scholarly journals The Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating ß-cell Autophagy

2021 ◽  
Author(s):  
Tal Israeli ◽  
Yael Riahi ◽  
Perla Garzon ◽  
Ruy Andrade Louzada ◽  
Joao Pedro Werneck-de-Castro ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Secretion ◽  
Amino Acid ◽  
B Cells ◽  
Single Amino Acid ◽  
Dependent Manner ◽  
Fasting State ◽  
Glucose Stimulation ◽  
Dynamic Regulation ◽  
Stimulation Of

The dynamic regulation of autophagy in b-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In b-cells mTORC1 is inhibited while fasting, and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when b-cells are continuously exposed to nutrients. Inhibition of mTORC1 by <i>Raptor</i> knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion, whereas moderate inhibition of autophagy under these conditions rescued insulin secretion. These results show that mTORC1 regulates insulin secretion through modulation of autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner and its stimulation is required to keep insulin levels low, thereby preventing hypoglycemia. Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyperinsulinemia by inhibiting autophagy.

scholarly journals The Nutrient Sensor mTORC1 Regulates Insulin Secretion by Modulating ß-cell Autophagy

2021 ◽  
Author(s):  
Tal Israeli ◽  
Yael Riahi ◽  
Perla Garzon ◽  
Ruy Andrade Louzada ◽  
Joao Pedro Werneck-de-Castro ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Secretion ◽  
Amino Acid ◽  
B Cells ◽  
Single Amino Acid ◽  
Dependent Manner ◽  
Fasting State ◽  
Glucose Stimulation ◽  
Dynamic Regulation ◽  
Stimulation Of

The dynamic regulation of autophagy in b-cells by cycles of fasting-feeding and its effects on insulin secretion are unknown. In b-cells mTORC1 is inhibited while fasting, and is rapidly stimulated during refeeding by a single amino acid, leucine, and glucose. Stimulation of mTORC1 by nutrients inhibited the autophagy initiator ULK1 and the transcription factor TFEB, thereby preventing autophagy when b-cells are continuously exposed to nutrients. Inhibition of mTORC1 by <i>Raptor</i> knockout mimicked the effects of fasting and stimulated autophagy while inhibiting insulin secretion, whereas moderate inhibition of autophagy under these conditions rescued insulin secretion. These results show that mTORC1 regulates insulin secretion through modulation of autophagy under different nutritional situations. In the fasting state, autophagy is regulated in an mTORC1-dependent manner and its stimulation is required to keep insulin levels low, thereby preventing hypoglycemia. Reciprocally, stimulation of mTORC1 by elevated leucine and glucose, which is common in obesity, may promote hyperinsulinemia by inhibiting autophagy.

scholarly journals Glucose stimulation of insulin secretion from the isolated pancreas of foetal and newborn rats

Diabetologia ◽  
1969 ◽  
Vol 5 (4) ◽  
pp. 260-262 ◽  
Author(s):  
K. Asplound ◽  
S. Westman ◽  
C. Hellerste�m
Keyword(s):  
Insulin Secretion ◽  
Newborn Rats ◽  
Glucose Stimulation ◽  
Isolated Pancreas ◽  
Stimulation Of

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.

Hyperinsulinemia of preobese and obese fa/fa rats is partly vagus nerve mediated

1983 ◽  
Vol 244 (4) ◽  
pp. E317-E322 ◽  
Author(s):  
F. Rohner-Jeanrenaud ◽  
A. C. Hochstrasser ◽  
B. Jeanrenaud
Keyword(s):  
Electrical Stimulation ◽  
Insulin Secretion ◽  
B Cells ◽  
Vagus Nerve ◽  
Zucker Rats ◽  
Glucose Load ◽  
Parasympathetic System ◽  
Enhanced Sensitivity ◽  
Stimulation Of

In vivo glucose-induced insulin secretion was greater in preweaned preobese 17-day-old Zucker rats than in the corresponding controls. This hypersecretion of insulin was reversed to normal by acute pretreatment with atropine. A short-lived (30 s) electrical stimulation of the vagus nerve preceding a glucose load potentiated the in vivo glucose-induced insulin release in adult animals (6-9 wk) and more so in obese Zucker (fa/fa) than in lean rats. This suggested the existence of enhanced sensitivity and/or responsiveness of the B cells of obese animals to the parasympathetic system. That the parasympathetic tone was increased in adult obese Zucker (fa/fa) rats was corroborated by the observation that acute vagotomy of these animals resulted in a significant decrease in glucose-induced insulin secretion, whereas no such effect was seen in lean rats. Also, perfused pancreases from adult obese (fa/fa) rats oversecreted insulin during a stimulation by arginine when compared with controls, an oversecretion that was restored toward normal by superimposed infusion of atropine. It is concluded that a) the increased insulin secretion of preobese Zucker fa/fa rats is an early abnormality that is mediated by the vagus nerve, and b) increased secretion of insulin in adult obese fa/fa rats continues to be partly vagus-nerve mediated, although a decreased sympathetic tone and other unknown defects could conceivably play a role as well.

scholarly journals Molecular-genetic mechanisms of regulation of dihydroflavonol reductase and transcription factor Hy5 by exogenous 5-aminolevulinic acid in winter rape plants

2020 ◽  
Vol 64 (3) ◽  
pp. 317-324
Author(s):  
N. G. Averina ◽  
H. V. Yemelyanava ◽  
T. G. Kaliaha ◽  
S. M. Savina
Keyword(s):  
Transcription Factor ◽  
Light Intensity ◽  
Aminolevulinic Acid ◽  
Molecular Level ◽  
Molecular Genetic ◽  
High Light Intensity ◽  
Dependent Manner ◽  
Winter Rape ◽  
Additional Increase ◽  
Stimulation Of

The effect of exogenous 5-aminolevulinic acid (ALA) on the activity of dihydroflavonol-4-reductase (DFR), the expression of the dfr gene and the hy5 gene of the transcription factor Hy5 and the light effect of different intensities in combination with the ALA action on the accumulation of anthocyanins in cotyledonous leaves of winter rape (Brassica napus L.) were studied. It was shown that the stimulation of the accumulation of anthocyanins under the exogenous ALA action at the molecular level was provided by increasing the expression level of the dfr and hy5 genes and the activity of the DFR enzyme. Increasing the light intensity from 40.5 to 66.2 μmol photons/m2·s enhanced the ability of plants to accumulate anthocyanins on average by 35 %. The ALA action at concentrations of 50, 100, 150 and 200 mg/L led to an additional increase in the accumulation of anthocyanins at the two used levels of illumination, and in a dose-dependent manner. The stimulating effect of ALA under high light intensity was much higher than in the case of lower illumination. Thus, the stimulation of the anthocyanin accumulation under illumination of 40.5 μmol photons/m2·s was 106 % when using 50 mg/L ALA, 165 % – when using 100 mg/L ALA, 222 % – in the case of 150 mg/L ALA and 350 % – under the action of 200 mg/L ALA compared with light control without of ALA treatment. At an illumination of 66.2 μmol photons/m2·s, these indicators were 164, 262, 359 and 583 % respectively. Thus, it was demonstrated that the stimulation of the accumulation of anthocyanins under the action of ALA in winter rape plants was due to its positive effect on the transcription of the dfr and hy5 genes at the molecular level.

scholarly journals Extreme Suppression of Lateral Floret Development by a Single Amino Acid Change in the VRS1 Transcription Factor

2017 ◽  
Vol 175 (4) ◽  
pp. 1720-1731 ◽  
Author(s):  
Shun Sakuma ◽  
Udda Lundqvist ◽  
Yusuke Kakei ◽  
Venkatasubbu Thirulogachandar ◽  
Takako Suzuki ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Amino Acid Change ◽  
Single Amino Acid ◽  
Lateral Floret ◽  
Single Amino Acid Change

scholarly journals Two monomers of yeast transcription factor ADR1 bind a palindromic sequence symmetrically to activate ADH2 expression.

1991 ◽  
Vol 11 (3) ◽  
pp. 1566-1577 ◽  
Author(s):  
S K Thukral ◽  
A Eisen ◽  
E T Young
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Dna Binding ◽  
Dimethyl Sulfate ◽  
Binding Activity ◽  
Single Amino Acid ◽  
Minor Effect ◽  
Palindromic Sequence ◽  
Amino Terminal ◽  
Dna Binding Activity

ADR1 is a transcription factor from Saccharomyces cerevisiae that regulates ADH2 expression through a 22-bp palindromic sequence (UAS1). Size fractionation studies revealed that full-length ADR1 and a truncated ADR1 protein containing the first 229 amino acids, which has the complete DNA-binding domain, ADR1:17-229, exist as monomers in solution. However, two complexes were formed with target DNA-binding sites. UV-cross-linking studies suggested that these two complexes represent one and two molecules of ADR1 bound to DNA. Studies of ADR1 complexes formed with wild-type UAS1, asymmetrically altered UAS1, and one half of UAS1 showed that ADR1 can bind to one half of UAS1 and gives rise to a complex containing one molecule of ADR1. Dimethyl sulfate interference studies were consistent with this interpretation and in addition indicated that purine contact sites in each half of UAS1 were identical. Increasing the distance between the two halves of UAS1 had at most a minor effect of the thermodynamics of formation of the two complexes. These data are more consistent with ADR1 binding as two independent monomers, one to each half of UAS1. However, binding of two ADR1 monomers at UAS1 is apparently essential for transactivation in vivo. Further, we have identified a stretch of 18 amino acid residues amino terminal to the zinc two-finger domains of ADR1 which is essential for DNA-binding activity. Single amino acid substitutions of residues in this region resulted in severely reduced DNA-binding activity.

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.

The Zinc Finger Protein Gfi1 Controls TLR4-Mediated Inflammatory Response by Directly Antagonizing NF-κB Transcription Factor

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 469-469
Author(s):  
Ehssan Sharif-Askari ◽  
Hui Zeng ◽  
Lothar Vassen ◽  
Christian Kosan ◽  
Cyrus Khandanpour ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Direct Interaction ◽  
Innate Immune ◽  
Dependent Manner ◽  
Negative Regulators ◽  
Tlr Signaling ◽  
Tnf Α ◽  
Dose Dependent ◽  
Lps Treatment ◽  
Stimulation Of

Abstract Inflammatory responses are complex and comprise multiple mediators including cytokines such as TNF-alpha (TNF-α) and IL-1beta. These cytokines are synthesized and secreted in response to signaling by plasma membrane receptors of the Toll-like receptor (TLR) family. A central downstream element of TLR-dependent signaling is the transcription factor NF-kappaB (NF-κB), which plays a pivotal role in controlling the proper sequence of events during an inflammatory response. In unstimulated cells, NF-κB is bound to inhibitory IkappaB (IκB) proteins and remains sequestered in the cytoplasm. Stimulation of TLRs triggers a signaling cascade that leads to phosphorylation and proteasomal degradation of IκB, resulting in the translocation of NF-κB to the nucleus, where it acts as a transcriptional activator of target genes. To keep the innate immune system under control, the TLR signaling cascade is under a tight control of many positive and negative regulators. We have previously shown that the transcription factor Growth Factor Independence 1 (Gfi1) represents a novel factor limiting the inflammatory immune response including TNF-α. Gfi1-deficient (Gfi1−/−) mice show a very strong systemic response to the TLR4 ligand and endotoxin LPS and die rapidly within 36 h with symptoms of septic shock. Here, we investigated the molecular mechanism of this exaggerated TNF-α production in the absence of Gfi1. It is known that endotoxin stimulation results in the activation of the transcription factor NF-κB through TLR4, leading to TNF-α production. This activation also resulted in rapid and de novo expression of Gfi1 in the nucleus in a time- and dose-dependent manner. The expression of Gfi1 was not due to feedback regulation from secreted TNF, since TNF-deficient macrophages were also able to upregulate Gfi1 mRNA following LPS stimulation. As expected, LPS stimulation of Gfi1−/− macrophages resulted in significantly higher levels of TNF-α mRNA, and secreted TNF-α cytokine. Strikingly and in contrast to most known negative regulators of TLRs, Gfi1 did not affect the activity or the expression levels of the cytoplasmic components of TLR signaling pathway. Additionally, NF-κB phosphorylation and nuclear translocation post- LPS treatment were intact in both Gfi1−/− and Gfi1+/+ macrophages. Immunoprecipitation analysis from cells endogenously expressing Gfi1 and NF-κB or over-expressing these two proteins post transfection, clearly revealed a direct interaction between Gfi1 and the p65 subunit of NF-κB. Immunofluorescence staining of macrophages post-LPS treatment confirmed direct interaction of these two proteins in the nucleus at the endogenous level. Gfi1 represses transcription by binding to DNA recognition sequences in target gene promoters. Thus, aiming to investigate the effect of Gfi1 expression on NF-κB nuclear signaling, we found that LPS treatment enhances NF-κB DNA binding activity in Gfi1−/− macrophages as compared to Gfi1+/+ cells. Furthermore, over expression of Gfi1 protein resulted in negative regulation of NF-κB mediated gene activation in a dose-dependent manner. Chromatin immune precipitation with anti-p65 antibodies from LPS stimulated Gfi1+/+ and Gfi1−/− macrophages revealed enhanced NF-κB promoter occupancy at the TNF gene in Gfi1−/− macrophages as compared to Gfi1+/+ cells. In conclusion, our findings reveal a novel function for Gfi1 in the innate immune response by directly antagonizing NF-κB function. This molecular perceptive of TNF-α regulation during inflammation may provide an attractive strategy for therapeutic intervention in chronic inflammatory diseases and certain cancers.

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