Calcium-independent potentiation of insulin release by cyclic AMP in single β-cells

The oxidation of alanine, arginine, leucine, glucose, and pyruvate was studied in microdissected pancreatic islets of obese–hyperglycaemic mice. The following main observations were made. The oxidation of glucose was enhanced severalfold when its concentration was raised from 3 to 20mm. At the latter concentration the rate was about 65mmol/h per kg dry wt. The oxidation of 17mm-pyruvate amounted to 20mmol/h per kg dry wt. indicating a significant entry of this compound into the β-cells. Leucine oxidation was little affected by concentration changes above 5mm, the rate at 20mm corresponding to about 25% of that obtained with 20mm-glucose. In the absence of glucose, the oxidation of alanine or arginine was barely significant. Glucose stimulated the oxidation of alanine but depressed that of leucine. These effects of glucose were blocked by mannoheptulose or iodoacetamide but were not influenced by adrenaline, diazoxide, dibutyryl 3′:5′-cyclic AMP, or glibenclamide. The rate of alanine oxidation was doubled in the presence of 17mm-pyruvate but was unaffected by citrate or succinate. Succinate depressed the oxidation of leucine. Neither alanine nor leucine significantly affected the oxidation of glucose. It is suggested that the effects of glucose on the oxidation of alanine and leucine were mediated by metabolism of the sugar, and that amino acids do not act as insulin secretagogues by serving as fuels for the β-cells. The results are consistent with the existence of mechanisms auxiliary to glucose metabolism for control of insulin release.

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STUDIES ON THE MECHANISM OF SOMATOSTATIN ACTION ON INSULIN RELEASE IN MAN

Acta Endocrinologica ◽

10.1530/acta.0.0810743 ◽

1976 ◽

Vol 81 (4) ◽

pp. 743-752 ◽

Cited By ~ 15

Author(s):

S. Efendić ◽

R. Luft ◽

A. Claro

Keyword(s):

Cyclic Amp ◽

Adenylate Cyclase ◽

Insulin Release ◽

Healthy Subjects ◽

Β Cells ◽

Amp System ◽

Glycogenolytic Effect ◽

Order Of Magnitude ◽

Competitive Nature

ABSTRACT Somatostatin in as small a dose as 70 μg given over a period of 90 min to seven healthy subjects inhibited insulin release induced by glucose (500 mg/kg as a bolus ± 20 mg/kg/min). This inhibition seemed to be of competitive nature since the effect was nearly overcome when the glucose dose was raised considerably. Somatostatin in nine subjects also inhibited insulin release induced by glucagon and tolbutamide, and this inhibition was of the same order of magnitude as that of glucose induced insulin release. Since all these insulinogogues enhance the accumulation of cyclic AMP in the β-cells, it is suggested that the adenylate cyclase-cyclic AMP system might be involved in the action of somatostatin. Somatostatin did not seem to interfere with the glycogenolytic effect of glucagon on the liver.

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Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00172.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1447-E1455 ◽

Cited By ~ 13

Author(s):

Saleem S. Qader ◽

Javier Jimenez-Feltström ◽

Mats Ekelund ◽

Ingmar Lundquist ◽

Albert Salehi

Keyword(s):

Nitric Oxide ◽

Cyclic Amp ◽

Insulin Release ◽

Inducible Nitric Oxide Synthase ◽

Cyclic Gmp ◽

Inos Expression ◽

Β Cells ◽

Lipid Infusion ◽

Oxide Synthase ◽

Inducible Nitric Oxide

Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to β-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to β-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in β-cells.

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ON THE ACTION OF TOLBUTAMIDE IN NORMAL MAN

Acta Endocrinologica ◽

10.1530/acta.0.0720532 ◽

1973 ◽

Vol 72 (3) ◽

pp. 532-544 ◽

Cited By ~ 7

Author(s):

A. Widström ◽

E. Cerasi

Keyword(s):

Glucose Metabolism ◽

Cyclic Amp ◽

Insulin Release ◽

Insulin Response ◽

Phosphodiesterase Inhibitor ◽

Adenyl Cyclase ◽

Β Cells ◽

Β Cell ◽

Normal Man ◽

Relationship Of

ABSTRACT Previous studies in normal man suggest that tolbutamide exerts its insulinogenic effect by modulating glucose-induced insulin release. This is probably achieved by increasing the sensitivity of the β-cells to the action of glucose in eliciting an insulinogenic signal, rather than by influencing the glucose metabolism of the islets. The present paper reports on studies on the relation of tolbutamide to the cyclic AMP system of the islets. Aminophylline, which decreases the breakdown of cyclic AMP, was without effect on tolbutamide-induced insulin release. This indicates that tolbutamide probably does not act by stimulating adenyl cyclase. In contrast, the insulin response to glucagon, an agent known to stimulate adenyl cyclase, was markedly potentiated by tolbutamide. Tolbutamide. in this respect, also showed synergism with arginine, which probably acts by enhancing the formation of cyclic AMP. It is therefore concluded that tolbutamide may influence insulin release by acting as a phosphodiesterase inhibitor or as a potentiator of the action of cyclic AMP on the release mechanisms. The possible relationship of the tolbutamide action with the postulated insulinogenic signal of glucose in the β-cell is discussed.

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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.

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Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response

Endocrinology ◽

10.1210/en.2015-2003 ◽

2016 ◽

Vol 157 (6) ◽

pp. 2243-2258 ◽

Cited By ~ 14

Author(s):

Annalisa Natalicchio ◽

Giuseppina Biondi ◽

Nicola Marrano ◽

Rossella Labarbuta ◽

Federica Tortosa ◽

...

Keyword(s):

Protein Expression ◽

Insulin Release ◽

Binding Protein ◽

Camp Response Element Binding ◽

Β Cells ◽

Pancreatic Β Cells ◽

Camp Response Element ◽

Element Binding Protein ◽

Viral Oncogene Homolog ◽

Erk Kinase

The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.

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