scholarly journals Glucose-regulated pulsatile insulin release from mouse islets via the K(ATP) channel-independent pathway

2001 ◽  
pp. 667-675 ◽  
Author(s):  
J Westerlund ◽  
H Ortsater ◽  
F Palm ◽  
T Sundsten ◽  
P Bergsten
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Prolonged Exposure ◽  
Pulse Frequency ◽  
Secretory Rate ◽  
Pulsatile Release ◽  
Glucose Signaling ◽  
K Concentration ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion

OBJECTIVE: Regulation of insulin release by glucose involves dual pathways, including or not inhibition of ATP-sensitive K(+) channels (K(ATP) channels). Whereas the K(ATP) channel-dependent pathway produces pulsatile release of insulin it is not clear whether the independent pathway also generates such kinetics. DESIGN AND METHODS: To clarify this matter, insulin secretion and cytoplasmic Ca(2+) ([Ca(2+)](i)) were studied in perifused pancreatic islets from ob/ob mice. Insulin release was measured by ELISA technique and [Ca(2+)](i) by dual-wavelength fluorometry. RESULTS: Insulin secretion was pulsatile (0.2--0.3/min) at 3 mmol/l glucose when [Ca(2+)](i) was low and stable. Stimulation with 11 mmol/l of the sugar increased the amplitude of the insulin pulses with maintained frequency and induced oscillations in [Ca(2+)](i). Permanent opening of the K(ATP) channels with diazoxide inhibited glucose-stimulated insulin secretion back to basal levels with maintained pulsatility despite stable and basal [Ca(2+)](i) levels. Increase of the K(+) concentration to 30.9 mmol/l in the continued presence of diazoxide and 11 mmol/l glucose restored the secretory rate with maintained pulsatility and caused stable elevation in [Ca(2+)](i). Simultaneous introduction of diazoxide and elevation of K(+) augmented average insulin release almost 30-fold in 3 mmol/l glucose with maintained pulse frequency. Subsequent elevation of the glucose concentration to 11 and 20 mmol/l increased the release levels. After prolonged exposure to diazoxide, elevated K(+) and 20 mmol/l glucose, the pulse frequency decreased significantly. CONCLUSIONS: Not only glucose signaling via the K(ATP) channel-dependent but also that via the independent pathway generates amplitude-modulated pulsatile release of insulin from isolated islets.

Acute and long-term effects of metformin on the function and insulin secretory responsiveness of clonal β-cells

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Joan M. McKiney ◽  
Nigel Irwin ◽  
Peter R. Flatt ◽  
Clifford J. Bailey ◽  
Neville H. McClenaghan
Keyword(s):  
Insulin Secretion ◽  
Cell Viability ◽  
Palmitic Acid ◽  
Insulin Release ◽  
Prolonged Exposure ◽  
Long Term Effects ◽  
Β Cell ◽  
Beneficial Effects ◽  
Intracellular Ca ◽  
Glucose Stimulated Insulin Secretion

Abstract Functional effects of acute and prolonged (48 h) exposure to the biguanide drug metformin were examined in the clonal pancreatic β-cell line, BRIN-BD11. Effects of metformin on prolonged exposure to excessive increased concentrations of glucose and palmitic acid were also assessed. In acute 20-min incubations, 12.5–50 μm metformin did not alter basal (1.1 mm glucose) or glucose-stimulated (16.7 mm glucose) insulin secretion. However, higher concentrations of metformin (100–1000 μm) increased (1.3–1.5-fold; p<0.001) insulin release at basal glucose concentrations, but had no effect on glucose-stimulated insulin secretion. There were no apparent acute effects of metformin on intracellular Ca2+ concentrations, but metformin enhanced (p<0.05 to p<0.01) the acute insulinotropic actions of GIP and GLP-1. Exposure for 48 h to 200 μm metformin improved aspects of β-cell insulin secretory function, whereas these benefits were lost at 1 mm metformin. Prolonged glucotoxic and lipotoxic conditions impaired β-cell viability and insulin release in response to glucose and to a broad range of insulin secretagogues. Concomitant culture with 200 μm metformin partially reversed many of the adverse effects of prolonged glucotoxic conditions. However, there were no beneficial effects of metformin under prolonged culture with elevated concentrations of palmitic acid. The results suggest that metformin exerts direct effects on β-cell viability, function and survival that could contribute to the use of this agent in the treatment of type 2 diabetes.

scholarly journals Nitric oxide inhibits, and carbon monoxide activates, islet acid α-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion

2006 ◽  
Vol 190 (3) ◽  
pp. 681-693 ◽  
Author(s):  
Henrik Mosén ◽  
Albert Salehi ◽  
Ragnar Henningsson ◽  
Ingmar Lundquist
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Direct Effect ◽  
Appreciable Effect ◽  
Intact Mouse ◽  
Glucose Stimulated Insulin Secretion ◽  
Glucoside Hydrolases

We have studied the influence of nitric oxide (NO) and carbon monoxide (CO), putative messenger molecules in the brain as well as in the islets of Langerhans, on glucose-stimulated insulin secretion and on the activities of the acid α-glucoside hydrolases, enzymes which we previously have shown to be implicated in the insulin release process. We have shown here that exogenous NO gas inhibits, while CO gas amplifies glucose-stimulated insulin secretion in intact mouse islets concomitant with a marked inhibition (NO) and a marked activation (CO) of the activities of the lysosomal/vacuolar enzymes acid glucan-1,4-α-glucosidase and acid α-glucosidase (acid α-glucoside hydrolases). Furthermore, CO dose-dependently potentiated glucose-stimulated insulin secretion in the range 0.1–1000 μM. In intact islets, the heme oxygenase substrate hemin markedly amplified glucose-stimulated insulin release, an effect which was accompanied by an increased activity of the acid α-glucoside hydrolases. These effects were partially suppressed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. Hemin also inhibited inducible NO synthase (iNOS)-derived NO production probably through a direct effect of CO on the NOS enzyme. Further, exogenous CO raised the content of both cGMP and cAMP in parallel with a marked amplification of glucose-stimulated insulin release, while exogenous NO suppressed insulin release and cAMP, leaving cGMP unaffected. Emiglitate, a selective inhibitor of α-glucoside hydrolase activities, was able to markedly inhibit the stimulatory effect of exogenous CO on both glucose-stimulated insulin secretion and the activityof acid glucan-1,4-α-glucosidase and acid α-glucosidase, while no appreciable effect on the activities of other lysosomal enzyme activities measured was found. We propose that CO and NO, both produced in significant quantities in the islets of Langerhans, have interacting regulatory roles on glucose-stimulated insulin secretion. This regulation is, at least in part, transduced through the activity of cGMP and the lysosomal/vacuolar system and the associated acid α-glucoside hydrolases, but probably also through a direct effect on the cAMP system.

scholarly journals Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Minglin Pan ◽  
Guang Yang ◽  
Xiuli Cui ◽  
Shao-Nian Yang
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Adrenergic Agonist ◽  
Signaling Systems ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulin Secretory Response ◽  
Adrenergic Activation ◽  
Gi Proteins

The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

scholarly journals Metabolic cycling in control of glucose-stimulated insulin secretion

2008 ◽  
Vol 295 (6) ◽  
pp. E1287-E1297 ◽  
Author(s):  
Mette V. Jensen ◽  
Jamie W. Joseph ◽  
Sarah M. Ronnebaum ◽  
Shawn C. Burgess ◽  
A. Dean Sherry ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pyruvate Metabolism ◽  
Coupling Factors ◽  
Stimulus Secretion Coupling ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet β-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and α-ketoglutarate, in control of GSIS.

scholarly journals Activation of protein kinase C partially alleviates noradrenaline inhibition of insulin secretion

1993 ◽  
Vol 289 (2) ◽  
pp. 497-501 ◽  
Author(s):  
S J Persaud ◽  
P M Jones ◽  
S L Howell
Keyword(s):  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Inhibitory Effect ◽  
Kinase C ◽  
Dependent Protein ◽  
Glucose Stimulated Insulin Secretion ◽  
Rat Islets Of Langerhans

The sympathetic neurotransmitter noradrenaline (NA) fully inhibited both phases of glucose-stimulated insulin secretion from rat islets of Langerhans. The secretory response to the protein kinase C (PKC) activator, 4 beta-phorbol myristate acetate (4 beta PMA), in the absence of exogenous glucose was also abolished by NA. However, at 20 mM glucose 4 beta PMA partially alleviated the inhibitory effect of NA both on insulin release and on cyclic AMP generation. Inhibition of insulin release by NA, albeit much decreased, was still observed in the presence of maximal stimulatory concentrations of both 4 beta PMA and dibutyryl cyclic AMP. The relieving effect of 4 beta PMA on the inhibition of insulin secretion by NA was not overcome by the competitive antagonist of cyclic AMP-dependent protein kinase, Rp-adenosine 3′,5′-cyclic phosphorothioate. Down-regulation of islet PKC activity by overnight exposure to 4 beta PMA did not affect the inhibitory capacity of NA. These results suggest that NA inhibits insulin release independently of interaction with PKC, but that activation of this enzyme decreases the inhibitory effect of NA at stimulatory concentrations of glucose. This protective effect of 4 beta PMA could not be attributed to a decrease in NA inhibition of cyclic AMP generation.

scholarly journals Potassium ions and the secretion of insulin by islets of Langerhans incubated in vitro

1968 ◽  
Vol 108 (1) ◽  
pp. 17-24 ◽  
Author(s):  
S. L. Howell ◽  
K W Taylor
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Potassium Ions ◽  
Collagenase Digestion ◽  
Islet Tissue ◽  
Rabbit Pancreas ◽  
K Concentration

1. A method was devised for the isolation of islets of Langerhans from rabbit pancreas by collagenase digestion in order to study the influx and efflux of K+ in islets during insulin secretion. 2. Glucose-induced insulin release was accompanied by an increased rate of uptake of 42K+ by the islets of Langerhans, though this was not the case for secretion in response to tolbutamide. Ouabain significantly inhibited the uptake of 42K+ by islet tissue. 3. No significant increase in the rate of efflux of 42K+ was demonstrated during active insulin secretion. 4. Slices of rabbit pancreas were incubated in media of different K+ content, and rates of insulin release were determined. Alteration of the K+ concentration of the medium between 3 and 8mm had no effect on the rate of insulin release by pancreas slices. However, decrease of the K+ concentration to 1mm resulted in inhibition of secretion in response to both glucose and to tolbutamide. Conversely, an increase in K+ concentration increased rates of insulin release in response to both these stimuli. 5. It is concluded that, though unphysiological concentrations of K+ may influence the secretion of insulin, fluxes of K+ in the islets do not appear to be important in the initiation of insulin secretion.

scholarly journals Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue

1984 ◽  
Vol 219 (1) ◽  
pp. 189-196 ◽  
Author(s):  
U Panten ◽  
S Zielmann ◽  
J Langer ◽  
B J Zünkler ◽  
S Lenzen
Keyword(s):  
Insulin Secretion ◽  
Oxidative Phosphorylation ◽  
B Cell ◽  
Insulin Release ◽  
Prolonged Exposure ◽  
Mitochondrial Fraction ◽  
Second Phase ◽  
O2 Uptake ◽  
Hydrogen Supply ◽  
Kinetics Of

In mouse pancreatic islets the kinetics of insulin secretion and O2 uptake in response to the non-metabolizable leucine analogue (+/-)-BCH (2-endo- aminonorbornane −2-carboxylic acid) were compared. In addition, the fuel-mobilizing effect of (+/-)-BCH was studied with a mitochondrial fraction from islets. (1) Within 2 min 20 mM-(+/-)-BCH markedly enhanced insulin release or O2 consumption by islets respiring in the absence of exogenous fuels. During prolonged exposure to 20 mM-(+/-)-BCH secretion declined more rapidly than O2 uptake. (2) L-Glutamine (10 mM) prevented the decrease of both insulin release and O2 uptake of islets exposed to 20mM-(+/-)-BCH. During the second phase of insulin release in response to 20 mM-(+/-)-BCH + 10 mM-L-glutamine, kinetics of secretion and respiration correlated closely. (3) Initial peaks were consistently seen in the (+/-)-BCH-induced secretory profiles, but never in the respiratory profiles. (4) In contrast with L-glycerol 3-phosphate, L-malate or pyruvate, L-glutamine or L-glutamate maintained low rates of oxidative phosphorylation in B-cell mitochondria. The effects of L-glutamine or L-glutamate were potentiated severalfold by (+/-)-BCH. (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity. (6) The results support the view that (+/-)-BCH stimulates insulin secretion via a primary enhancement of hydrogen supply to the respiratory chain of B-cell mitochondria.

scholarly journals A Microfluidic Hanging-Drop-Based Islet Perifusion System for Studying Glucose-Stimulated Insulin Secretion From Multiple Individual Pancreatic Islets

2021 ◽  
Vol 9 ◽  
Author(s):  
Patricia Wu Jin ◽  
Nassim Rousset ◽  
Andreas Hierlemann ◽  
Patrick M. Misun
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Sampling Interval ◽  
Liquid Volume ◽  
High Temporal Resolution ◽  
Diabetes Research ◽  
Hanging Drop ◽  
Biphasic Insulin Release ◽  
Glucose Stimulated Insulin Secretion

Islet perifusion systems can be used to monitor the highly dynamic insulin release of pancreatic islets in glucose-stimulated insulin secretion (GSIS) assays. Here, we present a new generation of the microfluidic hanging-drop-based islet perifusion platform that was developed to study the alterations in insulin secretion dynamics from single pancreatic islet microtissues at high temporal resolution. The platform was completely redesigned to increase experimental throughput and to reduce operational complexity. The experimental throughput was increased fourfold by implementing a network of interconnected hanging drops, which allows for performing GSIS assays with four individual islet microtissues in parallel with a sampling interval of 30 s. We introduced a self-regulating drop-height mechanism that enables continuous flow and maintains a constant liquid volume in the chip, which enables simple and robust operation. Upon glucose stimulation, reproducible biphasic insulin release was simultaneously observed from all islets in the system. The measured insulin concentrations showed low sample-to-sample variation as a consequence of precise liquid handling with stable drop volumes, equal flow rates in the channels, and accurately controlled sampling volumes in all four drops. The presented device will be a valuable tool in islet and diabetes research for studying dynamic insulin secretion from individual pancreatic islets.

scholarly journals Perilipin Is Present in Islets of Langerhans and Protects against Lipotoxicity When Overexpressed in the β-Cell Line INS-1

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3049-3057 ◽  
Author(s):  
Jörgen Borg ◽  
Cecilia Klint ◽  
Nils Wierup ◽  
Kristoffer Ström ◽  
Sara Larsson ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Line ◽  
Islets Of Langerhans ◽  
Prolonged Exposure ◽  
Human Islets ◽  
Lipid Storage ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
In Cells

Lipids have been shown to play a dual role in pancreatic β-cells: a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse, and human islets of Langerhans as well as the rat clonal β-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in β-cells. To examine whether the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the β-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 h. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared with control cells. Whereas glucose-stimulated insulin secretion was retained after palmitate exposure in cells overexpressing perilipin, it was completely abolished in control β-cells. Thus, overexpression of perilipin appears to confer protection against the development of β-cell dysfunction after prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis.

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