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A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 Diabetes

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A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 Diabetes CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Cell Metabolism Article A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 Diabetes Thomas Koeck,1 Anders H. Olsson,1 Marloes Dekker Nitert,1 Vladimir V. Sharoyko,1 Claes Ladenvall,1 Olga Kotova,1 Erwin Reiling,2 Tina Ro¨ nn,1 Hemang Parikh,1 Jalal Taneera,1 Johan G. Eriksson,3,4 Metodi D. Metodiev,5 Nils-Go¨ ran Larsson,5 Alexander Balhuizen,1 Holger Luthman,1 Alena Stanca ´ kova´ ,6 Johanna Kuusisto,6 Markku Laakso,6 Pernille Poulsen,7,8 Allan Vaag,7 Leif Groop,1 Valeriya Lyssenko,1 Hindrik Mulder,1,9 and Charlotte Ling1,9,* 1Department of Clinical Sciences, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmo¨ , Sweden 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands 3National Institute for Health and Welfare, Helsinki, Finland 4Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland 5Max Planck Institute for Biology of Ageing, Cologne D-50931, Germany 6Department of Medicine, University of Eastern Finland, 70210 Kuopio, Finland 7Steno Diabetes Center, 2820 Gentofte, Denmark 8Novo Nordisk, DK-2860 Soeborg, Denmark 9These authors contributed equally to this work *Correspondence: [email protected] DOI 10.1016/j.cmet.2010.12.007 SUMMARY and metabolized, generating metabolic coupling signals that trigger and amplify exocytosis (Henquin, 2009). In target tissues Type 2 diabetes (T2D) evolves when insulin secretion of insulin, the hormone controls glucose metabolism, including fails. Insulin release from the pancreatic b cell is regulation of mitochondrial metabolism. In view of these funda- controlled by mitochondrial metabolism, which mental principles, it is of no surprise that mitochondrial dysfunc- translates fluctuations in blood glucose into meta- tion has been implicated both in impaired insulin secretion and bolic coupling signals. We identified a common action. These pathogenic processes both precede manifest variant (rs950994) in the human transcription factor T2D. In fact, patients with mitochondrial dysfunction caused by mutations in mitochondrial DNA (mtDNA) often develop impaired B1 mitochondrial (TFB1M) gene associated with insulin secretion (Goto et al., 1990; Reardon et al., 1992; van den reduced insulin secretion, elevated postprandial Ouweland et al., 1992). Experimental studies have demonstrated glucose levels, and future risk of T2D. Because islet that insulin secretion is critically dependent on mtDNA expres- TFB1M mRNA levels were lower in carriers of the sion in pancreatic b cells (Silva et al., 2000). While several genes risk allele and correlated with insulin secretion, we with important functions in mitochondrial oxidative phosphoryla- examined mice heterozygous for Tfb1m deficiency. tion (OXPHOS) show reduced expression in patients with T2D, These mice displayed lower expression of TFB1M only a few polymorphisms in these genes have been associated in islets and impaired mitochondrial function and with the disease (Ling et al., 2007a, 2008; Mootha et al., 2003; released less insulin in response to glucose in vivo Ro¨ nn et al., 2008, 2009). and in vitro. Reducing TFB1M mRNA and protein The OXPHOS system, including the electron transport system in clonal b cells by RNA interference impaired (ETS) and ATP synthase, is located in the inner mitochondrial membrane. It consists of multiprotein complexes with approxi- complexes of the mitochondrial oxidative phosphor- mately 90 known subunits encoded by both the nuclear and ylation system. Consequently, nutrient-stimulated mitochondrial genomes (Scarpulla, 2008). The mitochondrial ATP generation was reduced, leading to perturbed genome, mtDNA, encodes 13 of the protein subunits present in insulin secretion. We conclude that a deficiency in the ETS and ATP synthase as well as two rRNAs and 22 tRNAs. TFB1M and impaired mitochondrial function contri- Transcription of mtDNA requires a specialized machinery, bute to the pathogenesis of T2D. including factors necessary for promoter recognition, such as mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M) (Falkenberg et al., 2002; Litonin INTRODUCTION et al., 2010; Metodiev et al., 2009; Scarpulla, 2008; Sologub et al., 2009). Mitochondrial transcription factor B1 (TFB1M) is Type 2 diabetes (T2D) is a multifactorial and polygenic disorder, a paralogue of TFB2M, but is probably not a transcription factor characterized by impaired insulin secretion from pancreatic (Litonin et al., 2010; Metodiev et al., 2009). Instead, TFB1M is b cells and insulin resistance in peripheral tissues. Insulin secre- an essential methyltransferase that dimethylates two highly tion is controlled by fuel metabolism in pancreatic b cells. When conserved adenines present in a conserved stem-loop structure plasma glucose levels rise, glucose is transported into the b cells at the 30 end of the 12S rRNA (Metodiev et al., 2009). The 80 Cell Metabolism 13, 80–91, January 5, 2011 ª2011 Elsevier Inc. Cell Metabolism TFB1M Is a Pathogenetic Factor in T2D Table 1. Clinical Characteristics of Participants in the Diabetes Genetics Initiative, DGI; the Prevalence, Prediction and Prevention of Diabetes, Botnia PPP; the Helsinki Birth Cohort Study; the METabolic Syndrome In Men Study, METSIM; and the Malmo¨ Preventive Project, MPP Helsinki Birth DGI (Controls) DGI (T2D) Botnia PPP Cohort Study METSIM MPP n (male/female) 1467 (707/760) 1464 (741/723) 4553 (2134/2419) 1618 (713/905) 6602 (6602/—) 16061 (10416/5645) Age (years) 58.8 ± 10.1 64.4 ± 10.2 48.4 ± 15.6 61.6 ± 3.0 57.1 ± 6.9 45.5 ± 6.9 BMI (kg/m2) 26.6 ± 3.7 28.5 ± 4.5 26.3 ± 4.3 27.1 ± 4.3 26.8 ± 3.8 24.3 ± 3.3 Fasting plasma glucose 5.3 ± 0.5 9.5 ± 3.1 5.28 ± 0.57 5.49 ± 0.56 5.70 ± 0.49 5.45 ± 0.56 (mmol/l) Glucose 30 min (mmol/l) 8.3 ± 1.5 13.3 ± 2.9 8.35 ± 1.55 9.10 ± 1.61 8.79 ± 1.43 9.97 ± 1.90 Glucose 120 min (mmol/l) 5.6 ± 1.3 14.7 ± 5.1 5.28 ± 1.64 6.88 ± 1.71 6.04 ± 1.68 6.39 ± 1.65 Fasting insulin (mU/l) 5.2 (4.3) 9.1 (9.0) 5.4 (4.2) 7.8 (6.5) 6.4 (5.7) — Insulin 30 min (mU/l) 50.2 (48.9) 28.0 (35.7) 50.3 (38.4) 62.0 (50.2) 52.6 (46.8) — Insulin 120 min (mU/l) 36.2 (29.7) 45.0 (50.3) 24.1 (26.7) 56.2 (56.6) 34.6 (42.6) — Insulinogenic index 14.1 (14.8) 3.5 (5.2) 15.8 (16.0) 15.9 (15.9) 16.2 (16.6) — Insulin sensitivity index (ISI) 8.6 (6.6) 3.8 (3.6) 8.0 (6.1) 5.0 (4.0) 6.2 (5.3) — Data are expressed as mean ± SD or median (interquartile range [IQR]). See also Table S2. modification of 12S rRNA is essential for the integrity of the a nominally increased risk of T2D (odds ratio [OR] = 1.13, 95% small mitochondrial ribosomal subunit and mitochondrial confidence interval [CI] = 1.02–1.25, p = 0.017) in DGI. translation is abolished in its absence (Metodiev et al., 2009). rs950994 is located in intron 2 of the TFB1M gene (Figure 1A TFB1M is alternatively known as dimethyladenosine transferase and Figure S1, available online). 1 mitochondrial (mDMAT1) in protein databases. In view of the important role of ATP production in metabolic Insulin Secretion and Postprandial Glucose Levels homeostasis, we examined whether polymorphisms in genes In Vivo of the OXPHOS system and the mtDNA transcription and trans- Next, we examined whether the association of TFB1M rs950994 lation machinery are associated with b cell dysfunction, insulin with impaired insulin secretion could be replicated in additional resistance and/or T2D. To this end, we examined data from cohorts (Tables 1 and 2). In accordance with the effect of a genome-wide association study (GWAS), the Diabetes rs950994 in DGI, A-allele carriers of rs950994 showed Genetics Initiative (DGI) (Saxena et al., 2007). We identified decreased insulinogenic index in the Botnia Prevalence, Predic- a common variant (rs950994) in the human TFB1M gene, which tion and Prevention of Diabetes (Botnia PPP) study (b = À0.045 ± was associated with an impaired insulin response to glucose, 0.018, p = 0.01); this effect was stronger in elderly individuals elevated glucose levels during an oral glucose tolerance test (age > median 50 yr, b = À0.085 ± 0.025, p = 0.001) (Table 2 (OGTT), increased future risk of T2D, and reduced islet TFB1M and Table S1). In the METabolic Syndrome in Men (METSIM) expression. Accordingly, we proceeded to study mice with study and the Helsinki Birth Cohort Study (HBCS), rs950994 a heterozygous deficiency of Tfb1m and clonal b cells, where did not exert a significant effect on insulin secretion (Table 2). Tfb1m had been silenced to mimic the human situation. We Given that the METSIM study only included males, we asked found that reduced levels of TFB1M caused impaired OXPHOS whether gender could affect the association of TFB1M and consequently decreased insulin secretion. This study rs950994 with impaired insulin secretion. It is not uncommon provides conclusive genetic and functional evidence that the that gender is a determinant of genetic associations (Galimberti TFB1M gene is associated with increased risk of T2D by causing et al., 2008; Joyner et al., 2009; Kolz et al., 2009; Miyashita et al., impaired insulin secretion. 2007; Rimol et al., 2010), and metabolism in itself is known to be influenced by sex hormones. Indeed, the A-allele of rs950994 RESULTS was associated with decreased insulinogenic index in females (Botnia PPP: b = À0.065 ± 0.024, p = 0.008; DGI: b =À0.20 ± Identification of a Genetic Locus Associated 0.06, p = 0.0005), but not in males (Botnia PPP: p = 0.46 and with Quantitative Metabolic Traits and T2D DGI: p = 0.10) (Table 2).
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