scholarly journals Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

APOPTOSIS ◽  
2017 ◽  
Vol 22 (11) ◽  
pp. 1380-1393 ◽  
Author(s):  
Sartaj Baidwan ◽  
Anil Chekuri ◽  
DiAnna L. Hynds ◽  
Anjaneyulu Kowluru
Keyword(s):  
Botulinum Toxin ◽  
Pancreatic Islet ◽  
Metabolic Dysfunction ◽  
Β Cells ◽  
Metabolic Defects

scholarly journals An AP-3-dependent mechanism drives synaptic-like microvesicle biogenesis in pancreatic islet β-cells

2010 ◽  
Vol 299 (1) ◽  
pp. E23-E32 ◽  
Author(s):  
Arthur T. Suckow ◽  
Branch Craige ◽  
Victor Faundez ◽  
William J. Cain ◽  
Steven D. Chessler
Keyword(s):  
Synaptic Vesicle ◽  
Pancreatic Islet ◽  
Membrane Trafficking ◽  
Protein Complexes ◽  
Brefeldin A ◽  
Adaptor Protein ◽  
Β Cells ◽  
Β Cell ◽  
Subunit Expression ◽  
Bona Fide

Pancreatic islet β-cells contain synaptic-like microvesicles (SLMVs). The origin, trafficking, and role of these SLMVs are poorly understood. In neurons, synaptic vesicle (SV) biogenesis is mediated by two different cytosolic adaptor protein complexes, a ubiquitous AP-2 complex and the neuron-specific AP-3B complex. Mice lacking AP-3B subunits exhibit impaired GABAergic (inhibitory) neurotransmission and reduced neuronal vesicular GABA transporter (VGAT) content. Since β-cell maturation and exocytotic function seem to parallel that of the inhibitory synapse, we predicted that AP-3B-associated vesicles would be present in β-cells. Here, we test the hypothesis that AP-3B is expressed in islets and mediates β-cell SLMV biogenesis. A secondary aim was to test whether the sedimentation properties of INS-1 β-cell microvesicles are identical to those of bona fide SLMVs isolated from PC12 cells. Our results show that the two neuron-specific AP-3 subunits β3B and μ3B are expressed in β-cells, the first time these proteins have been found to be expressed outside the nervous system. We found that β-cell SLMVs share the same sedimentation properties as PC12 SLMVs and contain SV proteins that sort specifically to AP-3B-associated vesicles in the brain. Brefeldin A, a drug that interferes with AP-3-mediated SV biogenesis, inhibits the delivery of AP-3 cargoes to β-cell SLMVs. Consistent with a role for AP-3 in the biogenesis of GABAergic SLMV in β-cells, INS-1 cell VGAT content decreases upon inhibition of AP-3 δ-subunit expression. Our findings suggest that β-cells and neurons share molecules and mechanisms important for mediating the neuron-specific membrane trafficking pathways that underlie synaptic vesicle formation.

scholarly journals Prenatal androgen exposure programs metabolic dysfunction in female mice

2010 ◽  
Vol 207 (2) ◽  
pp. 213-223 ◽  
Author(s):  
Alison V Roland ◽  
Craig S Nunemaker ◽  
Susanna R Keller ◽  
Suzanne M Moenter
Keyword(s):  
Pancreatic Islet ◽  
Polycystic Ovary ◽  
Islet Function ◽  
Metabolic Dysfunction ◽  
Isolated Pancreatic Islets ◽  
Female Mice ◽  
Metabolic Characteristics ◽  
Reproductive Axis ◽  
Androgen Exposure

Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice.

scholarly journals VEGF-B ablation in pancreatic β-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Frank Chenfei Ning ◽  
Nina Jensen ◽  
Jiarui Mi ◽  
William Lindström ◽  
Mirela Balan ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Glucose Homeostasis ◽  
Lipid Accumulation ◽  
Cell Function ◽  
Lipid Uptake ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Tissues ◽  
Β Cell Function ◽  
Triglyceride Content

AbstractType 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing β-cells may contribute to β-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in β-cells, and assessed glucose homeostasis, β-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that β-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by β-cell VEGF-B deficiency.

scholarly journals Distinct inwardly rectifying K+ channels mediate agonist-inhibition of hormone secretion between α and β cells of pancreatic islet

1999 ◽  
Vol 79 ◽  
pp. 92
Author(s):  
Yukiko Yoshimoto ◽  
Yoshiyuki Horio ◽  
Yuji Fukuyama ◽  
Atsushi Inanobe ◽  
Uchida Wataru ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Hormone Secretion ◽  
Β Cells ◽  
K Channels ◽  
Inwardly Rectifying

Species-Specific Effects of Fatty Acid-Dependent Lipid Droplet Homeostasis within Pancreatic Islet β cells

Metabolism ◽  
2020 ◽  
Vol 104 ◽  
pp. 154085
Author(s):  
Otokini S. Wokoma ◽  
Xin Tong ◽  
Chunhua Dai ◽  
Alvin C. Powers ◽  
Roland Stein
Keyword(s):  
Fatty Acid ◽  
Pancreatic Islet ◽  
Lipid Droplet ◽  
Β Cells ◽  
Specific Effects ◽  
Species Specific

scholarly journals Antibody-mediated activation of the FGFR1/Klothoβ complex corrects metabolic dysfunction and alters food preference in obese humans

2020 ◽  
Vol 117 (46) ◽  
pp. 28992-29000 ◽  
Author(s):  
Amos Baruch ◽  
Chin Wong ◽  
Leslie W. Chinn ◽  
Anjali Vaze ◽  
Junichiro Sonoda ◽  
...  
Keyword(s):  
Target Genes ◽  
Drinking Behavior ◽  
Chronic Administration ◽  
Sweet Taste ◽  
Pancreatic Acinar Cells ◽  
Fibroblast Growth Factor 21 ◽  
Metabolic Dysfunction ◽  
Fgf Receptor ◽  
Body Weight Reduction ◽  
Metabolic Defects

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

scholarly journals A Chronic Fetal Leucine Infusion Potentiates Fetal Insulin Secretion and Increases Pancreatic Islet Size, Vascularity, and β Cells in Late-Gestation Sheep

2020 ◽  
Vol 150 (8) ◽  
pp. 2061-2069
Author(s):  
Brit H Boehmer ◽  
Laura D Brown ◽  
Stephanie R Wesolowski ◽  
William W Hay ◽  
Paul J Rozance
Keyword(s):  
Insulin Secretion ◽  
Growth Factor ◽  
Pancreatic Islet ◽  
Repeated Measures ◽  
Late Gestation ◽  
Acid Mixture ◽  
Multiple Time ◽  
Β Cells ◽  
Fetal Sheep

ABSTRACT Background Infusion of a complete amino acid mixture into normal late-gestation fetal sheep potentiates glucose-stimulated insulin secretion (GSIS). Leucine acutely stimulates insulin secretion in late-gestation fetal sheep and isolated fetal sheep islets in vitro. Objectives We hypothesized that a 9-d leucine infusion would potentiate GSIS in fetal sheep. Methods Columbia-Rambouillet fetal sheep at 126 days of gestation received a 9-d leucine infusion to achieve a 50%–100% increase in leucine concentrations or a control infusion. At the end of the infusion we measured GSIS, pancreatic morphology, and expression of pancreatic mRNAs. Pancreatic islet endothelial cells (ECs) were isolated from fetal sheep and incubated with supplemental leucine or vascular endothelial growth factor A (VEGFA) followed by collection of mRNA. Data measured at multiple time points were compared with a repeated-measures 2-factor ANOVA. Data measured at 1 time point were compared using Student's t test or the Mann–Whitney test. Results Glucose-stimulated insulin concentrations were 80% higher in leucine-infused (LEU) fetuses than in controls (P < 0.05). In the pancreas, LEU fetuses had a higher proportion of islets >5000 μm2 than controls (75% more islets >5000 μm2; P < 0.05) and a larger proportion of the pancreas that stained for β cells (12% greater; P < 0.05). Pancreatic and pancreatic islet vascularity were both 25% greater in LEU fetuses (P < 0.05). Pancreatic VEGFA and hepatocyte growth factor (HGF) mRNA expressions were 38% and 200% greater in LEU fetuses than in controls (P < 0.05), respectively. In isolated islet ECs, HGF mRNA was 20% and 50% higher after incubation in supplemental leucine (P < 0.05) or VEGFA (P < 0.01), respectively. Conclusions A 9-d leucine infusion potentiates fetal GSIS, demonstrating that glucose and leucine act synergistically to stimulate insulin secretion in fetal sheep. A greater proportion of the pancreas being comprised of β cells and higher pancreatic vascularity contributed to the higher GSIS.

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