptors

Arginine vasopressin (AVP), bombesin, and ACh increase cytosolic free Ca2+ and potentiate glucose-induced insulin release by activating receptors linked to phospholipase C (PLC). We examined whether tolbutamide and diazoxide, which close or open ATP-sensitive K+ channels (KATP channels), respectively, interact with PLC-linked Ca2+ signals in HIT-T15 and mouse β-cells and with PLC-linked insulin secretion from HIT-T15 cells. In the presence of glucose, the PLC-linked Ca2+ signals were enhanced by tolbutamide (3–300 μM) and inhibited by diazoxide (10–100 μM). The effects of tolbutamide and diazoxide on PLC-linked Ca2+ signaling were mimicked by BAY K 8644 and nifedipine, an activator and inhibitor of L-type voltage-sensitive Ca2+channels, respectively. Neither tolbutamide nor diazoxide affected PLC-linked mobilization of internal Ca2+ or store-operated Ca2+ influx through non-L-type Ca2+ channels. In the absence of glucose, PLC-linked Ca2+ signals were diminished or abolished; this effect could be partly antagonized by tolbutamide. In the presence of glucose, tolbutamide potentiated and diazoxide inhibited AVP- or bombesin-induced insulin secretion from HIT-T15 cells. Nifedipine (10 μM) blocked both the potentiating and inhibitory actions of tolbutamide and diazoxide on AVP-induced insulin release, respectively. In glucose-free medium, AVP-induced insulin release was reduced but was again potentiated by tolbutamide, whereas diazoxide caused no further inhibition. Thus tolbutamide and diazoxide regulate both PLC-linked Ca2+signaling and insulin secretion from pancreatic β-cells by modulating KATP channels, thereby determining voltage-sensitive Ca2+ influx.

Download Full-text