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      Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 3 , 18 , 1 , 19 , 16 , 12 , 20 , 21 , 22 , 3 , 3 , 1 , 23 , 22 , 24 , 8 , 25 , 2 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 27 , 28 , 34 , 35 ,   8 , 30 , 36 , 37 , 38 , 27 , 28 , 39 , the GENESIS Consortium, the RISC Consortium, 10 , 11 , 22 , 3 , 40 , 34 , 41 , 42 , 43 , 44 , 45 , 46 , 16 , 47 , 48 , 49 , 50 , 12 , 51 , 52 , 15 , 3 , 17 , 34 , 53 , 54 , 55 , 43 , 56 , 14 , 57 , 25 , 13 , 58 , 59 , 60 , 61 , 62 , 3 , 8 , 63 , 64 , 6 , 46 , 65 , 1
      Diabetes
      American Diabetes Association

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          Abstract

          Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

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          Most cited references38

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          Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

          By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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            Glucose clamp technique: a method for quantifying insulin secretion and resistance.

            Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.
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              Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.

              Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                October 2013
                17 September 2013
                : 62
                : 10
                : 3589-3598
                Affiliations
                [1] 1Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
                [2] 2Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
                [3] 3MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K.
                [4] 4Department of Epidemiology, Biostatistics and Occupational Health, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
                [5] 5Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
                [6] 6General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts
                [7] 7Quantitative Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina
                [8] 8University of Eastern Finland, Kuopio, Finland
                [9] 9School of Health Sciences, Jackson State University, Jackson, Mississippi
                [10] 10Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland
                [11] 11Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland
                [12] 12Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
                [13] 13Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
                [14] 14Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
                [15] 15Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
                [16] 16Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
                [17] 17Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [18] 18Baylor College of Medicine and Methodist DeBakey Heart and Vascular Center, Houston, Texas
                [19] 19Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
                [20] 20Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
                [21] 21School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania
                [22] 22Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
                [23] 23Genetics of Diabetes, University of Exeter Medical School, Exeter, U.K.
                [24] 24Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland
                [25] 25First Department of Internal Medicine, St. Johann Spital, Paracelsus Private Medical University Salzburg, Salzburg, Austria
                [26] 26Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
                [27] 27Department of Medicine, Stanford University School of Medicine, Stanford, California
                [28] 28Cardiovascular Institute, Stanford University School of Medicine, Stanford, California
                [29] 29Department of Internal Medicine, University of Pisa, Pisa, Italy
                [30] 30Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
                [31] 31Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [32] 32Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
                [33] 33Division of Endocrinology, Diabetology, Nephrology, Vascular Medicine and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
                [34] 34Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
                [35] 35Steno Diabetes Center, Gentofte, Denmark
                [36] 36Hagedorn Research Institute, Copenhagen, Denmark
                [37] 37Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
                [38] 38Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
                [39] 39Department of Molecular and Clinical Medicine, The Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy, Gothenburg, Sweden
                [40] 40Department of Preventive Medicine, Mount Sinai School of Medicine, The Charles Bronfman Institute for Personalized Medicine, Institute of Child Health and Development, New York, New York
                [41] 41Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
                [42] 42Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
                [43] 43Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
                [44] 44Boston University School of Medicine, Boston, Massachusetts
                [45] 45Framingham Heart Study, Framingham, Massachusetts
                [46] 46Twin Research and Genetic Epidemiology, King’s College London, London, U.K.
                [47] 47Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
                [48] 48King Abdulaziz University, Jeddah, Saudi Arabia
                [49] 49Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain
                [50] 50Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
                [51] 51Department of Medicine, Turku University Hospital, Turku, Finland
                [52] 52Department of Medicine, University of Turku, Turku, Finland
                [53] 53The National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
                [54] 54University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Cambridge, U.K.
                [55] 55Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
                [56] 56Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, U.K.
                [57] 57Research Centre of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
                [58] 58Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
                [59] 59Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [60] 60Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [61] 61Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia
                [62] 62Department of Community Health and Preventive Medicine, Morehouse School of Medicine, Atlanta, Georgia
                [63] 63Quantitative Sciences, GlaxoSmithKline, Upper Merion, Pennsylvania
                [64] 64Department of Social Medicine, University of Bristol, Bristol, U.K.
                [65] 65Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada.
                Author notes
                Corresponding author: Timothy M. Frayling, tim.frayling@ 123456pms.ac.uk .
                Article
                0128
                10.2337/db13-0128
                3781444
                23835345
                59910446-9fea-4bd0-acab-de8dfed74cf4
                © 2013 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 28 January 2013
                : 25 June 2013
                Page count
                Pages: 10
                Categories
                Original Research
                Genetics/Genomes/Proteomics/Metabolomics

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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