nach oben

Erschienen in:

01.04.2011 | Article

Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B

verfasst von: M. L. Hribal, I. Presta, T. Procopio, M. A. Marini, A. Stančáková, J. Kuusisto, F. Andreozzi, A. Hammarstedt, P.-A. Jansson, N. Grarup, T. Hansen, M. Walker, N. Stefan, A. Fritsche, H. U. Häring, O. Pedersen, U. Smith, M. Laakso, G. Sesti, on behalf of the EUGENE2 Consortium

Erschienen in: Diabetologia | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry.

Methods

Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay.

Results

The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (−35.09 [95% CI 14.68–55.52], p = 0.0008 for CC+CT vs TT; and −29.45 [95% CI 9.51–49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20–1.95] for the meta-analysis of the three samples).

Conclusions/interpretation

Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.

Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR (1990) Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909–915PubMed

Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, Laakso M (1998) Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited: metabolic studies on offspring of diabetic probands. J Clin Invest 101:86–96PubMedCrossRef

Permutt MA, Wasson J, Cox N (2005) Genetic epidemiology of diabetes. J Clin Invest 115:1431–1439PubMedCrossRef

Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCrossRef

Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775PubMedCrossRef

Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in U.K. samples reveals risk loci for type 2 diabetes. Science 316:1336–1341PubMedCrossRef

Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1341–1345CrossRef

Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) Genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345PubMedCrossRef

Wellcome TCCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678CrossRef

10.

Grarup N, Rose CS, Andersson EA et al (2007) Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes 56:3105–3111PubMedCrossRef

11.

Hertel JK, Johansson S, Raeder H et al (2008) Genetic analysis of recently identified type 2 diabetes loci in 1,638 unselected patients with type 2 diabetes and 1,858 control participants from a Norwegian population-based cohort (the HUNT Study). Diabetologia 51:971–977PubMedCrossRef

12.

Duesing K, Fatemifar G, Charpentier G et al (2008) Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids. Diabetologia 51:821–826PubMedCrossRef

13.

Lee YH, Kang ES, Kim SH et al (2008) Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. J Hum Genet 53:991–998PubMedCrossRef

14.

Wu Y, Li H, Loos RJ et al (2008) Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 57:2834–2842PubMedCrossRef

15.

Tabara Y, Osawa H, Kawamoto R et al (2009) Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening. Diabetes 58:493–498PubMedCrossRef

16.

Lewis JP, Palmer ND, Hicks PJ et al (2008) Association analysis in African Americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. Diabetes 57:2220–2225PubMedCrossRef

17.

Rong R, Hanson RL, Ortiz D et al (2009) Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes 58:478–488PubMedCrossRef

18.

Moore AF, Jablonski KA, McAteer JB et al (2008) Diabetes Prevention Program Research Group. Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program. Diabetes 57:2503–2510PubMedCrossRef

19.

Moritani M, Yamasaki S, Kagami M et al (2005) Hypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-beta1. Mol Cell Endocrinol 229:175–184PubMedCrossRef

20.

Rane SG, Dubus P, Mettus RV et al (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22:44–52PubMedCrossRef

21.

Tsutsui T, Hesabi B, Moons DS et al (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27 (Kip1) activity. Mol Cell Biol 19:7011–7019PubMed

22.

Stancáková A, Kuulasmaa T, Paananen J et al (2009) Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes 58:2129–2136PubMedCrossRef

23.

Pascoe L, Tura A, Patel SK et al (2007) Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes 56:3101–3104PubMedCrossRef

24.

Groenewoud MJ, Dekker JM, Fritsche A et al (2008) Variants of CDKAL1 and IGF2BP2 affect first-phase insulin secretion during hyperglycaemic clamps. Diabetologia 51:1659–1663PubMedCrossRef

25.

Laakso M, Zilinskaite J, Hansen T et al (2008) Insulin sensitivity, insulin release and GLP-1 levels in subjects with IFG and/or IGT in the EUGENE2 Study. Diabetologia 51:502–511PubMedCrossRef

26.

Succurro E, Marini MA, Arturi F et al (2009) Elevated one-hour post-load plasma glucose levels identifies subjects with normal glucose tolerance but early carotid atherosclerosis. Atherosclerosis 207:245–249PubMedCrossRef

27.

Sesti G, Cardellini M, Marini MA et al (2003) A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 52:1280–1283PubMedCrossRef

28.

Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diab Care 9:1462–1470CrossRef

29.

Stumvoll M, van Haeften T, Fritsche A, Gerich J (2001) Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times. Diab Care 24:796–797CrossRef

30.

Der Simonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRef

31.

Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457PubMedCrossRef

32.

Krishnamurthy J, Torrice C, Ramsey MR et al (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307PubMed

33.

Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN (1999) Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab Invest 79:1137–1143PubMed

34.

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedCrossRef

35.

Cotsapas C, Prokunina-Olsson L, Welch C et al (2010) Expression analysis of loci associated with type 2 diabetes in human tissues. Diabetologia 53:2334–2339PubMedCrossRef

Titel: Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B
verfasst von: M. L. Hribal
I. Presta
T. Procopio
M. A. Marini
A. Stančáková
J. Kuusisto
F. Andreozzi
A. Hammarstedt
P.-A. Jansson
N. Grarup
T. Hansen
M. Walker
N. Stefan
A. Fritsche
H. U. Häring
O. Pedersen
U. Smith
M. Laakso
G. Sesti
on behalf of the EUGENE2 Consortium
Publikationsdatum: 01.04.2011
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 4/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-010-2038-8

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Die „Zehn Gebote“ des Endokarditis-Managements

30.04.2024 Endokarditis Leitlinie kompakt

Worauf kommt es beim Management von Personen mit infektiöser Endokarditis an? Eine Kardiologin und ein Kardiologe fassen die zehn wichtigsten Punkte der neuen ESC-Leitlinie zusammen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2011

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults

Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells

Intrahepatic and intramyocellular lipids are determinants of insulin resistance in prepubertal children

Relationship between ADIPOQ gene, circulating high molecular weight adiponectin and albuminuria in individuals with normal kidney function: evidence from a family-based study

Stressed hearts in children with obesity and diabetes: a cause for concern?