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  • Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes.

Nature communications (2018-06-15)
Viktoria Gusarova, Colm O'Dushlaine, Tanya M Teslovich, Peter N Benotti, Tooraj Mirshahi, Omri Gottesman, Cristopher V Van Hout, Michael F Murray, Anubha Mahajan, Jonas B Nielsen, Lars Fritsche, Anders Berg Wulff, Daniel F Gudbjartsson, Marketa Sjögren, Connor A Emdin, Robert A Scott, Wen-Jane Lee, Aeron Small, Lydia C Kwee, Om Prakash Dwivedi, Rashmi B Prasad, Shannon Bruse, Alexander E Lopez, John Penn, Anthony Marcketta, Joseph B Leader, Christopher D Still, H Lester Kirchner, Uyenlinh L Mirshahi, Amr H Wardeh, Cassandra M Hartle, Lukas Habegger, Samantha N Fetterolf, Teresa Tusie-Luna, Andrew P Morris, Hilma Holm, Valgerdur Steinthorsdottir, Patrick Sulem, Unnur Thorsteinsdottir, Jerome I Rotter, Lee-Ming Chuang, Scott Damrauer, David Birtwell, Chad M Brummett, Amit V Khera, Pradeep Natarajan, Marju Orho-Melander, Jason Flannick, Luca A Lotta, Cristen J Willer, Oddgeir L Holmen, Marylyn D Ritchie, David H Ledbetter, Andrew J Murphy, Ingrid B Borecki, Jeffrey G Reid, John D Overton, Ola Hansson, Leif Groop, Svati H Shah, William E Kraus, Daniel J Rader, Yii-Der I Chen, Kristian Hveem, Nicholas J Wareham, Sekar Kathiresan, Olle Melander, Kari Stefansson, Børge G Nordestgaard, Anne Tybjærg-Hansen, Goncalo R Abecasis, David Altshuler, Jose C Florez, Michael Boehnke, Mark I McCarthy, George D Yancopoulos, David J Carey, Alan R Shuldiner, Aris Baras, Frederick E Dewey, Jesper Gromada
PMID29899519
ABSTRACT

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

MATERIALS
Product Number
Brand
Product Description
RAB0017
Sigma-Aldrich
Human ANGPTL4 ELISA Kit, for serum, plasma and cell culture supernatants