Sulfated progesterone metabolites that enhance insulin secretion via TRPM3 are reduced in serum from women with gestational diabetes mellitus

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) UK-based European-ancestry women with or without GDM; 4) 11-13 week pregnant women with BMI≤25 or BMI≥35 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 TRPM3. Computer modelling using Molecular Operating Environment (MOE) generated 3D 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 (p<0.05). In islets, 50μM PM5S increased GSIS by at least 2-fold (P<0.001); isosakuranetin (TRPM3-inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modelling 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.