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.

Effects of glucose and d-3-hydroxybutyrate on human pancreatic islet cell function

1985 ◽  
Vol 68 (5) ◽  
pp. 567-572 ◽  
Author(s):  
C. J. Rhodes ◽  
I. L. Campbell ◽  
T. M. Szopa ◽  
T. J. Biden ◽  
P. D. Reynolds ◽  
...  
Keyword(s):  
Insulin Release ◽  
Human Tissue ◽  
Islet Cell ◽  
Cell Function ◽  
Human Islets ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Sigmoidal Curve ◽  
Β Cell Function ◽  
Islet Cell Function

1. β-Cell function in human islets derived from a number of kidney donors was investigated by using various types of islet preparations. 2. With fresh islets, both insulin release and biosynthesis were increased by raising glucose concentrations, although the response was a variable one. 3. In fresh islets, the effects of 5 mmol of glucose/l on release were potentiated by 10 mmol of d-3-hydroxybutyrate/l. 4. Insulin release at 20 mmol of glucose/l was inhibited by adrenaline (0.1 mmol/l), and potentiated by theophylline (10 mmol/l) in the presence of 5 mmol of glucose/l, in islets cultured for 4 days. 5. After culture for 8 days, islets still showed an increase in insulin release and biosynthesis in response to glucose. 6. Pancreas slices derived from fresh human tissue also responded to increasing concentrations of glucose with a sigmoidal curve for insulin release.

scholarly journals IgGs from patients with amyotrophic lateral sclerosis and diabetes target CaVα2δ1 subunits impairing islet cell function and survival

2019 ◽  
Vol 116 (52) ◽  
pp. 26816-26822
Author(s):  
Yue Shi ◽  
Kyoung Sun Park ◽  
Seung Hyun Kim ◽  
Jia Yu ◽  
Kaixuan Zhao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Function ◽  
Islet Cells ◽  
Causal Link ◽  
Mouse Islet ◽  
Voltage Dependent ◽  
Islet Cell Function ◽  
Als Patients ◽  
Lateral Sclerosis

Patients with amyotrophic lateral sclerosis (ALS) often show hallmarks of type 2 diabetes mellitus (T2DM). However, the causal link between ALS and T2DM has remained a mystery. We now demonstrate that 60% of ALS patients with T2DM (ALS-T2DM) have sera that exaggerated K+-induced increases in cytosolic free Ca2+concentration ([Ca2+]i) in mouse islet cells. The effect was attributed to the presence of pathogenic immunoglobulin Gs (IgGs) in ALS-T2DM sera. The pathogenic IgGs immunocaptured the voltage-dependent Ca2+(CaV) channel subunit CaVα2δ1 in the plasma membrane enhancing CaV1 channel-mediated Ca2+influx and [Ca2+]i, resulting in impaired mitochondrial function. Consequently, impairments in [Ca2+]idynamics, insulin secretion, and cell viability occurred. These data reveal that patients with ALS-T2DM carry cytotoxic ALS-T2DM-IgG autoantibodies that serve as a causal link between ALS and T2DM by immunoattacking CaVα2δ1 subunits. Our findings may lay the foundation for a pharmacological treatment strategy for patients suffering from a combination of these diseases.

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.

Norepinephrine inhibits islet lipid metabolism, 45Ca2+ uptake, and insulin secretion

1989 ◽  
Vol 257 (6) ◽  
pp. E923-E929 ◽  
Author(s):  
E. Vara ◽  
J. Tamarit-Rodriguez
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Acid Metabolism ◽  
De Novo ◽  
Neutral Lipids ◽  
Lipid Synthesis ◽  
Secretory Response ◽  
Chain Acyl ◽  
Mediated Reduction ◽  
Stimulation Of

We have previously shown that palmitate potentiates, in isolated islets, glucose-induced stimulation of insulin release, "de novo" lipid synthesis, and 45Ca2+ turnover in a correlative manner. Norepinephrine, a known inhibitor of the secretory response, has now been used to further investigate the relationships among the three phenomena. The amine decreased insulin secretion dose dependently in response to glucose and palmitate with alpha 2-adrenergic specificity. It also reduced similarly the oxidation of 1 mmol/l [U-14C]palmitate as well as the incorporation of 20 mmol/l D-[U-14C]glucose into islet phospholipids and neutral lipids through an alpha 2-adrenergic mechanism. These results indirectly suggest that alpha 2-adrenoceptor stimulation inhibits in islets both palmitate oxidation and esterification through an inactivation of long-chain acyl-CoA synthetase and other enzymes of glycerolipid synthesis. Islet uptake of 45Ca2+ was also decreased by norepinephrine with a similar sensitivity to that shown by insulin release and de novo lipid synthesis. Therefore, it is suggested that alpha 2-adrenoceptor-mediated reduction of the potentiation by palmitate of the secretory response to glucose depends on the inhibition of fatty acid metabolism and the resulting impairment of de novo lipid synthesis and 45Ca2+ turnover.

Diazoxide unmasks glucose inhibition of insulin release by counteracting entry of Ca2+

1988 ◽  
Vol 255 (4) ◽  
pp. E422-E427 ◽  
Author(s):  
P. Bergsten ◽  
E. Gylfe ◽  
N. Wesslen ◽  
B. Hellman
Keyword(s):  
Beta Cell ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Secretory Response ◽  
Glucose Stimulation ◽  
Glucose Inhibition ◽  
Insulin Secretory Response ◽  
Stimulation Of

The interaction of diazoxide with the effects of glucose on the insulin-releasing mechanism was analyzed in beta-cell-rich pancreatic islets isolated from ob/ob mice. When added at a concentration of 400 microM to a medium containing 1.28 mM Ca2+, diazoxide converted glucose stimulation of insulin release into inhibition. Further addition of 2 mM theophylline restored the insulin secretory response to glucose. The paradoxical glucose inhibition of insulin release was accounted for by a diazoxide interaction with the entry of Ca2+, unmasking a capacity of the sugar to lower cytoplasmic Ca2+ below its resting concentration.

Identification of iduronate-2-sulfatase in mouse pancreatic islets

2004 ◽  
Vol 287 (5) ◽  
pp. E983-E990 ◽  
Author(s):  
I. Coronado-Pons ◽  
A. Novials ◽  
S. Casas ◽  
A. Clark ◽  
R. Gomis
Keyword(s):  
Pancreatic Islets ◽  
Cell Function ◽  
Dermatan Sulfate ◽  
Islet Cells ◽  
Secretory Response ◽  
High Rate ◽  
Insulin Content ◽  
Dependent Manner ◽  
Mouse Pancreatic Islets ◽  
Mouse Islets

The lysosomal enzyme iduronate-2-sulfatase (IDS) is expressed in pancreatic islets and is responsible for degradation of proteoglycans, such as perlecan and dermatan sulfate. To determine the role of IDS in islets, expression and regulation of the gene and localization of the enzyme were investigated in mouse pancreatic islets and clonal cells. The Ids gene was expressed in mouse islets and β- and α-clonal cells, in which it was localized intracellularly in lysosomes. The transcriptional expression of Ids in mouse islets increased with glucose in a dose-dependent manner (11.5, 40.2, 88, and 179% at 5.5, 11.1, 16.7, and 24.4 mM, respectively, P < 0.01 for 16.7 and 24.4 mM glucose vs. 3 mM glucose). This increase was not produced by glyceraldehyde (1 mM) or 6-deoxyglucose (21.4 mM) and was blocked by the addition of mannoheptulose (21.4 mM). Neither insulin content nor secretory response to glucose (16.7 mM) was altered in mouse islets infected with lentiviral constructs carrying the IDS gene in sense orientation. Furthermore, no decrease in islet cell viability was observed in mouse islets carrying lentiviral contracts compared with controls. However, insulin content was reduced (35% vs. controls, P < 0.001) in islets infected with IDS antisense construct, while the secretory response of those islets to glucose was maintained. Inhibition of IDS by antisense infection led to an increase in lysosomal size and a high rate of insulin granule degradation via the crinophagic route in pancreatic β-cells. We conclude that IDS is localized in lysosomes in pancreatic islet cells and expression is regulated by glucose. IDS has a potential role in the normal pathway of lysosomal degradation of secretory peptides and is likely to be essential to maintain pancreatic β-cell function.

Somatostatin inhibition of glucose-induced electrical activity in cultured rat islet cells

1977 ◽  
Vol 233 (5) ◽  
pp. C164-C171 ◽  
Author(s):  
Caroline S. Pace ◽  
Mary Murphy ◽  
Susan Conant ◽  
Paul E. Lacy
Keyword(s):  
Electrical Activity ◽  
Insulin Release ◽  
Spike Activity ◽  
Inhibitory Action ◽  
Islet Cells ◽  
Secretory Response ◽  
Adrenergic Blockade ◽  
Ionic Fluxes ◽  
Electrophysiological Studies ◽  
Stimulus Secretion Coupling

Electrophysiological studies of rat islet cells in monolayer culture were undertaken to determine the role of transmembranous ionic fluxes in the inhibitory action of somatostatin on insulin release. In the presence of somatotropin release inhibiting factor (SRIF) (2.5 nM), hyperpolarization occured with or without glucose (16.6 mM) in the medium. SRIF also inhibited the incidence of glucose-induced spike activity. The inhibitory action of SRIF occurred within 5 min and was readily reversible. An increase in extracellular K+ (5–13 mM) or Ca2+ (2.3–4.6 mM) prevented SRIF inhibition of glucose-induced electrical activity. The secretory response of cultured islets to glucose (16.6 mM) was completely inhibited by SRIF (2.5 nM). The presence of high [Ca2+]0 or [K+]0, enhanced insulin release in the presence of SRIF and glucose. Although phentolamine (5.0 μg/ml) did not block the inhibition of glucose-induced electrical responses by SRIF, it prevented the inhibitory action of epinephrine (0.2 μg/ml). It is concluded that the primary action of SRIF is to alter transmembranous cationic fluxes, as manifested by hyperpolarization and a decrease in the incidence of spike activity, which may prevent glucose from eliciting a normal secretory response. insulin secretion; epinephrine; alpha-adrenergic blockade; stimulus-secretion coupling Submitted on February 14, 1977

scholarly journals Stimulation of proinsulin biosynthesis and insulin release by pyruvate and lactate

1978 ◽  
Vol 176 (1) ◽  
pp. 31-37 ◽  
Author(s):  
K Jain ◽  
S Asina ◽  
J Logothetopoulos
Keyword(s):  
Beta Cells ◽  
Insulin Release ◽  
Islet Cells ◽  
Substrate Utilization ◽  
Isolated Islets ◽  
Glycolytic Flux ◽  
Critical Degree ◽  
Proinsulin Biosynthesis ◽  
Stimulation Of

Increasing concentrations of pyruvate failed to stimulate proinsulin biosynthesis and insulin release in freshly isolated islets. Glycolytic flux (3H2O from [5-3H]glucose) decreased by 80-85%, but decarboxylation of [1(-14)C]pyruvate was unaffected in islets tested immediately after alloxan exposure. This strongly suggested that in freshly isolated islets, beta-cells, in relation to other islet cells, hardly contribute to the decarboxylation of pyruvate. Non-alloxan-treated cultured islets decarboxylated 2-2.5 times as much pyruvate as did alloxan-treated islets cultured for 15-18h. Thus the contribution of beta-cells to the metabolism of pyruvate after culturing markedly increased. Concomitantly beta-cells became responsive to pyruvate. At 20mM-pyruvate, release of prelabelled proinsulin and insulin and incorporation of [3H]leucine into proinsulin reached values approximately half of those obtained with 20mM-glucose. Lactate was as effective as pyruvate in inducing responses in cultured islets. The experiments indicate that a critical degree of substrate utilization is necessary for the generation of signals for insulin release and proinsulin biosynthesis.

scholarly journals Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

2002 ◽  
pp. 129-141 ◽  
Author(s):  
H Hui ◽  
R Perfetti
Keyword(s):  
Islet Cell ◽  
Glucose Transporter ◽  
Cell Function ◽  
Islet Cells ◽  
Cell Physiology ◽  
Islet Amyloid ◽  
Dominant Form ◽  
Insulin Promoter ◽  
Dual Action ◽  
Islet Cell Function

Pancreas duodenum homeobox-1 (PDX-1) (also known as insulin promoter factor-1, islet/duodenum homeobox-1, somatostatin transactivating factor-1, insulin upstream factor-1 and glucose-sensitive factor) is a transcription factor encoded by a Hox-like homeodomain gene. In humans and other animal species, the embryonic development of the pancreas requires PDX-1, as demonstrated by the identification of an individual with pancreatic agenesis resulting from a mutation that impaired the transcription of a functionally active PDX-1 protein. In adult subjects, PDX-1 is essential for normal pancreatic islet function as suggested by its regulatory action on the expression of a number of pancreatic genes, including insulin, somatostatin, islet amyloid polypeptide, the glucose transporter type 2 and glucokinase. Furthermore, heterozygous mutations of PDX-1 have been linked to a type of autosomal dominant form of diabetes mellitus known as maturity onset diabetes of the young type 4. The dual action of PDX-1, as a differentiation factor during embryogenesis and as a regulator of islet cell physiology in mature islet cells, underscores the unique role of PDX-1 in health and disease of the human endocrine pancreas.

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