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Optogenetic insulin

Hongxia Lei, Frédéric Preitner, Gwenaël Labouèbe, Rolf Gruetter, Bernard Thorens
Glucose transporter 2 ( Glut2)-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if Glut2-positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of Glut2, either globally ( ripglut1:glut2- / - ) or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
Agatha A van der Klaauw
BACKGROUND: The global rise in the prevalence of obesity and associated comorbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. CONTENT: Studies in rodents with the use of global and targeted gene disruption, and mapping of neurocircuitry by using optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) have greatly advanced our understanding of the neural control of body weight...
January 2018: Clinical Chemistry
Matthew J Westacott, Nurin W F Ludin, Richard K P Benninger
Understanding how heterogeneous cells within a multicellular system interact and affect overall function is difficult without a means of perturbing individual cells or subpopulations. Here we apply optogenetics to understand how subpopulations of β-cells control the overall [Ca2+ ]i response and insulin secretion dynamics of the islets of Langerhans. We spatiotemporally perturbed electrical activity in β-cells of channelrhodopsin2-expressing islets, mapped the [Ca2+ ]i response, and correlated this with the cellular metabolic activity and an in silico electrophysiology model...
September 5, 2017: Biophysical Journal
Fan Zhang, Emmanuel S Tzanakakis
Pancreatic β-cell insulin production is orchestrated by a complex circuitry involving intracellular elements including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of β-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in β-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from Beggiatoa (bPAC) was delivered to β-cells...
August 24, 2017: Scientific Reports
Chen Ji, Fan Fan, Xuelin Lou
Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) signaling is transient and spatially confined in live cells. How this pattern of signaling regulates transmitter release and hormone secretion has not been addressed. We devised an optogenetic approach to control PI(4,5)P2 levels in time and space in insulin-secreting cells. Combining this approach with total internal reflection fluorescence microscopy, we examined individual vesicle-trafficking steps. Unlike long-term PI(4,5)P2 perturbations, rapid and cell-wide PI(4,5)P2 reduction in the plasma membrane (PM) strongly inhibits secretion and intracellular Ca(2+) concentration ([Ca(2+)]i) responses, but not sytaxin1a clustering...
August 8, 2017: Cell Reports
Eulalia A Coutinho, Shiki Okamoto, Ayako Wendy Ishikawa, Shigefumi Yokota, Nobuhiro Wada, Takahiro Hirabayashi, Kumiko Saito, Tatsuya Sato, Kazuyo Takagi, Chen-Chi Wang, Kenta Kobayashi, Yoshihiro Ogawa, Seiji Shioda, Yumiko Yoshimura, Yasuhiko Minokoshi
The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology...
September 2017: Diabetes
Jiawei Shao, Shuai Xue, Guiling Yu, Yuanhuan Yu, Xueping Yang, Yu Bai, Sucheng Zhu, Linfeng Yang, Jianli Yin, Yidan Wang, Shuyong Liao, Sanwei Guo, Mingqi Xie, Martin Fussenegger, Haifeng Ye
With the increasingly dominant role of smartphones in our lives, mobile health care systems integrating advanced point-of-care technologies to manage chronic diseases are gaining attention. Using a multidisciplinary design principle coupling electrical engineering, software development, and synthetic biology, we have engineered a technological infrastructure enabling the smartphone-assisted semiautomatic treatment of diabetes in mice. A custom-designed home server SmartController was programmed to process wireless signals, enabling a smartphone to regulate hormone production by optically engineered cells implanted in diabetic mice via a far-red light (FRL)-responsive optogenetic interface...
April 26, 2017: Science Translational Medicine
Richard J McCloskey, Anthony D Fouad, Matthew A Churgin, Christopher Fang-Yen
Animals optimize survival and reproduction in part through control of behavioral states, which depend on an organism's internal and external environments. In the nematode Caenorhabditis elegans a variety of behavioral states have been described, including roaming, dwelling, quiescence, and episodic swimming. These states have been considered in isolation under varied experimental conditions, making it difficult to establish a unified picture of how they are regulated. Using long-term imaging, we examined C...
May 1, 2017: Journal of Neurophysiology
Giovanni Lenguito, Deborah Chaimov, Jonathan R Weitz, Rayner Rodriguez-Diaz, Siddarth A K Rawal, Alejandro Tamayo-Garcia, Alejandro Caicedo, Cherie L Stabler, Peter Buchwald, Ashutosh Agarwal
We report the design and fabrication of a robust fluidic platform built out of inert plastic materials and micromachined features that promote optimized convective fluid transport. The platform is tested for perfusion interrogation of rodent and human pancreatic islets, dynamic secretion of hormones, concomitant live-cell imaging, and optogenetic stimulation of genetically engineered islets. A coupled quantitative fluid dynamics computational model of glucose stimulated insulin secretion and fluid dynamics was first utilized to design device geometries that are optimal for complete perfusion of three-dimensional islets, effective collection of secreted insulin, and minimization of system volumes and associated delays...
February 28, 2017: Lab on a Chip
Natalie R Johnston, Ryan K Mitchell, Elizabeth Haythorne, Maria Paiva Pessoa, Francesca Semplici, Jorge Ferrer, Lorenzo Piemonti, Piero Marchetti, Marco Bugliani, Domenico Bosco, Ekaterine Berishvili, Philip Duncanson, Michael Watkinson, Johannes Broichhagen, Dirk Trauner, Guy A Rutter, David J Hodson
The arrangement of β cells within islets of Langerhans is critical for insulin release through the generation of rhythmic activity. A privileged role for individual β cells in orchestrating these responses has long been suspected, but not directly demonstrated. We show here that the β cell population in situ is operationally heterogeneous. Mapping of islet functional architecture revealed the presence of hub cells with pacemaker properties, which remain stable over recording periods of 2 to 3 hr. Using a dual optogenetic/photopharmacological strategy, silencing of hubs abolished coordinated islet responses to glucose, whereas specific stimulation restored communication patterns...
September 13, 2016: Cell Metabolism
Byung-Chang Suh, Jun-Hee Yeon, Cheon-Gyu Park
The PI(4,5)P2 level in the plasma membrane is dynamically regulated by cytoplasmic ATP production and receptor-mediated transmembrane signaling cascades. In this issue of Cell Chemical Biology, Xie et al. (2016) use optogenetics to micro-manipulate membrane PI(4,5)P2 and reveal how acute PI(4,5)P2 changes can alter intracellular Ca(2+) dynamics and insulin secretion in pancreatic β cells.
July 21, 2016: Cell Chemical Biology
Murat Artan, Dae-Eun Jeong, Dongyeop Lee, Young-Il Kim, Heehwa G Son, Zahabiya Husain, Jinmahn Kim, Ozlem Altintas, Kyuhyung Kim, Joy Alcedo, Seung-Jae V Lee
Environmental fluctuations influence organismal aging by affecting various regulatory systems. One such system involves sensory neurons, which affect life span in many species. However, how sensory neurons coordinate organismal aging in response to changes in environmental signals remains elusive. Here, we found that a subset of sensory neurons shortens Caenorhabditis elegans' life span by differentially regulating the expression of a specific insulin-like peptide (ILP), INS-6. Notably, treatment with food-derived cues or optogenetic activation of sensory neurons significantly increases ins-6 expression and decreases life span...
May 1, 2016: Genes & Development
Yingke Xu, Di Nan, Jiannan Fan, Jonathan S Bogan, Derek Toomre
Glucose transporter 4 (GLUT4; also known as SLC2A4) resides on intracellular vesicles in muscle and adipose cells, and translocates to the plasma membrane in response to insulin. The phosphoinositide 3-kinase (PI3K)-Akt signaling pathway plays a major role in GLUT4 translocation; however, a challenge has been to unravel the potentially distinct contributions of PI3K and Akt (of which there are three isoforms, Akt1-Akt3) to overall insulin action. Here, we describe new optogenetic tools based on CRY2 and the N-terminus of CIB1 (CIBN)...
May 15, 2016: Journal of Cell Science
Sophie M Steculorum, Johan Ruud, Ismene Karakasilioti, Heiko Backes, Linda Engström Ruud, Katharina Timper, Martin E Hess, Eva Tsaousidou, Jan Mauer, Merly C Vogt, Lars Paeger, Stephan Bremser, Andreas C Klein, Donald A Morgan, Peter Frommolt, Paul T Brinkkötter, Philipp Hammerschmidt, Thomas Benzing, Kamal Rahmouni, F Thomas Wunderlich, Peter Kloppenburg, Jens C Brüning
Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation...
March 24, 2016: Cell
Thomas M Reinbothe, Inês G Mollet
In light of the emerging diabetes epidemic, new experimental approaches in islet research are needed to elucidate the mechanisms behind pancreatic islet dysfunction and to facilitate the development of more effective therapies. Optogenetics has created numerous new experimental tools enabling us to gain insights into processes little was known about before. The spatial and temporal precision that it can achieve is also attractive for studying the cells of the pancreatic islet and we set out to explore the possibilities of this technology for our purposes...
2016: Methods in Molecular Biology
Jenny L Wilson, Pablo J Enriori
The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the nucleus of the solitary tract-area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH)...
December 15, 2015: Molecular and Cellular Endocrinology
T Kushibiki, S Okawa, T Hirasawa, M Ishihara
The present study assessed the ability of optogenetics techniques to provide a better understanding of the control of insulin secretion, particularly regarding pancreatic β-cell function in homeostasis and pathological conditions such as diabetes mellitus (DM). We used optogenetics to investigate whether insulin secretion and blood glucose homeostasis could be controlled by regulating intracellular calcium ion concentrations ([Ca(2+)]i) in a mouse pancreatic β-cell line (MIN6) transfected with the optogenetic protein channelrhodopsin-2 (ChR2)...
July 2015: Gene Therapy
Thomas M Reinbothe, Fatemeh Safi, Annika S Axelsson, Inês G Mollet, Anders H Rosengren
Insulin is secreted from the pancreatic β-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of β-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of β-cells in intact islets. We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter...
2014: Islets
Bernard Thorens
The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism...
February 2015: Diabetologia
Thomas M Reinbothe, Fatemeh Safi, Annika S Axelsson, Inês G Mollet, Anders H Rosengren
Insulin is secreted from the pancreatic β-cells in response to elevated glucose. In intact islets the capacity for insulin release is determined by a complex interplay between different cell types. This has made it difficult to specifically assess the role of β-cell defects to the insulin secretory impairment in type 2 diabetes. Here we describe a new approach, based on optogenetics, that enables specific investigation of β-cells in intact islets. We used transgenic mice expressing the light-sensitive cation channel Channelrhodopsin-2 (ChR2) under control of the insulin promoter...
February 18, 2014: Islets
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