Muller_2021_Diabetes.Metab.Res.Rev__e3504

AIMS: Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analyzed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians. MATERIALS AND METHODS: Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE. RESULTS: Among the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys-allele frequency =0.087) significantly associated with T2D (OR [95% CI]=1.38 [1.17-1.64], P =0.0002, adjusted for age, sex, birth year and the first 5 genetic principal components) and an earlier onset age of T2D (HR=1.22[1.09-1.36], P=0.0005). This variant was further analyzed for quantitative traits related to T2D. Among non-diabetic American Indians, those with the T2D risk Cys-allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys-allele, P=0.04) and a mixed meal test (0.08 log(10) microU/ml per Cys-allele, P=0.003), and had increased lipid oxidation rates post-absorptively and during insulin infusion (0.07 mg [kg estimated metabolic body size {EMBS}](-1) min(-1) per Cys-allele for both, P=0.01, 0.009 respectively) compared to individuals with the non-risk Arg-allele. In vitro functional studies showed that cells expressing the Cys-allele had a 17.2% decrease in lipolysis under isoproterenol stimulation (P = 0.03) and a 21.3% decrease in lipase enzyme activity measured by using P-Nitrophenyl Butyrate as substrate (P=0.04) compared to the Arg-allele. CONCLUSION: The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homeostasis and risk of T2D. This article is protected by copyright. All rights reserved.