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Summary Background: Peroxisome proliferator-activated receptor gamma (PPARg) is a key transcription factor in adipogene-sis, and also regulates a number of genes associated with lipid storage and insulin sensitivity. Single nucleotide polymorphisms (SNPs) in the PPARG gene have been associated with obesity and diabetes. In this study, we explored the relationship of three PPARG gene variants with the metabolic syndrome (MetS) and related traits in a population from Bosnia and Herzegovina. Methods: Anthropometric and biochemical parameters were measured in 43 patients with MetS and 43 healthy controls. Subjects were genotyped for Pro12Ala (rs1801282) and 1431C>T (rs3856806) SNPs by classic PCR–restriction fragment length polymorphism analysis, and for-681C>G (rs10865710) variant by real-time PCR. Results: The genotype distributions for the three polymorphisms were not significantly different between MetS patients and controls. The Pro12Ala and 1431C>T variants were associated with lower body mass index in the control subjects (p=0.012 and p=0.049, respectively). In this group, the carriers of Pro12Ala had also lower waist circumference compared to the wild-type homozygotes (p=0.045). Conclusions: Results of our preliminary study indicate a beneficial effect of a common Pro12Ala variant on the metabolic phenotype in healthy non-obese subjects.

INTRODUCTION: The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of the hormonally inactive cortisone to active cortisol, thus facilitating glucocorticoid receptor activation in target tissues. Increased expression of 11beta-HSD1 in adipose tissue has been associated with obesity and insulin resistance. In this study, we investigated the association of two 11beta-HSD1 gene (HSD11B1) polymorphisms with the metabolic syndrome (MetS) and its characteristics in the Bosnian population. MATERIALS AND METHODS: The study included 86 participants: 43 patients diagnosed with MetS and 43 healthy controls. Subjects were genotyped for two HSD11B1 gene polymorphisms: rs846910: G > A and rs45487298: insA, by the high resolution melting curve analysis. Genotype distribution and an influence of genotypes on clinical and biochemical parameters were assessed. RESULTS: There was no significant difference in the mutated allele frequencies for the two HSD11B1 gene polymorphisms between MetS patients and controls. In MetS patients, no significant associations between disease-associated traits and rs45487298: insA were found. Regarding rs846910: G > Avariant, heterozygous patients (G/A) had significantly lower systolic (P = 0.017) and diastolic blood pressure (P = 0.015), lower HOMA-IR index (P = 0.011) and higher LDL-cholesterol levels (P = 0.049), compared to the wild-type homozygotes. In the control group, rs45487298: insA polymorphism was associated with lower fasting plasma insulin levels (P = 0.041), lower homeostasis model assessment insulin resistance (HOMA-IR) index (P = 0.041) and lower diastolic blood pressure (P = 0.048). Significant differences between rs846910: G > A genotypes in controls were not detected. Haplotype analysis confirmed the association of rs45487298: insA with markers of insulin resistance in the control subjects. CONCLUSIONS: Our results indicate that a common rs45487298: insA polymorphism in HSD1181 gene may have a protective effect against insulin resistance.

ObjectiveThe insulin-resistant state of the polycystic ovary syndrome (PCOS) was found to be associated with a decreased glucose transporter GLUT4 expression in the insulin target tissues. This study was performed to explore whether the well-known clinical, hormonal and metabolic efficacy of metformin or rosiglitazone treatment is reflected in the modulation of adipocyte GLUT4 mRNA expression in patients with PCOS.MethodsWe enrolled 35 women with PCOS. They received either metformin or rosiglitazone for 6 months. A history, blood samples for the measurement of androgens and s.c. adipose tissue samples were taken at baseline and end point. Quantification of GLUT4 mRNA expression in adipose tissue was performed using real-time quantitative PCR. Homeostasis model assessment (HOMAIR) score calculation was applied as a measure for insulin resistance (IR).ResultsGLUT4 mRNA expression in adipose tissue increased significantly in both groups (PP=0.040). There was a statistically significant improvement of HOMAIRin both groups (P=0.008). After treatment, frequencies of menstrual bleeding were significantly higher (PP=0.001).ConclusionsA 6-month therapy with insulin sensitizers resulted in marked improvement in adipose tissue GLUT4 mRNA expression in PCOS patients, rosiglitazone being more effective when compared with metformin. The augmentation of the insulin signal transduction was accompanied by a significant improvement of HOMAIR, menstrual pattern and androgen profile.

Uvod: Inzulinska rezistencija je obilježena oslabljenim tkivnim odgovorom na djelovanje inzulina, a udružena je s pretilošću, šećernom bolesti tipa 2, metaboličkim sindromom, lipodistrofijama, sindromom policističnih jajnika (engl. polycystic ovary syndrome, PCOS) i kroničnom infekcijom. Inzulinska rezistencija je prisutna kod 50-70% bolesnica s PCOS. Peroksizomni proliferatorom aktivirani receptor gama (engl. peroxisome proliferator-activated receptor γ, PPARγ) je jezgreni receptor koji kontrolira transkripciju gena uključenih u metabolizam slobodnih masnih kiselina i lipogenezu, a važan je za diferencijaciju i preživljenje adipocita. Cilj ovoga probnog istraživanja bio je ispitati povezanost polimorfizama Pro12Ala i His477His PPARG gena s inzulinskom rezistencijom kod bolesnica s PCOS. Bolesnice i metode: U istraživanju je sudjelovalo 69 bolesnica s PCOS. Metodom PCR-RFLP analizirane su frekvencije genotipova. Glukoza natašte i glukoza nakon oralnog testa opterećenja glukozom (engl. oral glucose tolerance test, OGTT), inzulin, hsCRP (engl. high sensitivity C-reactive protein), tjelesna masa, visina, opseg struka, sistolični i dijastolični krvni tlak, indeks tjelesne mase (engl. body mass index, BMI) i indeks procjene modela homeostaze (engl. homeostasis model assessment, HOMA) izmjereni su rutinskim metodama ili su izračunati iz podataka. Rezultati: Pronađena je značajna povezanost između alela Ala polimorfizma Pro12Ala i nižeg BMI (P = 0,040) te između alela T polimorfizma His477His i niže koncentracije hsCRP (P = 0,047). Polimorfizmi Pro12Ala i His477His pokazali su značajnu neravnotežu povezanosti (engl. linkage disequilibrium) (D' = 0,727). Analiza diplotipova nije pokazala da postoji povezanost. Zaključak: U ovom preliminarnom istraživanju pronašli smo značajnu povezanost između alela Ala polimorfizma Pro12Ala i nižeg BMI te alela T polimorfizma His477His i nižeg hsCRP. Međutim, niti jedan od ova dva polimorfizma, pojedinačno ili u kombinaciji (diplotip), nije bio povezan s koncentracijama inzulina i glukoze natašte u plazmi, kao ni s indeksom HOMA, koji su znakoviti za inzulinsku rezistenciju. Stoga zaključujemo kako istraživani polimorfizmi nisu povezani s inzulinskom rezistencijom kod bolesnica s PCOS., Background: Insulin resistance is characterized by attenuated response of tissues to insulin action and is associated with obesity, type 2 diabetes mellitus, metabolic syndrome, lipodystrophies, polycystic ovary syndrome (PCOS) and chronic infection. Insulin resistance is present in 50%—70% of PCOS patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor which controls transcription of genes involved in free fatty acid uptake and lipogenesis, and is essential for diferentiation and survival of adipo-cytes. The aim of our pilot study was to investigate the association between Pro12Ala and His477His polymorphisms in PPARG gene with insulin resistance in PCOS patients. Patients and methods: The study included 69 PCOS patients. Genotype frequencies were analyzed by PCR-RFLP methods. Fasting glucose and glucose after oral glucose tolerance test, insulin, and high sensitivity C-reactive protein (hsCRP), body mass, height, waist circumference, systolic and diastolic blood pressure, body mass index (BMI) and homeostasis model assessment (HOMA) index were measured by routine methods or calculated from the findings obtained. Results: A signi;cant association was found between the Ala allele of the Pro12Ala polymorphism and lower BMI (P = 0.040) and between the T allele of the His477His polymorphism and lower hsCRP (P = 0.047). The Pro12Ala and the His477His polymorphisms were in considerable linkage disequilibrium (D' = 0.727). Diplotype analysis showed no association. Conclusions: In our preliminary study, we found a significant association between the Ala allele of the Pro12Ala polymorphism and lower BMI, and between the T allele of the His477His polymorphism and lower hsCRP. However, none of the two polymorphisms, individually or in combination (diplotype), was associated with fasting plasma insulin and glucose concentrations and HOMA index that are characteristic of insulin resistance. We therefore conclude that the polymorphisms investigated are not associated with insulin resistance in PCOS patients.

Inzulinska rezistencija je stanje poremećene sposobnosti odgovora na djelovanje inzulina. Najčešći osnovni uzrok je središnja pretilost, iako je primarna inzulinska rezistencija moguća i u osoba s normalnom težinom. Suvišno abdo-minalno masno tkivo otpušta povećane količine faktora tumorske nekroze α i slobodnih masnih kiselina, što izravno utječe na inzulinsko signaliziranje, smanjuje preuzimanje glukoze u mišićima, dovodi do pretjerane sinteze trigliceri-da i izaziva glukoneogenezu u jetri. Ostali čimbenici za koje se pretpostavlja da igraju ulogu u inzulinskoj rezistenciji su adiponektin (sniženje), leptin, IL-6 i neki drugi adipokini. Smatra se da je obična pretilost poligenog podrijetla uz utjecaj "pretilogene" okoline - povećan unos hrane i nedostatak tjelesne aktivnosti. Današnja visoka učestalost pretilosti mogla bi se objasniti evolucijskim pritiskom za odabir gena koji promiču pohranu masti za preživljenje u vrijeme gladovanja. Inzulinska rezistencija je prisutna zajedno sa središnjom pretilosti, hipertenzijom i dislipidemijom, koje se skupno označavaju kao metabolički sindrom. Ove pojavnosti predstavljaju snažne čimbenike rizika za šećernu bolest tipa 2 i kardiovaskularnu bolest., Insulin resistance is a state of impaired responsiveness to insulin action. The most common underlying cause is central obesity although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of tumor necrosis factor α and free fatty acids, which directly affect insulin signaling, diminish glucose uptake in the muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play a role in insulin resistance are adiponectin (a decrease), leptin, IL-6 and some other adipokines. Common obesity is thought to be of polygenic origin with influence of "obesogenic" environment, i.e. increased food intake and the lack of physical activity. Today's high prevalence of obesity could be explained by evolutionary pressure for selection of genes promoting fat storage to survive in starvation. Insulin resistance frequently coexists with central obesity, hypertension and dyslipidemia, which have collectively been denoted as metabolic syndrome. These manifestations represent strong risk factors for diabetes mellitus type 2 and cardiovascular disease.

To investigate association of two LPIN1 gene variations with main traits of metabolic syndrome (MS) (waist circumference, body mass index, blood pressure, triglycerides, HDL-cholesterol and fasting glucose levels) in population from Bosnia and Herzegovina.This study included 43 patients with metabolic syndrome and 43 healthy controls from General Hospital in Tešanj, Bosnia and Herzegovina. Subjects were genotyped for two LPIN1 gene variations (rs11693809: CT and rs2716610: CT) by real time PCR method.In control subjects LPIN1 polymorphism, rs2716610: CT, was significantly associated with a lower body mass index (BMI) (p=0.008) and waist circumference (p=0.008). The second analyzed rs11693809: CT polymorphism was associated with lower blood HbA1c levels (p=0.048) in a group of MS patients.Results of our study suggest that rs2716610: CT polymorphism of LPIN1 gene could have a protective effect against development of metabolic syndrome, while rs11693809: CT might affect a glucose control in patients with MS.

In a state of caloric excess, adipose tissue plays an essential role by storing lipids. Its expandability determines the onset of metabolic syndrome (central obesity, dyslipidemia, glucose intolerance and hypertension). When the adipocyte endoplasmic reticulum is no longer capable of processing the excess nutrients, the so-called “endoplasmic reticulum stress” develops. This triggers efflux of free fatty acids from adipocytes into the circulation and causes triglyceride overload in skeletal muscle, liver and pancreas. Adipose tissue hypoxia then develops, due to the failure of vasculature to expand with adipocyte hypertrophy. Increased catabolism in mitochondria leads there to oxidative stress. Both phenomena cause deranged adipokine secretion and low-grade inflammation. Inflammatory cytokines, reactive oxygen species and ectopic lipid deposition are the main mediators of insulin resistance and vascular impairment, which both lead finally to diabetes type 2 and cardiovascular disease. Recently, fibrosis of adipose tissue was also demonstrated in obesity, contributing to the interplay of deleterious factors forcing inflammation. The present paper reviews recent evidence for adipose tissue dysfunction, trying to define causes and consequences. In conclusion, insulin resistance and associated complications originate from excess lipids, which cannot be stored without limit in adipose tissue, thus affecting its integrity and adipokine secretion.

Background and Aims N-acetyltransferase 2 (NAT2) is a drug-metabolizing enzyme, which is genetically variable in human populations. Polymorphisms in the NAT2 gene have been associated with drug efficacy and toxicity as well as disease susceptibility. Recently, an association of NAT2 gene variation with risk of type 2 diabetes mellitus (T2DM) has been suggested. This is the first study performed in a population from Bosnia and Herzegovina (BH) in which the frequency of two common NAT2 polymorphisms, 341T>C ( NAT2∗ 5) and 590G>A ( NAT2∗6 ) was determined in diabetic patients. Methods The frequency of the NAT2∗5 (341T>C) and NAT2∗6 (590G>A) polymorphisms was analyzed by employing TaqMan SNP Genotyping Assays (Applied Biosystems) in a group of 63 patients with T2DM and 79 nondiabetic subjects. Results Our data demonstrated that the frequencies of NAT2∗5 (341T>C) and NAT2∗6 (590G>A) polymorphisms in BH population were in line with the Caucasians genotype data. The NAT2∗5 and NAT2∗6 alleles were in high linkage disequilibrium (D′ = 0.969). Strinkingly, there was a significant difference in genotype frequencies for NAT2∗5 ( p NAT2∗6 ( p NAT2∗5 polymorphism was associated with 2.4-fold increased risk for developing T2DM (adjusted OR = 2.40, 95% CI = 1.10–5.25, p = 0.028). On the contrary, NAT2∗6 variant significantly decreased by 5-fold susceptibility to the disease (adjusted OR = 0.20, 95% CI = 0.09–0.43, p Conclusions Our data demonstrated that NAT2 genetic variation appeared to be an important risk factor in development of T2DM.

Background: Polymorphisms in HSD11B1, the gene encoding 11β-hydroxysteroid dehydrogenase type 1 enzyme, have been associated with obesity, metabolic syndrome, and type 2 diabetes. In this study, we present an optimized high-resolution melting (HRM) method for genotyping two common polymorphisms of the HSD11B1 gene: rs846910: G>A and rs45487298: insA. Methods: One hundred DNA samples from patients with polycystic ovary syndrome and healthy controls were genotyped by HRM. The results were compared with those obtained with classic polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results: Various approaches were used during HRM specificity optimization. With the optimized method, genotyping accuracy of 100% was achieved. Conclusions: HRM analysis is a fast, simple, and cost-effective method compared with the alternative genotyping approaches. The work required for optimizing the method (improvement of specificity) is minor compared to the advantages.

Polycystic ovary syndrome (PCOS) is characterized by insulin resistance (IR) and central obesity. The impact of adipose tissue cortisol reactivation by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) on markers of obesity and IR was assessed in PCOS patients. Eighty-five PCOS patients and 43 controls were enrolled for subcutaneous adipose tissue biopsy; 25/85 patients and 29/43 controls underwent also visceral adipose tissue biopsy. HSD11B1 gene expression and expression of lipid metabolism genes were measured in subcutaneous and visceral adipose tissues. Anthropometric and biochemical markers of IR and PCOS were also assessed. HSD11B1 expression in visceral and subcutaneous adipose tissue was increased in PCOS patients compared to controls (p

ObjectiveIn polycystic ovary syndrome (PCOS), insulin resistance (IR) appears with high prevalence and represents the major cause of cardiometabolic complications. Lipin 1β regulates lipid metabolism and augments insulin sensitivity. The impact of lipin 1β expression in visceral and subcutaneous adipose tissue of PCOS patients on IR was studied for the first time.MethodsEighty-five PCOS patients and 44 controls were enrolled for subcutaneous tissue biopsy, of whom 25 patients and 30 controls also underwent visceral adipose tissue biopsy. Gene expression of lipin 1β was measured, together with that of peroxisome proliferator-activated receptor γ, lipoprotein lipase, hormone-sensitive lipase, adiponectin and glucose transporter 4 in subcutaneous and visceral adipose tissue. Markers of obesity, IR and PCOS were also measured.ResultsIn PCOS patients, lipin 1β expression in both adipose depots was lower than in controls: 0.76 (0.67–0.84) vs 1.16 (0.90–1.43) for visceral and 0.91 (0.73–1.10) vs 1.30 (1.03–1.57) for s.c. depot (both P−4). The difference remained significant after adjustment for body mass index (BMI) and also when comparing only lean patients with lean controls. In PCOS patients, visceral adipose lipin 1β expression correlated negatively with homeostasis model assessment–IR (r=−0.474, P=0.017), BMI (r=−0.511, P=0.009) and waist circumference (r=−0.473, P=0.017), waist circumference remaining significant (P=0.027) in multiple regression. Subcutaneous lipin 1β expression in PCOS correlated negatively with BMI, waist circumference and plasma triglycerides, and positively with high density lipoprotein-cholesterol. Subcutaneous, but not visceral lipin 1β expression, correlated positively with the studied genes.ConclusionsLipin 1β appears to be involved in the pathogenesis of IR in PCOS.

Insulin resistance is a state in which higher than normal concentrations of insulin are required for normal response. The most common underlying cause is central obesity, although primary insulin resistance in normal-weight individuals is also possible. Excess abdominal adipose tissue has been shown to release increased amounts of free fatty acids which directly affect insulin signalling, diminish glucose uptake in muscle, drive exaggerated triglyceride synthesis and induce gluconeogenesis in the liver. Other factors presumed to play the role in insulin resistance are tumour necrosis factor alpha, adiponectin, leptin, IL-6 and some other adipokines. Hyperinsulinaemia which accompanies insulin resistance may be implicated in the development of many pathological states, such as hypertension and hyperandrogenaemia. Insulin resistance underlies metabolic syndrome and is further associated with polycystic ovary syndrome and lipodystrophies. When beta-cells fail to secrete the excess insulin needed, diabetes mellitus type 2 emerges, which is, besides coronary heart disease, the main complication of insulin resistance and associated diseases.

We determined the frequency of galactose-1-phosphate uridyl transferase gene mutations: Q188R, K285N, and the Duarte allelle in 86 patients with idiopathic premature ovarian failure (POF) and 95 controls. No association of the mutations with POF was found.

In a retrospective case-control study, the frequencies of Q188R, K285N, N314D, and IVS5-24G>A mutations were determined with the use of polymerase chain reaction and restriction fragment length polymorphism in the group of infertile women and the controls. No statistically significant differences were observed in the allele frequencies between the infertile women and control groups.