Kovacova, Zuzana, Tharp, William G., Liu, Dianxin, Wei, Wan, Xie, Hui, Collins, Sheila, Pratley, Richard E.
funding text
This work was supported by institutional funds from Florida Hospital Translational Research Institute for Metabolism and Diabetes; institutional funds from Sanford Burnham Prebys Medical Discovery Institute; and an investigator initiated grant from Takeda Pharmaceuticals USA, Inc.
abstract
ObjectiveCardiac natriuretic peptides (NPs) bind to two receptors (NPRA-mediator of signaling; NPRC-clearance receptor) whose ratio, NPRR (NPRA/NPRC), determines the NP bioactivity. This study investigated the relationship of NP receptor gene expression in adipose tissue and muscle with obesity and glucose intolerance. Prospectively, the study also assessed whether changes in NP receptor expression and thermogenic gene markers accompanied improvements of insulin sensitivity. MethodsA cross-sectional study of subjects with a wide range of BMI and glucose tolerance (n=50) was conducted, as well as a randomized 12-week trial of subjects with type 2 diabetes mellitus (T2DM) treated with pioglitazone (n=9) or placebo (n=10). ResultsNPRR mRNA was significantly lower in adipose tissue of subjects with obesity when compared with lean subjects (P0.001). NPRR decreased with progression from normal glucose tolerance to T2DM (P<0.01) independently of obesity. Treatment of subjects with T2DM with pioglitazone increased NPRR in adipose tissue (P0.01) in conjunction with improvements in insulin sensitivity and increases of the thermogenic markers PPAR coactivator-1 and uncoupling protein 1 (P0.01). ConclusionsDecreased adipose tissue NPRR was associated with obesity, glucose intolerance, and insulin resistance. This relationship was not observed for skeletal muscle NPRR. Pharmacological improvement of insulin sensitivity in subjects with T2DM was tied to improvement in NPRR and increased expression of genes involved in thermogenic processes.