A5002310756- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Receptor Mechanisms and Signaling
- Diet, Metabolism, and Disease
- Diabetes Management and Research
- Diabetes and associated disorders
- Adenosine and Purinergic Signaling
- MicroRNA in disease regulation
- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Calcium signaling and nucleotide metabolism
- Nitric Oxide and Endothelin Effects
- Liver Disease Diagnosis and Treatment
- Cellular transport and secretion
- Organ Transplantation Techniques and Outcomes
- Neuropeptides and Animal Physiology
- Liver Disease and Transplantation
- Cannabis and Cannabinoid Research
- Ion channel regulation and function
- Circular RNAs in diseases
- Diet and metabolism studies
- Endoplasmic Reticulum Stress and Disease
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
Lund University
2016-2025
King's College Hospital
2013-2025
University of Gothenburg
2016-2024
Malmö University
2006-2024
King's College London
2006-2023
King's College Hospital NHS Foundation Trust
2021
Maidstone and Tunbridge Wells NHS Trust
2018
Skåne University Hospital
2010-2016
Queen Elizabeth Hospital
2016
Oxford Centre for Diabetes, Endocrinology and Metabolism
2013
In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, physiological role of GPR30 in vivo unknown, and it remains to be determined whether an also vivo. To this end, we studied effects disrupting gene female male mice. Female GPR30((-/-)) mice had hyperglycemia impaired glucose tolerance, reduced body growth, increased blood pressure, serum IGF-I levels. The growth correlated with proportional decrease skeletal development. elevated...
Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near risk variants, identified coexpression and protein-protein interaction networks that were strongly islet insulin secretion HbA1c. We integrated our data form a rank list putative which CHL1, LRFN2, RASGRP1, PPM1K validated INS-1 cells...
Several common genetic variations have been associated with type 2 diabetes, but the exact disease mechanisms are still poorly elucidated. Using congenic strains from diabetic Goto-Kakizaki rat, we identified a 1.4-megabase genomic locus that was linked to impaired insulin granule docking at plasma membrane and reduced beta cell exocytosis. In this locus, Adra2a, encoding alpha2A-adrenergic receptor [alpha(2A)AR], significantly overexpressed. Alpha(2A)AR mediates adrenergic suppression of...
The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation profiles diabetic nondiabetic donors. Islets from donors with T2D exhibited impaired was more pronounced lean than obese assessed impact 14 disease susceptibility on measures glucose...
Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation insulin secretion by cyclic AMP. Whereas PKA-independent (Rp-cAMPS–insensitive) component correlated with a rapid increase in ∼80 fF that plateaued within ∼200 ms, became prominent during depolarizations >450 ms. The components cAMP-stimulated exocytosis differed regard cAMP concentration dependence; Kd values 6 29 μM for mechanisms, respectively....
γ-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat β-cells release GABA by Ca2+-dependent exocytosis synaptic-like microvesicles. Here we demonstrate thus released can diffuse over sufficient distances within the islet interstitium activate GABAA receptors neighboring cells. Confocal immunocytochemistry revealed presence glucagon-secreting α-cells but not β- and δ-cells. RT-PCR analysis detected...
Glucagon, secreted from pancreatic islet alpha cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, variously attributed to neuronal control, paracrine control by neighbouring beta or an intrinsic glucose sensing the cells themselves. We examined hormone secretion Ca(2+) responses of within intact rodent human islets. Glucose-dependent suppression persisted when GABA Zn(2+) signalling was blocked, but reversed low...
Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered risk factor for type 2 diabetes rodents. Here we ERβ-/- mice to study whether ERβ involved rapid regulation K(ATP) channel activity, calcium signals insulin release elicited by environmentally relevant doses BPA (1 nM). We also investigated these effects β-cells whole islets Langerhans from humans....
Concerted activation of different voltage-gated Ca2+ channel isoforms may determine the kinetics insulin release from pancreatic islets. Here we have elucidated role R-type CaV2.3 channels in that process. A 20% reduction glucose-evoked secretion was observed CaV2.3-knockout (CaV2.3–/–) islets, close to 17% inhibition by blocker SNX482 but much less than 77% produced L-type antagonist isradipine. Dynamic insulin-release measurements revealed genetic or pharmacological ablation strongly...
Strategies aimed at mimicking or enhancing the action of incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives in pancreatic islets. Here, we examined mechanisms by which stimulates mouse and human We found that enhances GSIS a half-maximal effective concentration 0.4 pM. Moreover, determined activates PLC, increases submembrane diacylglycerol thereby PKC, resulting membrane...
Abstract Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal glucose levels by stimulation hepatic production. This counterregulatory mechanism impaired in Here we show mice that therapeutic concentrations insulin inhibit secretion an indirect (paracrine) mediated intra-islet somatostatin release. Insulin’s capacity to lost following genetic...
Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP-conducting mitochondrial outer membrane voltage-dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This caused by a glucotoxicity-induced transcriptional program, triggered with suboptimal blood control. Metformin counteracts VDAC1 induction. overexpression causes its...
Reduced insulin release has been linked to defect exocytosis in β-cells. However, whether expression of genes suggested be involved the exocytotic process (exocytotic genes) is altered pancreatic islets from patients with type 2 diabetes (T2D), and correlate secretion, needs further investigated. Analysing levels 23 using microarray revealed reduced five human T2D (χ(2)=13.25; p<0.001). Gene STX1A, SYT4, SYT7, SYT11, SYT13, SNAP25 STXBP1 correlated negatively vivo measurements HbA1c...
Abstract Glucagon secretion by pancreatic α-cells is triggered hypoglycemia and suppressed high glucose levels; impaired suppression of glucagon a hallmark both type 1 2 diabetes. Here, we show that α-cell glucokinase ( Gck ) plays role in the control secretion. Using mice with α-cell-specific inactivation αGckKO mice), find required for glucose-dependent increase intracellular ATP/ADP ratio closure K ATP channels at euglycemic hyperglycemic levels. display hyperglucagonemia fed state, which...
Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K+ channels (KATP channels) in control secretion from mouse pancreatic alpha-cells. In wild-type islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC50]=2.5 mmol/l) reduction release. Maximum inhibition (approximately 50%) was attained at concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 micromol/l) glibenclamide...