A5020082293- Pancreatic function and diabetes
- Metabolism, Diabetes, and Cancer
- Calcium signaling and nucleotide metabolism
- Diabetes and associated disorders
- Diabetes Treatment and Management
- Receptor Mechanisms and Signaling
- Cellular transport and secretion
- Diabetes Management and Research
- Phosphodiesterase function and regulation
- Protein Kinase Regulation and GTPase Signaling
- Diet, Metabolism, and Disease
- Adenosine and Purinergic Signaling
- Genetics and Neurodevelopmental Disorders
- Cell Adhesion Molecules Research
- Adipose Tissue and Metabolism
- Endoplasmic Reticulum Stress and Disease
- Ion channel regulation and function
- Diet and metabolism studies
- Advanced Fluorescence Microscopy Techniques
- Lipid Membrane Structure and Behavior
- Epigenetics and DNA Methylation
- Ion Channels and Receptors
- Pancreatitis Pathology and Treatment
- Regulation of Appetite and Obesity
- Mitochondrial Function and Pathology
Uppsala University
2016-2025
Science for Life Laboratory
2018
University of Cambridge
2009-2015
Stanford University
2002
Abstract Transplantation of pancreatic islet cells derived from human pluripotent stem is a promising treatment for diabetes. Despite progress in the generation stem-cell-derived islets (SC-islets), no detailed characterization their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during vitro...
Somatostatin from pancreatic δ-cells is a paracrine regulator of insulin and glucagon secretion, but the release kinetics whether secretion altered in diabetes unclear. This study aimed to improve understanding somatostatin by developing tool for real-time detection individual islets. Reporter cells responding with cytoplasmic Ca2+ concentration ([Ca2+]i) changes were generated co-expressing receptor SSTR2, G-protein Gα15 fluorescent sensor HeLa cells. induced dose-dependent [Ca2+]i...
The cytoplasmic Ca2+ concentration ([Ca2+]i) was measured in single pancreatic mouse islets superfused a system allowing concomitant recordings of insulin release. When glucose raised from 3 to 11 mM, [Ca2+]i responded by transient lowering followed rise an average level 192 +/- nM. In 77% the associated with gradual appearance oscillations, which were either fast (2-7/min), slow (0.3-0.9/min), or combination both types. characteristics oscillations those expected relationship electrical...
cAMP is a critical messenger for insulin and glucagon secretion from pancreatic β- α-cells, respectively. Dispersed β-cells show oscillations, but the signaling kinetics in cells within intact islets of Langerhans unknown.The subplasma-membrane concentration ([cAMP](pm)) was recorded α- mantle mouse using total internal reflection microscopy fluorescent translocation biosensor. Cell identification based on opposite effects adrenaline β-cells.In exposed to 3 mmol/L glucose, [cAMP](pm) low...
Circadian clocks operative in pancreatic islets participate the regulation of insulin secretion humans and, if compromised, development type 2 diabetes (T2D) rodents. Here we demonstrate that human islet α- and β-cells bear attenuated exhibit strongly disrupted glucagon granule docking exocytosis. To examine whether compromised play a role pathogenesis T2D humans, quantified parameters molecular at population, single islet, cell levels. Strikingly, our experiments reveal from patients...
Abstract Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin somatostatin. To understand the inadequately high glucagon levels contribute hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis membrane excitability of 68 non-diabetic 21 T2D human donors. We report moderately reduced donors, without changes voltage-dependent ion...
Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated control in diabetes. However, mechanisms by which controls glucagon from pancreatic alpha cells remain elusive. The aim this study was to investigate role intracellular messenger cAMP alpha-cell-intrinsic regulation release.Subplasmalemmal Ca2+ concentrations were recorded isolated islet-located using fluorescent reporters total internal reflection microscopy. mouse islets...
ATP links changes in glucose metabolism to electrical activity, Ca(2+) signalling and insulin secretion pancreatic beta cells. There is evidence that cell oscillates, but little known about dynamics at the plasma membrane, where regulation of ion channels exocytosis occur.The sub-plasma-membrane concentration ([ATP]pm) was recorded cells intact mouse human islets using total internal reflection microscopy fluorescent reporter Perceval.Glucose dose-dependently increased [ATP]pm with...
Cytoplasmic ATP and Ca(2+) are implicated in current models of glucose's control glucagon insulin secretion from pancreatic α- β-cells, respectively, but little is known about its relation to α-cells. We therefore expressed the fluorescent biosensor Perceval mouse islets loaded them with a indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations ([Ca(2+)]pm; [ATP]pm) superficial β-cells intact related signaling by immunoassay....
Highlights•In human islets GABA (≤μM) activates β cell-specific GABAA receptors that become supersensitive to in type 2 diabetes.•GABAA activity cells is enhanced by diazepam, anesthetics, the incretin GLP-1 but not hypnotic zolpidem.•GABA modulates rate of insulin granule exocytosis and glucose-stimulated secretion.GABA a signal molecule brain also secreted insulin-producing pancreatic islets. has many roles most aim at optimizing function survival cells. In report Korol, Jin et al. authors...
Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in handling wild-type is underinvestigated. Here, we have explored importance glucose-regulated 94 (GRP94), a prominent ER known fold insulin-like growth factors, within β-cells. We found that GRP94 coimmunoprecipitated with and inhibition function and/or expression reduced glucose-dependent insulin secretion, shortened half-life, lowered intracellular levels. This...
Pancreatic islets exposed to 11 mM glucose exhibited complex variations of cytoplasmic Ca 2+ concentration ([Ca ] i ) with slow (0.3‐0.9 min −1 or fast (2‐7 oscillations a mixed pattern. Using digital imaging and confocal microscopy we demonstrated that the pattern superimposed was due separate cell populations respective responses. In [Ca oscillations, exposure sarcoplasmic‐endoplasmic reticulum ‐ATPase inhibitors thapsigargin 2,5‐di‐ tert ‐butylhydroquinone (DTBHQ) resulted in selective...
Pulsatile insulin release from glucose-stimulated β-cells is driven by oscillations of the Ca2+ and cAMP concentrations in subplasma membrane space ([Ca2+]pm [cAMP]pm). To clarify mechanisms which regulates secretion, we performed parallel evanescent wave fluorescence imaging [cAMP]pm, [Ca2+]pm, phosphatidylinositol 3,4,5-trisphosphate (PIP3) plasma membrane. This lipid formed autocrine receptor activation was used to monitor kinetics single MIN6 β-cells. Elevation glucose concentration 3 11...
Capacitative Ca<sup>2+</sup> entry (CCE), which occurs through the plasma membrane as a result of store depletion, is mediated by stromal interacting molecule 1 (STIM1), sensor intracellular content, and pore-forming component Orai1. However, additional factors, such C-type transient receptor potential (TRPC) channels, may also participate in CCE apparatus. To explore whether store-dependent reconstituted coexpression Orai1 STIM1 has functional properties CCE, we used...
OBJECTIVE Ghrelin reportedly restricts insulin release in islet β-cells via the Gαi2 subtype of G-proteins and thereby regulates glucose homeostasis. This study explored whether ghrelin cAMP signaling this regulation induces insulinostatic cascade β-cells. RESEARCH DESIGN AND METHODS Insulin was measured rat perfused pancreas isolated islets production islets. Cytosolic concentrations ([cAMP]i) were monitored mouse MIN6 cells using evanescent-wave fluorescence imaging. In single β-cells,...