7700 Two Years Of Testosterone Therapy Reduces Glycemia In Males At High Risk Of Type 2 Diabetes Without Affecting Beta Cell Function: Results From A Randomised Controlled Trial And Cellular Model

Abstract Disclosure: M. Umapathysivam: None. S. Nawaz: None. K. Robledo: None. C.A. Allan: None. K. Bracken: None. M. Grossmann: None. D.J. Handelsman: None. W.J. Inder: None. D. Jesudason: None. B. Stuckey: None. B. Yeap: None. A. Januszewski: None. A. Jenkins: None. A. Conway: None. B. Hastoy: None. G.A. Wittert: Consulting Fee; Self; I-Nova. Grant Recipient; Self; Lawley pharmaceuticals, Bayer, Weight Watchers, Eli Lilly Self; Bayer, Inc., Amgen Inc, Besin Health Care. Background: In the Testosterone for the prevention of type 2 diabetes (T4DM) Study, treatment with testosterone (T)-undecanoate (1000 mg IM 3 monthly) vs placebo decreased fat mass and reduced the risk of T2D by 40% after 2 years. However, the mechanism(s) by which T therapy prevents or reverts T2D remain unclear. Aim: To assess (1) the impact of T treatment on insulin resistance (IR) and beta-cell function in the T4DM study and (2) the in-vitro effect of graded T exposure on glucose stimulated insulin secretion (GSIS) from the human beta-cell line EndoC-βH1. Methods: (1) T4DM study: Men (n= 1007) from the T4DM study aged, 50-74 years, waist circumference (WC) 95cm, with prediabetes, or newly diagnosed T2D (by OGTT) and serum testosterone (T) ≤ 14 nmol/L (chemiluminescent assay) treated with T-undecanoate (1000 mg IM 3 monthly) or placebo for 2 years. Men were included if they had fasting bloods at baseline, weeks 18, 66, and 102 (N=743). We compared the change in glycated albumin, and derived measures of beta-cell function (HOMA2-B) and insulin resistance (HOMA-IR) using fasting glucose and c-peptide in T and placebo treated men using linear regression models.(2) EndoC-βH1 were incubated with T 5nM, 10nM and 15nM for 20 min and 15nM T for 2-days. Insulin secretion and content were measured at baseline (1mM glucose) and after 20 min exposure 20mM glucose. Results: Treatment with T compared to placebo reduced glycated albumin (-3.4 umol/L; 95%CI:1.4-5.4, p0.001) maximally at week 66, along with C-peptide (corrected for baseline C-peptide and change in fasting glucose) (-0.12 nmol/L;-0.22,-0.02; p=0.01), HOMA2-B (-6.1; 95%CI: -16, 3.7; p=0.2) and HOMA-IR (-0.20; 95%CI: -0.59,0.20; p=0.3). In-vitro, acute exposure of EndoC-βH1 to 5nM and 10nM of T had no effect on GSIS, and 15nM T reduced GSIS (20%, p=0.002). T, at 15nM for 2 days was without effect on GSIS. EndoC-βH1 insulin content was not altered at any concentration or timeframe of T exposure. Conclusion: In men with pre-diabetes or early T2D, T treatment reduces glycemia without evidence either in vivo or in-vitro of an affect to increase insulin secretion. Presentation: 6/1/2024