scholarly journals Both Triggering and Amplifying Pathways Contribute to Fuel-induced Insulin Secretion in the Absence of Sulfonylurea Receptor-1 in Pancreatic β-Cells

2004 ◽  
Vol 279 (31) ◽  
pp. 32316-32324 ◽  
Author(s):  
Myriam Nenquin ◽  
Andras Szollosi ◽  
Lydia Aguilar-Bryan ◽  
Joseph Bryan ◽  
Jean-Claude Henquin
Keyword(s):  
Insulin Secretion ◽  
Sulfonylurea Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Sulfonylurea Receptor 1

scholarly journals A novel high-affinity inhibitor against the human ATP-sensitive Kir6.2 channel

2018 ◽  
Vol 150 (7) ◽  
pp. 969-976 ◽  
Author(s):  
Yajamana Ramu ◽  
Yanping Xu ◽  
Zhe Lu
Keyword(s):  
Insulin Secretion ◽  
Specific Inhibitor ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Sulfonylurea Receptor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
High Affinity ◽  
New Strategy ◽  
Extracellular Side

The adenosine triphosphate (ATP)-sensitive (KATP) channels in pancreatic β cells couple the blood glucose level to insulin secretion. KATP channels in pancreatic β cells comprise the pore-forming Kir6.2 and the modulatory sulfonylurea receptor 1 (SUR1) subunits. Currently, there is no high-affinity and relatively specific inhibitor for the Kir6.2 pore. The importance of developing such inhibitors is twofold. First, in many cases, the lack of such an inhibitor precludes an unambiguous determination of the Kir6.2's role in certain physiological and pathological processes. This problem is exacerbated because Kir6.2 knockout mice do not yield the expected phenotypes of hyperinsulinemia and hypoglycemia, which in part, may reflect developmental adaptation. Second, mutations in Kir6.2 or SUR1 that increase the KATP current cause permanent neonatal diabetes mellitus (PNDM). Many patients who have PNDM have been successfully treated with sulphonylureas, a common class of antidiabetic drugs that bind to SUR1 and indirectly inhibit Kir6.2, thereby promoting insulin secretion. However, some PNDM-causing mutations render KATP channels insensitive to sulphonylureas. Conceptually, because these mutations are located intracellularly, an inhibitor blocking the Kir6.2 pore from the extracellular side might provide another approach to this problem. Here, by screening the venoms from >200 animals against human Kir6.2 coexpressed with SUR1, we discovered a small protein of 54 residues (SpTx-1) that inhibits the KATP channel from the extracellular side. It inhibits the channel with a dissociation constant value of 15 nM in a relatively specific manner and with an apparent one-to-one stoichiometry. SpTx-1 evidently inhibits the channel by primarily targeting Kir6.2 rather than SUR1; it inhibits not only wild-type Kir6.2 coexpressed with SUR1 but also a Kir6.2 mutant expressed without SUR1. Importantly, SpTx-1 suppresses both sulfonylurea-sensitive and -insensitive, PNDM-causing Kir6.2 mutants. Thus, it will be a valuable tool to investigate the channel's physiological and biophysical properties and to test a new strategy for treating sulfonylurea-resistant PNDM.

Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

2020 ◽  
Vol 33 (5) ◽  
pp. 671-674
Author(s):  
Tashunka Taylor-Miller ◽  
Jayne Houghton ◽  
Paul Munyard ◽  
Yadlapalli Kumar ◽  
Clinda Puvirajasinghe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Newborn Period ◽  
Case Presentation ◽  
Male Baby ◽  
Common Causes ◽  
Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

scholarly journals Author Correction: CD44 variant inhibits insulin secretion in pancreatic β cells by attenuating LAT1-mediated amino acid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nana Kobayashi ◽  
Shogo Okazaki ◽  
Oltea Sampetrean ◽  
Junichiro Irie ◽  
Hiroshi Itoh ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Amino Acid ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Cd44 Variant

scholarly journals D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Mengmeng Liu ◽  
Lele Ren ◽  
Xiangqin Zhong ◽  
Yaqin Ding ◽  
Tao Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ion Channels ◽  
Β Cells ◽  
Pancreatic Β Cells

Jiawei Erzhiwan improves menopausal metabolic syndrome by enhancing insulin secretion in pancreatic β cells

2016 ◽  
Vol 14 (11) ◽  
pp. 823-834 ◽  
Author(s):  
Xiao-Meng WAN ◽  
Mu ZHANG ◽  
Pei ZHANG ◽  
Zhi-Shen XIE ◽  
Feng-Guo XU ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Brain-selective Kinase 2 (BRSK2) Phosphorylation on PCTAIRE1 Negatively Regulates Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

2012 ◽  
Vol 287 (36) ◽  
pp. 30368-30375 ◽  
Author(s):  
Xin-Ya Chen ◽  
Xiu-Ting Gu ◽  
Hexige Saiyin ◽  
Bo Wan ◽  
Yu-Jing Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Conditional expression of the FTO gene product in rat INS-1 cells reveals its rapid turnover and a role in the profile of glucose-induced insulin secretion

2011 ◽  
Vol 120 (9) ◽  
pp. 403-413 ◽  
Author(s):  
Mark A. Russell ◽  
Noel G. Morgan
Keyword(s):  
Insulin Secretion ◽  
Expression System ◽  
Proteasome Inhibitors ◽  
Inducible Promoter ◽  
Insulin Biosynthesis ◽  
Second Phase ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Peripheral Tissues ◽  
Conditional Expression

Common polymorphisms within the FTO (fat mass and obesity-associated) gene correlate with increased BMI (body mass index) and a rising risk of Type 2 diabetes. FTO is highly expressed in the brain but has also been detected in peripheral tissues, including the endocrine pancreas, although its function there is unclear. The aim of the present study was to investigate the role of FTO protein in pancreatic β-cells using a conditional expression system developed in INS-1 cells. INS-1 cells were stably transfected with FTO–HA (haemagluttinin) incorporated under the control of a tetracycline-inducible promoter. Induction of FTO protein resulted in localization of the tagged protein to the nucleus. The level of FTO–HA protein achieved in transfected cells was tightly regulated, and experiments with selective inhibitors revealed that FTO–HA is rapidly degraded via the ubiquitin/proteasome pathway. The nuclear localization was not altered by proteasome inhibitors, although following treatment with PYR-41, an inhibitor of ubiquitination, some of the protein adopted a perinuclear localization. Unexpectedly, modestly increased expression of FTO–HA selectively enhanced the first phase of insulin secretion when INS-1 monolayers or pseudoislets were stimulated with 20 mM glucose, whereas the second phase remained unchanged. The mechanism responsible for the potentiation of glucose-induced insulin secretion is unclear; however, further experiments revealed that it did not involve an increase in insulin biosynthesis or any changes in STAT3 (signal transducer and activator of transcription 3) expression. Taken together, these results suggest that the FTO protein may play a hitherto unrecognized role in the control of first-phase insulin secretion in pancreatic β-cells.

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

2017 ◽  
Vol 1861 (8) ◽  
pp. 2039-2047 ◽  
Author(s):  
Yun Xie ◽  
Canqi Cui ◽  
Aifang Nie ◽  
Yan Wang ◽  
Qicheng Ni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Metabolic Stress ◽  
Β Cells ◽  
Pancreatic Β Cells
Sign in / Sign up

Export Citation Format

Share Document