Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response

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1 Dietologi (2009) 52: DOI /s x ARTICLE Common genetic vrition in the meltonin receptor 1B gene (MTNR1B) is ssocited with decresed erly-phse insulin response C. Lngenerg & L. Pscoe & A. Mri & A. Tur & M. Lkso & T. M. Fryling & I. Brroso & R. J. F. Loos & N. J. Wrehm & M. Wlker & The RISC Consortium Received: 11 Ferury 2009 /Accepted: 9 April 2009 /Pulished online: 20 My 2009 # The Author(s) This rticle is pulished with open ccess t Springerlink.com Astrct Aims/hypothesis We investigted whether vrition in MTNR1B, which ws recently identified s common genetic determinnt of fsting glucose levels in helthy, dietes-free individuls, is ssocited with mesures of et cell function nd whole-ody insulin sensitivity. Methods We studied 1,276 helthy individuls of Europen ncestry t 19 centres of the Reltionship etween Insulin Sensitivity nd Crdiovsculr disese (RISC) study. Wholeody insulin sensitivity ws ssessed y euglycemic hyperinsulinemic clmp nd indices of et cell function were derived from 75 g orl glucose tolernce test (including 30 min insulin response nd glucose sensitivity). We studied rs in MTNR1B using dditive genetic models, djusting for ge, sex nd recruitment centre. Results The minor (G) llele of rs in MTNR1B (frequency 0.30 in HpMp Centre d Etude du Polymorphisme [Uth residents with northern nd western Europen ncestry] [CEU]; 0.29 in RISC prticipnts) ws ssocited with higher levels of fsting plsm glucose (stndrdised et [95% CI] 0.17 [0.085, 0.25] per G llele, p= ), consistent with recent oservtions. In ddition, the G-llele ws significntly ssocited with lower erly insulin response ( 0.19 [ 0.28, 0.10], p= ), s well s with decresed et cell glucose sensitivity ( 0.11 [ 0.20, 0.027], p=0.010). No ssocitions were oserved with clmp-ssessed insulin sensitivity (p=0.15) or different mesures of ody size (p>0.7 for ll). Conclusions/interprettion Genetic vrition in MTNR1B is ssocited with defective erly insulin response nd decresed et cell glucose sensitivity, which my contriute to the higher glucose levels of non-dietic individuls crrying the minor G llele of rs in MTNR1B. Electronic supplementry mteril The online version of this rticle (doi: /s x) contins list of the memers of the RISC Consortium, which is ville to uthorised users. C. Lngenerg (*) : R. J. F. Loos : N. J. Wrehm MRC Epidemiology Unit, Institute of Metolic Science, Addenrooke s Hospitl, Box 285, Cmridge CB2 0QQ, UK e-mil: cludi.lngenerg@mrc-epid.cm.c.uk L. Pscoe : M. Wlker Institute of Cellulr Medicine, Newcstle University, Newcstle upon Tyne, UK A. Mri : A. Tur CNR Institute of Biomedicl Engineering, Pdov, Itly M. Lkso Deprtment of Medicine, University of Kuopio nd Kuopio University Hospitl, Kuopio, Finlnd T. M. Fryling Dietes Genetics Group nd Genetics of Complex Trits, Peninsul Medicl School, Exeter, UK I. Brroso Metolic Disese Group, Wellcome Trust Snger Institute, Wellcome Trust Genome Cmpus, Hinxton, Cmridge, UK

2 1538 Dietologi (2009) 52: Keywords Genome-wide ssocition. Glucose sensitivity. Insulin resistnce. Insulin sensitivity. Meltonin receptor 1B. MTNR1B Arevitions GWAS Genome-wide ssocition studies RISC Reltionship etween Insulin Sensitivity nd Crdiovsculr disese SNP Single nucleotide polymorphism impirment of erly insulin response to orl nd intrvenous glucose, nd with fster deteriortion of insulin secretion over time [8]. Thus our ojective ws to study whether the ssocition etween MTNR1B nd fsting glucose is medited through reduced pncretic et cell function, insulin secretion or whole-ody insulin sensitivity in individuls prticipting in the Reltionship etween Insulin Sensitivity nd Crdiovsculr disese (RISC) study [9]. Introduction Compred with recent progress in the discovery of genes for type 2 dietes, knowledge of genetic influences on fsting glucose levels in helthy individuls is limited. Common sequence vrints relted to the GCK promoter [1 3], G6PC2 [2, 3] nd GCKR [4 6] re the most significnt determinnts of fsting glucose levels identified in recent lrge-scle genome-wide ssocition studies (GWAS), yet without demonstrle consistent effects on the risk of type 2 dietes [7]. Vice-vers, none of the estlished type 2 dietes genes hve emerged s convincing loci for fsting glucose within the norml rnge in recent GWAS [2, 7]. This suggests tht common vrints contriuting to smll physiologicl vrition in fsting glucose my e different from those tht increse type 2 dietes susceptiility. One exception is noteworthy; in recently pulished exchnge of top fsting glucose hits from four lrge GWAS consorti, vrints in the gene encoding the meltonin receptor 1B (MTNR1B) were not only consistently ssocited with fsting glucose cross ll studies totlling 36,610 helthy dult prticipnts in the met-nlysis of the MTNR1B region [7], ut crriers of the risk llele of the most significnt overll signl t rs (minor G llele; frequency 0.30 in HpMp Centre d Etude du Polymorphisme [Uth residents with northern nd western Europen ncestry] [CEU]) were lso t incresed risk of type 2 dietes (odds rtio [95% CI] 1.09 [1.05, 1.12]) in seprte met-nlysis of cse control studies [7]. The novel link etween MTNR1B nd type 2 dietes ws confirmed in two other studies, one investigting the sme vrint [8], nd nother reporting rs (r 2 with rs =0.70) to e the most significnt single nucleotide polymorphism (SNP) in GWAS of 2,151 French prticipnts [2]. Investigting the mechnisms through which MTNR1B contriutes to vrition in fsting glucose levels in helthy, non-dietic individuls my help to understnd wht underlies the MTNR1B-relted risk of progression to clinicl dietes. Lyssenko et l. hve reported tht the risk genotype ws ssocited with Methods The recruitment, methods, nd inclusion nd exclusion criteri of the RISC cohort hve een descried previously [9]. Briefly, helthy men nd women of Europen ncestry, ged etween 30 nd 60 yers, were recruited from 19 centres in 14 Europen countries. Individuls with dietes, hypertension or dyslipidemi were excluded [9]. Anlyses presented in this study re sed on 1,276 prticipnts who met the eligiility criteri nd for whom complete genotype dt were ville. Locl ethics committee pprovl ws otined y ech recruitment centre nd written consent ws otined from ll prticipnts. Prticipnts underwent 75 g OGTT with lood smpling efore nd t 30, 60, 90 nd 120 min fter the orl glucose lod. On seprte dy within 1 month of the OGTT, prticipnts underwent euglycemic hyperinsulinemic clmp s previously reported [9]. To ensure consistency cross study centres, the clmp procedure ws stndrdised nd ech centre underwent prestudy trining. Clmp dt were then trnsferred nd nlysed t the RISC coordinting centre (Pis, Itly) nd qulity ssured ginst preset criteri. These were s follows: clmped glucose levels within 20% of trget (fsting glucose concentrtion), coefficient of vrition of 15%, voidnce of hypoglycemi (glucose <3.5 mmol/l). Insulin sensitivity ws ssessed s the men glucose infusion rte over the lst 40 min of the clmp, corrected for the men plsm insulin levels chieved during the sme period. Pncretic et cell function ws ssessed using the OGTT dt. The 30 min insulin response ws clculted s the rtio of the insulin concentrtion increment to the 30 min glucose concentrtion (30 min insulin 0 min insulin/30 min glucose) [10]. We dditionlly performed sensitivity nlyses using other commonly derived indices of erly insulin response, including insulinogenic index (30 min insulin 0 min insulin/30 min glucose 0 min glucose) nd corrected insulin response [11]. Indices of et cell function vriles were derived from mthemticl nlysis of plsm glucose nd C-peptide, using C-peptide deconvolution, s previously descried in more detil [12]. In ddition, detiled nthropometric ssessment ws performed nd ft mss determined s the difference

3 Dietologi (2009) 52: etween ody weight nd ft-free mss determined y ioimpednce (Tnit Interntionl Division, Yiewsley, UK). Smples were processed nd stored loclly efore eing trnsferred to the centrl ssy lortories nd nlysed s previously reported [9]. Genomic DNA ws extrcted using kit (Nucleon BACC2; Tepnel Life Sciences, Mnchester, UK). All smples were genotyped t KBiosciences (KBiosciences, Hoddesdon, UK) [12]; the cll rte ws 98% nd genotype frequencies were in Hrdy Weinerg equilirium (p=0.33). Duplicte genotyping of 5% of DNA smples ws conducted with 100% success. We normlised the distriutions of OGTT nd clmp outcomes using the nturl logrithm; these dt re presented s medin nd interqurtile rnge. Liner regression nlyses using n dditive genetic model were performed to test for ssocitions etween rs nd selected phenotypes, djusting for ge, sex nd recruitment centre. Stndrdised mesures were used in regression nlyses; these were clculted y sutrcting the men of ech outcome from n individul s vlue nd dividing this y the stndrd devition, seprtely y sex, nd using log e trnsformed mesures. This results in norml distriution for ech mesure with men of 0 nd stndrd devition of 1, nd llows the strength of the genotype effect to e compred cross severl outcomes with different distriutions nd units. As previously reported [12], the cohort hd 80% power t p=0.01 to detect differences of 0.18 SD per llele for minor llele frequency of Results The minor (G) llele of rs ws significntly ssocited with higher fsting glucose levels (stndrdised et [95% CI] 0.17 [0.085, 0.25] per G llele, p= ) (Fig. 1) consistent with recent oservtions [7]. In ddition, we oserved significntly higher glucose levels t 30 nd 60 min (stndrdised et [95% CI] 0.15 [0.065, 0.23], p= nd 0.13 [0.046, 0.21], p= , respectively) (Fig. 1), ut not t 90 or 120 min during the OGTT (p=0.21 nd 0.93, respectively). Vrition t rs ws not ssocited with whole-ody insulin sensitivity mesured y euglycemic hyperinsulinemic clmps (stndrdised et [95% CI] [ 0.024, 0.15], p=0.15) (Fig. 2). In contrst, significnt differences in indices of pncretic et cell function were found. Individuls crrying the minor (G) llele hd significntly lower 30 min insulin response (stndrdised et [95% CI] 0.19 [ 0.28, 0.10], p= )(Fig.2), s well s et cell glucose sensitivity (stndrdised et [95% CI] 0.11 [ 0.20, 0.027], p=0.010). These ssocitions remined significnt fter dditionl djustment for whole-ody insulin sensitivity (p= nd respectively). Similr results were otined in Stndrdised glucose score Stndrdised insulin score sensitivity nlyses using the insulinogenic index (p= ) or corrected insulin response (p= ) s lterntive mesures of erly insulin response. Associtions with insulin (Fig. 1) nd C-peptide (dt not shown) mirrored these oservtions, with the only time point during the OGTT t which significnt differences were found eing t 30 min (stndrdised et [95% CI] 0.15 [ 0.23, 0.061], p= for insulin; [ 0.17, ], p=0.039 for C- peptide). No significnt ssocitions were oserved etween vrition in MTNR1B nd different mesures of ody size (Tle 1). Discussion Time t orl glucose tolernce test (min) Time t orl glucose tolernce test (min) Fig. 1 Effect of rs in MTNR1B on glucose () nd insulin () levels during the OGTT (per llele difference nd 95% CI). p= ; p= ; c p= ; d p=0.211; e p= p= 0.135; p= ; c p=0.868; d p=0.259; e p=0.727 Recent evidence from lrge-scle met-nlysis of GWAS showed tht vrition in MTNR1B is common genetic determinnt of fsting glucose in helthy, dietes-free individuls. We show here tht vrition in MTNR1B is significntly ssocited with erly insulin response nd et cell glucose sensitivity, while no effect on whole-ody insulin sensitivity ws oserved. The minor (G) risk llele of rs in MTNR1B ws ssocited with lower et cell glucose sensitivity nd 30 min insulin response efore nd fter ccounting for whole-ody insulin sensitivity levels. These findings re in keeping with primry defect of et cell function rther thn secondry chnges in response to ltered insulin sensitivity, nd support the oservtions of other studies, c c d d e e

4 1540 Dietologi (2009) 52: Stndrdised score Insulin response t 30 min Bet cell glucose sensitivity Fig. 2 Effect of rs in MTNR1B on erly insulin response, et cell glucose sensitivity nd whole-ody insulin sensitivity (M/I) (per llele difference nd 95% CI). p= ; p=0.010; c p=0.154 c M/I which hve reported decresed erly insulin response nd decresed disposition index in G llele crriers of the sme vrint [8, 13]. Interestingly, we found significnt ssocitions of rs with insulin nd C-peptide t 30 min during the OGTT, ut not t ny other time point, gin highlighting tht the min effect ppers to e on erlyphse insulin response. The emerging evidence strongly suggests tht the meltonin system directly modultes the insulin secretory response to glucose. It hs een shown tht MTNR1B is expressed in humn islets, nd specificlly in pncretic et nd lph cells [8, 14, 15]. Furthermore, MTNR1B gene expression ws incresed in isolted islets from older (>45 yers of ge) G llele crriers of rs , nd exposure of clonl et cells to meltonin Tle 1 Reltionships etween rs genotypes nd key phenotypic trits Phenotype Men (SD)/medin (IQR) Men (SD), medin (IQR) y genotype p vlue CC (mx n=655) GC (mx n=505) GG (mx n=114) Sex (% women) Age (yers) 43.9 (8.3) 44 (8.2) 44 (8.2) 43 (9.3) 0.34 BMI (kg/m 2 ) 25.7 (4.1) 25.5 (4.0) 25.6 (4.1) 25.8 (4.1) 0.81 Wist (cm) 86 (77 96) 85 (76 95) 86 (78 96) 88 (79 96) 0.93 Ft mss (kg) 21.2 (8.9) 21.2 (8.9) 21.0 (8.9) 20.2 (9.2) 0.78 Glucose (mmol/l) OGTT 0 min (fsting) 5.1 ( ) 5.0 ( ) 5.1 ( ) 5.2 ( ) OGTT 30 min 8.0 ( ) 7.8 ( ) 8.2 ( ) 7.9 ( ) OGTT 60 min 7.5 ( ) 7.2 ( ) 7.8 ( ) 7.7 ( ) OGTT 90 min 6.2 ( ) 6.1 ( ) 6.4 ( ) 6.2 ( ) 0.21 OGTT 120 min 5.6 ( ) 5.6 ( ) 5.6 ( ) 5.5 ( ) 0.93 Insulin (pmol/l) OGTT 0 min (fsting) 31.0 ( ) 31.0 ( ) 31.0 ( ) 28.5 ( ) 0.32 OGTT 30 min 240 ( ) 244 ( ) 238 ( ) 199 ( ) OGTT 60 min 269 ( ) 265 ( ) 266 ( ) 244 ( ) 0.87 OGTT 90 min 200 ( ) 196 ( ) 210 ( ) 197 ( ) 0.26 OGTT 120 min 153 (89 257) 147 (89 249) 151 (85 251) 159 (73 226) 0.73 C-peptide (pmol/l) OGTT 0 min (fsting) 540 ( ) 528 ( ) 562 ( ) 525 ( ) 0.88 OGTT 30 min 1,891 (1,502 2,387) 1,910 (1,517 2,403) 1,894 (1,511 2,391) 1,704 (1,416 2,095) OGTT 60 min 2,509 (2,008 3,098) 2,440 (1,961 3,029) 2,558 (2,066 3,182) 2,562 (1,927 3,022) 0.78 OGTT 90 min 2,406 (1,863 3,036) 2,336 (1,789 2,958) 2,509 (1,955 3,116) 2,512 (1,843 3,148) 0.24 OGTT 120 min 2,154 (1,642 2,777) 2,121 (1,598 2,743) 2,213 (1,677 2,789) 2,252 (1,603 2,777) min insulin response (pmol/mmol) 26.3 ( ) 28.0 ( ) 25.9 ( ) 22.0 ( ) Bet cell glucose sensitivity 113 (79 158) 118 (82 169) 109 (74 150) 102 (74 148) Insulin sensitivity 128 (92 177) 128 (90 175) 128 (92 180) 135 (99 175) 0.15 Comprisons etween genotypes (dditive model) re sed on liner regression nlysis of log e -trnsformed dt (where pplicle) nd using sex-specific stndrdised outcomes for OGTT nd clmp mesures, djusting for ge, sex nd recruitment centre Sex differences were tested using χ 2 test In pmol min 1 m 2 mmol 1 In μmol min 1 (kg ft-free mss) 1 nmol 1 IQR, interqurtile rnge

5 Dietologi (2009) 52: decresed the cute insulin secretory response to glucose [8]. It hs lso een postulted tht meltonin might influence insulin secretion through prcrine effect of glucgon [14]. We found tht vrition in MTNR1B ws not ssocited with fsting glucgon levels (dt not shown), ut we did not mesure the glucgon response during the OGTT. Meltonin plys role in regultion of the circdin clock, nd meltonin nd insulin oth show mrked circdin vriility [16, 17]. Dt from humn nd rodent studies suggest tht disturnces of circdin rhythmicity my ffect metolic control nd the risk of dietes [18, 19]. Moreover, overexpression of meltonin receptors hs een oserved in islets from ptients with type 2 dietes compred with non-dietic controls [20]. Tken together, these findings suggest tht n effect of MTNR1B on the insulin secretory response to glucose my underlie the reported ssocitions with fsting glucose nd the risk of type 2 dietes, dding to the ody of evidence linking circdin rhythm nd metolic control nd disese. A key oservtion of our study is tht there ws no significnt ssocition etween the MTNR1B vrint nd whole-ody insulin sensitivity, despite the fct tht this is one of the lrgest collections of helthy people of Europen ncestry to e phenotyped using the gold stndrd euglycemic hyperinsulinemic clmp technique. In ddition, we hve replicted with the RISC cohort the oservtions tht common FTO vrint nd the Pro12Al PPARG vrint influence whole-ody insulin sensitivity in mn [12]. This would suggest tht if vrition in MTNR1B does ffect insulin sensitivity, then it is likely to e functionlly wek nd of questionle clinicl significnce. In support of this, Stiger et l. recently reported tht none of five tgging SNPs covering ll common genetic vrition of the MTNR1B locus showed n ssocition with clmp-derived insulin sensitivity in selected group of 513 individuls t incresed risk of type 2 dietes [13]. We lso found no significnt ssocitions etween MTNR1B nd different mesures of ody size, suggesting tht the effects seen on et cell function re not influenced y n ltertion in diposity. As we recently reported, individul type 2 dietes risk lleles in TCF7L2, HHEX, IDE nd CDKAL1 comine in n dditive mnner to impct upon pncretic et cell function [21]. Bet cell glucose sensitivity ws decresed y 39% in individuls with five or more risk lleles compred with individuls who hd no risk lleles. Inclusion of the MTNR1B risk vrint in the nlysis led to 47% difference (p= ) etween the zero-llele group those with more thn six lleles. A similr chnge ws noted for the 30 min insulin response. We hd previously found 43% decrese etween the zero-llele group nd the group with more thn five lleles. Inclusion of the MTNR1B vrint incresed tht vlue to 49% etween the zero-llele group nd those with more thn six lleles. We conclude tht MTNR1B is ssocited with defective erly insulin response nd decresed et cell glucose sensitivity, oth of which my contriute to the higher glucose levels nd incresed dietes risk of individuls crrying the minor G llele of rs In contrst, no ssocition with whole-ody insulin sensitivity ws oserved in this lrge collection of helthy people of Europen ncestry. Acknowledgements The RISC Study is supported y Europen Union grnt QLG1-CT nd AstrZenec. L. Pscoe is the recipient of joint BBSRC nd Unilever UK cse PhD studentship. I. Brroso cknowledges funding from The Wellcome Trust grnt /Z/05/Z. Dulity of interest The uthors declre tht there is no dulity of interest ssocited with this mnuscript. Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution Noncommercil License which permits ny noncommercil use, distriution, nd reproduction in ny medium, provided the originl uthor(s) nd source re credited. References 1. Weedon MN, Clrk VJ, Qin Y et l (2006) A common hplotype of the glucokinse gene lters fsting glucose nd irth weight: ssocition in six studies nd popultion-genetics nlyses. Am J Hum Genet 79: Bouti-Nji N, Rocheleu G, Vn LL et l (2008) A polymorphism within the G6PC2 gene is ssocited with fsting plsm glucose levels. Science 320: Chen WM, Erdos MR, Jckson AU et l (2008) Vritions in the G6PC2/ABCB11 genomic region re ssocited with fsting glucose levels. J Clin Invest 118: Sxen R, Voight BF, Lyssenko V et l (2007) Genome-wide ssocition nlysis identifies loci for type 2 dietes nd triglyceride levels. Science 316: Vxillire M, Cvlcnti-Proenc C, Dechume A et l (2008) The common P446L polymorphism in GCKR inversely modultes fsting glucose nd triglyceride levels nd reduces type 2 dietes risk in the DESIR prospective generl French popultion. Dietes 57: Orho-Melnder M, Melnder O, Guiducci C et l (2008) Common missense vrint in the glucokinse regultory protein gene is ssocited with incresed plsm triglyceride nd C-rective protein ut lower fsting glucose concentrtions. Dietes 57: Prokopenko I, Lngenerg C, Florez JC et l (2009) Vrints in MTNR1B influence fsting glucose levels. Nture genetics 41: Lyssenko V, Ngorny CL, Erdos MR et l (2009) Common vrint in MTNR1B ssocited with incresed risk of type 2 dietes nd impired erly insulin secretion. Nture genetics 41: Hills SA, Blku B, Coppck SW et l (2004) The EGIR-RISC STUDY (The Europen group for the study of insulin resistnce: reltionship etween insulin sensitivity nd crdiovsculr disese risk): I. Methodology nd ojectives. Dietologi 47:

6 1542 Dietologi (2009) 52: Wrehm NJ, Phillips DI, Byrne CD, Hles CN (1995) The 30 minute insulin incrementl response in n orl glucose tolernce test s mesure of insulin secretion. Diet Med 12: Hnson RL, Prtley RE, Bogrdus C et l (2000) Evlution of simple indices of insulin sensitivity nd insulin secretion for use in epidemiologic studies. Am J Epidemiol 151: Pscoe L, Tur A, Ptel SK et l (2007) Common vrints of the novel type 2 dietes genes CDKAL1 nd HHEX/IDE re ssocited with decresed pncretic et-cell function. Dietes 56: Stiger H, Mchico F, Schfer SA et l (2008) Polymorphisms within the novel type 2 dietes risk locus MTNR1B determine et-cell function. PLoS ONE 3:e Rmrchey RD, Muller DS, Squires PE et l (2008) Function nd expression of meltonin receptors on humn pncretic islets. J Pinel Res 44: Bouti-Nji N, Bonnefond A, Cvlcnti-Proenc C et l (2009) A vrint ner MTNR1B is ssocited with incresed fsting plsm glucose levels nd type 2 dietes risk. Nture genetics 41: Boden G, Ruiz J, Urin JL, Chen X (1996) Evidence for circdin rhythm of insulin secretion. Am J Physiol 271:E246 E Stumpf I, Muhluer E, Peschke E (2008) Involvement of the cgmp pthwy in mediting the insulin-inhiitory effect of meltonin in pncretic et-cells. J Pinel Res 45: Turek FW, Joshu C, Kohsk A et l (2005) Oesity nd metolic syndrome in circdin clock mutnt mice. Science 308: Spiegel K, Leproult R, Vn Cuter E (1999) Impct of sleep det on metolic nd endocrine function. Lncet 354: Peschke E, Stumpf I, Bzwinsky I, Litvk L, Drlle H, Muhluer E (2007) Meltonin nd type 2 dietes possile link? J Pinel Res 42: Pscoe L, Fryling TM, Weedon MN et l (2008) Bet cell glucose sensitivity is decresed y 39% in non-dietic individuls crrying multiple dietes-risk lleles compred with those with no risk lleles. Dietologi 51:

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