Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-25T01:53:52.846Z Has data issue: false hasContentIssue false
  • English
  • Français

Genetics of the metabolic syndrome

Published online by Cambridge University Press:  09 March 2007

Leif Groop
Leif Groop*
Affiliation:
Department of Endocrinology, University Hospital MAS, Lund University, S-205 02, Malmö, Sweden
*
*Corresponding author: L. Groop, fax +46 40 337023, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The clustering of cardiovascular risk factors such as abdominal obesity, hypertension, dyslipidaemia and glucose intolerance in the same persons has been called the metabolic or insulin-resistance syndrome. In 1998 WHO proposed a unifying definition for the syndrome and chose to call it the metabolic syndrome rather than the insulin-resistance syndrome. Although insulin resistance has been considered as a common denominator for the different components of the syndrome, there is still debate as to whether it is pathogenically involved in all of the different components of the syndrome. Clustering of the syndrome in families suggests a genetic component. It is plausible that so-called thrifty genes, which have ensured optimal storage of energy during periods of fasting, could contribute to the phenotype of the metabolic syndrome. Common variants in a number of candidate genes influencing fat and glucose metabolism can probably, together with environmental triggers, increase susceptibility to the syndrome. Among these, the genes for β3-adrenergic receptor, hormone-sensitive lipase, lipoprotein lipase, IRS-1, PC-1, skeletal muscle glycogen synthase, etc. appear to increase the risk of the metabolic syndrome. In addition, novel genes may be identified by genome-wide searches.

Keywords

Abdominal obesityHypertensionDyslipidaemiaGlucose intoleranceMetabolic syndromeInsulin-resistance syndrome
Type
Research Article
Information
British Journal of Nutrition , Volume 83 , Issue S1 , June 2000 , pp. S39 - S48
Copyright
Copyright © The Nutrition Society 2000

References

Alberti, K, Zimmet, P & Consultation, W (1998) Definition diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation. Diabetic Medicine 15, 539–553.3.0.CO;2-S>CrossRefGoogle ScholarPubMed
Almind, K, Bjoerbaek, C, Vestergaard, H, Hansen, T, Echwald, S & Pedersen, O (1993) Amino acid polymorphism of the insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342, 828–832.CrossRefGoogle ScholarPubMed
Altsuler, D, Kruglyak, L & Lander, E (1998) Genetic polymorphism and disease. New England Journal of Medicine 338, 1626.CrossRefGoogle Scholar
Balkau, B, Charles, M & Group, E (1999) Comments on the provisional report from the WHO consultation. Diabetic Medicine 16, 442–443.Google ScholarPubMed
Banerji, M, Chaiken, R, Gordon, D, Kral, J & Lebovitz, H (1995) Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive?. Diabetes 44, 141–146.Google Scholar
Beck-Nielsen, H & Groop, L (1994) Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. Journal of Clinical Investigation 94, 1714–1721.CrossRefGoogle ScholarPubMed
Bonora, E, Kiechl, S, Willeit, J, Oberhollenzer, F, Egger, G, Targher, G, Alberiche, M, Bonadonna, R & Muggeo, M (1998) Prevalence of insulin resistance in metabolic disorders. The Bruneck Study. Diabetes 47, 1643–1649.CrossRefGoogle ScholarPubMed
Boss, O, Samec, S, Paoloni-Giacobino, A, Rossier, C, Dulloo, A, Seydoux, J, Muzzin, P, Giacobino, J-P (1997) Uncoupling protein 3: a member of the mitochondrial carrier family with tissue specific expression. FEBS Letters 408, 39–42.CrossRefGoogle ScholarPubMed
Bouchard, C (1996) Genetics of body fat content. In Progress in Obesity Research 7, pp. 33–41 [H, Angel, H, Anderson, C, Bouchard, D, Lau, L, Leiter, R, Mendelson, editors]. London: John Libbey.Google Scholar
Bouchard, C, Perusse, L, Leblanc, C, Tremblay, A & Theriault, G (1988) Inheritance of the amount and distribution of human body fat. International Journal of Obesity 12, 205–215.Google ScholarPubMed
Bouchard, C, Rice, T, Lemieux, S, Despres, J, Perusse, L & Rao, D (1996) Major gene for abdominal visceral fat area in the Quebec Family Study. International Journal of Obesity 20, 420–427.Google ScholarPubMed
Carey, D, Nguyen, T, Campbell, L, Chisholm, D & Kelly, P (1996) Genetic influences on central abdominal fat: a twin study. International Journal of Obesity 20, 722–726.Google ScholarPubMed
Chagnon, Y, Chen, W, Perusse, L, Chagnon, M, Nadeau, A, Wilkinson, B & Bouchard, C (1997) Linkage and association studies between the melanocortin receptor-4 and receptor-5 genes and obesity-related phenotypes in the Quebec family study. Molecular Medicine 3, 663–673.CrossRefGoogle Scholar
Chung, W, Luke, A & Cooper, R (1999) Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis. Diabetes 48, 1890–1895.Google Scholar
Clausen, J, Hansen, T, Bjoerbaek, C, Echwald, S, Urhammer, S, Rasmussen, S, Andersen, C, Hansen, L, Almind, K, Winther, K, Haraldsdottir, J, Borch-Johnsen, K & Pedersen, O (1995) Insulin resistance: interactions between obesity and a common variant of the insulin receptor substrate-1. Lancet 346, 397–402.Google Scholar
Clément, K, Ruiz, J, Cassard-Doulcier, A (1996) Additive effect of A–G (–3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta-3-adrenergic receptor gene on weight gain in morbid obesity. International Journal of Obesity 20, 1062–1066.Google ScholarPubMed
Clément, K, Vaisse, C & Lahlou, N (1998) A mutation in the leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401.CrossRefGoogle ScholarPubMed
Clément, K, Vaisse, C, Manning, B, Basdevant, A, Guy-Grand, B, Ruiz, J, Silver, K, Shuldiner, A, Froguel, P & Strosberg, A (1995) Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. New England Journal of Medicine 333, 352–354.Google Scholar
Coleman, D (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298.CrossRefGoogle ScholarPubMed
Coleman, D (1979) Obesity genes: beneficial effects in heterozygous mice. Science 203, 663–665.Google Scholar
Comuzzie, A, Hixson, J, Almasy, L, Mitchell, B, Mahaney, M, Dyer, T, Stern, M, MacCluer, J & Blangero, J (1997) A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nature Genetics 15, 273–276.CrossRefGoogle Scholar
Consindine, R, Consindine, E, William, C, Nyce, M, Magosin, S, Bauer, T, Rosato, E, Colberg, J & Caro, J (1995) Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. Journal of Clinical Investigation 95, 2986–2988.CrossRefGoogle Scholar
Deeb, S, Fajas, L, Nemoto, M, Laakso, M, Fujimoto, W & Auwerx, J (1998) A Pro 12Ala substitution in the human peroxisome proliferator-activated receptor gamma2 is associated with decreased receptor activity, improved insulin sensitivity and lowered body mass index. Nature Genetics 20, 284–287.Google Scholar
DeFronzo, R & Ferrannini, E (1991) Insulin resistance: a multifacet syndrome responsible for NIDDM obesity, hypertension dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14, 173–194.CrossRefGoogle Scholar
Ek, J, Urhammer, S, Sorensen, F, Anderson, T, Auwerx, J & Pedersen, O (1999) Homozygosity of the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2): divergent modulating effects on body mass index in obese and lean men of Caucasian origin. Diabetologia 42, 892–895.Google Scholar
Emorine, L, Marullo, S, Briend-Sutren, M, Patey, G, Tate, K, Delavier-Klutchko, C & Strosberg, A (1989) Molecular characterization of the human beta-3-adrenergic receptor. Science 245, 1118–1121.Google Scholar
Enerbäck, S, Jacobsson, A, Simpson, E, Guerra, C, Yamashita, H, Harper, M-E & Kozak, L (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–93.Google Scholar
Eriksson, J, Franssila-Kallunki, A, Ekstrand, A, Saloranta, C, Widèn, E, Schalin, C & Groop, L (1989) Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. New England Journal of Medicine 321, 337–343.CrossRefGoogle ScholarPubMed
Fan, W, Boston, B, Kesterson, R, Hurby, V & Cone, R (1997) Role of melanocrotinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168.CrossRefGoogle ScholarPubMed
Fernandéz-Real, J, Gutierrez, C, Ricart, W, Casamitjana, R, Fernandéz-Castanér, M, Vendrell, J, Richart, C & Soler, J (1997) The TNF-alpha gene NcoI polymorphism influences the relationship among insulin resistance, percent body fat and increased serum leptin levels. Diabetes 46, 1468–1472.CrossRefGoogle ScholarPubMed
Ferrannini, E, Buzzigoli, G, Bonadonna, R, Giorico, M, Oleggini, M, Pedrinelli, R, Brandi, L & Bevilacqua, S (1987) Insulin resistance in essential hypertension. New England Journal of Medicine 317, 350–357.CrossRefGoogle ScholarPubMed
Forsblom, C, Eriksson, J, Ekstrand, A, Teppo, A-M, Taskinen, M-R & Groop, L (1995) Insulin resistance and abnormal albumin excretion in non-diabetic first-degree relatives of patients with NIDDM. Diabetologia 38, 363–369.CrossRefGoogle ScholarPubMed
Forsblom, C, Kanninen, T, Lehtovirta, T, Kaprio, JCS & Groop, L (1999) Albumin excretion is an inherited trait in families with NIDDM?. Diabetologia 42, 1359–1366.CrossRefGoogle Scholar
Fujisawa, T, Ikegami, H, Kawaguchi, Y & Ogihara, T (1998) Meta-analysis of the association of the Trp64Arg polyomorphism of the beta-3-adrenergic receptor gene with body mass index. Journal of Clinical Endocrinology and Metabolism 83, 2441–2444.Google ScholarPubMed
Gagnon, J, Mauriege, P, Roy, S, Sjöström, D, Chagnon, Y, Dionne, F, Oppert, J-M, Perussé, L, Sjöström, L & Bouchard, C (1996) The Trp64Arg mutation of the beta-3-adrenergic receptor gene has no effect on obesity phenotypes in the Quebec family study and Swedish obese subjects cohort. Journal of Clinical Investigation 98, 2086–2093.Google Scholar
Ghosh, S, Watanabe, R & Hauser, E (1999) Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proceedings of the National Academy of Sciences, USA 96, 2198–2203.Google Scholar
Green, S, Turki, J, Innis, M & Liggett, S (1994) Aminoterminal polymorphisms of the human beta-2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 33,.Google ScholarPubMed
Groop, L & Ferrannini, E (1993) Insulin action and substrate competition. Baillière's Clinical Endocrinology and Metabolism 7, 1007–1032.CrossRefGoogle ScholarPubMed
Groop, L & Tuomi, T (1997) Non-insulin-dependent diabetes mellitus — a collision between thrifty genes and an affluent society. Annals of Medicine 29, 37–53.Google Scholar
Groop, L, Kankuri, M, Schalin-Jäntti, C, Ekstrand, A, Nikula-Ijäs, P, Widèn, E, Kuismanen, E, Eriksson, J, Franssila-Kallunki, A, Saloranta, C & Koskimies, S (1993) Association between polymorphism of the glycogen synthase gene and non-insulin-dependent diabetes mellitus. New England Journal of Medicine 328, 10–14.CrossRefGoogle ScholarPubMed
Groop, L, Forsblom, C, Lehtovirta, M, Tuomi, T, Karanko, S, Nissén, M, Ehrnström, B-O, Forsén, B, Isomaa, B, Snickars, B, Taskinen, M-R (1996) Metabolic consequences of a family history of NIDDM (The Botnia Study). Diabetes 45, 1585–1593.CrossRefGoogle ScholarPubMed
Haffner, S, Valdez, R, Hazuda, H, Mitchell, B, Morales, P & Stern, M (1992) Prospective analysis of the insulin-resistance syndrome (Syndrome X). Diabetes 41, 715–722.CrossRefGoogle ScholarPubMed
Haffner, S, Howard, G, Mayer, E, Bergman, R, Savage, P, Rewers, M, Mykkänen, L, Karter, A, Hamman, R & Saad, M (1997) Insulin sensitivity and acute insulin response in African-Americans, non-Hispanic whites and Hispanics with NIDDM: the Insulin Resistance Atherosclerosis Study. Diabetes 46, 63–69.CrossRefGoogle ScholarPubMed
Hales, C & Barker, D (1992) Type 2 diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601.CrossRefGoogle ScholarPubMed
Hanis, C, Boerwinkle, E & Chakraborty, R (1996) A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genetics 13, 161–166.CrossRefGoogle Scholar
Hästbacka, J, De la Chapelle, A, Mahtani, M, Clines, G, Reeve-Daly, M, Daly, M, Hamilton, B, Kusumi, K, Trivedi, B, Weawer, A, Coloma, A, Lovett, M, Buckler, A, Kaitila, I & Lander, E (1994) The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 78, 1073–1087.CrossRefGoogle ScholarPubMed
Hattersley, A, Beards, F, Ballantyne, E, Appleton, M, Harvey, R & Ellard, S (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nature Genetics 19, 268–270.CrossRefGoogle ScholarPubMed
Hoffstedt, J, Poirier, O, Thörne, A, Lönnqvist, F, Herrrmann, S, Cambien, F & Arner, P (1999) Polymorphism of the human beta-3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. Diabetes 48, 203–205.Google Scholar
Hong, Y, Rice, T, Gagnon, J, Després, J-P, Nadeau, A, Pérusse, L, Bouchard, C, Leon, A, Skinner, J, Wilmore, J & Rao, D (1998) Familial clustering of insulin and abdominal visceral fat: the HERITAGE family study. Journal of Clinical Endocrinology and Metabolism 83, 4239–4245.Google ScholarPubMed
Hotamisligil, G, Shargill, N & Spiegelman, B (1993) Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259, 87–91.CrossRefGoogle ScholarPubMed
Hotamisigil, G, Arner, P, Caro, J, Atkinson, R & Spiegelman, B (1995) Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. Journal of Clinical Investigation 95, 2409–2415.CrossRefGoogle Scholar
Jackson, R, Creemers, J, Ohagi, S, Raffin-Sanson, M-L, Sanders, L, Montague, C, Hutton, J, O'Rahilly, S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nature Genetics 16, 303–306.CrossRefGoogle ScholarPubMed
Kellerer, M, Rett, K, Renn, W, Groop, L, Häring, H (1996) Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity and insulin sensitivity in man. Hormone and Metabolic Research 28, 737–743.Google Scholar
Klannemark, M, Orho, M & Groop, L (1998) No relationship between variants in the uncoupling protein 2 gene and energy expenditure. European Journal of Endocrinology 139, 217–221.CrossRefGoogle ScholarPubMed
Klannemark, M, Orho, M, Langin, D, Laurell, H, Holm, C, Reynisdottir, S, Arner, P & Groop, L (1998) The putative role of the hormone sensitive lipase gene in the pathogenesis of the metabolic syndrome. Diabetologia 41, 1515–1522.Google Scholar
Knudsen, P, Murtomäki, S, Antikainen, M, Ehnholm, S, Lahdenperä, S, Ehnholm, C, Taskinen, M-R (1997) The Asn291-Ser and Ser-477-stop mutations of the lipoprotein lipase gene and their significance for lipid metabolism in patients with hypertriglyceridemia. European Journal of Clinical Investigation 27, 928–935.CrossRefGoogle Scholar
Krief, S, Lönnqvist, F, Raimbault, S, Baude, B, Van Spronsen, A, Arner, P, Strosberg, A, Ricquier, D & Emorine, L (1993) Tissue distribution of beta-3-adrenergic receptor mRNA in man. Journal of Clinical Investigation 91, 344–349.CrossRefGoogle ScholarPubMed
Krude, H, Biebermann, H, Luck, W, Horn, R, Brabant, G & Grueters, A (1998) Severe early-onset obesity adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics 19, 155–157.CrossRefGoogle ScholarPubMed
Kylin, E (1923) Studien ueber das Hypertonie-Hyperglykämie-Hyperurikämiesyndrom. Zentralblatt fuer Innere Medizin 44, 105–127.Google Scholar
Large, V, Hellström, I, Reynisdottir, S, Lönnqvist, F, Eriksson, P, Lannfelt, L & Arner, P (1997) Human beta-2-adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adiipocyte beta-2-adrenoceptor function. Journal of Clinical Investigation 100, 3005–3013.CrossRefGoogle ScholarPubMed
Lee, G-H, Proenca, R, Montez, J, Carroll, K, Darvishzadeh, J, Lee, J & Friedman, J (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635.Google Scholar
Lehto, M, Stoffel, M, Groop, L, Espinosa, R, LeBeau, M & Bell, G (1993) Assignment of the gene encoding gycogen synthase to human chromosome 19 band q13.3. Genomics 15, 460–461.Google Scholar
Lehtovirta, M, Kaprio, J, Forsblom, C, Eriksson, JJT & Groop, L (2000) Insulin secretion and insulin sensitivity in monozygotic and dizygotic twins Diabetologia.Google Scholar
Lembertas, A, Perusse, L, Chagnon, Y, Fisler, J, Warden, C, Purcell-Huynh, D, Dionne, F, Gagnon, J, Nadeau, A, Lusis, A & Bouchard, C (1997) Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on human homologous region 20q. Journal of Clinical Investigation 100, 1240–1247.CrossRefGoogle ScholarPubMed
Lönnqvist, F, Thörne, A, Nilsell, K, Hoffstedt, J & Arner, P (1995) A pathogenetic role of visceral fat beta-3-adrenoreceptors in obesity. Journal of Clinical Investigation 95, 1109–1116.Google Scholar
Lowell, B, Susulic, V, Hamman, A, Lawitts, J, Himms-Hagen, J, Boyer, B, Kozak, L & Flier, J (1993) Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742.CrossRefGoogle ScholarPubMed
Maddux, B, Sbraccia, P, Kumakura, S, Sasson, S, Youngren, J, Fisher, A, Spemcer, S, Grupe, A, Henzel, W, Stewart, T, Reaven, G & Goldfine, I (1995) Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373, 448–451.Google Scholar
Maffei, M, Halaas, J, Ravussin, E, Pratley, R, Lee, G, Zhang, Y, Fei, H, Kim, S, Lallone, R, Ranganathan, S, Kern, P & Friedman, J (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1, 1155–1161.Google Scholar
Mahtani, MM, Widèn, E & Lehto, M (1996) Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nature Genetics 14, 90–94.CrossRefGoogle ScholarPubMed
Majer, M, Mott, D, Mochizuki, H, Rowles, J, Pedersen, O, Knowler, W, Bogardus, C & Prochazka, M (1996) Association of the glycogen synthase locus 19q13 with NIDDM in Pima Indians. Diabetologia 39, 314–321.Google Scholar
Meigs, J, D'Agostino, RS, Wilson, P, Cupples, L, Nathan, D & Singer, D (1997) Risk variable clustering in the insulin resistance syndrome. The Framingham offspring study. Diabetes 46, 1594–1600.CrossRefGoogle ScholarPubMed
Melander, O, Mattiasson, IKM, Groop, L, Hulthén, L (1999) Heredity for hypertension influences intrauterine growth and the relation between foetal growth and adult blood pressure. Journal of Hypertension 17, 1557–1561.Google Scholar
Mitchell, B, Blangero, J, Comuzzie, A, Almasy, L, Shuldiner, A, Silver, K, Stern, M, MacCluer, J & Hixson, J (1998) A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. Journal of Clinical Investigation 101, 584–587.CrossRefGoogle ScholarPubMed
Mitchell, B, Cole, S, Comuzzie, A, Almasy, L, Blangero, J, MacCluer, J & Hixson, J (1999) A quantitative trait locus influencing BMI maps to the region of beta-3-adrenergic receptor. Diabetes 48, 1863–1867.Google Scholar
Modan, M, Halkin, H, Almog, S, Lusky, A, Eshkol, A, Shefi, M, Shitrit, A & Fuchs, Z (1985) Hyperinsulinemia: a link between hypertension obesity and glucose intolerance. Journal of Clinical Investigation 75, 807–817.Google Scholar
Montague, C, Farroqi, S, Whitehead, J, Soos, M, Rau, H, Wareham, N, Sewter, C, Digby, J, Mohammed, S, Hurst, J, Cheetham, C, Earley, A, Barnett, A, Prins, J &, O'Rahilly, S (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908.CrossRefGoogle ScholarPubMed
Mykkänen, L, Zaccaro, D, Wagenknecht, L, Robbins, D, Gabriel, M & Haffner, S (1998) Microalbuminuria is associated with insulin resistance in nondiabetic subjects. Diabetes 47, 703–800.Google Scholar
Naggert, J, Fricker, L, Varlamov, O, Nishina, P, Roille, Y, Steiner, D, Carroll, R, Paigen, B & Leiter, E (1995) Hyperproinsulinemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genetics 10, 135–142.Google Scholar
Neel, V (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by progress?. American Journal of Human Genetics 14, 352–362.Google ScholarPubMed
Norman, R, Thompson, D, Foroud, T, Garvey, W, Bennett, P, Bogardus, C & Ravussin, E (1996) Genome-wide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21–q22. American Journal of Human Genetics 60, 166–173.Google Scholar
Ogawa, Y, Masuzaki, H, Isse, N, Okazaki, T, Mori, K, Shigemoto, M, Satoh, N, Tamura, N, Hosohoda, K, Yoshimasa, Y, Jingami, H, Kawada, T & Nakao, K (1995) Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/fa) rats. Journal of Clinical Investigation 96, 1647–1652.CrossRefGoogle ScholarPubMed
Ollman, M, Wilson, B, Yang, Y, Kerns, J, Chen, Y, Gantz, I & Barsch, G (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138.Google Scholar
Orho, M, Nikula-Ijäs, P, Schalin-Jäntti, C, Permutt, M & Groop, L (1995) Isolation and characterization of the human muscle glycogen synthase gene. Diabetes 44, 1099–1105.Google Scholar
Orho-Melander, M, Almgren, P, Kanninen, T, Forsblom, C & Groop, L (1999) A paired sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene. Diabetologia 42, 1138–1145.Google Scholar
Pelleymounter, M, Cullen, M, Baker, M, Hecht, R, Winters, D, Boone, T & Collins, F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–542.CrossRefGoogle ScholarPubMed
Pietro-Rouxel, F, Manning, B, Gros, J & Strosberg, D (1997) The biological effect of the naturally occurring Trp64-Arg mutation on human beta-3-adrenoceptor activity. European Journal of Biochemistry 247, 1174–1179.Google Scholar
Pizzuti, A, Frititta, L, Argiolas, A, Baratta, R, Goldfine, I, Bozzali, M, Ercolino, T, Scarlato, G, Iacovello, L, Vigneri, R, Tassi, V & Trischitta, V (1999) A polymorphism (K12Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes 48, 1881–1884.CrossRefGoogle Scholar
Rantala, A, Kauma, H, Lilja, M, Savolainen, M, Reunanen, A, Kesäniemi, Y (1999) Prevalence of the metabolic syndrome in drug-treated hypertensive patients and control subjects. Journal of Internal Medicine 245, 163–174.CrossRefGoogle ScholarPubMed
Reaven, G (1988) Role of insulin resistance in human disease. Diabetes 37, 1595–1607.Google Scholar
Reymer, P, Gagné, E & Groenemeyer, B (1995) A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nature Genetics 10, 28–34.Google Scholar
Reynisdotter, S, Wahrenberg, H, Carlström, K, Rössner, S & Arner, P (1994) Catecholamine resistance in fat cells of women with upper-body obesity due to decreased expression of beta-2-adrenoceptors. Diabetologia 37, 428–435.Google Scholar
Ristow, M, Muller-Wieland, D, Pfeiffer, A, Krone, W & Kahn, C (1998) Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. New England Journal of Medicine 339, 953–959.Google Scholar
Saghizadeh, M, Ong, J, Garvey, W, Henry, R & Kern, P (1996) The expression of TNFalfa by human muscle. Relationship to insulin resistance. Journal of Clinical Investigation 97, 1111–1116.CrossRefGoogle Scholar
Sakane, N, Yoshida, T, Umekawa, T, Kondo, M, Sakai, Y & Takahashi, T (1997) Beta-3-adrenergic receptor polymorphism: a genetic marker for visceral fat obesity and the insulin resistance syndrome. Diabetologia 40, 200–204.Google Scholar
Samaras, K, Spector, T, Nguyen, T, Baan, K, Campbell, L & Kelly, P (1997) Independent genetic factors determine the amount and distribution of fat in women after the menopause. Journal of Clinical Endocrinology and Metabolism 82, 781–785.Google Scholar
Seldin, M, Mott, D, Bhat, D, Petro, A, Kuhn, C, Kingsmore, S, Bogardus, C, Opara, E, Feinglos, M & Surwit, R (1994) Glycogen synthase: a putative locus for diet-induced hyperglycemia. Journal of Clinical Investigation 94, 1–8.CrossRefGoogle ScholarPubMed
Shihara, N, Yasuda, K, Moritani, T, Ue, H, Adachi, T, Tanaka, H, Tsuda, K & Seino, Y (1999) The association between Trp64Arg polymorphism of the beta-3-adrenergic receptor and autonomic nervous system activity. Journal of Clinical Endocrinology and Metabolism 84, 1623–1627.Google ScholarPubMed
Sipiläinen, R, Uusitupa, M, Heikkinen, S, Rissanen, A & Laakso, M (1997) Polymorphism of the beta-3-adrenergic receptor gene affects basal metabolic rate in obese Finns. Diabetes 46, 77–80.Google Scholar
Stephens, T, Basinski, M, Bristow, P, Bue-Valleskey, J, Burgett, S, Craft, L, Hale, J, Hoffmann, J, Hsiung, H, Kriauciunas, A, MacKellar, W, Rosteck, P, Schoner, B, Smith, D, Tinsley, F, Zhang, X-Y & Heiman, M (1995) The role of neuropeptide Y in the anti-obesity action of the obese gene product. Nature 377, 530–532.Google Scholar
Storlien, L, Jenkins, A, Chisholm, D, Pasqoe, W, Kohouri, S & Kraegen, E (1991) Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid. Diabetes 40, 280–289.CrossRefGoogle ScholarPubMed
Sun, X, Rothenberg, P, Kahn, R, Backer, J, Arakai, E, Wilden, P, Cahill, D, Goldhill, B & & White, M (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77.CrossRefGoogle ScholarPubMed
Tahvanainen, E, Syvänne, M, Frick, M, Murtomäki-Repo, S, Antikainen, M, Kesäniemi, A, Kauma, H, Pasternak, A, Taskinen, M-R, Ehnholm, C & Study, L (1998) Association of variation in hepatic lipase activity with promoter variation in the hepatic lipase gene. Journal of Clinical Investigation 101, 956–960.Google Scholar
Tartaglia, L, Dembski, M, Weng, X, Deng, N, Culpepper, J, Devos, R, Richards, G, Campfield, L, Clark, F, Dees, J, Muir, C, Sanker, S, Moriarty, A, Moore, K, Smutko, J, Mays, G, Woolf, E, Monroe, C & Tepper, R (1996) Identification and expression cloning of a leptin receptor ob-R. Cell 83, 1263–1271.CrossRefGoogle Scholar
Vaisse, C, Clement, K, Guy-Grand, B & Froguel, P (1998) A frameshift mutation in human MCR4 is associated with a dominant form of obesity. Nature Genetics 20, 113–114.CrossRefGoogle Scholar
Vidal-Puig, A, Solanes, G, Grujic, DJS & Lowell, B (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochemical and Biophysical Research Communications 235, 79–82.CrossRefGoogle ScholarPubMed
Walston, J, Silver, K, Bogardus, C, Knowler, W, Celi, F, Austin, S, Manning, B, Strosberg, D, Stern, M, Raben, N, Sorkin, J, Roth, J & Shuldiner, A (1995) Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta3-adrenergic receptor gene. New England Journal of Medicine 333, 343–347.CrossRefGoogle Scholar
Walston, J, Seibert, M, Jen-Yen, C, Cheskin, L & Andersen, R (1999) Tumor necrosis factor-alpha-238 and -308 polymorphisms do not associate with traits related to obesity and insulin resistance. Diabetes 48, 2096–2098.CrossRefGoogle Scholar
Widèn, E, Ekstrand, A, Saloranta, C, Franssila-Kallunki, A, Eriksson, J, Schalin-Jäntti, C & Groop, L (1992) Insulin resistance in Type 2 diabetic patients with hypertriglyceridemia. Diabetologia 35, 1140–1145.CrossRefGoogle Scholar
Widèn, E, Lehto, M, Kanninen, T, Walston, J, Shuldiner, A & Groop, L (1995) Association of a polymorphism in the beta-3-adrenergic receptor gene with features of the insulin resistance syndrome in Finns. New England Journal of Medicine 333, 348–351.CrossRefGoogle ScholarPubMed
Yamada, K, Ishiyama-Shigemoto, S, Ichikawa, F, Yuan, X, Koyanagi, A, Koyama, W & & Nonaka, K (1999) Polymorphism in the 5′-leader cistron of the beta-2-adrenergic receptor gene associated with obesity and type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 84, 1754–1757.Google Scholar
Yeo, G, Farooqi, I, Aminian, S, Halsell, D, Stanhope, R, O'Rahilly, S (1998) A frameshift mutation in MCR4R associated with dominantly inherited human obesity. Nature Genetics 20, 111–112.Google Scholar
Zhang, Y, Proenca, R, Maffei, M, Baron, M, Leopold, L & Friedman, J (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.Google Scholar
Zouali, H, Hani, E, Philippi, A, Vionnet, N, Beckmann, J, Demenais, F & Froguel, P (1997) A susceptibility locus for early-onset non-insulin-dependent (type 2) diabetes mellitus maps to chromosome 20q proximal to the phosphoenolpyruvate carboxykinase gene. Human Molecular Genetics 6, 1401–1408.Google Scholar