Citations 2
First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes
Cousminer, Diana L. , Ahlqvist, Emma , Mishra, Rajashree, Andersen, Mette K. , Chesi, Alessandra , Hawa, M. I., Davis, Asa K., Hodge, Kenyaita M., Bradfield, Jonathan P., Zhou, Kaixin , Guy, Vanessa C., Åkerlund, Mikael, Wod, Mette , Fritsche, Lars G. , Vestergaard, Henrik , Snyder, James W. , Højlund, Kurt , Linneberg, Allan , Käräjämäki, Annemari , Brandslund, Ivan , Kim, Cecilia E, Witte, Daniel R. , Sørgjerd, Elin Pettersen , Brillon, David J., Pedersen, Oluf , Beck‐Nielsen, Henning , Grarup, Niels , Rickels, Michael R. , Melander, Olle , Harris, Ronald I., Varvel, Stephen A. , Grill, Valdemar , Håkonarson, Håkon , Froguel, Philippe , Lonsdale, John T., Mauricio, Dı́dac , Schloot, Nanette C. , Khunti, Kamlesh , Greenbaum, Carla J. , Åsvold, Bjørn Olav , Yderstræde, Knud Bonnet , Pearson, Ewan R. , Schwartz, Stanley S. , Voight, Benjamin F. , Hansen, Torben , Tuomi, Tiinamaija , Boehm, Bernhard O. , Groop, Leif , Leslie, Richard David , Grant, Struan F.A. , Study, Bone Mineral Density in Childhood, Mitchell, Jonathan A. , Lappe, Joan M. , Gilsanz, Vicente , Rickels, Michael R , Vella, Adrian , Hakonarson, Hakon , Mauricio, Didac , Schloot, Nanette C , Khunti, Kamlesh , Greenbaum, Carla J , Hansen, Torben , Tuomi, Tiinamaija , Leslie, R David , Froguel, Phillippe , Grant, Struan F A , Ahlqvist, Emma , Snyder, James, Pratley, Richard E. , Vella, Adrian , Ovalle, Fernando , Lonsdale, John T., Study, Bone Mineral Density in Childhood, McCormack, Shana Erin , Kelly, Andrea True , Kalkwarf, Heidi J. , Shepherd, John , Oberfield, Sharon E. , Zemel, Babette S.
Diabetes Care | September 25, 2018 | Volume: 41 | Issue: 11 | Pages: 2396-2403
OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
Increased Reactive Oxygen Species Production and Lower Abundance of Complex I Subunits and Carnitine Palmitoyltransferase 1B Protein Despite Normal Mitochondrial Respiration in Insulin-Resistant Human Skeletal Muscle
Lefort, Natalie , Glancy, Brian , Willis, Wayne T. , Bailowitz, Zachary, Filippis, Elena A. De, Brophy, Colleen M., Højlund, Kurt , Yi, Zhengping , Mandarino, Lawrence J. , Bowen, Benjamin P. , Meyer, Christian , Glancy, Brian
Diabetes | August 4, 2010 | Volume: 59 | Issue: 10 | Pages: 2444-2452
OBJECTIVE The contribution of mitochondrial dysfunction to skeletal muscle insulin resistance remains elusive. Comparative proteomics are being applied to generate new hypotheses in human biology and were applied here to isolated mitochondria to identify novel changes in mitochondrial protein abundance present in insulin-resistant muscle. RESEARCH DESIGN AND METHODS Mitochondria were isolated from vastus lateralis muscle from lean and insulin-sensitive individuals and from obese and insulin-resistant individuals who were otherwise healthy. Respiration and reactive oxygen species (ROS) production rates were measured in vitro. Relative abundances of proteins detected by mass spectrometry were determined using a normalized spectral abundance factor method. RESULTS NADH- and FADH2-linked maximal respiration rates were similar between lean and obese individuals. Rates of pyruvate and palmitoyl-dl-carnitine (both including malate) ROS production were significantly higher in obesity. Mitochondria from obese individuals maintained higher (more negative) extramitochondrial ATP free energy at low metabolic flux, suggesting that stronger mitochondrial thermodynamic driving forces may underlie the higher ROS production. Tandem mass spectrometry identified protein abundance differences per mitochondrial mass in insulin resistance, including lower abundance of complex I subunits and enzymes involved in the oxidation of branched-chain amino acids (BCAA) and fatty acids (e.g., carnitine palmitoyltransferase 1B). CONCLUSIONS We provide data suggesting normal oxidative capacity of mitochondria in insulin-resistant skeletal muscle in parallel with high rates of ROS production. Furthermore, we show specific abundance differences in proteins involved in fat and BCAA oxidation that might contribute to the accumulation of lipid and BCAA frequently associated with the pathogenesis of insulin resistance.