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.

• Authors: 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, Hanns-Ulrich Marschall, Catherine Williamson
• Journal: Diabetes (Diabetes) Vol. 71 Issue 4 Pg. 837-852 (04 01 2022) ISSN: 1939-327X [Electronic] United States
• PMID: 35073578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Insulin
• Sulfates
• TRPM Cation Channels
• TRPM3 protein, human
• TRPM3 protein, mouse
• Progesterone
• Calcium

Topics

• Animals
• Blood Glucose (metabolism)
• Calcium (metabolism)
• Diabetes, Gestational
• Female
• HEK293 Cells
• Humans
• Insulin (metabolism)
• Insulin Secretion
• Mice
• Pregnancy
• Progesterone
• Sulfates (metabolism)
• TRPM Cation Channels