2023-08-16·bioRxiv : the preprint server for biology
Leucine suppresses glucagon secretion from pancreatic islets by directly modulating α-cell cAMP.
作者: Emily R Knuth ; Hannah R Foster ; Erli Jin ; Matthew J Merrins
Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed, and hypoglycemic conditions, yet metabolic regulation of α-cells remains poorly understood. Here, we identified a previously unexplored role for physiological levels of leucine, which is classically regarded as a β-cell fuel, in the intrinsic regulation of α-cell glucagon release.
GcgCre ERT :CAMPER and GcgCre ERT :GCaMP6s mice were generated to perform dynamic, high-throughput functional measurements of α-cell cAMP and Ca 2+ within the intact islet. Islet perifusion assays were used for simultaneous, time-resolved measurements of glucagon and insulin release from mouse and human islets. The effects of leucine were compared with glucose and the mitochondrial fuels 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH, non-metabolized leucine analog that activates glutamate dehydrogenase), α-ketoisocaproate (KIC, leucine metabolite), and methyl-succinate (complex II fuel). CYN154806 (Sstr2 antagonist), diazoxide (K ATP activator, which prevents Ca 2+ -dependent exocytosis from α, β, and δ-cells), and dispersed α-cells were used to inhibit islet paracrine signaling and identify α-cell intrinsic effects.
Mimicking the effect of glucose, leucine strongly suppressed amino acid-stimulated glucagon secretion. Mechanistically, leucine dose-dependently reduced α-cell cAMP at physiological concentrations, with an IC 50 of 57, 440, and 1162 μM at 2, 6, and 10 mM glucose, without affecting α-cell Ca 2+ . Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonist or diazoxide, as well as dispersed α-cells, indicating an α-cell intrinsic effect. The effect of leucine was matched by KIC and the glutamate dehydrogenase activator BCH, but not methyl-succinate, indicating a dependence on mitochondrial anaplerosis. Glucose, which stimulates anaplerosis via pyruvate carboxylase, had the same suppressive effect on α-cell cAMP but with lower potency. Similarly to mouse islets, leucine suppressed glucagon secretion from human islets under hypoglycemic conditions.
These findings highlight an important role for physiological levels of leucine in the metabolic regulation of α-cell cAMP and glucagon secretion. Leucine functions primarily through an α-cell intrinsic effect that is dependent on glutamate dehydrogenase, in addition to the well-established α-cell regulation by β/δ-cell paracrine signaling. Our results suggest that mitochondrial anaplerosis-cataplerosis facilitates the glucagonostatic effect of both leucine and glucose, which cooperatively suppress α-cell tone by reducing cAMP.
Leucine inhibits glucagon secretion from mouse and human isletsLeucine suppresses α-cell cAMP via both direct and paracrine effectsAnaplerosis via glutamate dehydrogenase is sufficient to suppress α-cell cAMPLeucine suppresses α-cell cAMP and glucagon secretion more potently than glucose.
2023-07-20·Journal of nuclear medicine : official publication, Society of Nuclear Medicine
68Ga-SSO-120 PET for Initial Staging of Small Cell Lung Cancer Patients: A Single-Center Retrospective Study.
作者: David Kersting ; Patrick Sandach ; Miriam Sraieb ; Marcel Wiesweg ; Martin Metzenmacher ; Kaid Darwiche ; Filiz Oezkan ; Servet Bölükbas ; Martin Stuschke ; Lale Umutlu ; Michael Nader ; Rainer Hamacher ; Wolfgang P Fendler ; Johannes Wienker ; Wilfried E E Eberhardt ; Martin Schuler ; Ken Herrmann ; Hubertus Hautzel
PET imaging using the somatostatin receptor 2 (SSTR2) antagonist satoreotide trizoxetan (SSO-120, previously OPS-202) could offer accurate tumor detection and screening for SSTR2-antagonist radionuclide therapy in patients with SSTR2-expressing small cell lung cancer (SCLC). The aim of this single-center study was to investigate tumor uptake and detection rates of 68Ga-SSO-120 in comparison to 18F-FDG PET in the initial staging of SCLC patients. Methods: Patients with newly diagnosed SCLC who underwent additional whole-body 68Ga-SSO-120 PET/CT during the initial diagnostic workup were retrospectively included. The mean administered activity was 139 MBq, and the mean uptake time was 60 min. Gold-standard staging 18F-FDG PET/CT was evaluated if available within 2 wk before or after 68Ga-SSO-120 PET if morphologic differences in CT images were absent. 68Ga-SSO-120- or 18F-FDG-positive lesions were reported in 7 anatomic regions (primary tumor, thoracic lymph node metastases, and distant metastases including pleural, contralateral pulmonary, liver, bone, and other) according to the TNM classification for lung cancer (eighth edition). Consensus TNM staging (derived from CT, endobronchial ultrasound-guided transbronchial needle aspiration, PET, and brain MRI) by a clinical tumor board served as the reference standard. Results: Thirty-one patients were included, 12 with limited and 19 with extensive disease according to the Veterans Administration Lung Study Group classification. 68Ga-SSO-120-positive tumor was detected in all patients (100%) and in 90 of the 217 evaluated regions (41.5%). Thirteen patients (42.0%) had intense average 68Ga-SSO-120 uptake (region-based mean SUVmax ≥ 10); 28 patients (90.3%) had average 68Ga-SSO-120 uptake greater than liver uptake (region-based mean peak tumor-to-liver ratio > 1). In 25 patients with evaluable 18F-FDG PET, primary tumor, thoracic lymph node metastases, and distant metastases were detected in 100%, 92%, and 64%, respectively, of all investigated patients by 68Ga-SSO-120 and in 100%, 92%, and 56%, respectively, by 18F-FDG PET. 68Ga-SSO-120 PET detected additional contralateral lymph node, liver, and brain metastases in 1, 1, and 2 patients, respectively (no histopathology available), and 18F-FDG PET detected additional contralateral lymph node metastases in 3 patients (1 confirmed, 1 systematic endobronchial ultrasound-guided transbronchial needle aspiration-negative, and 1 without available histopathology). None of these differences altered Veterans Administration Lung Study Group staging. The region-based monotonic correlation between 68Ga-SSO-120 and 18F-FDG uptake was low (Spearman ρ = 0.26-0.33). Conclusion:68Ga-SSO-120 PET offers high diagnostic precision with comparable detection rates and additional complementary information to the gold standard, 18F-FDG PET. Consistent uptake in most patients warrants exploration of SSTR2-directed radionuclide therapy.
2023-07-15·European journal of nuclear medicine and molecular imaging
Comparison of 99mTc radiolabeled somatostatin antagonist with [68 Ga]Ga-DOTA-TATE in a patient with advanced neuroendocrine tumor.
作者: Marta Opalinska ; Luka Lezaic ; Clemens Decristoforo ; Petra Kolenc ; Renata Mikolajczak ; Andrej Studen ; Urban Simoncic ; Irene Virgolini ; Malgorzata Trofimiuk-Muldner ; Piotr Garnuszek ; Christine Rangger ; Melpomeni Fani ; Boguslaw Glowa ; Konrad Skorkiewicz ; Alicja Hubalewska-Dydejczyk