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https://www.readbyqxmd.com/read/28432726/combination-therapy-with-glp-1-receptor-agonist-and-sglt2-inhibitor
#1
REVIEW
Ralph A DeFronzo
The SGLT2 inhibitors (SGLTi) and glucagon-like-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most likely by different mechanisms. SGLT2i appear to exert their CV protective actions by hemodynamic effects, while GLP-1 RAs work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with these two classes may produce additive CV benefits...
April 22, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28428225/empagliflozin-and-kinetics-of-renal-glucose-transport-in-healthy-and-type-2-diabetic-individuals
#2
Hussein Al-Jobori, Giuseppe Daniele, Eugenio Cersosimo, Curtis Triplitt, Luke Norton, Ralph A DeFronzo, Muhammad Abdul-Ghani
Renal glucose reabsorption was measured with the stepped-hyperglycemic clamp in 15 T2DM and 15 non-diabetic subjects after 2 days and after more chronic (14 days) treatment with empagliflozin. T2DM patients had significantly greater maximal renal glucose transport (TmG) compared to nondiabetic subjects at baseline (459±53 vs 337±25 mg/min, p<0.05). Empagliflozin treatment for 48 hours reduced the TmG in both diabetic and non-diabetic individuals by 44±7% and 53±6%, respectively (both p<0.001). TmG was further reduced by empagliflozin in both groups on day 14 (by 65±5% and 75±3%, respectively)...
April 20, 2017: Diabetes
https://www.readbyqxmd.com/read/28341696/a-low-frequency-inactivating-akt2-variant-enriched-in-the-finnish-population-is-associated-with-fasting-insulin-levels-and-type-2-diabetes-risk
#3
Alisa Manning, Heather M Highland, Jessica Gasser, Xueling Sim, Taru Tukiainen, Pierre Fontanillas, Niels Grarup, Manuel A Rivas, Anubha Mahajan, Adam E Locke, Pablo Cingolani, Tune H Pers, Ana Viñuela, Andrew A Brown, Ying Wu, Jason Flannick, Christian Fuchsberger, Eric R Gamazon, Kyle J Gaulton, Hae Kyung Im, Tanya M Teslovich, Thomas W Blackwell, Jette Bork-Jensen, Noël P Burtt, Yuhui Chen, Todd Green, Christopher Hartl, Hyun Min Kang, Ashish Kumar, Claes Ladenvall, Clement Ma, Loukas Moutsianas, Richard D Pearson, John R B Perry, N William Rayner, Neil R Robertson, Laura J Scott, Martijn van de Bunt, Johan G Eriksson, Antti Jula, Seppo Koskinen, Terho Lehtimäki, Aarno Palotie, Olli T Raitakari, Suzanne Br Jacobs, Jennifer Wessel, Audrey Y Chu, Robert A Scott, Mark O Goodarzi, Christine Blancher, Gemma Buck, David Buck, Peter S Chines, Stacey Gabriel, Anette P Gjesing, Christopher J Groves, Mette Hollensted, Jeroen R Huyghe, Anne U Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S Small, Heather M Stringham, Joseph Trakalo, Eric Banks, Jason Carey, Mauricio O Carneiro, Mark DePristo, Yossi Farjoun, Timothy Fennell, Jacqueline I Goldstein, George Grant, Martin Hrabé de Angelis, Jared Maguire, Benjamin M Neale, Ryan Poplin, Shaun Purcell, Thomas Schwarzmayr, Khalid Shakir, Joshua D Smith, Tim M Strom, Thomas Wieland, Jaana Lindstrom, Ivan Brandslund, Cramer Christensen, Gabriela L Surdulescu, Timo A Lakka, Alex S F Doney, Peter Nilsson, Nicholas J Wareham, Claudia Langenberg, Tibor V Varga, Paul W Franks, Olov Rolandsson, Anders H Rosengren, Vidya S Farook, Farook Thameem, Sobha Puppala, Satish Kumar, Donna M Lehman, Christopher P Jenkinson, Joanne E Curran, Daniel Esten Hale, Sharon P Fowler, Rector Arya, Ralph A DeFronzo, Hanna E Abboud, Ann-Christine Syvänen, Pamela J Hicks, Nicholette D Palmer, Maggie C Y Ng, Donald W Bowden, Barry I Freedman, Tõnu Esko, Reedik Mägi, Lili Milani, Evelin Mihailov, Andres Metspalu, Narisu Narisu, Leena Kinnunen, Lori L Bonnycastle, Amy Swift, Dorota Pasko, Andrew R Wood, João Fadista, Toni I Pollin, Nir Barzilai, Gil Atzmon, Benjamin Glaser, Barbara Thorand, Konstantin Strauch, Annette Peters, Michael Roden, Martina Müller-Nurasyid, Liming Liang, Jennifer Kriebel, Thomas Illig, Harald Grallert, Christian Gieger, Christa Meisinger, Lars Lannfelt, Solomon K Musani, Michael Griswold, Herman A Taylor, Gregory Wilson, Adolfo Correa, Heikki Oksa, William R Scott, Uzma Afzal, Sian-Tsung Tan, Marie Loh, John C Chambers, Jobanpreet Sehmi, Jaspal Singh Kooner, Benjamin Lehne, Yoon Shin Cho, Jong-Young Lee, Bok-Ghee Han, Annemari Käräjämäki, Qibin Qi, Lu Qi, Jinyan Huang, Frank B Hu, Olle Melander, Marju Orho-Melander, Jennifer E Below, David Aguilar, Tien Yin Wong, Jianjun Liu, Chiea-Chuen Khor, Kee Seng Chia, Wei Yen Lim, Ching-Yu Cheng, Edmund Chan, E Shyong Tai, Tin Aung, Allan Linneberg, Bo Isomaa, Thomas Meitinger, Tiinamaija Tuomi, Liisa Hakaste, Jasmina Kravic, Marit E Jørgensen, Torsten Lauritzen, Panos Deloukas, Kathleen E Stirrups, Katharine R Owen, Andrew J Farmer, Timothy M Frayling, Stephen P O'Rahilly, Mark Walker, Jonathan C Levy, Dylan Hodgkiss, Andrew T Hattersley, Teemu Kuulasmaa, Alena Stančáková, Inês Barroso, Dwaipayan Bharadwaj, Juliana Chan, Giriraj R Chandak, Mark J Daly, Peter J Donnelly, Shah B Ebrahim, Paul Elliott, Tasha Fingerlin, Philippe Froguel, Cheng Hu, Weiping Jia, Ronald C W Ma, Gilean McVean, Taesung Park, Dorairaj Prabhakaran, Manjinder Sandhu, James Scott, Rob Sladek, Nikhil Tandon, Yik Ying Teo, Eleftheria Zeggini, Richard M Watanabe, Heikki A Koistinen, Y Antero Kesaniemi, Matti Uusitupa, Timothy D Spector, Veikko Salomaa, Rainer Rauramaa, Colin N A Palmer, Inga Prokopenko, Andrew D Morris, Richard N Bergman, Francis S Collins, Lars Lind, Erik Ingelsson, Jaakko Tuomilehto, Fredrik Karpe, Leif Groop, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Johanna Kuusisto, Gonçalo Abecasis, Graeme I Bell, John Blangero, Nancy J Cox, Ravindranath Duggirala, Mark Seielstad, James G Wilson, Josee Dupuis, Samuli Ripatti, Craig L Hanis, Jose C Florez, Karen L Mohlke, James B Meigs, Markku Laakso, Andrew P Morris, Michael Boehnke, David Altshuler, Mark I McCarthy, Anna L Gloyn, Cecilia M Lindgren
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders...
March 24, 2017: Diabetes
https://www.readbyqxmd.com/read/28331967/decreased-basal-hepatic-glucose-uptake-in-impaired-fasting-glucose
#4
Mariam Alatrach, Christina Agyin, John Adams, Ralph A DeFronzo, Muhammad A Abdul-Ghani
AIMS/HYPOTHESIS: This research aimed to define the pathophysiological defects responsible for the elevated fasting plasma glucose (FPG) concentration and excessive rise in post-load plasma glucose observed in individuals with impaired fasting glucose (IFG). METHODS: We used tracer techniques to quantify basal splanchnic (primarily hepatic) glucose uptake and glucose fluxes following glucose ingestion in individuals with normal glucose tolerance (NGT; n = 10) and IFG (n = 10)...
March 22, 2017: Diabetologia
https://www.readbyqxmd.com/read/28324053/hepatic-insulin-resistance-and-altered-gluconeogenic-pathway-in-premature-baboons
#5
Lisa McGill-Vargas, Amalia Gastaldelli, Hanyu Liang, Diana Anzueto Guerra, Teresa Johnson-Pais, Steven Seidner, Donald McCurnin, Giovanna Muscogiuri, Ralph DeFronzo, Nicolas Musi, Cynthia Blanco
Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extra-uterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content and gene expression of key insulin signaling/gluconeogenic molecules...
January 17, 2017: Endocrinology
https://www.readbyqxmd.com/read/28324038/efficacy-of-exenatide-plus-pioglitazone-versus-basal-bolus-insulin-in-t2dm-patients-with-very-high-hba1c
#6
Muhammad Abdul-Ghani, Osama Mujahid, Ayman Mujahid, Ralph A DeFronzo, Mahmoud Zirie, Amin Jayyousi
Aim: To examine the efficacy and safety of combination therapy with exenatide plus pioglitazone versus basal-bolus insulin in poorly controlled type 2 diabetic patients with very high HbA1c (HbA1c>10%) on metformin plus sulfonylurea and long duration of disease. Research Design and Methods: 101 participants in Qatar Study with very poor glycemic control (HbA1c > 10%) and long duration of diabetes (10.9 years) on maximum/near-maximum doses of sulfonylurea plus metformin were randomized to receive: (i) pioglitazone plus weekly exenatide (Combination Therapy), or (ii) basal plus prandial insulin (Insulin Therapy) to maintain HbA1c <7...
February 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28128510/determinants-of-the-increase-in-fasting-plasma-ketone-concentration-during-sglt2-inhibition-in-ngt-ifg-and-t2dm-patients
#7
Hussein Al Jobori, Giuseppe Daniele, John Adams, Eugenio Cersosimo, Curtis Triplitt, Ralph A DeFronzo, Muhammad Abdul-Ghani
AIM: To examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration RESEARCH DESIGN AND METHODS: Fasting plasma glucose, insulin, glucagon, free fatty acid and ketone concentrations were measured in 15 type 2 diabetes mellitus (T2DM) and 16 non-diabetic subjects before and at 1 and 14 days after treatment with empagliflozin. RESULTS: Empagliflozin caused 38 mg/dl reduction in the fasting plasma glucose (FPG) concentration in T2DM patients...
January 27, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28096223/combination-therapy-with-exenatide-plus-pioglitazone-versus-basal-bolus-insulin-in-poorly-controlled-patients-with-type-2-diabetes-on-sulfonylurea-plus-metformin-the-qatar-study
#8
Muhammad Abdul-Ghani, Osama Migahid, Ayman Megahed, John Adams, Curtis Triplitt, Ralph A DeFronzo, Mahmoud Zirie, Amin Jayyousi
OBJECTIVE: The Qatar Study was designed to examine the efficacy of combination therapy with exenatide plus pioglitazone versus basal-bolus insulin in patients with long-standing poorly controlled type 2 diabetes mellitus (T2DM) on metformin plus a sulfonylurea. RESEARCH DESIGN AND METHODS: The study randomized 231 patients with poorly controlled (HbA1c >7.5%, 58 mmol/mol) T2DM on a sulfonylurea plus metformin to receive 1) pioglitazone plus weekly exenatide (combination therapy), or 2) basal plus prandial insulin (insulin therapy) to maintain HbA1c <7...
January 17, 2017: Diabetes Care
https://www.readbyqxmd.com/read/28095040/consensus-statement-by-the-american-association-of-clinical-endocrinologists-and-american-college-of-endocrinology-on-the-comprehensive-type-2-diabetes-management-algorithm-2017-executive-summary
#9
Alan J Garber, Martin J Abrahamson, Joshua I Barzilay, Lawrence Blonde, Zachary T Bloomgarden, Michael A Bush, Samuel Dagogo-Jack, Ralph A DeFronzo, Daniel Einhorn, Vivian A Fonseca, Jeffrey R Garber, W Timothy Garvey, George Grunberger, Yehuda Handelsman, Irl B Hirsch, Paul S Jellinger, Janet B McGill, Jeffrey I Mechanick, Paul D Rosenblit, Guillermo E Umpierrez
A1C = hemoglobin A1C AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ACEI = angiotensin-converting enzyme inhibitor ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation AGI = alpha-glucosidase inhibitor apo B = apolipoprotein B ASCVD = atherosclerotic cardiovascular disease BAS = bile acid sequestrant BMI = body mass index BP = blood pressure CHD = coronary heart disease CKD = chronic kidney disease CVD = cardiovascular disease DASH = Dietary Approaches to Stop Hypertension DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial LDL-C = low-density lipoprotein cholesterol LDL-P = low-density lipoprotein particle Look AHEAD = Look Action for Health in Diabetes NPH = neutral protamine Hagedorn OSA = obstructive sleep apnea SFU = sulfonylurea SGLT-2 = sodium glucose cotransporter-2 SMBG = self-monitoring of blood glucose T2D = type 2 diabetes TZD = thiazolidinedione VADT = Veterans Affairs Diabetes Trial...
February 2017: Endocrine Practice
https://www.readbyqxmd.com/read/28052966/role-of-adipose-tissue-insulin-resistance-in-the-natural-history-of-t2dm-results-from-the-san-antonio-metabolism-study
#10
Amalia Gastaldelli, Melania Gaggini, Ralph A DeFronzo
In the transition from normal glucose tolerance (NGT) to type 2 diabetes mellitus (T2DM), the role of β-cell dysfunction and peripheral insulin resistance (IR) is well established. However, the impact of dysfunctional adipose tissue has not been fully elucidated. The aim of the present study is to evaluate the role of resistance to the antilipolytic effect of insulin (Adipo-IR) in a large group of NGT, IGT and T2DM subjects.302 subjects with varying glucose tolerance received OGTT and euglycemic insulin clamp...
January 4, 2017: Diabetes
https://www.readbyqxmd.com/read/27987376/pioglitazone-inhibits-mitochondrial-pyruvate-metabolism-and-glucose-production-in-hepatocytes
#11
Christopher E Shannon, Giuseppe Daniele, Cynthia Galindo, Muhammad A Abdul-Ghani, Ralph A DeFronzo, Luke Norton
Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2...
December 17, 2016: FEBS Journal
https://www.readbyqxmd.com/read/27941935/renal-metabolic-and-cardiovascular-considerations-of-sglt2-inhibition
#12
REVIEW
Ralph A DeFronzo, Luke Norton, Muhammad Abdul-Ghani
The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity...
January 2017: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27871675/glucagon-like-peptide-1-and-the-central-peripheral-nervous-system-crosstalk-in-diabetes
#13
REVIEW
Giovanna Muscogiuri, Ralph A DeFronzo, Amalia Gastaldelli, Jens J Holst
Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary tract that project to multiple regions expressing GLP-1 receptors (GLP-1Rs). Treatment with GLP-1R agonists (GLP-1-RAs) reduces ischemia-induced hyperactivity, oxidative stress, neuronal damage and apoptosis, cerebral infarct volume, and neurologic damage, after cerebral ischemia, in experimental models...
February 2017: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/27639082/exenatide-improves-both-hepatic-and-adipose-tissue-insulin-resistance-a-dynamic-pet-study
#14
Amalia Gastaldelli, Melania Gaggini, Giuseppe Daniele, Demetrio Ciociaro, Eugenio Cersosimo, Devjit Tripathy, Curtis Triplitt, Peter Fox, Nicolas Musi, Ralph DeFronzo, Patricia Iozzo
GLP-1 receptor agonists (GLP-1-RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP-1-RAs act on liver and adipose tissue to reduce insulin resistance (IR). Thus, we evaluated the acute effects of exenatide (EX) on hepatic (Hep-IR) and adipose (Adipo-IR) insulin resistance and glucose uptake. 15 male subjects (age=56±8 y, BMI=29±1 kg/m(2) , A1c=5.7±0.1%) were studied on two occasions, with a double blind subcutaneous injection of exenatide (5 mcg) or placebo (PLC) 30 min before a 75-gram oral glucose tolerance test (OGTT)...
September 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27624579/islet-amyloid-polypeptide-response-to-maximal-hyperglycemia-and-arginine-is-altered-in-impaired-glucose-tolerance-and-type-2-diabetes-mellitus
#15
Rodolfo Guardado-Mendoza, Alberto O Chávez, Lilia M Jiménez-Ceja, Andrea Hansis-Diarte, Ralph A DeFronzo, Franco Folli, Devjit Tripathy
AIMS: Pancreatic islet amyloid deposition is a characteristic feature of type 2 diabetes mellitus (T2DM). Islet amyloid polypeptide (IAPP) is co-secreted with insulin, but its secretion profile and relationship to insulin and C-peptide in response to glucose and non-glucose stimuli has not been clearly defined. METHODS: Forty subjects (13 NGT, 12 IGT and 15 T2DM) participated in an OGTT and two-step hyperglycemic (225 and 400 mg/dl) clamp (80 min/step) followed by an IV arginine bolus...
January 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/27585671/pioglitazone-is-equally-effective-for-diabetes-prevention-in-older-versus-younger-adults-with-impaired-glucose-tolerance
#16
Sara E Espinoza, Chen-Pin Wang, Devjit Tripathy, Stephen C Clement, Dawn C Schwenke, Mary Ann Banerji, George A Bray, Thomas A Buchanan, Robert R Henry, Abbas E Kitabchi, Sunder Mudaliar, Frankie B Stentz, Peter D Reaven, Ralph A DeFronzo, Nicolas Musi
To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, β cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA...
December 2016: Age (2005-)
https://www.readbyqxmd.com/read/27561923/dapagliflozin-enhances-fat-oxidation-and-ketone-production-in-patients-with-type-2-diabetes
#17
Giuseppe Daniele, Juan Xiong, Carolina Solis-Herrera, Aurora Merovci, Roy Eldor, Devjit Tripathy, Ralph A DeFronzo, Luke Norton, Muhammad Abdul-Ghani
OBJECTIVE: Insulin resistance is associated with mitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production...
November 2016: Diabetes Care
https://www.readbyqxmd.com/read/27489336/discordance-between-central-brain-and-pancreatic-action-of-exenatide-in-lean-and-obese-subjects
#18
Roy Eldor, Giuseppe Daniele, Claudia Huerta, Mariam Al-Atrash, John Adams, Ralph DeFronzo, Timothy Duong, John Lancaster, Mahmoud Zirie, Amin Jayyousi, Muhammad Abdul-Ghani
OBJECTIVE: This study examined the effect of exenatide on brain activity measured by functional (f)MRI and on insulin secretion in lean and obese normal-glucose-tolerant individuals. RESEARCH DESIGN AND METHODS: The brain fMRI signal in response to high-calorie-content food pictures was measured with and without intravenous exenatide infusion in 10 lean and 10 obese healthy volunteers. Insulin secretion was measured with a two-step (+100 and +200 mg/dL) hyperglycemic clamp with exenatide and with saline infusion...
October 2016: Diabetes Care
https://www.readbyqxmd.com/read/27440828/positioning-sglt2-inhibitors-incretin-based-therapies-in-the-treatment-algorithm
#19
REVIEW
John P H Wilding, Surya Panicker Rajeev, Ralph A DeFronzo
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin)...
August 2016: Diabetes Care
https://www.readbyqxmd.com/read/27398621/the-genetic-architecture-of-type-2-diabetes
#20
Christian Fuchsberger, Jason Flannick, Tanya M Teslovich, Anubha Mahajan, Vineeta Agarwala, Kyle J Gaulton, Clement Ma, Pierre Fontanillas, Loukas Moutsianas, Davis J McCarthy, Manuel A Rivas, John R B Perry, Xueling Sim, Thomas W Blackwell, Neil R Robertson, N William Rayner, Pablo Cingolani, Adam E Locke, Juan Fernandez Tajes, Heather M Highland, Josee Dupuis, Peter S Chines, Cecilia M Lindgren, Christopher Hartl, Anne U Jackson, Han Chen, Jeroen R Huyghe, Martijn van de Bunt, Richard D Pearson, Ashish Kumar, Martina Müller-Nurasyid, Niels Grarup, Heather M Stringham, Eric R Gamazon, Jaehoon Lee, Yuhui Chen, Robert A Scott, Jennifer E Below, Peng Chen, Jinyan Huang, Min Jin Go, Michael L Stitzel, Dorota Pasko, Stephen C J Parker, Tibor V Varga, Todd Green, Nicola L Beer, Aaron G Day-Williams, Teresa Ferreira, Tasha Fingerlin, Momoko Horikoshi, Cheng Hu, Iksoo Huh, Mohammad Kamran Ikram, Bong-Jo Kim, Yongkang Kim, Young Jin Kim, Min-Seok Kwon, Juyoung Lee, Selyeong Lee, Keng-Han Lin, Taylor J Maxwell, Yoshihiko Nagai, Xu Wang, Ryan P Welch, Joon Yoon, Weihua Zhang, Nir Barzilai, Benjamin F Voight, Bok-Ghee Han, Christopher P Jenkinson, Teemu Kuulasmaa, Johanna Kuusisto, Alisa Manning, Maggie C Y Ng, Nicholette D Palmer, Beverley Balkau, Alena Stancáková, Hanna E Abboud, Heiner Boeing, Vilmantas Giedraitis, Dorairaj Prabhakaran, Omri Gottesman, James Scott, Jason Carey, Phoenix Kwan, George Grant, Joshua D Smith, Benjamin M Neale, Shaun Purcell, Adam S Butterworth, Joanna M M Howson, Heung Man Lee, Yingchang Lu, Soo-Heon Kwak, Wei Zhao, John Danesh, Vincent K L Lam, Kyong Soo Park, Danish Saleheen, Wing Yee So, Claudia H T Tam, Uzma Afzal, David Aguilar, Rector Arya, Tin Aung, Edmund Chan, Carmen Navarro, Ching-Yu Cheng, Domenico Palli, Adolfo Correa, Joanne E Curran, Denis Rybin, Vidya S Farook, Sharon P Fowler, Barry I Freedman, Michael Griswold, Daniel Esten Hale, Pamela J Hicks, Chiea-Chuen Khor, Satish Kumar, Benjamin Lehne, Dorothée Thuillier, Wei Yen Lim, Jianjun Liu, Yvonne T van der Schouw, Marie Loh, Solomon K Musani, Sobha Puppala, William R Scott, Loïc Yengo, Sian-Tsung Tan, Herman A Taylor, Farook Thameem, Gregory Wilson, Tien Yin Wong, Pål Rasmus Njølstad, Jonathan C Levy, Massimo Mangino, Lori L Bonnycastle, Thomas Schwarzmayr, João Fadista, Gabriela L Surdulescu, Christian Herder, Christopher J Groves, Thomas Wieland, Jette Bork-Jensen, Ivan Brandslund, Cramer Christensen, Heikki A Koistinen, Alex S F Doney, Leena Kinnunen, Tõnu Esko, Andrew J Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E Jørgensen, Torben Jørgensen, Claes Ladenvall, Johanne Marie Justesen, Annemari Käräjämäki, Jennifer Kriebel, Wolfgang Rathmann, Lars Lannfelt, Torsten Lauritzen, Narisu Narisu, Allan Linneberg, Olle Melander, Lili Milani, Matt Neville, Marju Orho-Melander, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Amy Swift, Anders H Rosengren, Kathleen Stirrups, Andrew R Wood, Evelin Mihailov, Christine Blancher, Mauricio O Carneiro, Jared Maguire, Ryan Poplin, Khalid Shakir, Timothy Fennell, Mark DePristo, Martin Hrabé de Angelis, Panos Deloukas, Anette P Gjesing, Goo Jun, Peter Nilsson, Jacquelyn Murphy, Robert Onofrio, Barbara Thorand, Torben Hansen, Christa Meisinger, Frank B Hu, Bo Isomaa, Fredrik Karpe, Liming Liang, Annette Peters, Cornelia Huth, Stephen P O'Rahilly, Colin N A Palmer, Oluf Pedersen, Rainer Rauramaa, Jaakko Tuomilehto, Veikko Salomaa, Richard M Watanabe, Ann-Christine Syvänen, Richard N Bergman, Dwaipayan Bharadwaj, Erwin P Bottinger, Yoon Shin Cho, Giriraj R Chandak, Juliana C N Chan, Kee Seng Chia, Mark J Daly, Shah B Ebrahim, Claudia Langenberg, Paul Elliott, Kathleen A Jablonski, Donna M Lehman, Weiping Jia, Ronald C W Ma, Toni I Pollin, Manjinder Sandhu, Nikhil Tandon, Philippe Froguel, Inês Barroso, Yik Ying Teo, Eleftheria Zeggini, Ruth J F Loos, Kerrin S Small, Janina S Ried, Ralph A DeFronzo, Harald Grallert, Benjamin Glaser, Andres Metspalu, Nicholas J Wareham, Mark Walker, Eric Banks, Christian Gieger, Erik Ingelsson, Hae Kyung Im, Thomas Illig, Paul W Franks, Gemma Buck, Joseph Trakalo, David Buck, Inga Prokopenko, Reedik Mägi, Lars Lind, Yossi Farjoun, Katharine R Owen, Anna L Gloyn, Konstantin Strauch, Tiinamaija Tuomi, Jaspal Singh Kooner, Jong-Young Lee, Taesung Park, Peter Donnelly, Andrew D Morris, Andrew T Hattersley, Donald W Bowden, Francis S Collins, Gil Atzmon, John C Chambers, Timothy D Spector, Markku Laakso, Tim M Strom, Graeme I Bell, John Blangero, Ravindranath Duggirala, E Shyong Tai, Gilean McVean, Craig L Hanis, James G Wilson, Mark Seielstad, Timothy M Frayling, James B Meigs, Nancy J Cox, Rob Sladek, Eric S Lander, Stacey Gabriel, Noël P Burtt, Karen L Mohlke, Thomas Meitinger, Leif Groop, Goncalo Abecasis, Jose C Florez, Laura J Scott, Andrew P Morris, Hyun Min Kang, Michael Boehnke, David Altshuler, Mark I McCarthy
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups...
August 4, 2016: Nature
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