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

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.

SUBMITTER: Gusarova V

PROVIDER: S-EPMC5997992 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Gusarova Viktoria V O'Dushlaine Colm C Teslovich Tanya M TM Benotti Peter N PN Mirshahi Tooraj T Gottesman Omri O Van Hout Cristopher V CV Murray Michael F MF Mahajan Anubha A Nielsen Jonas B JB Fritsche Lars L Wulff Anders Berg AB Gudbjartsson Daniel F DF Sjögren Marketa M Emdin Connor A CA Scott Robert A RA Lee Wen-Jane WJ Small Aeron A Kwee Lydia C LC Dwivedi Om Prakash OP Prasad Rashmi B RB Bruse Shannon S Lopez Alexander E AE Penn John J Marcketta Anthony A Leader Joseph B JB Still Christopher D CD Kirchner H Lester HL Mirshahi Uyenlinh L UL Wardeh Amr H AH Hartle Cassandra M CM Habegger Lukas L Fetterolf Samantha N SN Tusie-Luna Teresa T Morris Andrew P AP Holm Hilma H Steinthorsdottir Valgerdur V Sulem Patrick P Thorsteinsdottir Unnur U Rotter Jerome I JI Chuang Lee-Ming LM Damrauer Scott S Birtwell David D Brummett Chad M CM Khera Amit V AV Natarajan Pradeep P Orho-Melander Marju M Flannick Jason J Lotta Luca A LA Willer Cristen J CJ Holmen Oddgeir L OL Ritchie Marylyn D MD Ledbetter David H DH Murphy Andrew J AJ Borecki Ingrid B IB Reid Jeffrey G JG Overton John D JD Hansson Ola O Groop Leif L Shah Svati H SH Kraus William E WE Rader Daniel J DJ Chen Yii-Der I YI Hveem Kristian K Wareham Nicholas J NJ Kathiresan Sekar S Melander Olle O Stefansson Kari K Nordestgaard Børge G BG Tybjærg-Hansen Anne A Abecasis Goncalo R GR Altshuler David D Florez Jose C JC Boehnke Michael M McCarthy Mark I MI Yancopoulos George D GD Carey David J DJ Shuldiner Alan R AR Baras Aris A Dewey Frederick E FE Gromada Jesper J

Nature communications 20180613 1

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 ...[more]

PMID: 29899519

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Project description:Background and aimsApolipoprotein A-I (ApoA-I), the main component of high-density lipoprotein (HDL), not only promotes reverse cholesterol transport (RCT) in atherosclerosis but also increases insulin secretion in pancreatic β-cells, suggesting that interventions which raise HDL levels may be beneficial in diabetes-associated cardiovascular disease (CVD). Previously, we showed that TNF-related apoptosis-inducing ligand (TRAIL) deletion in Apolipoprotein Eknockout (Apoe-/- ) mice results in diabetes-accelerated atherosclerosis in response to a "Western" diet. Here, we sought to identify whether reconstituted HDL (rHDL) could improve features of diabetes-associated CVD in Trail-/-Apoe-/- mice.Methods and resultsTrail-/-Apoe-/- and Apoe-/- mice on a "Western" diet for 12 weeks received 3 weekly infusions of either PBS (vehicle) or rHDL (containing ApoA-I (20 mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine). Administration of rHDL reduced total plasma cholesterol, triglyceride, and glucose levels in Trail-/-Apoe-/- but not in Apoe-/- mice, with no change in weight gain observed. rHDL treatment also improved glucose clearance in response to insulin and glucose tolerance tests. Immunohistological analysis of pancreata revealed increased insulin expression/production and a reduction in macrophage infiltration in mice with TRAIL deletion. Furthermore, atherosclerotic plaque size in Trail-/-Apoe-/- mice was significantly reduced associating with increased expression of the M2 macrophage marker CD206, suggesting HDL's involvement in the polarization of macrophages. rHDL also increased vascular mRNA expression of RCT transporters, ABCA1 and ABCG1, in Trail-/-Apoe-/- but not in Apoe-/- mice. Conclusions. rHDL improves features of diabetes-associated atherosclerosis in mice. These findings support the therapeutic potential of rHDL in the treatment of atherosclerosis and associated diabetic complications. More studies are warranted to understand rHDL's mechanism of action.

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

Publications

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

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