Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus

Hei Man Fan; Alice L Mitchell; Elena Bellafante; Saraid McIlvride; Laura I Primicheru; Mirko Giorgi; Ivano Eberini; Argyro Syngelaki; Anita Lövgren-Sandblom; Peter Jones; David McCance; Nithya Sukumar; Nishanthi Periyathambi; Yonas Weldeselassie; Katharine F Hunt; Kypros H Nicolaides; David Andersson; Stuart Bevan; Paul T Seed; Gavin A Bewick; James E Bowe; Franca Fraternali; Ponnusamy Saravanan; HannsUlrich Marschall; Catherine Williamson

doi:10.2337/db21-0702

Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus

Hei Man Fan, Alice L Mitchell, Elena Bellafante, Saraid McIlvride, Laura I Primicheru, Mirko Giorgi, Ivano Eberini, Argyro Syngelaki, Anita Lövgren-Sandblom, Peter Jones, David McCance, Nithya Sukumar, Nishanthi Periyathambi, Yonas Weldeselassie, Katharine F Hunt, Kypros H Nicolaides, David Andersson, Stuart Bevan, Paul T Seed, Gavin A BewickJames E Bowe, Franca Fraternali, Ponnusamy Saravanan, HannsUlrich Marschall, Catherine Williamson

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Abstract

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.

Original language	English
Pages (from-to)	837-852
Number of pages	16
Journal	Diabetes
Volume	71
Issue number	4
Early online date	24 Jan 2022
DOIs	https://doi.org/10.2337/db21-0702
Publication status	Published - 1 Apr 2022

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Fan, H. M., Mitchell, A. L., Bellafante, E., McIlvride, S., Primicheru, L. I., Giorgi, M., Eberini, I., Syngelaki, A., Lövgren-Sandblom, A., Jones, P., McCance, D., Sukumar, N., Periyathambi, N., Weldeselassie, Y., Hunt, K. F., Nicolaides, K. H., Andersson, D., Bevan, S., Seed, P. T., ... Williamson, C. (2022). Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus. Diabetes, 71(4), 837-852. https://doi.org/10.2337/db21-0702

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title = "Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus",

abstract = "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.",

author = "Fan, {Hei Man} and Mitchell, {Alice L} and Elena Bellafante and Saraid McIlvride and Primicheru, {Laura I} and Mirko Giorgi and Ivano Eberini and Argyro Syngelaki and Anita L{\"o}vgren-Sandblom and Peter Jones and David McCance and Nithya Sukumar and Nishanthi Periyathambi and Yonas Weldeselassie and Hunt, {Katharine F} and Nicolaides, {Kypros H} and David Andersson and Stuart Bevan and Seed, {Paul T} and Bewick, {Gavin A} and Bowe, {James E} and Franca Fraternali and Ponnusamy Saravanan and HannsUlrich Marschall and Catherine Williamson",

note = "Funding Information: Acknowledgments. The authors thank Kristina Schoonjans, {\'E}cole Poly-technique F{\'e}d{\'e}rale de Lausanne, Lausanne, Switzerland, for providing the Fxr−/− and Tgr5−/− knockout mice. Funding. This research is funded by Tommy{\textquoteright}s Charity, the Fetal Medicine Foundation, the Lauren Page Trust, the John Coates Charitable Trust and the National Institute for Health Research (NIHR) Biomedical Research Centres at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215-20006). C.W. is funded by an NIHR Senior Investigator award. Publisher Copyright: {\textcopyright} 2022 by the American Diabetes Association.",

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doi = "10.2337/db21-0702",

language = "English",

volume = "71",

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Fan, HM , Mitchell, AL , Bellafante, E , McIlvride, S , Primicheru, LI, Giorgi, M, Eberini, I, Syngelaki, A, Lövgren-Sandblom, A, Jones, P, McCance, D, Sukumar, N, Periyathambi, N, Weldeselassie, Y, Hunt, KF , Nicolaides, KH , Andersson, D , Bevan, S , Seed, PT , Bewick, GA , Bowe, JE , Fraternali, F, Saravanan, P, Marschall, H & Williamson, C 2022, 'Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus', Diabetes, vol. 71, no. 4, pp. 837-852. https://doi.org/10.2337/db21-0702

TY - JOUR

T1 - Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus

AU - Fan, Hei Man

AU - Mitchell, Alice L

AU - Bellafante, Elena

AU - McIlvride, Saraid

AU - Primicheru, Laura I

AU - Giorgi, Mirko

AU - Eberini, Ivano

AU - Syngelaki, Argyro

AU - Lövgren-Sandblom, Anita

AU - Jones, Peter

AU - McCance, David

AU - Sukumar, Nithya

AU - Periyathambi, Nishanthi

AU - Weldeselassie, Yonas

AU - Hunt, Katharine F

AU - Nicolaides, Kypros H

AU - Andersson, David

AU - Bevan, Stuart

AU - Seed, Paul T

AU - Bewick, Gavin A

AU - Bowe, James E

AU - Fraternali, Franca

AU - Saravanan, Ponnusamy

AU - Marschall, HannsUlrich

AU - Williamson, Catherine

N1 - Funding Information: Acknowledgments. The authors thank Kristina Schoonjans, École Poly-technique Fédérale de Lausanne, Lausanne, Switzerland, for providing the Fxr−/− and Tgr5−/− knockout mice. Funding. This research is funded by Tommy’s Charity, the Fetal Medicine Foundation, the Lauren Page Trust, the John Coates Charitable Trust and the National Institute for Health Research (NIHR) Biomedical Research Centres at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (IS-BRC-1215-20006). C.W. is funded by an NIHR Senior Investigator award. Publisher Copyright: © 2022 by the American Diabetes Association.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - 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.

AB - 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.

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JO - Diabetes

JF - Diabetes

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ER -

Sulfated Progesterone Metabolites That Enhance Insulin Secretion Via Trpm3 are Reduced in Serum From Women with Gestational Diabetes Mellitus

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