scholarly journals Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2072-2079 ◽  
Author(s):  
Eva Hammar ◽  
Alejandra Tomas ◽  
Domenico Bosco ◽  
Philippe A. Halban
Keyword(s):  
Extracellular Matrix ◽  
Insulin Secretion ◽  
Actin Cytoskeleton ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
And Function

Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.

The role of small molecule GPR119 agonist, AS1535907, in glucose-stimulated insulin secretion and pancreatic β-cell function

2010 ◽  
Vol 13 (1) ◽  
pp. 34-41 ◽  
Author(s):  
S. Yoshida ◽  
T. Ohishi ◽  
T. Matsui ◽  
H. Tanaka ◽  
H. Oshima ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Small Molecule ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Gpr119 Agonist ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Bioactive Phytochemicals Isolated from Akebia quinata Enhances Glucose-Stimulated Insulin Secretion by Inducing PDX-1

Plants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1087
Author(s):  
Dahae Lee ◽  
Jin Su Lee ◽  
Jurdas Sezirahiga ◽  
Hak Cheol Kwon ◽  
Dae Sik Jang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Experimental Studies ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Etoh Extract ◽  
Chemical Structures ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phosphoinositide 3 Kinase

Chocolate vine (Akebia quinata) is consumed as a fruit and is also used in traditional medicine. In order to identify the bioactive components of A. quinata, a phytosterol glucoside stigmasterol-3-O-β-d-glucoside (1), three triterpenoids maslinic acid (2), scutellaric acid (3), and hederagenin (4), and three triterpenoidal saponins akebia saponin PA (5), hederacoside C (6), and hederacolchiside F (7) were isolated from a 70% EtOH extract of the fruits of A. quinata (AKQU). The chemical structures of isolates 1–7 were determined by analyzing the 1D and 2D nuclear magnetic resonance (NMR) spectroscopic data. Here, we evaluated the effects of AKQU and compounds 1–7 on insulin secretion using the INS-1 rat pancreatic β-cell line. Glucose-stimulated insulin secretion (GSIS) was evaluated in INS-1 cells using the GSIS assay. The expression levels of the proteins related to pancreatic β-cell function were detected by Western blotting. Among the isolates, stigmasterol-3-O-β-d-glucoside (1) exhibited strong GSIS activity and triggered the overexpression of pancreas/duodenum homeobox protein-1 (PDX-1), which is implicated in the regulation of pancreatic β-cell survival and function. Moreover, isolate 1 markedly induced the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), insulin receptor substrate-2 (IRS-2), phosphoinositide 3-kinase (PI3K), and Akt, which regulate the transcription of PDX-1. The results of our experimental studies indicated that stigmasterol-3-O-β-d-glucoside (1) isolated from the fruits of A. quinata can potentially enhance insulin secretion, and might alleviate the reduction in GSIS during the development of T2DM.

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.

Glucose-Stimulated Insulin Secretion in Gastric Bypass Patients with Hypoglycemic Syndrome: No Evidence for Inappropriate Pancreatic β-cell Function

2010 ◽  
Vol 20 (8) ◽  
pp. 1110-1116 ◽  
Author(s):  
Sun H. Kim ◽  
Fahim Abbasi ◽  
Cindy Lamendola ◽  
Gerald M. Reaven ◽  
Tracey McLaughlin
Keyword(s):  
Gastric Bypass ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Programming of defective rat pancreatic β-cell function in offspring from mothers fed a low-protein diet during gestation and the suckling periods

2004 ◽  
Vol 107 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Wendy E. HEYWOOD ◽  
Nasi MIAN ◽  
Peter J. MILLA ◽  
Keith J. LINDLEY
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Later Life ◽  
Protein Diet ◽  
Control Group ◽  
Adult Offspring ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Poor fetal and infant nutrition has been linked to impaired glucose tolerance in later life. We studied the effect of protein deficiency during gestation and the suckling period in a rat model and found that poor nutrition ‘programmes’ pancreatic β-cell GK (glucokinase; known as the glucose sensor) and glucose-stimulated insulin secretion response in newborn, suckling and adult rat offspring. Pregnant female rats were divided into three groups: a control group was kept on a normal protein (20%) diet, another group was fed a low-protein (LP) (6%) diet during gestation and suckling periods (LP-G + S group) and another was fed a LP diet during gestation then a normal protein diet during the suckling period (LP-G group). The pulsatile glucose-stimulated insulin secretion response was acutely disrupted and the peak insulin secretion was markedly decreased in newborn and 3-week-old offspring of the LP-G + S group compared with the control group. Also, there was an altered pulsatile secretory response in adults of the LP-G + S and 3-week-old and adult offspring of the LP-G groups compared with the control group. GK protein levels, detected by Western blotting, were decreased in newborn and 3-week-old offspring of both LP-G + S and LP-G groups compared with the control groups. The Km and Vmax of GK were altered. The prenatal and postnatal LP diet appeared to have a permanent effect in increasing the affinity of GK for glucose (indicated by decreased Km values) and decreasing the Vmax. This showed that the critical period of programming of the function of GK was after birth and during the postnatal weaning period, since the adult offspring of the LP-G + S group when fed a normal protein diet showed no reversal in the Km values of the enzyme. Similar experiments in adult offspring of the LP-G group showed normalization of the Km values of GK at 3 weeks of age. In conclusion, fetal and infantile nutrition ‘programmes’ pancreatic β-cell function; poor nutrition during this period caused irreversible effects on glucose homoeostatic mechanisms in the offspring, which may predispose the offspring to diabetes in later life.

scholarly journals Role of Phosphatidylinositol 3-Kinaseγ in the β-Cell: Interactions with Glucagon-Like Peptide-1

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3318-3325 ◽  
Author(s):  
Li-Xin Li ◽  
Patrick E. MacDonald ◽  
Diane S. Ahn ◽  
Gavin Y. Oudit ◽  
Peter H. Backx ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Protein Kinase ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

Glucagon-like peptide-1 (GLP-1) increases β-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-Kγ is known to be activated by Gβγ. Therefore, the role of PI3-Kγ in the chronic effects of GLP-1 on the β-cell was investigated using PI3-Kγ knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially normalized by chronic Ex4 treatment (P < 0.05). In contrast, insulin content was increased in PBS-KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P < 0.05–0.01). Transfection of INS-1E β-cells with small interfering RNA for PI3-Kγ similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for β-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS-KO mice (P < 0.05–0.001) and, although they were increased by Ex4 treatment of WT animals (P < 0.05), they were decreased in Ex4-KO mice (P < 0.05–0.01). These findings indicate that PI3-Kγ deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of β-cell mass. These studies reveal a new role for PI3-Kγ as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal β-cell function.

scholarly journals mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

2012 ◽  
Vol 216 (1) ◽  
pp. 21-29 ◽  
Author(s):  
Olivier Le Bacquer ◽  
Gurvan Queniat ◽  
Valery Gmyr ◽  
Julie Kerr-Conte ◽  
Bruno Lefebvre ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Antagonistic Effect ◽  
Dominant Negative ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Direct Role ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion

Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of β-cells. mTORC1 has long been known to impact β-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

scholarly journals Functional Role of Serotonin in Insulin Secretion in a Diet-Induced Insulin-Resistant State

Endocrinology ◽  
2014 ◽  
Vol 156 (2) ◽  
pp. 444-452 ◽  
Author(s):  
Kyuho Kim ◽  
Chang-Myung Oh ◽  
Mica Ohara-Imaizumi ◽  
Sangkyu Park ◽  
Jun Namkung ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cell Function ◽  
Β Cell ◽  
Pancreas Perfusion ◽  
Insulin Resistant ◽  
Β Cell Function ◽  
Resistant State ◽  
Insulin Resistant State

The physiological role of serotonin, or 5-hydroxytryptamine (5-HT), in pancreatic β-cell function was previously elucidated using a pregnant mouse model. During pregnancy, 5-HT increases β-cell proliferation and glucose-stimulated insulin secretion (GSIS) through the Gαq-coupled 5-HT2b receptor (Htr2b) and the 5-HT3 receptor (Htr3), a ligand-gated cation channel, respectively. However, the role of 5-HT in β-cell function in an insulin-resistant state has yet to be elucidated. Here, we characterized the metabolic phenotypes of β-cell-specific Htr2b−/− (Htr2b βKO), Htr3a−/− (Htr3a knock-out [KO]), and β-cell-specific tryptophan hydroxylase 1 (Tph1)−/− (Tph1 βKO) mice on a high-fat diet (HFD). Htr2b βKO, Htr3a KO, and Tph1 βKO mice exhibited normal glucose tolerance on a standard chow diet. After 6 weeks on an HFD, beginning at 4 weeks of age, both Htr3a KO and Tph1 βKO mice developed glucose intolerance, but Htr2b βKO mice remained normoglycemic. Pancreas perfusion assays revealed defective first-phase insulin secretion in Htr3a KO mice. GSIS was impaired in islets isolated from HFD-fed Htr3a KO and Tph1 βKO mice, and 5-HT treatment improved insulin secretion from Tph1 βKO islets but not from Htr3a KO islets. Tph1 and Htr3a gene expression in pancreatic islets was not affected by an HFD, and immunostaining could not detect 5-HT in pancreatic islets from mice fed an HFD. Taken together, these results demonstrate that basal 5-HT levels in β-cells play a role in GSIS through Htr3, which becomes more evident in a diet-induced insulin-resistant state.

scholarly journals Improvement of insulin secretion and pancreatic β-cell function in streptozotocin-induced diabetic rats treated with Aloe vera extract

2017 ◽  
Vol 9 (5) ◽  
pp. 99 ◽  
Author(s):  
Ayesha Noor ◽  
S Gunasekaran ◽  
MA Vijayalakshmi
Keyword(s):  
Insulin Secretion ◽  
Cell Function ◽  
Aloe Vera ◽  
Diabetic Rats ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function

scholarly journals Rice Bran Phenolic Extracts Modulate Insulin Secretion and Gene Expression Associated with β-Cell Function

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1889 ◽  
Author(s):  
Nancy Saji ◽  
Nidhish Francis ◽  
Lachlan J. Schwarz ◽  
Christopher L. Blanchard ◽  
Abishek B. Santhakumar
Keyword(s):  
Insulin Secretion ◽  
Rice Bran ◽  
Cell Function ◽  
Β Cell ◽  
Free Radical Damage ◽  
Glucose Transporter 2 ◽  
Expression Of Genes ◽  
Β Cell Function ◽  
Glucose Stimulated Insulin Secretion ◽  
Phenolic Extracts

Oxidative stress is known to modulate insulin secretion and initiate gene alterations resulting in impairment of β-cell function and type 2 diabetes mellitus (T2DM). Rice bran (RB) phenolic extracts contain bioactive properties that may target metabolic pathways associated with the pathogenesis of T2DM. This study aimed to examine the effect of stabilized RB phenolic extracts on the expression of genes associated with β-cell function such as glucose transporter 2 (Glut2), pancreatic and duodenal homeobox 1 (Pdx1), sirtuin 1 (Sirt1), mitochondrial transcription factor A (Tfam), and insulin 1 (Ins1) in addition to evaluating its impact on glucose-stimulated insulin secretion. It was observed that treatment with different concentrations of RB phenolic extracts (25-250 µg/mL) significantly increased the expression of Glut2, Pdx1, Sirt1, Tfam, and Ins1 genes and glucose-stimulated insulin secretion under both normal and high glucose conditions. RB phenolic extracts favourably modulated the expression of genes involved in β-cell dysfunction and insulin secretion via several mechanisms such as synergistic action of polyphenols targeting signalling molecules, decreasing free radical damage by its antioxidant activity, and stimulation of effectors or survival factors of insulin secretion.

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