Obesity is now a worldwide epidemic, with overweight, obesity, and morbid obesity all increasing. Recently, there is increasing support that obesity is a major risk factor for developing insulin resistance and type 2 diabetes mellitus (T2D). Plasma soluble low-density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of atherosclerosis, and has also been linked to the metabolism of triglyceride-rich lipoproteins and adiposity. To assess the relationship between sLR11 levels and T2D, we analyzed the sLR11 levels in T2D patients. Serum sLR11 levels were measured in 70 patients with T2D (mean age 60.8 ± 7.0, 68.6% males, and BMI 24.7 ± 3.2) and 76 healthy control subjects (mean age 58.5 ± 6.5, 65.8% males, and BMI 24.1 ± 2.5) by ELISA. Circulating sLR11 levels were significantly increased in T2D patients compared with healthy control subjects (10.2 ± 4.2 vs. 8.3 ± 2.1, P = 1.4 × 10-3). Stepwise multivariate regression analysis showed that serum sLR11 levels were significantly associated with HOMA-IR (β = 0.26, P = 4.8 × 10-3), BMI (β = 0.24, P = 1.0 × 10-2) and age (β = 0.20, P = 2.7 × 10-2). Logistic regression analyses indicated that sLR11 was independently associated with HOMA-IR (odds ratio [OR], sLR11 tertile increment: 6.81; 95% confidence interval [CI]: 1.71—27.13) and BMI (OR, sLR11 tertile increment: 1.86; 95% CI: 1.03—3.35). We then analyzed a gene-dosage effect that links LR11 expression to insulin resistance and obesity using db/db mice with genetic loss of LR11 (LR11-KO db/db). LR11-KO db/db mice displayed significantly lower fasting plasma glucose and insulin levels, and improved glucose tolerance compared with age-matched db/db mice, although there was no significant difference in body weight between them. Our findings imply that LR11 may be mechanistically involved in the prevalence and development of insulin resistance and T2D.
H. Unoki-Kubota: None. M. Jiang: None. H. Kajio: None. R. Yamamoto-Honda: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co. M. Noda: None. H. Bujo: None. Y. Kaburagi: None.