Publications
165 results found
Mehta ZB, Johnston NR, Nguyen-Tu M-S, et al., 2017, Remote control of glucose homeostasis in vivo using photopharmacology, Scientific Reports, Vol: 7, ISSN: 2045-2322
Photopharmacology describes the use of light to precisely deliver drug activity in space and time. Such approaches promise to improve drug specificity by reducing off-target effects. As a proof-of-concept, we have subjected the fourth generation photoswitchable sulfonylurea JB253 to comprehensive toxicology assessment, including mutagenicity and maximum/repeated tolerated dose studies, as well as in vivo testing in rodents. Here, we show that JB253 is well-tolerated with minimal mutagenicity and can be used to optically-control glucose homeostasis in anesthetized mice following delivery of blue light to the pancreas. These studies provide the first demonstration that photopharmacology may one day be applicable to the light-guided treatment of type 2 diabetes and other metabolic disease states in vivo in humans.
Fine NHF, Doig CL, Elhassan Y, et al., 2017, A steroid-regulated feedback loop preserves insulin secretion in the face of perturbed beta cell function, DIABETIC MEDICINE, Vol: 34, Pages: 41-41, ISSN: 0742-3071
Podewin T, Broichhagen J, Fine NHF, et al., 2017, Constitutive activation and trafficking of the glucagon-like peptide-1 receptor using tethered pharmacology, Publisher: WILEY, Pages: 41-41, ISSN: 0742-3071
Romano N, Guillou A, Hodson DJ, et al., 2017, Multiple-scale neuroendocrine signals connect brain and pituitary hormone rhythms, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 114, Pages: 2379-2382, ISSN: 0027-8424
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- Citations: 12
Le Tissier P, Campos P, Lafont C, et al., 2016, An updated view of hypothalamic–vascular–pituitary unit function and plasticity, Nature Reviews Endocrinology, Vol: 13, Pages: 257-267, ISSN: 1759-5029
The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic–pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment.
Johnston NR, Mitchell RK, Haythorne E, et al., 2016, Beta cell hubs dictate pancreatic islet responses to glucose, Cell Metabolism, Vol: 24, Pages: 389-401, ISSN: 1932-7420
The arrangement of beta cells within islets of Langerhans is critical for insulin release through thegeneration of rhythmic activity. A privileged role for individual beta cells in orchestrating theseresponses has long-been suspected, but not directly demonstrated. We show here that the beta cellpopulation in situ is operationally heterogeneous. Mapping of islet functional architecturerevealed the presence of hub cells with pacemaker properties, which remain stable over recordingperiods of 2-3 hours. Using a dual optogenetic/photopharmacological strategy, silencing of hubsabolished coordinated islet responses to glucose, whereas specific stimulation restoredcommunication patterns. Hubs were metabolically-adapted and targeted by both proinflammatoryand glucolipotoxic insults to induce widespread beta cell dysfunction. Thus, theislet is wired by hubs, whose failure may contribute to type 2 diabetes mellitus.
Rutter GA, Mitchell RK, Hodson DJ, 2016, Pax6 is required for the functional identity of the adult pancreatic beta cell, 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: Springer Verlag, Pages: S168-S169, ISSN: 0012-186X
Frank JA, Yushchenko DA, Hodson DJ, et al., 2016, Photoswitchable diacylglycerols enable optical control of protein kinase C., Nature Chemical Biology, Vol: 12, Pages: 755-762, ISSN: 1552-4469
Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling.
Mondragon A, Hodson D, Semplici F, et al., 2016, 1964-P: PAS-domain containing protein kinase (PASK) is required for the regulation of food intake and glucose homeostasis, Annual Professional Conference of the American Diabetes Association, Publisher: American Diabetes Association, Pages: A504-A504, ISSN: 0012-1797
Broichhagen J, Johnston NR, vonOhlen Y, et al., 2016, Allosterische optische Steuerung eines Klasse‐B‐G‐Protein‐gekoppelten Rezeptors, Angewandte Chemie, Vol: 128, Pages: 5961-5965, ISSN: 0044-8249
<jats:title>Abstract</jats:title><jats:p>Die allosterische Regulation von G‐Protein‐gekoppelten Rezeptoren (GPCRs) erhöht deren Arzneimittelspezifität und ermöglicht so neue therapeutische Ansätze. Dennoch ist die heutige Wirkstoffentwicklung gehemmt, da die allosterische Bindestelle nur unzureichend präzise kontrollierbar ist. Hier beschreiben wir Design, Synthese und Anwendung von PhotoETP, einem lichtabhängigen positiven allosterischen Regulator des Klasse‐B‐GPCR GLP‐1R (“glucagon‐like peptide‐1 receptor”), der an der Aufrechterhaltung der Glukose‐Homöostase beteiligt ist. PhotoETP ermöglicht die von GLP‐1 und dessen Metaboliten abhängige Potenzierung von Ca<jats:sup>2+</jats:sup>‐, cAMP‐ und Insulin‐Antworten nach Bestrahlung von Zellen und Pankreasgewebe mit blauem Licht. PhotoETP bietet somit eine Vorlage für die Entwicklung von niedermolekularen allosterischen Photoschaltern für Klasse‐B‐GPCRs, und es könnte nützlich dabei sein, die positive Kooperativität des GLP‐1R zu verstehen.</jats:p>
Osterstock G, Mitutsova V, Barre A, et al., 2016, Somatostatin triggers rhythmic electrical firing in hypothalamic GHRH neurons, Scientific Reports, Vol: 6, ISSN: 2045-2322
Hypothalamic growth hormone-releasing hormone (GHRH) neurons orchestrate body growth/maturation and have been implicated in feeding responses and ageing. However, the electrical patterns that dictate GHRH neuron functions have remained elusive. Since the inhibitory neuropeptide somatostatin (SST) is considered to be a primary oscillator of the GH axis, we examined its acute effects on GHRH neurons in brain slices from male and female GHRH-GFP mice. At the cellular level, SST irregularly suppressed GHRH neuron electrical activity, leading to slow oscillations at the population level. This resulted from an initial inhibitory action at the GHRH neuron level via K+ channel activation, followed by a delayed, sst1/sst2 receptor-dependent unbalancing of glutamatergic and GABAergic synaptic inputs. The oscillation patterns induced by SST were sexually dimorphic, and could be explained by differential actions of SST on both GABAergic and glutamatergic currents. Thus, a tripartite neuronal circuit involving a fast hyperpolarization and a dual regulation of synaptic inputs appeared sufficient in pacing the activity of the GHRH neuronal population. These “feed-forward loops” may represent basic building blocks involved in the regulation of GHRH release and its downstream sexual specific functions.
Broichhagen J, Johnston NR, von Ohlen Y, et al., 2016, Allosteric optical control of a class B G-protein-coupled receptor, Angewandte Chemie - International Edition, Vol: 55, Pages: 5865-5868, ISSN: 1433-7851
Broichhagen J, von Ohlen Y, Johnston NR, et al., 2016, Optical control of the glucagon-like peptide-1 receptor allosteric site, DIABETIC MEDICINE, Vol: 33, Pages: 60-60, ISSN: 0742-3071
Rutter GA, Chabosseau P, Bellomo EA, et al., 2016, Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?, PROCEEDINGS OF THE NUTRITION SOCIETY, Vol: 75, Pages: 61-72, ISSN: 0029-6651
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- Citations: 49
Rutter GA, Hu M, Mitchell RK, et al., 2016, Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance, Molecular Endocrinology, Vol: 30, ISSN: 1944-9917
Zinc Transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells where it mediates zinc (Zn²⁺) uptake into secretory granules. Whilst a common non-synonymous polymorphism (R325W), which lowers activity, is associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterise new mouse models to explore the impact on glucose homeostasis of graded changes in ZnT8 activity in the β cell. Firstly, Slc30a8 was deleted highly selectively in these cells using the novel deleter strain, Ins1Cre. The resultant Ins1CreZnT8KO mice displayed significant (p<0.05) impairments in glucose tolerance at 10 weeks of age versus littermate controls and glucose-induced increases in circulating insulin were inhibited in vivo. Whilst insulin release from Ins1CreZnT8KO islets was normal, Zn²⁺ release was severely impaired. Conversely, transgenic ZnT8Tg mice, over-expressing the transporter inducibly in the adult β cell using an insulin promoter-dependent Tet-On system, showed significant (p<0.01) improvements in glucose tolerance compared to control animals. Glucose-induced insulin secretion from ZnT8Tg islets was severely impaired, whereas Zn²⁺ release was significantly enhanced. Our findings demonstrate that glucose homeostasis in the mouse improves as β cell ZnT8 activity increases and, remarkably, these changes track Zn²⁺ rather than insulin release in vitro. Activation of ZnT8 in β cells might therefore provide the basis of a novel approach to treating type 2 diabetes.
Hodson DJ, Rutter GA, 2016, Studying Incretin Action on the Pancreatic β Cell, INCRETIN BIOLOGY: A PRACTICAL GUIDE, Editors: Rutter, ZacVarghese, Publisher: IMPERIAL COLL PRESS, Pages: 49-77, ISBN: 978-1-78326-736-1
Michau A, Hodson DJ, Fontanaud P, et al., 2015, Metabolism regulates exposure of pancreatic islets to circulating molecules in vivo., Diabetes, Vol: 65, Pages: 463-475, ISSN: 0012-1797
Pancreatic beta cells modulate insulin secretion through rapid sensing of blood glucose and integration of gut-derived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass, and leads to gestational and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory beta cell expansion may be key to developing novel anti-diabetic therapies. Here, using 2-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high fat diet-feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of beta cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping beta cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules.
Broichhagen J, Podewin T, Meyer-Berg H, et al., 2015, Optical control of insulin secretion using an incretin switch, Angewandte Chemie International Edition, Vol: 54, Pages: 15565-15569, ISSN: 1433-7851
Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.
Rutter GA, Solomou A, Meur G, et al., 2015, The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α cells for hypoglycemia-induced glucagon secretion, Journal of Biological Chemistry, Vol: 290, Pages: 21432-21442, ISSN: 0021-9258
SLC30A8 encodes a zinc transporter ZnT8 largely restrictedto pancreatic islet - and -cells, and responsible for zinc accumulationinto secretory granules. Although common SLC30A8variants, believed to reduce ZnT8 activity, increase type 2 diabetesrisk in humans, rare inactivating mutations are protective.To investigate the role of Slc30a8 in the control of glucagonsecretion, Slc30a8 was inactivated selectively in-cells by crossingmice with alleles floxed at exon 1 to animals expressing Crerecombinase under the pre-proglucagon promoter. Furthercrossing to Rosa26:tdRFP mice, and sorting of RFP : glucagon cells from KO mice, revealed recombination in 30% of -cells,of which 50% were ZnT8-negative (14 1.8% of all -cells).Although glucose and insulin tolerance were normal, femaleZnT8KO mice required lower glucose infusion rates duringhypoglycemic clamps and displayed enhanced glucagon release(p < 0.001) versus WT mice. Correspondingly, islets isolatedfrom ZnT8KO mice secreted more glucagon at 1 mM glucose,but not 17 mM glucose, than WT controls (n 5; p 0.008).Although the expression of other ZnT family members wasunchanged, cytoplasmic (n 4 mice per genotype; p < 0.0001)and granular (n 3, p < 0.01) free Zn2 levels were significantlylower in KO -cells versus control cells. In response to low glucose,the amplitude and frequency of intracellular Ca2 increases were unchanged in -cells of ZnT8KO KO mice.ZnT8 is thus important in a subset of -cells for normalresponses to hypoglycemia and acts via Ca2 -independentmechanisms.
Solomou A, Meur G, Bellomo E, et al., 2015, The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic alpha-cells for hypoglycemia-induced glucagon secretion, Journal of Biological Chemistry, Vol: 290, Pages: 21432-21442, ISSN: 1083-351X
SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP+: glucagon+ cells from KO mice, revealed recombination in ∼30% of α-cells, of which ∼50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn2+ levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca2+ increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca2+-independent mechanisms.
Swisa A, Granot Z, Tamarina N, et al., 2015, Loss of liver kinase B1 (LKB1) in beta cells enhances glucose-stimulated insulin secretion despite profound mitochondrial defects, Journal of Biological Chemistry, Vol: 290, Pages: 20934-20946, ISSN: 1083-351X
The tumor suppressor Liver Kinase B1 (LKB1) is an important regulator of pancreatic β cell biology. LKB1-dependent phosphorylation of distinct AMPK family members determines proper β cell polarity and restricts β cell size, total β cell mass and glucose-stimulated insulin secretion (GSIS). However the full spectrum of LKB1 effects and the mechanisms involved in the secretory phenotype remains incompletely understood. We report here that in the absence of LKB1 in β cells, GSIS is dramatically and persistently improved. The enhancement is seen both in vivo and in vitro, and cannot be explained by altered cell polarity, increased β cell number or increased insulin content. Increased secretion does require membrane depolarization and calcium influx, but appears to rely mostly on a distal step in the secretion pathway. Surprisingly, enhanced GSIS is seen despite profound defects in mitochondrial structure and function in LKB1-deficient β cells, expected to greatly diminish insulin secretion via the classic triggering pathway. Thus LKB1 is essential for mitochondrial homeostasis in β cells, and in parallel is a powerful negative regulator of insulin secretion. This study shows that β cells can be manipulated to enhance GSIS to supra-normal levels even in the face of defective mitochondria, and without deterioration over months.
Rutter GA, Soedling H, Hodson D, et al., 2015, Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells, Molecular Metabolism, Vol: 4, Pages: 619-630, ISSN: 2212-8778
Aims/hypothesis: The adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis.Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and otherbrain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains,respectively, to explore the roles of LepR in pancreatic b and a cells. Here, we use two newly-developed Cre lines to explore the role of leptinsignalling in insulin and proglucagon-expressing cells.Methods: Leptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR.Mice lacking leptin signalling in pancreatic b, or in a and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediatedrecombination respectively of flox’d leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology andhormone secretion from isolated islets were assessed using standard techniques.Results: Leptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptinsignalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in b cells exhibited no abnormalitiesin glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2 3.2% decrease in areaunder curve; p < 0.05), and improved (39.0 13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seenbetween genotypes in body weight, fasting glucose or b/a cell ratio. Deletion of LepR from a-cells, a minority of b cells, and a subset ofproglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretionassessed in vivo and in vitr
Hodson DJ, Legros C, Desarménien MG, et al., 2015, Roles of connexins and pannexins in (neuro)endocrine physiology., Cellular and Molecular Life Sciences, Vol: 72, Pages: 2911-2928, ISSN: 1420-9071
To ensure appropriate secretion in response to demand, (neuro)endocrine tissues liberate massive quantities of hormones, which act to coordinate and synchronize biological signals in distant secretory and nonsecretory cell populations. Intercellular communication plays a central role in this control. With regard to molecular identity, junctional cell-cell communication is supported by connexin-based gap junctions. In addition, connexin hemichannels, the structural precursors of gap junctions, as well as pannexin channels have recently emerged as possible modulators of the secretory process. This review focuses on the expression of connexins and pannexins in various (neuro)endocrine tissues, including the adrenal cortex and medulla, the anterior pituitary, the endocrine hypothalamus and the pineal, thyroid and parathyroid glands. Upon a physiological or pathological stimulus, junctional intercellular coupling can be acutely modulated or persistently remodeled, thus offering multiple regulatory possibilities. The functional roles of gap junction-mediated intercellular communication in endocrine physiology as well as the involvement of connexin/pannexin-related hemichannels are also discussed.
Rutter GA, Pullen TJ, Hodson DJ, et al., 2015, Pancreatic β-cell identity, glucose sensing and the control of insulin secretion, BIOCHEMICAL JOURNAL, Vol: 466, Pages: 203-218, ISSN: 0264-6021
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- Citations: 243
Mitchell RK, Mondragon A, Chen L, et al., 2015, Selective disruption of <i>Tcf7l2</i> in the pancreatic β cell impairs secretory function and lowers β cell mass, HUMAN MOLECULAR GENETICS, Vol: 24, Pages: 1390-1399, ISSN: 0964-6906
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- Citations: 75
Rutter GA, Hodson DJ, 2015, Beta cell connectivity in pancreatic islets: a type 2 diabetes target?, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 72, Pages: 453-467, ISSN: 1420-682X
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- Citations: 47
Sun G, Da Silva Xavier G, Gorman T, et al., 2015, LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia, Molecular Metabolism, Vol: 4, Pages: 277-286, ISSN: 2212-8778
Aims/Hypothesis: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production invivo is unclear. Methods: Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ~45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (. PPG) Cre. Results: Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p<0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p<0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p=0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets. Conclusions/Interpretation: An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
Le Tissier PR, Hodson DJ, Martin AO, et al., 2015, Plasticity of the Prolactin (PRL) Axis: Mechanisms Underlying Regulation of Output in Female Mice, RECENT ADVANCES IN PROLACTIN RESEARCH, Vol: 846, Pages: 139-162, ISSN: 0065-2598
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- Citations: 23
Broichhagen J, Frank JA, Johnston NR, et al., 2015, A red-shifted photochromic sulfonylurea for the remote control of pancreatic beta cell function, CHEMICAL COMMUNICATIONS, Vol: 51, Pages: 6018-6021, ISSN: 1359-7345
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- Citations: 41
Rutter GA, Broichhagen J, Schönberger M, et al., 2014, Optical control of insulin release using a photoswitchable sulfonylurea, Nature Communications, Vol: 5, ISSN: 2041-1723
Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM.
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