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M Laakso

Publications and source records attributed to M Laakso.

At least 37 records · Page 2Linked to original sources
PubMed2005

The G-250A substitution in the promoter region of the hepatic lipase gene is associated with the conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial.

OBJECTIVES: Dyslipidaemia that includes high levels of triglycerides and low high-density lipoprotein cholesterol is a risk factor for type 2 diabetes. Hepatic lipase gene encoding a lipolytic enzyme participating in remodelling of plasma lipoproteins and formation of serum lipid profile is a promising candidate gene for type 2 diabetes. The purpose of the study was to investigate whether the G-250A promoter polymorphism of the LIPC gene predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes. SUBJECTS AND DESIGN: Study population comprised of subjects who participated in the STOP-NIDDM trial aiming to investigate the effect of acarbose compared with placebo on the prevention of type 2 diabetes in subjects with IGT. RESULTS: Compared with subjects carrying the G-250G genotype, subjects with the A-250A genotype of the LIPC gene had a 2.35-fold [95% confidence interval (CI) 1.27-4.33, P = 0.006] higher risk of developing type 2 diabetes. Subjects in the placebo group and all women carrying the A-250A genotype had an especially high risk for the conversion to type 2 diabetes [odds ratio (OR) 2.74, 95% CI 1.14-6.61, P = 0.024 and OR 3.70, 95% CI 1.35-10.1, P = 0.011 respectively]. CONCLUSION: The G-250A promoter polymorphism of the LIPC gene is associated with an increased risk of development of type 2 diabetes in high-risk subjects with IGT. Therefore, genes regulating atherogenic dyslipidaemia are promising candidate genes for type 2 diabetes.

Chi-Square Distribution↗
PubMed2005

Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus.

AIM: Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea. METHODS: Data in this report are from two multicentre, randomized, double-blind, double-dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12-week forced titration period and a 40-week maintenance period. HbA(1c), fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log(10) FSI + log(10) FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance. RESULTS: As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean +/- sem]; pioglitazone [0.303 +/- 0.001 vs. 0.321 +/- 0.001; P < 0.001] and metformin [0.304 +/- 0.001 vs. 0.315 +/- 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 +/- 0.001 vs. 0.319 +/- 0.001; P < 0.001] and metformin + sulphonylurea [0.306 +/- 0.001 vs. 0.317 +/- 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea. CONCLUSION: Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.

Adult↗
PubMed2005

Prevention of type 2 diabetes.

Changes in the human environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes in the world. The rapid escalation of the number of people with type 2 diabetes (T2DM) and diabetes-related cardiovascular disease demands urgent action on prevention. The Finnish Diabetes Prevention Study and The Diabetes Prevention Program showed that the prevention (or delaying) of T2DM is feasible and effective. Both of these trials led to a reduction of 58% in the conversion to diabetes in subjects with impaired glucose tolerance. Compared to lifestyle changes, drug treatment in the prevention of diabetes in people at high risk for T2DM has been less beneficial. Metformin (31%) or acarbose (25%) treatment obtained only about a half of the reduction in the conversion to diabetes compared to lifestyle changes. These drugs require monitoring, and have significant side-effects. Also the effect of orlistat (37%) did not reach the effect of lifestyle modification. Results of the Troglitazone in Prevention of Diabetes study are suggestive for the prevention, but the trial was too small, and included only one ethnic group (Hispanic) and one gender (women). On the basis of the evidence available, we do not have a definite proof that T2DM is prevented in any of these trials. However, we can safely conclude that the current evidence strongly favors the notion that lifestyle changes are the primary means to tackle the epidemic of T2DM.

Acarbose↗
PubMed2004

Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.

AIM/HYPOTHESIS: We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2; Pro12Ala) and in PPAR-gamma coactivator 1alpha (PGC-1alpha; Gly482Ser) genes on the conversion from impaired glucose tolerance to type 2 diabetes in participants in the STOP-NIDDM trial. This trial aimed to study the effect of acarbose in the prevention of type 2 diabetes. METHODS: Genotyping was performed in 770 study subjects whose DNA was available. The Gly482Ser variant in the PGC-1alpha gene was determined with the polymerase chain reaction amplification, Hpa II enzyme digestion, and gel electrophoresis. The Pro12Ala polymorphism of the PPAR-gamma2 gene was determined by the polymerase chain reaction-single-strand conformation polymorphism analysis. RESULTS: The Pro12Pro genotype of the PPAR-gamma2 gene predicted the conversion to diabetes in women in the acarbose group (odds ratio 2.89, 95% CI 1.20 to 6.96; p=0.018). The 482Ser allele of the PGC-1alpha gene had a significant interaction with the mode of treatment (p=0.012), and in the placebo group the 482Ser allele was associated with a 1.6-fold higher risk for type 2 diabetes compared to the Gly482Gly genotype (95% CI 1.06 to 2.33; p=0.023). Acarbose prevented the development of diabetes independently of the genotype of the PPAR-gamma2 gene, but only the carriers of the 482Ser allele of the PGC-1alpha gene were responsive to acarbose treatment. CONCLUSION/INTERPRETATION: We conclude that the Pro12Pro genotype of the PPAR-gamma2 gene and the 482Ser allele of the PGC-1alpha gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.

Acarbose↗
PubMed2004

Association between a deletion/insertion polymorphism in the alpha2B-adrenergic receptor gene and insulin secretion and Type 2 diabetes. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Impaired insulin secretion has a strong genetic component. In this study we investigated whether the 12Glu9 polymorphism in the gene encoding the alpha2B-adrenergic receptor ( ADRA2B) is associated with insulin secretion and/or the incidence of Type 2 diabetes in individuals with impaired glucose tolerance. METHODS: We investigated a total of 506 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study (DPS). Participants were randomly assigned to an intervention group or a control group. Anthropometric measurements and an oral glucose tolerance test were performed at baseline and at annual follow-up. In a subgroup of patients (n=83), a frequently sampled intravenous glucose tolerance test (FSIGT) was performed at baseline. RESULTS: All patients had similar anthropometric measurements and insulin and glucose levels at baseline. Multiple logistic regression analysis revealed significant interaction (p=0.003) between study group and genotype across the entire study population. In the control group, subjects with the Glu9 allele had an increased risk of developing Type 2 diabetes compared with subjects with the Glu12/12 genotype (odds ratio [OR]=2.68, 95% CI 1.02-7.09, p=0.047 for Glu12/12, and OR=5.17, 95% CI 1.76-15.21, p=0.003 for Glu9/9). This increased risk was not observed in the intervention group, who showed significant weight loss during the trial. In the subgroup who underwent the FSIGT, subjects with the Glu9/9 genotype showed the lowest acute insulin response (p=0.005 for trend). CONCLUSIONS/INTERPRETATION: The 12Glu9 polymorphism of ADRA2B is associated with impaired first-phase insulin secretion and may predict the development of Type 2 diabetes in subjects with impaired glucose tolerance who are not subjected to a lifestyle intervention.

Blood Glucose↗
PubMed2004

Acarbose for the prevention of Type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data.

The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations. In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper. Of the study population, 9.3% had a fasting plasma glucose of > or =7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria. The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT.

Acarbose↗
PubMed2004

Common polymorphisms in the genes regulating the early insulin signalling pathway: effects on weight change and the conversion from impaired glucose tolerance to Type 2 diabetes. The Finnish Diabetes Prevention Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a complex disorder with strong heritability. The aim of our study was to investigate whether common polymorphisms in the genes regulating the early insulin signalling pathway (insulin; A-23T, insulin-like growth factor 1 receptor [IGF-1R]; GAG1013GAA, plasma cell membrane glycoprotein 1 [PC-1]; K121Q, insulin receptor substrate [IRS-1]; G972R, insulin receptor substrate 2 [IRS-2]; G1057D and phosphatidylinositol 3-kinase p85 alpha [PI3K]; M326I) affect the weight change and development of Type 2 diabetes in the Finnish Diabetes Prevention Study. METHODS: We screened for the polymorphisms in 490 overweight subjects with impaired glucose tolerance whose DNA was available from the Finnish Diabetes Prevention Study. These subjects were randomly allocated into a control group and an intervention group characterised by intensive, individualised diet and exercise. RESULTS: In carriers of the GAA1013GAA genotype of IGF-1R, the R972 allele of IRS-1 and the D1057D genotype of IRS-2, lifestyle intervention did not lead to significant differences in weight loss between the intervention and control groups, implying a role of these risk genotypes in the regulation of body weight. We observed a statistically significant difference in the conversion rate from IGT to diabetes between the genotypes of the IGF-1R gene (GAG1013GAG: 18.6%, GAG1013GAA: 10.4%, GAA1013GAA: 19.5%, p=0.033). Common polymorphisms in the insulin, PC-1 and PI3K genes did not regulate weight change or conversion to diabetes. CONCLUSIONS/INTERPRETATION: The common polymorphisms of the IGF-1R, IRS-1 and IRS-2 genes may modify the weight change response to a lifestyle intervention but not the conversion from IGT to Type 2 diabetes, whereas IGF-1R may also regulate the risk of developing Type 2 diabetes.

Body Mass Index↗
PubMed2004

Inducibility of life-threatening ventricular arrhythmias is related to maximum left ventricular thickness and clinical markers of sudden cardiac death in patients with hypertrophic cardiomyopathy attributable to the Asp175Asn mutation in the alpha-tropomyosin gene.

We investigated inducibility of life-threatening arrhythmias with programmed ventricular stimulation (PVS) in relation to clinical markers of sudden cardiac death (SCD) in subjects with hypertrophic cardiomyopathy (HCM) attributable to the Asp175Asn mutation in the alpha-tropomyosin gene (TPM1-Asp175Asn). PVS was performed with up to three extrastimuli and distribution of markers of SCD was evaluated in 21 adult subjects with the TPM1-Asp175Asn. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in seven of 21 subjects (33%). Inducible subjects had more severe left ventricular hypertrophy (LVH) and an increased number of markers of SCD (family history of SCD, syncope or presyncope, fall in systolic blood pressure (BP) during exercise, documented non-sustained VT (NSVT), and marked LVH) compared to non-inducible subjects (IVS 2.4 +/- 0.3 cm vs. 1.6 +/- 0.5 cm, P < 0.001; and two to three vs. one to two markers of SCD, P = 0.007, respectively). In conclusion, in HCM attributable to the Asp175Asn mutation in the alpha-tropomyosin gene, life-threatening arrhythmias were induced in one third of the patients. Inducibility was associated with the maximum left ventricular (LV) thickness and the number of markers of SCD, suggesting that in HCM patients with an identical causative mutation, susceptibility to ventricular arrhythmias is related to the cardiomyopathic phenotype.

Adult↗
PubMed2004

Aldose reductase gene polymorphisms and susceptibility to microvascular complications in Type 2 diabetes.

AIMS: The gene encoding the human aldose reductase, the first and rate-limiting enzyme of the polyol pathway of glucose metabolism, is a promising candidate gene which may contribute to diabetic microvascular complications. We investigated the association of two previously reported DNA sequence variants of this gene, the C-106T polymorphism and the (CA)(n) dinucleotide repeat marker, with the risk of albuminuria and retinopathy in Finnish Type 2 diabetic patients and non-diabetic control subjects. METHODS: The study population included 85 Finnish, middle-aged, newly diagnosed Type 2 diabetic patients and 126 non-diabetic control subjects. Genetic analyses were performed using the polymerase chain reaction, restriction fragment length polymorphism, and automated laser fluorescence scanning analyses. Microvascular complications were determined using 10-year follow-up data of urinary albumin excretion measurements and ophthalmological examinations. RESULTS: The C and Z-2 alleles of the C-106T polymorphism and the (CA)(n) repeat marker, respectively, were found to be more frequent in Type 2 diabetic subjects than in non-diabetic subjects. The C and Z-2 alleles were in 60% linkage disequilibrium in diabetic subjects. At the time of diagnosis, diabetic subjects with the T allele of the C-106T polymorphism had significantly higher urinary albumin excretion rate and prevalence of albuminuria than subjects with the C-106C genotype (prevalence of albuminuria: 33.3 vs. 13.8%, P = 0.036, odds ratio = 3.9, 95% confidence interval 1.1, 14.7). The Z-2 allele of the (CA)(n) repeat marker was not consistently associated with the prevalence of albuminuria. No associations were observed between the polymorphisms examined and the prevalence of retinopathy at any point of the follow-up. CONCLUSIONS: The present study suggests that the C-106T polymorphism of the aldose reductase gene could be involved in the early development of microalbuminuria in Finnish Type 2 diabetic patients.

Aldehyde Reductase↗
PubMed2003

Characterisation of new KATP-channel mutations associated with congenital hyperinsulinism in the Finnish population.

AIMS/HYPOTHESIS: ATP-sensitive potassium (K(ATP)) channels are crucial for the regulation of insulin secretion from pancreatic beta cells and mutations in either the Kir6.2 or SUR1 subunit of this channel can cause congenital hyperinsulinism (CHI). The aim of this study was to analyse the functional consequences of four CHI mutations (A1457T, V1550D and L1551V in SUR1, and K67N in Kir6.2) recently identified in the Finnish population. METHODS: Wild type or mutant Kir6.2 and SUR1 subunits were coexpressed in Xenopus oocytes. The functional properties of the channels were examined by measuring currents in intact oocytes or giant inside-out membrane patches. Surface expression was measured by enzyme-linked immunosorbance assay, using HA-epitope-tagged subunits. RESULTS: Two mutations (A1457T and V1550D) prevented trafficking of the channel to the plasma membrane. The L1551V mutation reduced surface expression 40-fold, and caused loss of MgADP and diazoxide activation. Both these factors will contribute to the lack of K(ATP) current activation observed in response to metabolic inhibition in intact oocytes. The L1551V mutation also increased the channel open probability, thereby producing a reduction in ATP-sensitivity (from 10 micro mol/l to 120 micro mol/l). The fourth mutation (K67N mutation in Kir6.2) did not affect surface expression nor alter the properties of K(ATP) channels in excised patches, but resulted in a reduced K(ATP) current amplitude in intact cells on metabolic inhibition, through an unidentified mechanism. CONCLUSION/INTERPRETATION: The four CHI mutations disrupted K(ATP) channel activity by different mechanisms. Our results are discussed in relation to the CHI phenotype observed in patients with these mutations.

ATP-Binding Cassette Transporters↗
PubMed2003

The effects of the Pro12Ala polymorphism of the PPARgamma-2 gene on lipid metabolism interact with body size at birth.

Body size at birth is an indicator of the intrauterine environment. The effects of the Pro12Pro genotype and the 12Ala allele of the PPARgamma-2 gene on glucose and insulin metabolism in adult life depend on body size at birth. A low birth weight is associated with insulin resistance and type 2 diabetes. The peroxisome proliferator-activated receptor-gamma (PPARgammas) are also regulators of adipocyte differentiation, and the PPARgamma-2 gene could also contribute to the development of dyslipidemia. Therefore, the effects of the Pro12Ala polymorphisms of the PPARgamma-2 gene on lipid metabolism were measured in 476 elderly persons whose birth weight was known. The Ala12 allele was associated with increased serum total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol concentrations but only among those who had birth weights below 3000 g. These interactions between the effects of the PPARgamma-2 gene on adult traits and the effects of birth weight may be interpreted as examples of gene-environmental interactions, which underlie plasticity during development.

Aged↗
PubMed2003

Associations of blood pressure with carotid intima-media thickness in elderly Finns with diabetes mellitus or impaired glucose tolerance.

The aim of the present study was to evaluate the associations of ultrasonographic manifestations of carotid atherosclerosis with systolic (SBP) and diastolic blood pressure (DBP) and pulse pressure (PP) in 65-year-old Finns drawn from a population-based cohort. Carotid ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance (IGT) and 57 normoglycaemic subjects (NGT). The subjects were classified into four quartiles of SBP, DBP and PP. SBP, DBP, PP and the use of antihypertensive drugs increased along with the deterioration of glucose status. The maximal intima-media thickness (IMT) of the common carotid artery (CCA) from the lowest to the highest quartiles of SBP was 0.98+/-0.34, 1.00+/-0.35, 1.03+/-0.29, 1.18+/- 0.52 mm (P=0.038), respectively. SBP was higher (161+/-22 mmHg) in the subjects with severe intima-media thickening (maximal IMT CCA > or =1.2 mm) than in those with maximal IMT CCA of <1.2 mm (153+/- 20 mmHg) (P=0.030). DBP and PP tended to be higher in the former than the latter group (DBP: 89+/-9 mmHg vs 86+/-9 mmHg, P=0.055 and PP: 72+/-18 mmHg vs 67+/-17 mmHg, P=0.159). The prevalence of severe intima-media thickening was 39% in the subjects in the highest SBP quartile (> or =170 mmHg) and 20% in the subjects with lower SBP (P=0.008). In multiple regression analysis, the adjusted OR for severe intima-media thickening was 2.9 (95% CI 1.1-7.9) in the subjects in the highest SBP quartile compared to the subjects with lower SBP. In the present study, high SBP was associated with severe carotid intima-media thickening. We suggest that the results can be generalized to apply to elderly Finnish subjects with DM and IGT, but not to normoglycaemic subjects, on the basis of this study.

Aged↗
PubMed2003

Association of the PRO12ALA polymorphism of the PPAR-gamma2 gene with oxidized low-density lipoprotein and cardiolipin autoantibodies in nondiabetic and type 2 diabetic subjects.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a key component in adipocyte differentiation and fat-specific gene expression and may modulate macrophage functions, like proinflammatory activities, and stimulate oxidized low-density lipoprotein (ox-LDL) uptake. We hypothesized that the Pro12Ala polymorphism of the PPAR-gamma2 gene may affect the immune response to ox-LDL. Therefore, we investigated the association of the Pro12Ala polymorphism of the PPAR-gamma2 gene with ox-LDL autoantibodies, as well anticardiolipin antibodies, in a 10-year prospective study. The Pro12Ala polymorphism was genotyped in 119 nondiabetic subjects (age, 45 to 64 years; body mass index [BMI], 19 to 46 kg/m(2)) and 70 type 2 diabetic patients (age, 45 to 65 years; BMI, 19 to 46 kg/m(2)) by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method. Ox-LDL autoantibodies and anticardiolipin antibodies were determined at baseline and after 10 years of follow-up. At baseline, the Pro12Ala polymorphism was not associated with ox-LDL autoantibodies in nondiabetic subjects, whereas type 2 diabetic patients having the Pro12Ala or the Ala12Ala genotypes tended to have higher levels of ox-LDL autoantibodies than did type 2 diabetic patients with the Pro12Pro genotype. At the 10-year follow-up, diabetic subjects having the Ala12 allele had higher ox-LDL autoantibody levels than did diabetic subjects with the Pro12Pro genotype (P =.043 after adjustment for age, gender, BMI, and hemoglobin A(1c) [HbA(1c)] at 5 years). In nondiabetic subjects and regarding anticardiolipin antibodies, no such relationship was observed. We conclude that the Pro12Ala polymorphism of the PPAR-gamma2 gene was associated with increased ox-LDL autoantibodies in type 2 diabetic subjects. Genotype may therefore modulate the oxidative modification of LDL in hyperglycemic milieu.

Alanine↗
PubMed2003

Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in women with polycystic ovary syndrome.

BACKGROUND: In view of the strong evidence implicating peroxisome proliferator-activated receptor-gamma (PPARgamma) in adiposity and insulin resistance a study was carried out to investigate PPARgamma genotype frequencies in women with polycystic ovary syndrome (PCOS) and to elucidate its role in the pathogenesis of the syndrome. METHODS: The study involved 135 women with PCOS and 115 healthy control women who were genotyped for a known functional variant of the PPARgamma gene using single strand conformation polymorphism (SSCP) analysis. RESULTS: A significantly different allele distribution of the Pro12 Ala polymorphism of the PPARgamma gene was observed between the two groups, with the frequency of the variant Ala isoform being significantly reduced in the PCOS group (12.6%) when compared with the control group (19.1%) (P = 0.045), at an odds ratio of 0.609 (95% confidence interval: 0.374-0.991). The genotype distributions of the Pro12 Ala polymorphism in the PCOS and control groups were different with borderline significance (P = 0.051). CONCLUSIONS: Our data support a role for PPARgamma gene polymorphism in the pathogenesis of PCOS, the presence of the Ala isoform being protective against the development of PCOS.

Alleles↗
PubMed2003

Effect of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue of massively obese subjects.

The aim was to study the effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene on the expression of PPARgamma target genes in adipose tissue. Adipose tissue samples were collected from 30 massively obese subjects (10 men and 20 women) from omental, sc abdominal, and femoral depots. The mRNA expression of PPARgamma1, PPARgamma2, lipoprotein lipase, p85alpha phosphatidylinositol 3-kinase, and uncoupling protein 2 were quantified by reverse transcription-competitive PCR. The genotypes of Pro12Ala polymorphism were determined by single-strand conformation polymorphism analysis. The frequency of the Ala12 allele was 13.3% (8 Pro12Ala and 22 Pro12Pro). There were no differences in body weight, fat mass, and fasting serum leptin between the genotypes. The mRNA expression of p85alpha phosphatidylinositol 3-kinase was significantly lower in the omental fat of the Pro12Ala carriers than the Pro12Pro carriers (P < 0.01). It also appeared that PPARgamma2 expression was higher in men with Ala12 allele (P < 0.01). Interestingly, particularly in women, the expression of both PPARgamma splice variants was lower in omental than sc fat independently of the genotype (P < 0.05-0.01). The common Pro12Ala polymorphism of the PPARgamma2 gene has minor influence on mRNA expression of PPARgamma target genes in adipose tissue of obese subjects. Expression of both PPARgamma splice variants is dependent on fat depot: omental fat shows lower mRNA levels, compared with sc fat depots.

Adipose Tissue↗
PubMed2002

A meta-analytic investigation of linkage and association of common leptin receptor (LEPR) polymorphisms with body mass index and waist circumference.

METHODS: We analyzed data pooled from nine studies on the human leptin receptor (LEPR) gene for the association of three alleles (K109R, Q223R and K656N) of LEPR with body mass index (BMI; kg/m(2)) and waist circumference (WC). A total of 3263 related and unrelated subjects from diverse ethnic backgrounds including African-American, Caucasian, Danish, Finnish, French Canadian and Nigerian were studied. We tested effects of individual alleles, joint effects of alleles at multiple loci, epistatic effects among alleles at different loci, effect modification by age, sex, diabetes and ethnicity, and pleiotropic genotype effects on BMI and WC. RESULTS: We found that none of the effects were significant at the 0.05 level. Heterogeneity tests showed that the variations of the non-significant effects are within the range of sampling variation. CONCLUSIONS: We conclude that, although certain genotypic effects could be population-specific, there was no statistically compelling evidence that any of the three LEPR alleles is associated with BMI or WC in the overall population.

Alleles↗