Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes

Gandasi, Nikhil R.; Yin, Peng; Riz, Michela; Chibalina, Margarita V.; Cortese, Giuliana; Lund, Per; Matveev, Victor; Rorsman, Patrik; Sherman, Arthur; Pedersen, Morten Gram; Barg, Sebastian

doi:10.1172/jci88491

Cited by 76 publications

(81 citation statements)

References 65 publications

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“…Calcium sensors GCaMP5G (20) and R‐GECO (21) were obtained from Addgene (Watertown, MA, USA). GFP—calcium channel, voltage dependent, L type, α1C subunit (CaV 1.2 ) and calcium channel, voltage dependent, L type, α1D subunit (CaV 1.3 )‐GFP were generously provided by Rorsman (University of Oxford, Oxford, U.K.) (22) and Hockerman (Purdue University, West Lafayette, IN, USA) (23). Neuropeptide Y—mCherry and dynamin‐1—GFP were gifts from Sebastian Barg (Uppsala University, Uppsala, Sweden).…”

Section: Methodsmentioning

confidence: 99%

Feedback regulation of insulin secretion by extended synaptotagmin‐1

2018

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Endoplasmic reticulum (ER)—plasma membrane (PM) contacts are dynamic structures with important roles in the regulation of calcium (Ca2+) and lipid homeostasis. The extended synaptotagmins (E‐Syts) are ER‐localized lipid transport proteins that interact with PM phosphatidylinositol 4,5‐bisphosphate in a Ca2+‐dependent manner. E‐Syts bidirectionally transfer glycerolipids, including diacylglycerol (DAG), between the 2 juxtaposed membranes, but the biologic significance of this transport is still unclear. Using insulin‐secreting cells and live‐cell imaging, we now show that Ca2+‐triggered exocytosis of insulin granules is followed, in sequence, by PM DAG formation and E‐Syt1 recruitment. E‐Syt1 counteracted the depolarization‐induced DAG formation through a mechanism that required both voltage‐dependent Ca2+ influx and Ca2+ release from the ER. E‐Syt1 knockdown resulted in prolonged accumulation of DAG in the PM, resulting in increased glucose‐stimulated insulin secretion. We conclude that Ca2+‐triggered exocytosis is temporally coupled to Ca2+‐triggered E‐Syt1 PM recruitment and removal of DAG to negatively regulate the same process.—Xie, B., Nguyen, P. M., Idevall‐Hagren, O. Feedback regulation of insulin secretion by extended synaptotagmin‐1. FASEB J. 33, 4716–4728 (2019). http://www.fasebj.org

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Section: Methodsmentioning

confidence: 99%

Feedback regulation of insulin secretion by extended synaptotagmin‐1

2018

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“…These cells are being widely used for preliminary investigations on beta‐cell biology and drug targets. For example, recent investigations include exploration of dopamine receptor signalling, lipidomic profiling, antidiabetic actions of dogfish glucagon analogues, high‐throughput screening for inhibitors of beta‐cell apoptosis, Ca 2+ channel clustering with insulin granules in diabetes, mitochondrial dynamics and bioenergetics as well as involvement of neuronal K + Cl − cotransporter in insulin secretion . These investigations lay a foundation for further studies on understanding of beta‐cell biology in health and disease.…”

Section: Development and Experimental Use Of Rodent Beta‐cell Linesmentioning

confidence: 99%

Cellular models for beta‐cell function and diabetes gene therapy

2018

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Diabetes is characterized by the destruction and/or relative dysfunction of insulin-secreting beta-cells in the pancreatic islets of Langerhans. Consequently, considerable effort has been made to understand the physiological processes governing insulin production and secretion in these cells and to elucidate the mechanisms involved in their deterioration in the pathogenesis of diabetes. To date, considerable research has exploited clonal beta-cell lines derived from rodent insulinomas. Such cell lines have proven to be a great asset in diabetes research, in vitro drug testing, and studies of beta-cell physiology and provide a sustainable, and in many cases, more practical alternative to the use of animals or primary tissue. However, selection of the most appropriate rodent beta cell line is often challenging and no single cell line entirely recapitulates the properties of human beta-cells. The generation of stable human beta-cell lines would provide a much more suitable model for studies of human beta-cell physiology and pathology and could potentially be used as a readily available source of implantable insulin-releasing tissue for cell-based therapies of diabetes. In this review, we discuss the history, development, functional characteristics and use of available clonal rodent beta-cell lines, as well as reflecting on recent advances in the generation of human-derived beta-cell lines, their use in research studies and their potential for cell therapy of diabetes.

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“…K + -stimulated exocytosis clearly followed a biphasic timecourse and was reduced by 37±10% or 47±7% in the presence of 7 mM, compared with both 1 and 10 mM glucose, respectively. This reduction was entirely due to a slower initial phase of exocytosis, which may correspond to the immediately releasable pool of granules in β-cells 47 . In parallel, we observed a reduction in docked granules at 7 mM glucose, compared with both 1 and 10 mM ( Fig S3 A), giving further support to the notion that the exocytotic capacity in α-cells is related to docked granules.…”

Section: Intrinsic Regulation Of Glucagon Secretionmentioning

confidence: 95%

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Omar‐Hmeadi

Lund

Gandasi

et al. 2019

Preprint

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AbstractGlucagon is secreted from pancreatic α-cells to activate gluconeogenesis and other pathways that raise blood glucose during hypoglycemia. Glucose-dependent regulation of glucagon secretion involves both α-cell-intrinsic mechanisms and paracrine control through insulin and somatostatin. In type-2 diabetes (T2D) inadequately high glucagon levels contribute to hyperglycemia. To understand these disease-associated changes at the cellular level, and to isolate intrinsic and paracrine effects, we analyzed glucagon granule exocytosis and membrane excitability in isolated α-cells from 56 non-diabetic (ND) and 15 T2D human donors. High resolution imaging showed that glucagon granule exocytosis had a U-shaped sensitivity to glucose, with the slowest rate around 7 mM glucose, and accelerated rates at <5 and >10 mM glucose. Exocytosis was reduced in T2D α-cells, but their glucose sensitivity remained intact and there were no changes in voltage-dependent ion currents or granule trafficking. Instead, α-cells from T2D donors were markedly insensitive to somatostatin and insulin, which rapidly inhibited exocytosis and electrical activity in ND cells. Thus, intrinsic mechanisms do not inhibit glucagon secretion at hyperglycemia, and elevated glucagon levels in human T2D reflect an insensitivity of α-cells to paracrine inhibition.

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Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes

Cited by 76 publications

References 65 publications

Feedback regulation of insulin secretion by extended synaptotagmin‐1

Feedback regulation of insulin secretion by extended synaptotagmin‐1

Cellular models for beta‐cell function and diabetes gene therapy

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

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