1799-P: Insulin Secretion during a Graded Glucose Infusion Correlates with GPS2 mRNA Expression in Adipocytes

Abstract

The transcriptional corepressor GPS2 plays a key role in human adipose tissue homeostasis. Decreased expression of GPS2 in adipocytes was associated with increased expression of inflammatory genes and with a pro-diabetic status. Here we assessed associations of GPS2 expression in adipocytes with insulin secretion in human volunteers. Dose response relationships between glucose and insulin secretion rates (ISR) were studied in 22 people (7 with normal glucose tolerance and 15 with type 2 diabetes; aged 48±12 years; men 68%) following a stepped intravenous glucose infusion at 2, 4, 6, 8 and 10 mg/kg/min. ISR was derived by deconvolution of plasma C-peptide level. GPS2 mRNA was quantified in adipose tissue biopsies by RT-qPCR. Participants were stratified by GPS2 mRNA expression into low (Lexp) or high expression (Hexp), defined by values below or above the median. Basal glucose level and ISR were higher in Lexp than in Hexp participants: 8.0±0.5 vs. 5.6±0.3 mmol/l, mean±SEM, p=0.0008, and 3.04±0.19 vs. 2.12±0.17 pmol/kg/min, p=0.002, respectively. Following glucose infusion, glucose level increased by 178±17% and 174±23% (p=0.88) in Lexp and Hexp participants, with average values of 14.9±0.6 and 11.4±0.78 mmol/l (p=0.002), respectively. Concomitant ISR increased by 236±40% and 487±75% (p=0.006) in Lexp and Hexp participants. Average ISR following glucose infusion (10-200 min) was 5.40±0.67 vs. 8.49±0.75 pmol/kg/min, p=0.01, respectively. Average ISR correlated positively with GPS2 expression: r2=0.34, p=0.004. Analysis of the glucose/ISR response curve demonstrated significantly higher ISR in Hexp than in Lexp participants at all glucose levels (p=0.005, adjusted for sex, age, BMI, and glycemic status). It was ∼52%, ∼60% and ∼45% higher at 7, 10 and 15 mmol/l glucose, respectively. Our results suggest a potential role for GPS2 in adipocyte-pancreatic beta cells cross-talk regulation of insulin secretion response to glucose, in line with previous experimental findings. Disclosure G. Velho: None. K. Drareni: None. J. Nguewa: None. R. Roussel: Advisory Panel; Self; Abbott, AstraZeneca, Diabnext, Eli Lilly and Company, Merck & Co., Inc., Mundipharma International, Novo Nordisk A/S, Sanofi-Aventis. J. Riveline: None. N. Venteclef: None. J. Gautier: None.