Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus.

Autor:	Fan HM; School of Life Course Sciences, King's College London, London, U.K., Mitchell AL; School of Life Course Sciences, King's College London, London, U.K., Bellafante E; School of Life Course Sciences, King's College London, London, U.K., McIlvride S; School of Life Course Sciences, King's College London, London, U.K., Primicheru LI; Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, U.K., Giorgi M; Randall Division of Cell and Molecular Biophysics, King's College London, London, U.K., Eberini I; Department of Pharmacological and Biomolecular Sciences, University of Milan La Statale, Milan, Italy., Syngelaki A; School of Life Course Sciences, King's College London, London, U.K., Lövgren-Sandblom A; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Jones P; School of Life Course Sciences, King's College London, London, U.K., McCance D; Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, U.K., Sukumar N; Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K.; Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K., Periyathambi N; Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K.; Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K., Weldeselassie Y; Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K.; Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K., Hunt KF; School of Life Course Sciences, King's College London, London, U.K., Nicolaides KH; School of Life Course Sciences, King's College London, London, U.K., Andersson D; Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, U.K., Bevan S; Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, U.K., Seed PT; School of Life Course Sciences, King's College London, London, U.K., Bewick GA; School of Life Course Sciences, King's College London, London, U.K., Bowe JE; School of Life Course Sciences, King's College London, London, U.K., Fraternali F; Randall Division of Cell and Molecular Biophysics, King's College London, London, U.K., Saravanan P; Department of Diabetes, Endocrinology and Metabolism, George Eliot Hospital, Nuneaton, U.K.; Populations, Evidence and Technologies, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, U.K., Marschall HU; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden., Williamson C; School of Life Course Sciences, King's College London, London, U.K.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2022 Apr 01; Vol. 71 (4), pp. 837-852.
DOI:	10.2337/db21-0702
Abstrakt:	Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography-tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11-13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets. (© 2022 by the American Diabetes Association.)
Databáze:	MEDLINE
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