ECE2020 Oral Communications Diabetes, Obesity, Metabolism and Nutrition (7 abstracts)
Circulating follistatin predicts type 2 diabetes risk
Chuanyan Wu 1 , Yan Borné 1 , Rui Gao 2 , Maykel López Rodriguez 3 , William Roell 4 , Jonathan Wilson 4 , Emma Ahlqvist 1 , Cheng Luan 1 , Andreas Peter 5 , Jürgen Machann 5 , Mun-Gwan Hong 6 , Jochen Schwenk 6 , Peter Nilsson 1 , Angela Shore 7 , Faisel Khan 8 , Andrea Natali 9 , Olle Melander 1 , Marju Orho-Melander 1 , Jan Nilsson 1 , Erik Renström 1 , Claes Wollheim 1 , Ewan Pearson 8 , Paul Franks 1 , Morris White 10 , Kevin Duffin 4 , Allan Vaag 11 , Markku Laakso 3 , Norbert Stefan 5 , Leif Groop 1 & Yang De Marinis 1
1Lund University, Dep. of Clinical Sciences, Malmo, Sweden; 2Shandong University, China; 3University of Eastern Finland; 4Lilly Research Laboratories; 5University of Tübingen; 6KTH Royal Institute of Technology; 7University of Exeter; 8University of Dundee; 9University of Pisa; 10Harvard Medical School; 11University of Copenhagen
Follistatin is a hepatokine found to be elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. We report that elevated baseline circulating follistatin levels predict future T2D incidence in longitudinal cohorts including up to 5274 individuals. Individuals with elevated circulating follistatin had higher risk of developing type 2 diabetes during follow-up of 4 years (IMI-DIRECT-METSIM, n = 1079, Finland), 5 and 19 years (MDC-CC, n = 4195, Sweden). The hazard ratios (HRs) for incident T2D adjusted for multiple risk factors by quartiles of follistatin were 2.26 (95% CI: 0.98-5.22; P for trend = 9.00E-16) for 4 years; 4.22 (95% CI: 1.38-2.94, P for trend = 0.012) for 5 years; and 1.36 (95% CI: 1.06-1.74, P for trend = 0.014) for 19 years. K-means clustering on 4-year follow-up cohorts (IMI-DIRECT and its four sub-cohorts, in total n = 1701, Denmark, Finland, Sweden and the Netherlands) identified a fast glycemia progression subgroup with higher follistatin and C-peptide levels. Circulating follistatin, adipose tissue insulin sensitivity and liver fat content were studied in a TDFS cohort (n = 210, Germany); and follistatin levels associated significantly with adipose tissue insulin resistance and circulating follistatin was elevated in non-alcoholic fatty liver disease (NAFLD). In human stem cell-induced adipocytes, follistatin dose-dependently attenuated insulin-inhibited lipolysis and increased free fatty acid release. To identify genetic factors that influence plasma follistatin levels, genome-wide association studies (GWAS) was performed on MDC-CC (n = 4239), and identified 13 genetic variants, including rs780094 (P = 1.11E-11), rs780093 (P = 1.91E-11) and rs1260326 (P = 2.77E-11) in strong linkage disequilibrium (LD) within the glucokinase regulatory protein (GCKR) gene to be associated with plasma follistatin. The results were replicated on SUMMIT-VIP cohort (n = 885, UK, Italy and Sweden). Regulation of follistatin production in liver cells by GCKR in addition to insulin and glucagon was confirmed in HepG2 cells in vitro. Thus, we present a new aspect and mechanism in the development of type 2 diabetes (T2D) which involves hepatokine follistatin. Elevated circulating follistatin predicts T2D, and may predispose to diabetes risk and NAFLD by promoting adipose tissue insulin resistance and adipocyte free fatty acid release. Liver follistatin secretion is regulated by insulin, glucagon and GCKR. Our study suggests that follistatin predicts and mediates type 2 diabetes, and play an important role in the pathogenesis of T2D.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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