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

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Diabetes, Atherosclerosis, Cardiovascular, Metabolic and endocrine, Amino Acid Substitution, Angiopoietin-Like Protein 4, Animals, Blood Glucose, Case-Control Studies, Diabetes Mellitus, Type 2, Female, Gene Silencing, Genetic Association Studies, Genetic Variation, Heterozygote, Homeostasis, Humans, Insulin Resistance, Lipoprotein Lipase, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Risk Factors, Exome Sequencing
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.

Published
2018

9. Iron Treatment in Patients with Iron Deficiency Before and After Metabolic and Bariatric Surgery: A Narrative Review.

Author

Kaberi-Otarod, Jila, Still, Christopher D., Wood, G. Craig, and Benotti, Peter N.

Abstract

Iron is an essential nutrient in living organisms with multiple vital functions. Iron deficiency (ID) can cause long term health consequences beyond iron deficiency anemia (IDA). The high prevalence of ID and its long-term effects in patients with obesity and after metabolic and bariatric surgery (MBS) is recognized. Nevertheless, there is limited knowledge of the optimal route or dose for treatment of patients with obesity and post-MBS, and an evidence-based universal guideline for prevention and treatment of ID in short- and long-term post-MBS (PMBS) is not yet available. ID in the general population is currently treated with oral or parenteral iron, where oral iron treatment is considered the preferred option with parenteral iron as a second-line treatment in case there is intolerance or lack of response to oral iron. In patients with obesity with chronic low-grade inflammation and PMBS patients with altered gut anatomy and function, there are also alterations in the bioavailability and higher risks of side effects of available oral irons. The conclusions of current studies exploring effective treatment of iron deficiency in this population have been inconsistent and further well-planned randomized and prospective studies are needed. This is a narrative review of the literature on the available treatment options and strategies for treatment of ID in PMBS patients to recognize the knowledge gaps and provides topics of future research. [ABSTRACT FROM AUTHOR]

Published
2024
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36. Abstract P618: Visceral and Subcutaneous Adipokine Expression and Serum Adipokine Levels Are Differentially Associated With Metabolic Risk

Author

Ozkan, Bige, primary, Wallace, Amelia S, additional, Hamo, Carine, additional, Wolf, Risa, additional, Echouffo Tcheugui, Justin B, additional, Arking, Alexander, additional, Gerstenblith, Gary, additional, Chu, Xin, additional, Wood, G. Craig, additional, Benotti, Peter, additional, Wong, G William, additional, Coresh, Josef, additional, and Ndumele, Chiadi E, additional

Published
2023
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