scholarly journals Palmitic acid acutely inhibits acetylcholine- but not GLP-1-stimulated insulin secretion in mouse pancreatic islets

2010 ◽  
Vol 299 (3) ◽  
pp. E475-E485 ◽  
Author(s):  
Nicolai M. Doliba ◽  
Wei Qin ◽  
Sergei A. Vinogradov ◽  
David F. Wilson ◽  
Franz M. Matschinsky
Keyword(s):  
Fatty Acids ◽  
Oxygen Consumption ◽  
Insulin Secretion ◽  
Insulin Release ◽  
Cell Function ◽  
Hormone Secretion ◽  
Albumin Concentration ◽  
Dependent Manner ◽  
Fixed Concentration ◽  
Stimulation Of

Fatty acids, acetylcholine, and GLP-1 enhance insulin secretion in a glucose-dependent manner. However, the interplay between glucose, fatty acids, and the neuroendocrine regulators of insulin secretion is not well understood. Therefore, we studied the acute effects of PA (alone or in combination with glucose, acetylcholine, or GLP-1) on isolated cultured mouse islets. Two different sets of experiments were designed. In one, a fixed concentration of 0.5 mM of PA bound to 0.15 mM BSA was used; in the other, a PA ramp from 0 to 0.5 mM was applied at a fixed albumin concentration of 0.15 mM so that the molar PA/BSA ratio changed within the physiological range. At a fixed concentration of 0.5 mM, PA markedly inhibited acetylcholine-stimulated insulin release, the rise of intracellular Ca2+, and enhancement of cAMP production but did not influence the effects of GLP-1 on these parameters of islet cell function. 2-ADB, an IP3 receptor inhibitor, reduced the effect of acetylcholine on insulin secretion and reversed the effect of PA on acetylcholine-stimulated insulin release. Islet perfusion for 35–40 min with 0.5 mM PA significantly reduced the calcium storage capacity of ER measured by the thapsigargin-induced Ca2+ release. Oxygen consumption due to low but not high glucose was reduced by PA. When a PA ramp from 0 to 0.5 mM was applied in the presence of 8 mM glucose, PA at concentrations as low as 50 μM significantly augmented glucose-stimulated insulin release and markedly reduced acetylcholine's effects on hormone secretion. We thus demonstrate that PA acutely reduces the total oxygen consumption response to glucose, glucose-dependent acetylcholine stimulation of insulin release, Ca2+, and cAMP metabolism, whereas GLP-1's actions on these parameters remain unaffected or potentiated. We speculate that acute emptying of the ER calcium by PA results in decreased glucose stimulation of respiration and acetylcholine potentiation of insulin secretion.

Direct effect of parathyroid hormone on insulin secretion from pancreatic islets

1990 ◽  
Vol 258 (6) ◽  
pp. E975-E984 ◽  
Author(s):  
G. Z. Fadda ◽  
M. Akmal ◽  
L. G. Lipson ◽  
S. G. Massry
Keyword(s):  
Insulin Secretion ◽  
Parathyroid Hormone ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Direct Effect ◽  
Indirect Evidence ◽  
Cytosolic Calcium ◽  
Dependent Manner ◽  
Stimulation Of

Indirect evidence indicates that parathyroid hormone (PTH) interacts with pancreatic islets and modulates their insulin secretion. This property of PTH has been implicated in the genesis of impaired insulin release in chronic renal failure. We examined the direct effect of PTH-(1-84) and PTH-(1-34) on insulin release using in vitro static incubation and dynamic perifusion of pancreatic islets from normal rats. Both moieties of the hormone stimulated in a dose-dependent manner glucose-induced insulin release but higher doses inhibited glucose-induced insulin release. This action of PTH was modulated by the calcium concentration in the media. The stimulatory effect of PTH was abolished by its inactivation and blocked by its antagonist [Tyr-34]bPTH-(7-34)NH2. PTH also augmented phorbol ester (TPA)-induced insulin release, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation by pancreatic islets, and significantly increased (+50 +/- 2.7%, P less than 0.01) their cytosolic calcium. Verapamil inhibited the stimulatory effect of PTH on insulin release. The data show that 1) pancreatic islets are a PTH target and may have PTH receptors, 2) stimulation of glucose-induced insulin release by PTH is mediated by a rise in cytosolic calcium, 3) stimulation of cAMP production by PTH and a potential indirect activation of protein kinase C by PTH may also contribute to the stimulatory effect on glucose-induced insulin release, and 4) this action of PTH requires calcium in incubation or perifusion media.

scholarly journals Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans

2002 ◽  
Vol 173 (1) ◽  
pp. 73-80 ◽  
Author(s):  
C Gravena ◽  
PC Mathias ◽  
SJ Ashcroft
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Insulin Release ◽  
Islets Of Langerhans ◽  
Saturated Fatty Acids ◽  
Human Islets ◽  
Dependent Manner ◽  
Acute Effects ◽  
Rat Islets ◽  
Human Islets Of Langerhans

Fatty acids have both stimulatory and inhibitory effects on insulin secretion. Long-term exposure to fatty acids results in impaired insulin secretion whilst acute exposure has generally been found to enhance insulin release. However, there are conflicting data in the literature as to the relative efficacy of various fatty acids and on the glucose dependency of the stimulatory effect. Moreover, there is little information on the responses of human islets in vitro to fatty acids. We have therefore studied the acute effects of a range of fatty acids on insulin secretion from rat and human islets of Langerhans at different glucose concentrations. Fatty acids (0.5 mM) acutely stimulated insulin release from rat islets of Langerhans in static incubations in a glucose-dependent manner. The greatest effect was seen at high glucose concentration (16.7 mM) and little or no response was elicited at 3.3 or 8.7 mM glucose. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate). Stimulation of insulin secretion by fatty acids was also studied in perifused rat islets. No effects were observed at 3.3 mM glucose but fatty acids markedly potentiated the effect of 16.7 mM glucose. The combination of fatty acid plus glucose was less effective when islets had been first challenged with glucose alone. The insulin secretory responses to fatty acids of human islets in static incubations were similar to those of rat islets. In order to examine whether the responses to glucose and to fatty acids could be varied independently we used an animal model in which lactating rats are fed a low-protein diet during early lactation. Islets from rats whose mothers had been malnourished during lactation were still able to respond effectively to fatty acids despite a lowered secretory response to glucose. These data emphasise the complex interrelationships between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis during undernutrition.

scholarly journals Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin-Secreting BRIN-BD11 Cells

2001 ◽  
Vol 2 (1) ◽  
pp. 19-27 ◽  
Author(s):  
Sally F. Picton ◽  
Peter R. Flatt ◽  
Neville H. McClenaghan
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Succinic Acid ◽  
Insulin Release ◽  
Beta Cell Function ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Dependent Manner ◽  
Pancreatic Beta Cell Function ◽  
Monomethyl Ester

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.

scholarly journals A single mechanism for the stimulation of insulin release and 86Rb+ efflux from rat islets by cationic amino acids

1982 ◽  
Vol 208 (2) ◽  
pp. 301-308 ◽  
Author(s):  
Stanislas Charles ◽  
Tatsuo Tamagawa ◽  
Jean-Claude Henquin
Keyword(s):  
Amino Acids ◽  
B Cells ◽  
Insulin Release ◽  
Cell Function ◽  
Dependent Manner ◽  
Free Medium ◽  
Rat Islets ◽  
Related Substances ◽  
Cationic Amino Acids ◽  
Stimulation Of

The mechanisms by which cationic amino acids influence pancreatic B-cell function have been studied by monitoring simultaneously 86Rb+ efflux and insulin release from perifused rat islets. The effects of two reference amino acids arginine and lysine were compared with those of closely related substances to define the structural requirements for recognition of these molecules as secretagogues. Arginine accelerated 86Rb+ efflux and increased insulin release in the absence or in the presence of 7mm-glucose. Its effects on efflux did not require the presence of extracellular Ca2+ or Na+, but its insulinotropic effects were suppressed in a Ca2+-free medium and inhibited in an Na+-free medium. Among arginine derivatives, only 2-amino-3-guanidinopropionic acid mimicked its effects on 86Rb+ efflux and insulin release; citrulline, guanidinoacetic acid, 3-guanidinopropionic acid and guanidine were inactive. Norvaline and valine also increased 86Rb+ efflux, but their effect required the presence of extracellular Na+; they did not stimulate insulin release. Lysine as well as the shorter-chain cationic amino acids ornithine and 2,4-diaminobutyric acid accelerated 86Rb+ efflux in a Ca2+- and Na+-independent manner. Their stimulation of insulin release was suppressed by Ca2+ omission, but only partially inhibited in an Na+-free medium. The uncharged glutamine and norleucine increased the rate of 86Rb+ efflux in the presence of glucose, only if extracellular Na+ was present. Norleucine slightly increased release in a Ca2+- and Na+-dependent manner. The effects of lysine on efflux and release were not mimicked by other related substances such as 1,5-diaminopentane and 6-aminohexanoic acid. The results suggest that the depolarizing effect of cationic amino acids is due to accumulation of these positively charged molecules in B-cells. This causes acceleration of the efflux of K+ (86Rb+) and activation of the influx of Ca2+ (which triggers insulin release). The prerequisite for the stimulation of B-cells by this mechanism appears to be the presence of a positive charge on the side chain of the amino acid, rather than a specific group.

Effects of l-leucine, its 2-keto acid metabolite and its nonmetabolized analogue on rat tumoral islet cell function

1988 ◽  
Vol 1 (1) ◽  
pp. 69-76 ◽  
Author(s):  
V. Leclercq-Meyer ◽  
J. Marchand ◽  
A. Sener ◽  
F. Blachier ◽  
W. J. Malaisse
Keyword(s):  
Insulin Release ◽  
Cell Function ◽  
Islet Cells ◽  
Adenine Nucleotides ◽  
Secretory Response ◽  
Acid Metabolite ◽  
Dual Effect ◽  
Islet Cell Function ◽  
Insulinoma Cells ◽  
Stimulation Of

ABSTRACT l-Leucine and 2-ketoisocaproate stimulated insulin release from perifused rat tumoral islet cells (RINm5F line). The secretory response coincided with an increase in the intracellular ATP/ADP ratio, a stimulation of 45Ca outflow from cells perifused in the presence of extracellular Ca2+, and an increase in 32P efflux from cells prelabelled with radioactive orthophosphate. In contrast to d-glucose, however, l-leucine or 2-ketoisocaproate failed to decrease 86Rb outflow, to inhibit 45Ca outflow from cells perifused in the absence of Ca2+ and to enhance the labelling of inositol-containing phospholipids in cells exposed to myo-[2-3H]inositol. These findings suggest that d-glucose, l-leucine and 2-ketoisocaproate exert dissimilar effects on the subcellular distribution of adenine nucleotides and/or 86Rb. The nonmetabolized analogue of l-leucine, 2-aminobicyclo-[2.2.1]heptane-2-carboxylic acid (BCH), also caused an initial stimulation of insulin release and 32P efflux, but this was soon followed by a severe and irreversible inhibition of insulin output, associated with a permanent enhancement of 86Rb outflow. The dual ionic and secretory response to BCH is interpreted in the light of its dual effect on the catabolism of endogenous amino and fatty acids, and raises the view that BCH could be used to interfere with the function of insulinoma cells.

Impact of lack of suppression of glucagon on glucose tolerance in humans

1999 ◽  
Vol 277 (2) ◽  
pp. E283-E290 ◽  
Author(s):  
Pankaj Shah ◽  
Ananda Basu ◽  
Rita Basu ◽  
Robert Rizza
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Cell Function ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

scholarly journals Adrenaline Stimulation of Phospholipid Metabolism in Adipocyte Ghosts

1987 ◽  
Vol 40 (4) ◽  
pp. 405
Author(s):  
David Mann ◽  
Audrey M Bersten
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Linoleic Acid ◽  
Adenylate Cyclase ◽  
Phospholipid Metabolism ◽  
Dependent Manner ◽  
Long Chain Fatty Acids ◽  
Membrane Phospholipids ◽  
Dose Dependent ◽  
Stimulation Of

The incorporation of long-chain fatty acids into phospholipids has been detected in adipocyte ghosts that were incubated with [1_14 C] stearic, [1_14 C] linoleic or [l_14C] arachidonic acid. Adrenaline and adenosine activated this incorporation within 15 s of exposure of the ghosts to the hormones and the response was dose dependent. Maximum incorporation of labelled linoleic acid occurred at 10-5 M adrenaline and 10-7 M adenosine. The a-agonist phenylephrine and the ~-agonist isoproterenol were also shown to stimulate the incorporation of fatty acid in a dose dependent manner. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol were each labelled preferentially with linoleic or arachidonic acid. p-Bromophenacylbromide, quinacrine and centrophenoxine inhibited the adrenaline-stimulated incorporation of fatty acids into ghost membrane phospholipids, and p-bromophenacylbromide also reduced the activation of adenylate cyclase by adrenaline. NaF, an activator of adenylate cyclase, like adrenaline, stimulated the incorporation of linoleic acid into ghost membrane phospholipids.

Effect of galanin on glucose-, arginine-, or potassium-stimulated insulin release

1989 ◽  
Vol 256 (5) ◽  
pp. E619-E623
Author(s):  
T. Yoshimura ◽  
J. Ishizuka ◽  
G. H. Greeley ◽  
J. C. Thompson
Keyword(s):  
Insulin Release ◽  
High Glucose ◽  
Second Phase ◽  
Dependent Manner ◽  
Perfused Pancreas ◽  
Isolated Perfused Pancreas ◽  
Second Phases ◽  
High Concentrations ◽  
Dose Dependent ◽  
Stimulation Of

We have examined the effect of galanin infusion on glucose-stimulated release of insulin from the isolated perfused pancreas of the rat to better characterize the effect of galanin on the first and second phases of insulin release. The effects of galanin on insulin release stimulated by L-arginine or high concentrations of potassium were also examined. When perfusion of galanin was started 4 min before the start of perfusion of high glucose (16.7 mM), galanin (10(-8)-10(-11) M) inhibited both the first and second phases of insulin release in a dose-dependent manner. When perfusion of galanin (10(-8) or 10(-9) M) was started simultaneously with high glucose (16.7 mM), only the second phase of insulin release was suppressed (P less than 0.05). Galanin (10(-9) M) failed to inhibit insulin release stimulated by L-arginine (10 and 5 mM) or potassium (25 and 20 mM). These findings suggest that the inhibitory action of galanin on glucose-stimulated insulin release is exerted on early intracellular events that occur during the stimulation of insulin release and that are common to both phases. Because galanin does not inhibit insulin release stimulated by L-arginine or potassium, galanin may inhibit glucose-stimulated closure of potassium channels.

scholarly journals Functional Coupling of Rab3-interacting Molecule 1 (RIM1) and L-type Ca2+ Channels in Insulin Release

2011 ◽  
Vol 286 (18) ◽  
pp. 15757-15765 ◽  
Author(s):  
María A. Gandini ◽  
Alejandro Sandoval ◽  
Ricardo González-Ramírez ◽  
Yasuo Mori ◽  
Michel de Waard ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Hormone Secretion ◽  
Functional Coupling ◽  
Functional Link ◽  
Whole Cell ◽  
Hek 293 ◽  
Auxiliary Subunit ◽  
Intracellular Signals ◽  
Channel Expression

Insulin release by pancreatic β-cells is regulated by diverse intracellular signals, including changes in Ca2+ concentration resulting from Ca2+ entry through voltage-gated (CaV) channels. It has been reported that the Rab3 effector RIM1 acts as a functional link between neuronal CaV channels and the machinery for exocytosis. Here, we investigated whether RIM1 regulates recombinant and native L-type CaV channels (that play a key role in hormone secretion) and whether this regulation affects insulin release. Whole-cell patch clamp currents were recorded from HEK-293 and insulinoma RIN-m5F cells. RIM1 and CaV channel expression was identified by RT-PCR and Western blot. RIM1-CaV channel interaction was determined by co-immunoprecipitation. Knockdown of RIM1 and CaV channel subunit expression were performed using small interference RNAs. Insulin release was assessed by ELISA. Co-expression of CaV1.2 and CaV1.3 L-type channels with RIM1 in HEK-293 cells revealed that RIM1 may not determine the availability of L-type CaV channels but decreases the rate of inactivation of the whole cell currents. Co-immunoprecipitation experiments showed association of the CaVβ auxiliary subunit with RIM1. The lack of CaVβ expression suppressed channel regulation by RIM1. Similar to the heterologous system, an increase of current inactivation was observed upon knockdown of endogenous RIM1. Co-immunoprecipitation showed association of CaVβ and RIM1 in insulin-secreting RIN-m5F cells. Knockdown of RIM1 notably impaired high K+-stimulated insulin secretion in the RIN-m5F cells. These data unveil a novel functional coupling between RIM1 and the L-type CaV channels via the CaVβ auxiliary subunit that contribute to determine insulin secretion.

scholarly journals Stimulation of insulin secretion by acetylenic fatty acids in insulinoma MIN6 cells through FFAR1

2020 ◽  
Vol 522 (1) ◽  
pp. 68-73 ◽  
Author(s):  
Katsutoshi Nishino ◽  
Haruka Uesugi ◽  
Akira Hirasawa ◽  
Anna Ohtera ◽  
Yusaku Miyamae ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Min6 Cells ◽  
Acetylenic Fatty Acids ◽  
Stimulation Of
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