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1.  Adipose Tissue TCF7L2 Splicing Is Regulated by Weight Loss and Associates With Glucose and Fatty Acid Metabolism 
Diabetes  2012;61(11):2807-2813.
We investigated the effects of obesity surgery-induced weight loss on transcription factor 7-like 2 gene (TCF7L2) alternative splicing in adipose tissue and liver. Furthermore, we determined the association of TCF7L2 splicing with the levels of plasma glucose and serum free fatty acids (FFAs) in three independent studies (n = 216). Expression of the short mRNA variant, lacking exons 12, 13, and 13a, decreased after weight loss in subcutaneous fat (n = 46) and liver (n = 11) and was more common in subcutaneous fat of subjects with type 2 diabetes than in subjects with normal glucose tolerance in obese individuals (n = 54) and a population-based sample (n = 49). Additionally, there was a positive correlation between this variant and the level of fasting glucose in nondiabetic individuals (n = 113). This association between TCF7L2 splicing and plasma glucose was independent of the TCF7L2 genotype. Finally, this variant was associated with high levels of serum FFAs during hyperinsulinemia, suggesting impaired insulin action in adipose tissue, whereas no association with insulin secretion or insulin-stimulated whole-body glucose uptake was observed. Our study shows that the short TCF7L2 mRNA variant in subcutaneous fat is regulated by weight loss and is associated with hyperglycemia and impaired insulin action in adipose tissue.
PMCID: PMC3478533  PMID: 23086040
2.  Dietary Fat in Relation to Erythrocyte Fatty Acid Composition in Men 
Lipids  2013;48:1093-1102.
Erythrocyte membrane fatty acid (EMFA) composition is used in the validation of food frequency questionnaires (FFQ) and the evaluation of dietary fat quality. In this cross-sectional study we aimed to investigate associations of diet with EMFA. Altogether, 1,033 randomly selected Finnish men, aged from 47 to 75 years filled in a FFQ and their EMFA composition was analyzed. Marine polyunsaturated fatty acid (PUFA) intake correlated positively with erythrocyte eicosapentaenoic and docosahexaenoic acids (rs = 0.415 and rs = 0.340, respectively, P < 0.001) and inversely with all n-6 PUFA analyzed (P < 0.001). PUFA intake from spreads and cooking fats correlated positively with alpha-linolenic (ALA), linoleic (LNA) and nervonic acids (rs = 0.229, rs = 0.160 and rs = 0.143, respectively, P < 0.001). Milk fat intake was associated with myristic and behenic acids (rs = 0.186 and rs = 0.132, respectively P < 0.001). Butter users had lower ALA and LNA proportions (mol%) than non-users (0.16 ± 0.04 vs. 0.19 ± 0.05, P < 0.001 and 7.77 ± 1.02 vs. 8.12 ± 1.11, P = 0.001). Higher PUFA intake from meat was related to decreased long-chain n-3 (P < 0.001) and increased n-6 PUFA (P < 0.001) proportions. In conclusion, EMFA composition reflects particularly well the intakes of n-3 PUFA, whereas other associations remained lower. Yet, all main sources of dietary fat were related with EMFA. The dietary effect on the nervonic acid proportion was confirmed.
PMCID: PMC3824229  PMID: 23975575
Dietary fatty acids; Erythrocyte phospholipids; Food frequency questionnaire; Fat quality
3.  Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women 
Diabetes Care  2012;35(8):1749-1756.
Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level.
Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 years for 618 individuals in one of the cohorts. Metabolites were quantified by nuclear magnetic resonance spectroscopy from fasting serum samples. Associations were studied by linear regression models adjusted for established risk factors.
Nineteen circulating metabolites, including amino acids, gluconeogenic substrates, and fatty acid measures, were cross-sectionally associated with fasting and/or postload glucose (P < 0.001). Among these metabolic intermediates, branched-chain amino acids, phenylalanine, and α1-acid glycoprotein were predictors of both fasting and 2-h glucose at 6.5-year follow-up (P < 0.05), whereas alanine, lactate, pyruvate, and tyrosine were uniquely associated with 6.5-year postload glucose (P = 0.003–0.04). None of the fatty acid measures were prospectively associated with glycemia. Changes in fatty acid concentrations were associated with changes in fasting and postload glycemia during follow-up; however, changes in branched-chain amino acids did not follow glucose dynamics, and gluconeogenic substrates only paralleled changes in fasting glucose.
Alterations in branched-chain and aromatic amino acid metabolism precede hyperglycemia in the general population. Further, alanine, lactate, and pyruvate were predictive of postchallenge glucose exclusively. These gluconeogenic precursors are potential markers of long-term impaired insulin sensitivity that may relate to attenuated glucose tolerance later in life.
PMCID: PMC3402262  PMID: 22563043
4.  Exome array analysis identifies novel loci and low-frequency variants for insulin processing and secretion 
Nature genetics  2012;45(2):197-201.
Insulin secretion plays a critical role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion1,2; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5% to 5%) and rare (MAF<0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 non-diabetic Finnish males. We identified low-frequency coding variants associated with fasting proinsulin levels at the SGSM2 and MADD GWAS loci and three novel genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1, and PAM. We also demonstrate that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs nearby and megabases (Mb) away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.
PMCID: PMC3727235  PMID: 23263489
5.  A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion 
Nature genetics  2008;41(1):82-88.
Genome wide association studies revealed that variation in the Melatonin Receptor 1B gene (MTNR1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the Melatonin Receptor 1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in β-cells in islets. Non-diabetic individuals carrying the risk allele and patients with T2D showed increased expression of the receptor in islets. Insulin release from clonal β-cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of Melatonin Receptor 1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on β-cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.
PMCID: PMC3725650  PMID: 19060908
6.  Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry 
PLoS Genetics  2013;9(7):e1003607.
Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
Author Summary
We undertook analyses in 111,421 adults of European descent to examine whether physical activity diminishes the genetic risk of obesity predisposed by 12 single nucleotide polymorphisms, as previously reported in a study of 20,000 UK adults (Li et al, PLoS Med. 2010). Although the study by Li et al is widely cited, the original report has not been replicated to our knowledge. Therefore, we sought to confirm or refute the original study's findings in a combined analysis of 111,421 adults. Our analyses yielded a statistically significant interaction effect (Pinteraction = 0.015), confirming the original study's results; we also identified an interaction between the FTO locus and physical activity (Pinteraction = 0.003), verifying previous analyses (Kilpelainen et al, PLoS Med., 2010), and we detected a novel interaction between the SEC16B locus and physical activity (Pinteraction = 0.025). We also examined the power constraints of interaction analyses, thereby demonstrating that sources of within- and between-study heterogeneity and the manner in which data are treated can inhibit the detection of interaction effects in meta-analyses that combine many cohorts with varying characteristics. This suggests that combining many small studies that have measured environmental exposures differently may be relatively inefficient for the detection of gene × environment interactions.
PMCID: PMC3723486  PMID: 23935507
7.  Hyperglycemia and a Common Variant of GCKR Are Associated With the Levels of Eight Amino Acids in 9,369 Finnish Men 
Diabetes  2012;61(7):1895-1902.
We investigated the association of glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes with amino acid levels in the population-based Metabolic Syndrome in Men (METSIM) Study, including 9,369 nondiabetic or newly diagnosed type 2 diabetic Finnish men. Plasma levels of eight amino acids were measured with proton nuclear magnetic resonance spectroscopy. Increasing fasting and 2-h plasma glucose levels were associated with increasing levels of several amino acids and decreasing levels of histidine and glutamine. Alanine, leucine, isoleucine, tyrosine, and glutamine predicted incident type 2 diabetes in a 4.7-year follow-up of the METSIM Study, and their effects were largely mediated by insulin resistance (except for glutamine). We also found significant correlations between insulin sensitivity (Matsuda insulin sensitivity index) and mRNA expression of genes regulating amino acid degradation in 200 subcutaneous adipose tissue samples. Only 1 of 43 risk single nucleotide polymorphisms for type 2 diabetes or hyperglycemia, the glucose-increasing major C allele of rs780094 of GCKR, was significantly associated with decreased levels of alanine and isoleucine and elevated levels of glutamine. In conclusion, the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia, reflecting, at least in part, insulin resistance. Only one single nucleotide polymorphism regulating hyperglycemia was significantly associated with amino acid levels.
PMCID: PMC3379649  PMID: 22553379
8.  Non-Cholesterol Sterol Levels Predict Hyperglycemia and Conversion to Type 2 Diabetes in Finnish Men 
PLoS ONE  2013;8(6):e67406.
We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.
PMCID: PMC3696087  PMID: 23840693
9.  SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome 
Molecular cell  2011;44(2):177-190.
Acetylation is increasingly recognized as an important metabolic regulatory post-translational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (wt) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both wt and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point-mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.
PMCID: PMC3563434  PMID: 21856199
10.  Insulin Secretion and Its Determinants in the Progression of Impaired Glucose Tolerance to Type 2 Diabetes in Impaired Glucose-Tolerant Individuals 
Diabetes Care  2012;35(2):211-217.
We investigated the effect of early-phase insulin secretion on the incidence of type 2 diabetes in individuals with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study (DPS). We examined how a lifestyle intervention affected early-phase insulin secretion (ratio of total insulin area under the curve [AUC] and total glucose AUC [AIGR] from 0 to 30 min) during a 4-year follow-up intervention trial and whether AIGR0–30 response was modified by insulin sensitivity (IS) and obesity.
A total of 443 participants with IGT originally randomized to a lifestyle intervention or control group were studied. IS and AIGR0–30 were estimated from an oral tolerance glucose test administered annually during the 4-year follow-up trial and were related to the risk of diabetes onset over a 6-year follow-up.
Lifestyle intervention resulted in higher IS (P = 0.02) and lower unadjusted AIGR0–30 (P = 0.08) during the 4-year follow-up. A higher IS and a lower BMI during the follow-up were associated with a lower unadjusted AIGR0–30 during the follow-up, independently of study group (P < 0.001). A greater increase in IS on the median cutoff point of a 0.69 increase was associated with higher IS-adjusted AIGR0–30 during the follow-up (P = 0.002). In multivariate models, IS and IS-adjusted AIGR0–30 were both inversely associated with diabetes incidence (P < 0.001). Participants who progressed to type 2 diabetes were more obese and had lower IS and Matsuda IS index-AIGR0–30 than nonprogressors.
Our results indicate that the reduction in the risk of developing type 2 diabetes after lifestyle intervention is related to the improvement of IS along with weight loss. Improved IS may also have beneficial effects on preservation of β-cell function.
PMCID: PMC3263888  PMID: 22210578
11.  Adipose Co-expression networks across Finns and Mexicans identify novel triglyceride-associated genes 
BMC Medical Genomics  2012;5:61.
High serum triglyceride (TG) levels is an established risk factor for coronary heart disease (CHD). Fat is stored in the form of TGs in human adipose tissue. We hypothesized that gene co-expression networks in human adipose tissue may be correlated with serum TG levels and help reveal novel genes involved in TG regulation.
Gene co-expression networks were constructed from two Finnish and one Mexican study sample using the blockwiseModules R function in Weighted Gene Co-expression Network Analysis (WGCNA). Overlap between TG-associated networks from each of the three study samples were calculated using a Fisher’s Exact test. Gene ontology was used to determine known pathways enriched in each TG-associated network.
We measured gene expression in adipose samples from two Finnish and one Mexican study sample. In each study sample, we observed a gene co-expression network that was significantly associated with serum TG levels. The TG modules observed in Finns and Mexicans significantly overlapped and shared 34 genes. Seven of the 34 genes (ARHGAP30, CCR1, CXCL16, FERMT3, HCST, RNASET2, SELPG) were identified as the key hub genes of all three TG modules. Furthermore, two of the 34 genes (ARHGAP9, LST1) reside in previous TG GWAS regions, suggesting them as the regional candidates underlying the GWAS signals.
This study presents a novel adipose gene co-expression network with 34 genes significantly correlated with serum TG across populations.
PMCID: PMC3543280  PMID: 23217153
Mexicans; Finns; RNA sequencing; Triglycerides; Adipose tissue; Weighted gene co-expression network analysis
12.  Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits 
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS.
Methods and Results
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.
PMCID: PMC3378651  PMID: 22399527
metabolic syndrome; risk factors; genome-wide association study; meta-analysis; lipids
13.  Pleiotropic Effects of GIP on Islet Function Involve Osteopontin 
Diabetes  2011;60(9):2424-2433.
The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function.
Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation.
The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells.
These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans.
PMCID: PMC3161325  PMID: 21810601
14.  Expression of the Splicing Factor Gene SFRS10 is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis 
Cell metabolism  2011;14(2):208-218.
Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, down-regulated in both obese human liver and muscle and in high fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic β isoform of LPIN1. Importantly, LPIN1β-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.
PMCID: PMC3167228  PMID: 21803291
15.  Physical Activity, High-Sensitivity C-Reactive Protein, and Total and Cardiovascular Disease Mortality in Type 2 Diabetes 
Diabetes Care  2011;34(7):1492-1496.
Physical activity reduces high-sensitivity C-reactive protein (hs-CRP), cardiovascular disease (CVD), and total mortality in type 2 diabetic patients. However, it is not known whether the effects of physical activity on mortality depend on the levels of hs-CRP in patients with type 2 diabetes.
We prospectively followed-up on 569 type 2 diabetic patients, aged 45–64 years, who were free of CVD at baseline. Participants were stratified according to the level of hs-CRP (<1.0, 1.0–3.0, or >3.0 mg/L) and the degree of physical activity (0–4 metabolic equivalent tasks [METs] or >4 METs). The Cox proportional hazards model was used to estimate the joint association between physical activity and hs-CRP levels and the risk of mortality.
During an 18-year follow-up, 356 patients died, 217 of whom died of CVD. Those who were physically more active had significantly reduced total, CVD and coronary heart disease (CHD) mortality among patients with elevated hs-CRP levels (>3 mg/L). These findings persisted in multivariable analyses. However, in patients with an hs-CRP level <1 mg/L or between 1 and 3 mg/L, there was no statistically significant relationship between physical activity and CVD or CHD mortality.
Physical activity reduces total, CVD, and CHD mortality in type 2 diabetic patients with elevated hs-CRP levels. This suggests that the anti-inflammatory effect of physical activity may counteract increased CVD and CHD morbidity and mortality associated with high CRP levels.
PMCID: PMC3120189  PMID: 21602429
16.  Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production 
EMBO Molecular Medicine  2012;4(7):633-646.
Hexokinase-II (HKII) is highly expressed in the heart and can bind to the mitochondrial outer membrane. Since cardiac hypertrophy is associated with a substrate switch from fatty acid to glucose, we hypothesized that a reduction in HKII would decrease cardiac hypertrophy after pressure overload. Contrary to our hypothesis, heterozygous HKII-deficient (HKII+/−) mice displayed increased hypertrophy and fibrosis in response to pressure overload. The mechanism behind this phenomenon involves increased levels of reactive oxygen species (ROS), as HKII knockdown increased ROS accumulation, and treatment with the antioxidant N-acetylcysteine (NAC) abrogated the exaggerated response. HKII mitochondrial binding is also important for the hypertrophic effects, as HKII dissociation from the mitochondria resulted in de novo hypertrophy, which was also attenuated by NAC. Further studies showed that the increase in ROS levels in response to HKII knockdown or mitochondrial dissociation is mediated through increased mitochondrial permeability and not by a significant change in antioxidant defenses. Overall, these data suggest that HKII and its mitochondrial binding negatively regulate cardiac hypertrophy by decreasing ROS production via mitochondrial permeability.
PMCID: PMC3407950  PMID: 22517678
hexokinase; hypertrophy; mitochondria; mitochondrial permeability transition; reactive oxygen species
17.  Evidence of mechanism how rs7575840 influences apolipoprotein B containing lipid particles 
Recent genome-wide association studies (GWAS) identified a variant rs7575840 in the apolipoprotein B (APOB) gene region to be associated with LDL-C. However, the underlying functional mechanism of this variant that resides 6.5 kb upstream of APOB has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB containing lipid particles; for replication in a non-Caucasian Mexican population; and for underlying functional mechanism.
Methods and Results
Our data show that rs7575840 is associated with serum apoB levels (P=4.85×10−10) and apoB containing lipid particles, very small VLDL, IDL and LDL particles (P=2×10−5 - 9×10−7) in the Finnish METSIM study sample (n=7,710). Fine mapping of the APOB region using 43 SNPs replicated the association of rs7575840 with apoB in a Mexican study sample (n=2,666, P=3.33×10−05). Furthermore, our transcript analyses of adipose RNA samples from 175 Finnish METSIM subjects indicate that rs7575840 alters expression of APOB (P=1.13×10−10) and a regional non-coding RNA (BU630349) (P=7.86×10−6) in adipose tissue.
It has been difficult to convert GWAS associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB containing lipid particles as well as influences expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant SNP rs7575840 may affect serum apoB, LDL-C, and TC levels.
PMCID: PMC3081410  PMID: 21393584
Apolipoprotein B; association analysis; gene expression; adipose tissue; Mexicans
18.  Effects of 34 Risk Loci for Type 2 Diabetes or Hyperglycemia on Lipoprotein Subclasses and Their Composition in 6,580 Nondiabetic Finnish Men 
Diabetes  2011;60(5):1608-1616.
We investigated the effects of 34 genetic risk variants for hyperglycemia/type 2 diabetes on lipoprotein subclasses and particle composition in a large population-based cohort.
The study included 6,580 nondiabetic Finnish men from the population-based Metabolic Syndrome in Men (METSIM) study (aged 57 ± 7 years; BMI 26.8 ± 3.7 kg/m2). Genotyping of 34 single nucleotide polymorphism (SNPs) for hyperglycemia/type 2 diabetes was performed. Proton nuclear magnetic resonance spectroscopy was used to measure particle concentrations of 14 lipoprotein subclasses and their composition in native serum samples.
The glucose-increasing allele of rs780094 in GCKR was significantly associated with low concentrations of VLDL particles (independently of their size) and small LDL and was nominally associated with low concentrations of intermediate-density lipoprotein, all LDL subclasses, and high concentrations of very large and large HDL particles. The glucose-increasing allele of rs174550 in FADS1 was significantly associated with high concentrations of very large and large HDL particles and nominally associated with low concentrations of all VLDL particles. SNPs rs10923931 in NOTCH2 and rs757210 in HNF1B genes showed nominal or significant associations with several lipoprotein traits. The genetic risk score of 34 SNPs was not associated with any of the lipoprotein subclasses.
Four of the 34 risk loci for type 2 diabetes or hyperglycemia (GCKR, FADS1, NOTCH2, and HNF1B) were significantly associated with lipoprotein traits. A GCKR variant predominantly affected the concentration of VLDL, and the FADS1 variant affected very large and large HDL particles. Only a limited number of risk loci for hyperglycemia/type 2 diabetes significantly affect lipoprotein metabolism.
PMCID: PMC3292337  PMID: 21421807
19.  Heart in Diabetes: A Microvascular Disease 
Diabetes Care  2011;34(Suppl 2):S145-S149.
PMCID: PMC3632152  PMID: 21525446
20.  Long-Term Effects of Placental Growth on Overweight and Body Composition 
Obesity is programmed in utero and small babies generally have small placentas. In some circumstances, an undernourished fetus can expand its placental surface to extract more nutrients. We hypothesize that this results in an imbalanced nutrient supply to the fetus leading to obesity. To determine whether placental size determines overweight and body composition, we studied 2003 subjects in adult life. Associations between placental surface area and indices of overweight were restricted to people who carried the Pro12Pro genotype of the PPARγ2 gene. For every 1 SD increase in placental surface area, the odds ratio for overweight was 1.37 (95% CI 1.10 to 1.71; P = 0.005). Expansion of the placental surface in compensation for fetal undernutrition increases the risk of overweight and a higher body fat percentage in people carrying the Pro12Pro genotype. We suggest that similar underlying multifactorial mechanisms affect the development of obesity in general.
PMCID: PMC3337610  PMID: 22570665
21.  Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy 
Heart  2012;98(13):1007-1013.
To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM).
Clinical study.
Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects.
Main outcome measures
Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected.
Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1β, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI.
A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.
PMCID: PMC3368494  PMID: 22447464
Hypertrophic cardiomyopathy; inflammation; fibrosis; genetics; late gadolinium enhancement; coronary angioplasty; aortic stenosis; invasive cardiology; coronary artery disease; cardiomyopathy hypertrophic; tissue characters; HCM; MRI; myocardial function; myocardial perfusion; myocardial ischaemia; myocardial infarction; arrhythmias; endocrinology
22.  Impact of Positive Family History and Genetic Risk Variants on the Incidence of Diabetes 
Diabetes Care  2011;34(2):418-423.
We aimed to investigate the influence of positive family history (FH+) of diabetes and 19 known genetic risk loci on the effectiveness of lifestyle changes and their predictive value on the incidence of type 2 diabetes in the Finnish Diabetes Prevention Study (DPS).
A total of 522 subjects with impaired glucose tolerance (IGT) were randomized into the control (n = 257) and intervention (n = 265) groups. The mean follow-up was 6.2 years (median 7 years), and the lifestyle intervention, aimed at weight reduction, healthy diet, and increased physical activity, lasted for 4 years (range 1–6 years). An oral glucose tolerance test (OGTT) and assessment of basic clinical variables were performed annually.
The effect of intervention on the incidence of diabetes was almost similar in subjects with FH+ compared with subjects with a negative family history (FH−) of diabetes during the entire follow-up. In the Cox model, including FH, genetic risk SNPs, and randomization group, and adjusted for the effects of age, sex, BMI, and study center, only lifestyle intervention had a significant effect (hazard ratio 0.55, 95% CI 0.41–0.75, P < 0.001) on the incidence of diabetes. Further analyses showed that in addition to the baseline glucose and insulin values, 1-year changes in 2-h glucose and 2-h insulin achieved by lifestyle intervention had a significant effect on the incidence of diabetes.
These results emphasize the effectiveness of lifestyle intervention in reducing the risk of diabetes in high-risk individuals independently of genetic or familial risk of type 2 diabetes.
PMCID: PMC3024360  PMID: 20980412
23.  The Adipocyte-Expressed Forkhead Transcription Factor Foxc2 Regulates Metabolism Through Altered Mitochondrial Function 
Diabetes  2011;60(2):427-435.
Previous findings demonstrate that enhanced expression of the forkhead transcription factor Foxc2 in adipose tissue leads to a lean and insulin-sensitive phenotype. These findings prompted us to further investigate the role of Foxc2 in the regulation of genes of fundamental importance for metabolism and mitochondrial function.
The effects of Foxc2 on expression of genes involved in mitochondriogenesis and mitochondrial function were assessed by quantitative real-time PCR. The potential of a direct transcriptional regulation of regulated genes was tested in promoter assays, and mitochondrial morphology was investigated by electron microscopy. Mitochondrial function was tested by measuring oxygen consumption and extracellular acidification rates as well as palmitate oxidation.
Enhanced expression of FOXC2 in adipocytes or in cells with no endogenous Foxc2 expression induces mitochondriogenesis and an elongated mitochondrial morphology. Together with increased aerobic metabolic capacity, increased palmitate oxidation, and upregulation of genes encoding respiratory complexes and of brown fat-related genes, Foxc2 also specifically induces mitochondrial fusion genes in adipocytes. Among tested forkhead genes, Foxc2 is unique in its ability to trans-activate the nuclear-encoded mitochondrial transcription factor A (mtTFA/Tfam) gene—a master regulator of mitochondrial biogenesis. In human adipose tissue the expression levels of mtTFA/Tfam and of fusion genes also correlate with that of Foxc2.
We previously showed that a high-calorie diet and insulin induce Foxc2 in adipocytes; the current findings identify a previously unknown role for Foxc2 as an important metabo-regulator of mitochondrial morphology and metabolism.
PMCID: PMC3028341  PMID: 21270254
24.  Reduction in Hexokinase II Levels Results in Decreased Cardiac Function and Altered Remodeling after Ischemia-Reperfusion Injury 
Circulation research  2010;108(1):60-69.
Cardiomyocytes switch substrate utilization from fatty acid to glucose under ischemic conditions, however, it is unknown how perturbations in glycolytic enzymes affect cardiac response to ischemia-reperfusion (I/R). Hexokinase (HK) II is a HK isoform that is expressed in the heart and it can bind to the mitochondrial outer membrane.
We sought to define how HKII and its binding to mitochondria play a role in cardiac response and remodeling after I/R.
Methods and Results
We first showed that HKII levels and its binding to mitochondria are reduced 2 days after I/R. We then subjected the hearts of wild type and heterozygote HKII knockout (HKII+/−) mice to I/R by coronary ligation. At baseline, HKII+/− mice have normal cardiac function, however, they display lower systolic function after I/R compared to wild type animals. The mechanism appears to be through an increase in cardiomyocyte death and fibrosis and a reduction in angiogenesis, the latter is through a decrease in HIF-dependent pathway signaling in cardiomyocytes. HKII mitochondrial binding is also critical for cardiomyocyte survival, as its displacement in tissue culture with a synthetic peptide increases cell death. Our results also suggest that HKII may be important for the remodeling of the viable cardiac tissue as its modulation in vitro alters cellular energy levels, O2 consumption and contractility.
These results suggest that reduction in HKII levels causes altered remodeling of the heart in I/R by increasing cell death and fibrosis and reducing angiogenesis, and that mitochondrial binding is needed for protection of cardiomyocytes.
PMCID: PMC3017633  PMID: 21071708
Hexokinase; Ischemia-reperfusion; Mitochondria; Vascular endothelial growth factor (VEGF); Apoptosis
25.  The Birth Weight Lowering C-Allele of rs900400 Near LEKR1 and CCNL1 Associates with Elevated Insulin Release following an Oral Glucose Challenge 
PLoS ONE  2011;6(11):e27096.
Background and Aim
The first genome-wide association study on birth weight was recently published and the most significant associated birth weight lowering variant was the rs900400 C-allele located near LEKR1 and CCNL1. We aimed to replicate the association with birth weight in the Danish Inter99 study and furthermore to evaluate associations between rs900400 and indices of insulin secretion and insulin sensitivity obtained by oral glucose tolerance tests in adults from the Danish Inter99 study and the Finnish, Metabolic Syndrome in Men (METSIM) sample.
For 4,744 of 6,784 Inter99 participants, midwife journals were traced through the Danish State Archives and association of rs900400 with birth weight was examined. Associations between rs900400 and fasting serum insulin, fasting plasma glucose, insulinogenic index, homeostasis model assessment of insulin resistance (HOMA-IR) and disposition index were studied in 5,484 Danish and 6,915 Finnish non-diabetic individuals and combined in meta-analyses.
The C-allele of rs900400 was associated with a 22.1 g lower birth weight ([−41.3;−3.0], P = 0.024) per allele. Moreover, in combined analyses of the Danish Inter99 study and the Finnish METSIM study we found that the birth weight lowering allele was associated with increased insulin release measured by the insulinogenic index (β = 2.25% [0.59; 3.91], P = 0.008) and with an increased disposition index (β = 1.76% [0.04; 3.49], P = 0.05).
The birth weight lowering effect of the C-allele of rs900400 located near LEKR1 and CCNL1 was replicated in the Danish population. Furthermore the C-allele was associated with increased insulin response following oral glucose stimulation in a meta-analysis based on Danish and Finnish non-diabetic individuals.
PMCID: PMC3208566  PMID: 22073261

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