scholarly journals Effects of Liraglutide on β-Cell-Specific Glucokinase-Deficient Neonatal Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3066-3075 ◽  
Author(s):  
Jun Shirakawa ◽  
Ritsuko Tanami ◽  
Yu Togashi ◽  
Kazuki Tajima ◽  
Kazuki Orime ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Sensor ◽  
Liver Steatosis ◽  
Survival Rates ◽  
Glycolytic Enzyme ◽  
Β Cells ◽  
Β Cell ◽  
Newborn Mice ◽  
Glucose Levels ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor agonist liraglutide is used to treat diabetes. A hallmark of liraglutide is the glucose-dependent facilitation of insulin secretion from pancreatic β-cells. In β-cells, the glycolytic enzyme glucokinase plays a pivotal role as a glucose sensor. However, the role of glucokinase in the glucose-dependent action of liraglutide remains unknown. We first examined the effects of liraglutide on glucokinase haploinsufficient (Gck+/−) mice. Single administration of liraglutide significantly improved glucose tolerance in Gck+/− mice without increase of insulin secretion. We also assessed the effects of liraglutide on the survival rates, metabolic parameters, and histology of liver or pancreas of β-cell-specific glucokinase-deficient (Gck−/−) newborn mice. Liraglutide reduced the blood glucose levels in Gck−/− neonates but failed to prolong survival, and all the mice died within 1 wk. Furthermore, liraglutide did not improve glucose-induced insulin secretion in isolated islets from Gck−/− neonates. Liraglutide initially prevented increases in alanine aminotransferase, free fatty acids, and triglycerides in Gck−/− neonates but not at 4 d after birth. Liraglutide transiently prevented liver steatosis, with reduced triglyceride contents and elevated glycogen contents in Gck−/− neonate livers at 2 d after birth. Liraglutide also protected against reductions in β-cells in Gck−/− neonates at 4 d after birth. Taken together, β-cell glucokinase appears to be essential for liraglutide-mediated insulin secretion, but liraglutide may improve glycemic control, steatosis, and β-cell death in a glucokinase-independent fashion.

scholarly journals Human EndoC-βH1 β-cells form pseudoislets with improved glucose sensitivity and enhanced GLP-1 signaling in the presence of islet-derived endothelial cells

2018 ◽  
Vol 314 (5) ◽  
pp. E512-E521 ◽  
Author(s):  
Michael G. Spelios ◽  
Lauren A. Afinowicz ◽  
Regine C. Tipon ◽  
Eitan M. Akirav
Keyword(s):  
Endothelial Cells ◽  
Insulin Secretion ◽  
Cell Biology ◽  
Three Dimensional ◽  
Cell Types ◽  
Human Islets ◽  
Glucose Sensing ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels

Three-dimensional (3D) pseudoislets (PIs) can be used for the study of insulin-producing β-cells in free-floating islet-like structures similar to that of primary islets. Previously, we demonstrated the ability of islet-derived endothelial cells (iECs) to induce PIs using murine insulinomas, where PI formation enhanced insulin production and glucose responsiveness. In this report, we examined the ability of iECs to spontaneously induce the formation of free-floating 3D PIs using the EndoC-βH1 human β-cell line murine MS1 iEC. Within 14 days, the coculturing of both cell types produced fully humanized EndoC-βH1 PIs with little to no contaminating murine iECs. The size and shape of these PIs were similar to primary human islets. iEC-induced PIs demonstrated reduced dysregulated insulin release under low glucose levels and higher insulin secretion in response to high glucose and exendin-4 [a glucagon-like peptide-1 (GLP-1) analog] compared with monolayer cells cultured alone. Interestingly, iEC-PIs were also better at glucose sensing in the presence of extendin-4 compared with PIs generated on a low-adhesion surface plate in the absence of iECs and showed an overall improvement in cell viability. iEC-induced PIs exhibited increased expression of key genes involved in glucose transport, glucose sensing, β-cell differentiation, and insulin processing, with a concomitant decrease in glucagon mRNA expression. The enhanced responsiveness to exendin-4 was associated with increased protein expression of GLP-1 receptor and phosphokinase A. This rapid coculture system provides an unlimited number of human PIs with improved insulin secretion and GLP-1 responsiveness for the study of β-cell biology.

scholarly journals Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesco Volta ◽  
M. Julia Scerbo ◽  
Anett Seelig ◽  
Robert Wagner ◽  
Nils O’Brien ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Basal Body ◽  
Primary Cilia ◽  
Epithelial To Mesenchymal Transition ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Glucose Levels

Abstract Diabetes mellitus affects one in eleven adults worldwide. Most suffer from Type 2 Diabetes which features elevated blood glucose levels and an inability to adequately secrete or respond to insulin. Insulin producing β-cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. To better understand how β-cell cilia affect glucose handling, we ablate cilia from mature β-cells by deleting key cilia component Ift88. Here we report that glucose homeostasis and insulin secretion deteriorate over 12 weeks post-induction. Cilia/basal body components are required to suppress spontaneous auto-activation of EphA3 and hyper-phosphorylation of EphA receptors inhibits insulin secretion. In β-cells, loss of cilia/basal body function leads to polarity defects and epithelial-to-mesenchymal transition. Defective insulin secretion from IFT88-depleted human islets and elevated pEPHA3 in islets from diabetic donors both point to a role for cilia/basal body proteins in human glucose homeostasis.

scholarly journals Chop/Ddit3 depletion in β-cells alleviates ER stress and corrects hepatic steatosis

2020 ◽  
Author(s):  
Jing Yong ◽  
Vishal S. Parekh ◽  
Jonamani Nayak ◽  
Zhouji Chen ◽  
Cynthia Lebeaupin ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Liver Disease ◽  
Fatty Liver ◽  
Er Stress ◽  
Fatty Liver Disease ◽  
Therapeutic Strategy ◽  
Liver Steatosis ◽  
Β Cells ◽  
Β Cell ◽  
Therapeutic Benefits

AbstractType 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin (ProIns) misfolding that aggravates endoplasmic reticulum (ER) homeostasis in β cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high fat diet (HFD) fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells confers therapeutic benefits. First, we show that Chop deletion in β cells alleviates β cell ER stress and delays glucose-stimulated insulin secretion (GSIS) in HFD fed mice. Second, importantly, β cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary to Chop deletion modulates glucose-induced islet Ca2+ oscillations. Finally, using state-of-the-art GLP1-conjugated Chop AntiSense Oligonucleotides (GLP1-Chop ASO), we demonstrated that the Chop deletion induced GSIS change is a long term complex event in β cells. In summary, our results demonstrate that Chop depletion in β cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D.

scholarly journals Emerging role of testosterone in pancreatic β cell function and insulin secretion

2019 ◽  
Vol 240 (3) ◽  
pp. R97-R105 ◽  
Author(s):  
Weiwei Xu ◽  
Jamie Morford ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Visceral Obesity ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

scholarly journals A role for PAK1 mediated phosphorylation of β-catenin Ser552 in the regulation of insulin secretion

2021 ◽  
Author(s):  
Brie Sorrenson ◽  
Waruni C Dissanayake ◽  
Fengyun Hu ◽  
Kate L Lee ◽  
Peter R Shepherd
Keyword(s):  
Insulin Secretion ◽  
Hormonal Regulation ◽  
Cell Signalling ◽  
Cell Models ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Phosphorylation Event ◽  
A Cell ◽  
Glucose Stimulated Insulin Secretion

The presence of adherens junctions and the associated protein β-catenin are requirements for the development of glucose stimulated insulin secretion (GSIS) in β-cells. Evidence indicates that modulation of β-catenin function in response to changes in glucose levels can modulate the levels of insulin secretion from β-cells but the role of β-catenin phosphorylation in this process has not been established. We find that a Ser552Ala version of β-catenin attenuates glucose stimulated insulin secretion indicating a functional role for Ser552 phosphorylation of β-catenin in insulin secretion. This is associated with alterations F/G actin ratio  but not  transcriptional activity of β-catenin.   Both glucose and GLP-1 stimulated phosphorylation of the serine 552 residue on β-catenin.  We investigated the possibility that an EPAC-PAK1 pathway might be involved in this phosphorylation event.  We find that reduction in PAK1 levels using siRNA attenuates both glucose and GLP-1 stimulated phosphorylation of β-catenin Ser552 and the effects of these on insulin secretion in β-cell models. Further, both the EPAC inhibitor ESI-09 and the PAK1 inhibitor IPA3 do the same in both β-cell models and mouse islets. Together this identifies phosphorylation of β-catenin at Ser552 as part of a cell signalling mechanism linking nutrient and hormonal regulation of β-catenin to modulation of  insulin secretory capacity of β-cells and indicates this phosphorylation event is regulated downstream of EPAC and PAK1 in β-cells.

Identification of a pathway by which glucose regulates β-catenin signalling via the cAMP/protein kinase A pathway in β-cell models

2013 ◽  
Vol 449 (3) ◽  
pp. 803-811 ◽  
Author(s):  
Emmanuelle Cognard ◽  
Coralie G. Dargaville ◽  
Deborah L. Hay ◽  
Peter R. Shepherd
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Cell Function ◽  
Regulation Of Gene Expression ◽  
Cell Models ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Levels ◽  
Kinase A

Pancreatic β-cells are highly responsive to changes in glucose, but the mechanisms involved are only partially understood. There is increasing evidence that the β-catenin signalling pathway plays an important role in regulating β-cell function, but the mechanisms regulating β-catenin signalling in these cells is not well understood. In the present study we show that β-catenin levels and downstream signalling are regulated by changes in glucose levels in INS-1E and β-TC6-F7 β-cell models. We found a glucose-dependent increase in levels of β-catenin in the cytoplasm and nucleus of INS-1E cells. Expression of cyclin D1 also increased with glucose and required the presence of β-catenin. This was associated with an increase in phosphorylation of β-catenin on Ser552, which is known to stabilize the molecule and increase its transcriptional activity. In a search for possible signalling intermediates we found forskolin and cell-permeable cAMP analogues recapitulated the glucose effects, suggesting a role for cAMP and PKA (cAMP-dependent protein kinase/protein kinase A) downstream of glucose. Furthermore, glucose caused sustained increases in cAMP. Two different inhibitors of adenylate cyclase and PKA signalling blocked the effects of glucose, whereas siRNA (small interfering RNA) knockdown of PKA blocked the effects of glucose on β-catenin signalling. Finally, reducing β-catenin levels with either siRNA or pyrvinium impaired glucose- and KCl-stimulated insulin secretion. Taken together the results of the present study define a pathway by which changes in glucose levels can regulate β-catenin using a mechanism which involves cAMP production and the activation of PKA. This identifies a pathway that may be important in glucose-dependent regulation of gene expression and insulin secretion in β-cells.

scholarly journals SWELL1 is a glucose sensor required for β-cell excitability and insulin secretion

2017 ◽  
Author(s):  
Chen Kang ◽  
Susheel K. Gunasekar ◽  
Anil Mishra ◽  
Litao Xie ◽  
Yanhui Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Calcium Signaling ◽  
Glucose Sensor ◽  
Physiological Role ◽  
Ionic Currents ◽  
Cell Swelling ◽  
Β Cells ◽  
Β Cell ◽  
Glucose Stimulated Insulin Secretion

AbstractInsulin secretion from the pancreatic β-cell initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC depends on the β-cell membrane potential, which is in turn mediated by the balance of depolarizing (excitatory) and hyperpolarizing (inhibitory) ionic currents1-3. While much attention has focused on inhibitory potassium currents4-10 there is little knowledge about the excitatory currents required to depolarize the β-cell, including the molecular identity of these excitatory currents3. Here we show that SWELL1 (LRRC8a) mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELL and this is required for both glucose-stimulated and hypotonic swell-mediated activation of VGCC-dependent intracellular calcium signaling in β-cells. SWELL1 KO MIN6 cells and β-cell targeted SWELL1 KO murine islets exhibit significantly impaired glucose-stimulated insulin secretion, with preserved insulin content in vitro. Tamoxifen-inducible β-cell targeted SWELL1 KO mice have normal fasting insulin levels but display markedly impaired glucose-stimulated insulin secretion. Our results reveal a physiological role for SWELL1 as a glucose sensor - linking glucose-mediated β-cell swelling to SWELL1-dependent activation of VGCC-triggered calcium signaling, and highlights SWELL1-mediated “swell-secretion” coupling as required for glucose-stimulated insulin secretion.

scholarly journals Multivalent activation of GLP-1 and sulfonylurea receptors modulates β-cell second-messenger signaling and insulin secretion

2019 ◽  
Vol 316 (1) ◽  
pp. C48-C56
Author(s):  
Nathaniel J. Hart ◽  
Craig Weber ◽  
Klearchos K. Papas ◽  
Sean W. Limesand ◽  
Josef Vagner ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Single Molecule ◽  
Human Islets ◽  
Intracellular Camp ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Surface Receptors ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

Linking two pharmacophores that bind different cell surface receptors into a single molecule can enhance cell-targeting specificity to cells that express the complementary receptor pair. In this report, we developed and tested a synthetic multivalent ligand consisting of glucagon-like peptide-1 (GLP-1) linked to glibenclamide (Glb) (GLP-1/Glb) for signaling efficacy in β-cells. Expression of receptors for these ligands, as a combination, is relatively specific to the β-cell in the pancreas. The multivalent GLP-1/Glb increased both intracellular cAMP and Ca2+, although Ca2+ responses were significantly depressed compared with the monomeric Glb. Moreover, GLP-1/Glb increased glucose-stimulated insulin secretion in a dose-dependent manner. However, unlike the combined monomers, GLP-1/Glb did not augment insulin secretion at nonstimulatory glucose concentrations in INS 832/13 β-cells or human islets of Langerhans. These data suggest that linking two binding elements, such as GLP-1 and Glb, into a single bivalent ligand can provide a unique functional agent targeted to β-cells.

scholarly journals Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis

2020 ◽  
Author(s):  
Wenjuan Liu ◽  
Harry Kevin Lau ◽  
Dong Ok Son ◽  
Tianru Jin ◽  
Yehong Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Glucose Levels ◽  
Cell Counts ◽  
Therapeutic Benefits ◽  
Combined Use ◽  
Glucagon Like Peptide 1

γ-aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. Proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

scholarly journals Chop/Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice

2021 ◽  
Vol 13 (604) ◽  
pp. eaba9796
Author(s):  
Jing Yong ◽  
Vishal S. Parekh ◽  
Shannon M. Reilly ◽  
Jonamani Nayak ◽  
Zhouji Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Liver Disease ◽  
Fatty Liver ◽  
Er Stress ◽  
Fatty Liver Disease ◽  
Therapeutic Strategy ◽  
Liver Steatosis ◽  
Β Cells ◽  
Β Cell ◽  
Therapeutic Benefits

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high-fat diet (HFD)–fed mice and in leptin receptor–deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell–specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ oscillations, leading to transcriptional changes of ER chaperone profile (“ER remodeling”). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.

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