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The article focuses on the extended use of metformin in the clinic of gynaecological endocrinology, and in impaired glucose tolerance and Type 2 diabetes mellitus. Metformin is recommended for gynaecological endocrinology and some other treatments because of its hypoglycaemic effect, decrease in body mass, and lack of hypoglycaemia. The number of miscarriages is generally known to be high in women with polycystic ovarian syndrome (PCOS).

Abstract: Familial LCAT deficiency (FLD) is a rare genetic disorder associated with corneal opacities, anaemia and proteinuria with renal failure. Here we report detailed analyses on plasma lipids, lipoproteins, and the molecular defect in two siblings from a Polish family presenting classical symptoms of FLD and their family members with newly discovered Val309Met mutation in exon 6 of LCAT gene. Both patients displayed low total (2.19 and 2.94mmol/l) and HDL-cholesterol concentrations (0.52 and 0.48mmol/l), low percentage of cholesteryl esters (CE) (11.1 and 12%), and decreased apo AI and apo AII serum levels. Low LDL-cholesterol, apo B and Lp(a) levels, and increased oleate/linoleate ratios in CE could be of importance in the development of atherosclerosis in these patients with low HDL-cholesterol. LCAT activity was 10% of normal, α-LCAT activity was 0, and LCAT concentration was undetectable by immunoassay. Plasma CETP activity was at lower limits of normal. PCR and sequence analysis of DNA from the proband and affected brother revealed a novel G→A mutation in exon 6 of LCAT gene, which resulted in an amino acid substitution of valine for methionine (Val309Met). The proband and affected brother were both homozygous carriers, while the mother, siblings and children of patients were heterozygous carriers of a newly discovered mutation. This is the first LCAT mutation described in the Slavic population. [Copyright &y& Elsevier]

Aims: The effects of continuous subcutaneous insulin infusion (CSII) therapy with or without continuous glucose monitoring (CGM) on neonatal outcomes and glycemic outcomes of pregnant women with type 1 diabetes (T1D), living in Poland, were assessed. Methods: This prospective observational study enrolled women with T1D (N = 481, aged 18–45 years) who were pregnant or planned pregnancy. All used CSII therapy and a subset used CGM with CSII (CSII + CGM). Neonatal outcomes (e.g., rate of large for gestational age [LGA] delivery [birth weight > 90th percentile]) and maternal glycemia (e.g., HbA1c and percentage of time at sensor glucose ranges) were evaluated. Results: Overall HbA1c at trimesters 1, 2, and 3 was 6.8 ± 1.1% (50.9 ± 12.3 mmol/mol, N = 354), 5.8 ± 0.7% (40.1 ± 8.0 mmol/mol, N = 318), and 5.9 ± 0.7% (41.4 ± 8.0 mmol/mol, N = 255), respectively. A HbA1c target of < 6.0% (42 mmol/mol) at each trimester was achieved by 20.9% (74/354), 65.1% (207/318), and 58.0% (148/255), respectively. For women using CSII + CGM versus CSII only, HbA1c levels at trimesters 1, 2, and 3 were 6.5 ± 0.9% versus 7.1 ± 1.3% (47.8 ± 9.7 mmol/mol versus 54.3 ± 14.0 mmol/mol, p < 0.0001), 5.7 ± 0.6% versus 6.0 ± 0.9% (38.9 ± 6.5 mmol/mol versus 41.6 ± 9.3 mmol/mol, p = 0.0122), and 5.8 ± 0.6% versus 6.1 ± 0.8% (40.3 ± 6.9 mmol/mol versus 42.9 ± 9.1 mmol/mol, p = 0.0117), respectively. For the overall, CSII only, and CSII + CGM groups, rates of LGA delivery were 22.7% (74/326), 24.6% (34/138), and 21.3% (40/188), respectively. Conclusions: Observational assessment of women with T1D using CSII therapy demonstrated low HbA1c throughout pregnancy and low rates of LGA. The addition of CGM to CSII therapy compared to CSII therapy alone was associated with some improved maternal glycemic and neonatal outcomes. Clinicaltrials.gov identifier: NCT01779141 (January 2013). [ABSTRACT FROM AUTHOR]

Background: Glucometry is an essential part of diabetes treatment, but so far, no standard quality control procedure verifying blood glucose meter results is available. In this study, we evaluated the analytical performance of eight glucose meters: GX and Esprit™ (Bayer Diagn.), MediSense® Card Sensor, ExacTech (MediSense®) with strips Selfcare™ (Cambridge Diagn), One Touch® Basic, One Touch® II, One Touch® Profile (Lifescan) and Glucotrend® (Boehringer Mannheim/Roche). Methods: The evaluation included within-run imprecision, linearity, comparison with the laboratory method and calculation of differences between individual glucometers. Results: Within-run imprecision ranged from 1.5% to 4.5%, linearity assessed as the correlation between measured and calculated glucose concentrations yielded r2 values from 0.97 to 0.981. Analytical bias of glucose concentration values obtained by the glucometry amounted from 0.14% to 16.9% of values measured by the laboratory method. Bias higher than 5% was found for One Touch® Basic, II and Profile meters (however, glucose concentrations in plasma obtained by the laboratory method One Touch® meters showed analytical bias from 3.0% to 8.8%). The regression analysis yielded slope values from 0.77 to 1.09 and r2 values from 0.86 to 0.98. The best correlations with the laboratory method were found for One Touch® Basic, II Profile, Glucotrend® and Esprit™ meters. The calculated differences between the individual glucose meters can constitute 0.02–1.49 mmol/l (0.96–26.9%) at glucose concentration 5.55 mmol/l, and 0.16–4.16 mmol/l (0.96–24.96%) at glucose concentration 16.67 mmol/l. Error grid analyses have shown that Glucometers One Touch® Basic and One Touch® Profile yielded all results in zone A (acceptable). The remaining glucometers yielded 1–7% of results in zones B (insignificant errors), C or D (lack of detection and treatment). Conclusions: All studied glucometers had both small deviation from laboratory reference values (<10%) and high concurrence with results obtained by the laboratory method. [Copyright &y& Elsevier]

One of the attributes of CSII (continuous subcutaneous insulin infusion) is its ability to tailor prandial insulin delivery to the composition of a meal and anticipated glycemic effects. The dual-wave bolus (DWB) is a tool implemented in contemporary insulin pumps that delivers a combination of an instant insulin bolus followed by a square bolus (SB) infused over several hours. We assessed the effectiveness of DWB in 56 adult patients with type 1 diabetes (T1DM) who were on continuous subcutaneous insulin infusion via insulin pump for at least 2 years. We divided patients into frequent (DWB+, n = 32) and infrequent (DWB−, n = 24) DWB users (>20% vs. <20% of daily bolus dose delivered as SB). CSII implementation resulted in a decrease of adjusted HbA1c level by 0.80% (95% CI 0.67-0.93, P < 0.0001) and adjusted mean glycemia by 18.4 mg/dl (95% CI 15.3-21.4, P < 0.0001) in the whole cohort within the first year of observation. It was sustained in the second year, but without further improvement. Frequent DWB use was associated with male sex (59% vs. 17%, p = 0.001) and shorter duration of T1DM (3.4 vs. 11.3 yrs, p < 0.0001), but not with patients' age (25.7 vs. 27.0 years, P = 0.6). DWB+ patients improved their HbA1c by 0.45% more (95% CI 0.20-0.71, P = 0.0009) than DWB− individuals. In conclusion, DWB might be a tool potentially helping to improve glycemic control in T1DM adult users of insulin pumps. Male patients and those with a shorter duration of diabetes seem to use it more willingly. [ABSTRACT FROM AUTHOR]

Several association studies of type 2 diabetes mellitus (T2DM) and adiponectin gene polymorphisms have been reported with conflicting results. Our aim was to search for the association of three polymorphisms (−11.391G>A, +45T>G, and +276G>T) in the adiponectin gene with T2DM and prediabetic quantitative traits in Polish Caucasians. The study groups comprised 495 unrelated T2DM cases and 435 controls. We compared the distribution of genotypes between study groups. In addition, genotype-quantitative trait analyses were also done in the controls. The study subjects were genotyped using the restriction fragment length polymorphism technique. The frequencies of the minor alleles were as follows: 10.6 versus 8.2% for −11.391G>A ( p = 0.0722), 7.0 versus 8.0% for +45T>G ( p = 0.48), and 15.5% in T2DM versus 19.8% in controls ( p = 0.0145) for +276G>T, respectively. The difference for genotype distribution between the groups was statistically significant ( p = 0.0247) for the +276G>T variant: 71.31 versus 62.99%, 26.46 versus 34.48% and 2.22 versus 2.53%, respectively, for GG, GT and TT. In quantitative traits analysis, the T allele of +276G>T was associated ( p < 0.05) with lower insulin resistance (HOMA-IR, fasting insulin) among controls. Additionally, the A allele at position −11.391 was associated ( p < 0.05) with higher insulin resistance (HOMA-IR, fasting insulin). In multiple regression analysis, all identified association remained significant after the inclusion in the model of gender, BMI and age. In addition, in this model, −11.391G>A and +276G>T were independently associated with T2DM. Finally, we conclude that the adiponectin gene polymorphisms are associated with T2DM and prediabetic quantitative traits in Polish Caucasians. [ABSTRACT FROM AUTHOR]

Objective Mutations in the ABCC8 gene encoding the SUR1 subunits of the β-cell K-ATP channel cause neonatal diabetes (ND) mellitus. We aimed to determine the contribution of ABCC8 gene to ND in Poland, to describe the clinical phenotype associated with its mutations and to examine potential modifying factors. Patients The Nationwide Registry of ND in Poland includes patients diagnosed before 6 months of age. In total 16 Kir6·2 negative patients with ND, 14 permanent and 2 relapsed transient, were examined. Measurements ABCC8 gene mutations were detected by direct sequencing. Mutation carriers’ characteristics included clinical data and biochemical parameters. In addition, we performed the hyperinsulinaemic euglycaemic clamp and tested for islet-specific antibodies in diabetic subjects. Results We identified two probands with permanent ND (one heterozygous F132V mutation carrier and one compound heterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). One subject, a heterozygous relative with the R826W mutation, had adult onset diabetes. There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA1c of 7·3%, whereas the F132V mutation carrier was on 0·66 IU/kg/day of insulin with HbA1c of 11·7%. The C-peptide level varied from 0·1 ng/ml (F132V) to 0·75 ng/ml (V86A). We also observed a variable insulin resistance, from moderate ( M = 5·5 and 5·6 mg/kg/min, respectively, in the two R826W mutation carriers) to severe ( M = 2·6 mg/kg/min in the F132V mutation carrier). We were able to transfer two patients off insulin to sulphonylurea (SU) and to reduce insulin dose in one other patient. Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. All examined auto-antibodies were present in one of the subjects, the V86A mutation carrier, although this did not seem to influence the clinical picture, as we were able to transfer this girl off insulin. Conclusion Mutations in SUR1 are the cause of about 15% of Kir6·2 negative permanent ND in Poland. The clinical phenotype of SUR1 diabetic mutation carriers is heterogeneous and it appears to be modified by variable sensitivity to insulin. [ABSTRACT FROM AUTHOR]

Objective: 1,5-anhydroglucitol (1,5-AG) is a short-term marker of metabolic control in diabetes. Its renal loss is stimulated in hyperglycemic conditions by glycosuria, which results in a lowered plasma concentration. As a low renal threshold for glucose has been described in hepatocyte nuclear factor-1alpha (HNF-1alpha) maturity-onset diabetes of the young (MODY), the 1,5-AG level may be altered in these patients. The purpose of this study was to assess the 1,5-AG levels in patients with HNF-1alpha MODY and in type 2 diabetic subjects with a similar degree of metabolic control. In addition, we aimed to evaluate this particle as a biomarker for HNF-1alpha MODY.Research Design and Methods: We included 33 diabetic patients from the Polish Nationwide Registry of MODY. In addition, we examined 43 type 2 diabetic patients and 47 nondiabetic control subjects. The 1,5-AG concentration was measured with an enzymatic assay (GlycoMark). Receiver operating characteristic (ROC) curve analysis was used to evaluate 1,5-AG as a screening marker for HNF-1alpha MODY.Results: The mean 1,5-AG plasma concentration in diabetic HNF-1alpha mutation carriers was 5.9 microg/ml, and it was lower than that in type 2 diabetic patients (11.0 microg/ml, P = 0.003) and in nondiabetic control subjects (23.9 microg/ml, P < 0.00005). The ROC curve analysis revealed 85.7% sensitivity and 80.0% specificity of 1,5-AG in screening for HNF-1alpha MODY at the criterion of <6.5 microg/ml in patients with an A1C level between 6.5 and 9.0%.Conclusions: 1,5-AG may be a useful biomarker for differential diagnosis of patients with HNF-1alpha MODY with a specific range of A1C, although this requires further investigation. However, the clinical use of this particle in diabetic HNF-1alpha mutation carriers for metabolic control has substantial limitations. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- 1,5-anhydroglucitol (1,5-AG) is a short-term marker of metabolic control in diabetes. Its renal loss is stimulated in hyperglycemic conditions by glycosuria, which results in a lowered plasma concentration. As a low renal threshold for glucose has been described in hepatocyte nuclear factor-1α (HNF-1α) maturity-onset diabetes of the young (MODY), the 1,5-AG level may be altered in these patients. The purpose of this study was to assess the 1,5-AG levels in patients with HNF-1α MODY and in type 2 diabetic subjects with a similar degree of metabolic control. In addition, we aimed to evaluate this particle as a biomarker for HNF-1α MODY. RESEARCH DESIGN AND METHODS -- We included 33 diabetic patients from the Polish Nationwide Registry of MODY. In addition, we examined 43 type 2 diabetic patients and 47 nondiabetic control subjects. The 1,5-AG concentration was measured with an enzymatic assay (GlycoMark). Receiver operating characteristic (ROC) curve analysis was used to evaluate 1,5-AG as a screening marker for HNF-1α MODY. RESULTS -- The mean 1,5-AG plasma concentration in diabetic HNF-1α mutation carriers was 5.9 µg/ml, and it was lower than that in type 2 diabetic patients (11.0 µg/ml, P = 0.003) and in nondiabetic control subjects (23.9 µg/ml, P < 0.00005). The ROC curve analysis revealed 85.7% sensitivity and 80.0% specificity of 1,5-AG in screening for HNF-1α MODY at the criterion of <6.5 µg/ml in patients with an A1C level between 6.5 and 9.0%. CONCLUSIONS -- 1,5-AG may be a useful biomarker for differential diagnosis of patients with HNF-1α MODY with a specific range of A1C, although this requires further investigation. However, the clinical use of this particle in diabetic HNF-1α mutation carriers for metabolic control has substantial limitations. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Molecular background of diabetic retinopathy (DR) remains unknown. An interesting group of candidate genes encode proteins involved in insulin resistance. Aim: To search for association between the PPARγ, calpain 10, PTPN1 genes and DR in type 2 diabetes mellitus (T2DM). Methods: We examined 238 T2DM subjects without DR (NDR) and 121 with DR (mean diabetes duration: 9.1±6.8 and 15.1±7.7, respectively). The subjects were genotyped for four markers: Pro12Ala of PPARγ, SNP43 of calpain 10, rs3787345 and rs754118 of PTPN1. The distributions of the genotypes were compared using the χ2-test and Fisher exact test. Results: The alleles and genotypes were not associated with DR in non-stratified analysis. To investigate the impact of T2DM duration, we performed analysis that excluded short duration NDR subjects and long-duration DR subjects. It allowed obtaining groups with similar T2DM duration but different DR status (DR: 88 individuals, 11.4±5.3 years; NDR: 136 individuals, 13.2 years±6.2, respectively). This analysis suggested that the alanine variant of Pro12Ala might be associated with decreased risk of DR (p =0.026 for alleles, p =0.038 and p =0.014 for genotypes in additive and dominant models, respectively). In multivariable logistic regression that included non-genetic parameters, Pro12Ala was not an independent risk factor (p =0.28). Further analysis showed, however, that Pro12Ala remained significant when urea level was excluded from the model. Conclusion: The alanine variant of the Pro12Ala polymorphism of PPARγ might be associated with decreased risk of DR in T2DM. This effect may be indirect, at least in part, due to diabetic kidney disease. [Copyright &y& Elsevier]

The K121Q polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is associated with type 2 diabetes and obesity. The possibility of other ENPP1 polymorphisms influencing these phenotypes has received little attention. Our aim was to examine the associations of tagging single nucleotide polymorphisms (SNPs) and haplotypes of the linkage disequilibrium (LD) block containing K121Q polymorphism with type 2 diabetes in a Polish population, controlling for any effect of obesity. We genotyped 426 type 2 diabetic case and 370 control subjects for seven SNPs in ENPP1. In the total group, neither type 2 diabetes nor obesity was significantly associated with any SNP. However, in obese subjects, two SNPs were significantly associated with type 2 diabetes: the Q allele of K121Q (odds ratio 1.6 [95% CI 1.003-2.6]) and T allele of rs997509 (4.7 [1.6-13.9]). In the LD block, four SNPs plus the K121Q polymorphism distinguished six haplotypes, three of which carried the Q allele. Interestingly, the T allele of rs997509 sufficed to distinguish a 121Q-carrying haplotype that was significantly more associated with type 2 diabetes than the other two (4.2 [1.3-13.5]). These other two 121Q-carrying haplotypes were not associated with type 2 diabetes. In conclusion, we found a new SNP, rs997509, in intron I that is strongly associated with risk of type 2 diabetes in obese individuals. The molecular mechanisms underlying this association are unknown. Diabetes 55:2626-2630, 2006 [ABSTRACT FROM AUTHOR]

Introduction: It has recently been shown that polymorphisms of some genes might influence the genetic susceptibility to complex, multifactorial forms of type 2 diabetes mellitus (T2DM). One of those genes is peroxisome proliferator activated receptor γ (PPARγ). The PPARγ gene product is a nuclear hormone receptor that regulates adipogenesis and is a target for thiazolidinediones, medications enhancing sensitivity to insulin. The Pro12Ala amino acid variant of the PPARγ2 isoform is associated with T2DM in several populations. Aims: (1) To determine the allele and genotype frequency of the Pro12Ala PPARγ2 amino acid variant in a Polish population; (2) To search for the association of the Pro12Ala polymorphism with T2DM in the examined population. Methods: We included 644 individuals in this study: 366 T2DM patients with age of diagnosis greater than 35 years and 278 non-diabetic control subjects. The fragment of the PPARγ2 gene which contains the examined amino acid variant was amplified by polymerase chain reaction (PCR). Alleles and genotypes were determined based on electrophoresis of the DNA digestion products by the specific restriction enzyme BshI. Differences in distribution between the groups were examined by χ2 test. Results: The frequency of Pro/Ala alleles was similar in T2DM patients and in the control subjects (83.5%/16.5% vs. 84.5%/15.5%, respectively, P=0.607). Similarly, there was no difference between the groups when we analysed the genotype distribution. Stratification analyses based on age of diagnosis, body mass index (BMI), and family history of T2DM were performed. The Pro/Ala and Ala/Ala genotypes tended to be more frequent in T2DM cases with age of diagnosis >50 years than in controls (36.2% vs. 27.3%, P=0.046). This difference was not significant after Sheffe correction for multiple comparisons. The other stratification analyses did not show any difference between the groups. Conclusion: The frequency of the Pro12Ala PPARγ2 polymorphism in the Polish population studied is similar to that in other Caucasian populations. In the case-control study, we were not able to confirm earlier reports that the Pro allele conferred an increased risk for development of T2DM. Moreover, the results of the stratified analysis suggest an opposite trend in late onset T2DM. [Copyright &y& Elsevier]

Polymorphisms of the genes involved in the metabolism of vitamin D may predispose to type 2 diabetes mellitus (T2DM). For example, there is evidence suggesting that vitamin D binding protein (DBP) amino acid variants at codons 416 (aspartic acid→glutamic acid) and 420 (threonine→lysine) may affect genetic susceptibility to T2DM. The aims of this study are: (1) to determine the allele, genotype, haplotype and haplotype combination frequencies of those DBP amino acid variants in a Polish population and (2) to examine their role in the genetic susceptibility to T2DM in a Polish population. Overall 393 individuals were included in this study: 231 T2DM patients and 162 controls. The sequence of DBP exon 11, which contains both examined variants, was amplified by polymerase chain reaction (PCR). Alleles and genotypes were determined based on electrophoresis of the DNA digestion products by specific restriction enzymes HaeIII and StyI. Since variants of DBP were in very strong linkage disequilibrium, haplotypes could be assigned to phase-unknown individuals. Differences in distributions between the groups were examined by χ2 test. At codon 416 the frequency of Asp/Glu alleles was 44.6/55.4% in T2DM patients and 40.7/59.3% in controls (χ2=2.1, d.f.=1, P=0.28). At codon 420 the frequency of Thr/Lys alleles were 69.4/30.6% and 71.6/28.4%, (χ2=0.41, d.f.=1, P=0.52), respectively. Distribution of genotypes, haplotypes and haplotype combinations were similar in both groups. In conclusion, the frequency of amino acid variants at codons 416 and 420 of vitamin D binding protein gene in a Polish population is similar to other Caucasian populations, but differs significantly from other races. No evidence was found for an association between DBP frequent polymorphisms and T2DM in this population. [Copyright &y& Elsevier]

The article discusses the results of a study which aims to assess the relationship between asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and diabetic retinopathy in type 2 diabetes. The study reveals that patients with diabetic retinopathy have the highest ADMA level while control subjects have the lowest rate. It cites that the level of SDMA was greater in patients with diabetic retinopathy than those without such ailment. It notes that elevated levels of ADMA are typical of chronic renal failure.

The article discusses a study on islet-specific antibody seroconversion caused by mutations in the KCNJ11 gene. It notes that patients with long duration of permanent neonatal diabetes (PNDM) may be immunonegative at onset yet show presence of the antibodies in the long run. The results of the study show that of the 11 patients, 5 were positive for islet antibodies. It stresses that immune reaction against β-cells are not limited in patients with type 1 diabetes.

The article presents a study on the transfer of Kir6.2 mutations from insulin to sulfonylurea therapy in adult subjects with permanent neonatal diabetes. The successful transfer off insulin to sulfonylurea is feasible in adults, and age should not be considered the contraindication for such a transfer. Some patients, however, may require up to several months of exposure to large sulfonylurea doses before they become fully insulin independent.

The article discusses the results of a study on the possible link between renal malformations and mutations in the hepatocyte nuclear factor-1α gene. An autosomal-dominant form of disease characterized by β-cell defects and early age of diagnosis is the maturity-onset diabetes of the young (MODY). The cause of the most frequent MODY3 subtype is the mutations in the hepatocyte nuclear factor-1α gene, a transcription factor expressed in pancreas, kidney, liver, and gut.

While many non-genetic factors were associated with diabetic retinopathy (DR) in type 2 diabetes (T2DM), its molecular background remains unknown. An interesting group of candidate genes are proteins involved in insulin resistance. The objective of the study was to search for association between the polymorhisms in PPARγ, calpain 10, and protein tyrosine phosphatase-N1 (PTPN1) genes and DR in T2DM. We examined 359 subjects, all European Caucasians, with T2DM (mean age at examination: 60.8 yrs ± 9.7): 238 without DR (NDR) and 121 with DR. The diagnosis of DR was based on ophthalmologic examination with photographic documentation. The subjects were genotyped for four markers: Pro12Ala of PPARγ, SNP43 of calpain 10, rs3787345 and rs754118 of PTPN1. We also measured potentially important clinical covariables. The distributions of the alleles and genotypes were compared using the chi² test. Multivariable logistic regression analysis was carried out to analyze the significance of polymorphisms. The alleles and genotypes of examined markers were not associated with DR in non-stratified analysis. To investigate the impact of T2DM duration on development of DR, we performed additional analysis that excluded short duration DR subjects (below 50th percentile) and long-duration DR subjects (above 75th percentile). It allowed obtaining groups of T2DM patients with similar diabetes duration but different DR status (DR: 88 individuals, mean diabetes duration 11.4±5.3 yrs, NDR: 136 individuals, mean disease duration 13.2 yrs±6.2, respectively). This analysis suggested that the alanine variant of Pro12Ala might be associated with decreased risk of DR (p=0.026 for alleles, p=0.04 and p=0.014 for genotypes in additive and dominant models, respectively). In multivariable logistic regression analysis that included the clinical, non-genetic parameters proven to be risk factors in univariate analysis (diabetes duration, HbA1c level, non-smoking status, and urea level), Pro12Ala was not an independent risk factor (p=0.28). Further analysis showed, however, that Pro12Ala remained significant when urea level was excluded from the model. In conclusion, our data suggests that the alanine variant of the Pro12Ala polymorphism of PPARγ might be associated with decreased risk of DR in T2DM. This effect may be indirectly, at least in part, due to diabetic kidney disease. [ABSTRACT FROM AUTHOR]

A correction to the article "Variants of the adiponectin gene and type 2 diabetes in a Polish population," that was published in the October 29, 2009 issue is presented.

Heterozygous activating mutations in the KCNJ11 gene are the most common cause of permanent neonatal diabetes mellitus (PNDM). In contrast to the autoimmune type 1 diabetes, patients with KCNJ11 mutations do not have pancreatic auto-antibodies at onset. However, gain-of-function mutations in Kir6.2 severely disturb metabolism of pancreatic beta cells and could possibly lead to enhanced apoptosis, exposure of beta cell antigens and immunization. We therefore hypothesized that immunonegative at onset carders of KCNJ11 mutation could show seroconversion in the course of the disease. In the present study, sera from 11 patients with Kir6.2 mutations were tested for beta cell auto-antibodies. Cytoplasmic islet cell antibodies (ICAs) were determined by a standard immunofluorescence method using cryostat sections of human pancreas. Autoantibodies against glutamic acid decarboxylase 65 (GADA) and against tyrosine phosphatase IA 2 (IA2-Ab) were measured by commercial ELISAs. Two patients were positive for both ICAs and IA2-Ab, one patient had ICAs detectable and other two subjects were positive for IA2-Ab. All tested sera were negative for GADA. Among patients with over 10-year duration of neonatal diabetes more than a half showed the presence of at least one beta cell specific auto-antibody. Of 5 sera collected from the R201H mutation carders two (age 13 and 50) were positive for pancreatic auto-antibodies. We did not find any evidence that the type of mutation is related to the presence of auto-antibodies. In this subgroup of patients autoimmune pancreatic islets destruction may occur as a secondary effect to Kir6.2 mutation, which possibly evokes apoptosis of the beta cells. Despite detectable markers of isletspecific autoimmune process, all 5 patients responded well to sulfonylurea treatment, which indicates that sufficient number of beta cells remained to maintain glucose homeostasis. However, ongoing autoimmune process and successive destruction of beta cells may limit successful treatment with sulfonylureas in patients with PNDM caused by Kir6.2 mutation. Thus, our finding could provide an explanation for failure to transfer from insulin to sulfonylureas observed in some patients with long duration of PNDM. [ABSTRACT FROM AUTHOR]

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been reported to be associated with atherosclerosis in non-diabetic populations and with vascular diabetic complications such as nephropathy. It is not known whether there is any association of ADMA with diabetic retinopathy. The objective of the study was to evaluate in cross-sectional analysis the relationship between plasma ADMA and the occurrence of diabetic retinopathy in type 2 diabetes (T2DM). We examined 234 subjects: 52 healthy, well-matched controls (mean age 54.5±7.1 years), 111 T2DM patients without diabetic retinopathy (NDR), and 71 T2DM subjects with diabetic retinopathy (DR) (mean age 55.7±6.2 and 57.1±7.0, respectively). All were European Caucasians. Plasma ADMA levels were measured by high-performance liquid chromatography. The diagnosis of DR was based on ophthalmic examination with photographic documentation. Potentially important clinical covariables were also measured. Determinants of DR were identified via stepwise multivariable logistic regression analysis. ADMA level was highest in the group of T2DM patients with DR (0.60±0.06 micromol/L), intermediate in the subjects with T2DM and NDR (0.51±0.06), and lowest among the controls (0.45±0.05). The plasma ADMA levels were highly significantly different between the groups (p<0.001 for all comparisons). In stepwise multivariable logistic regression, the level of ADMA remained independent predictor of the presence of DR (p<0.0001, OR = 1.73, 95%CI: 1.43 - 2.1) in T2DM patients. In addition, DR was also associated with the age at examination(p<0.0001, OR = 0.78, 95%CI: 0.69 - 0.88) and duration of diabetes (p= 0.035, OR = 1.1, 95%CI: 1.006 - 1.19). The plasma creatinine level reached borderline significance (p = 0.05, OR = 0.98, 95%CI: 0.96 - 1). DR was not associated with smoking, levels of glycated hemoglobin or lipids in our study. In conclusion, our data suggest that elevated circulating ADMA level is associated with the presence of retinopathy in T2DM. This seems to be independent of renal function. [ABSTRACT FROM AUTHOR]