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[show abstract]
[hide abstract]
ABSTRACT: AIMS/HYPOTHESIS: Most pregnant women with type 1 diabetes mellitus achieve HbA(1c) targets; however, macrosomia remains prevalent and better pregnancy glycaemic markers are therefore needed. 1,5-Anhydroglucitol (1,5-AG) is a short-term marker of glycaemia, reflecting a period of 1 to 2 weeks. Its excretion rate depends on the renal glucose threshold and thus it is unclear whether it may be used in pregnant type 1 diabetes women. We evaluated 1,5-AG as a glycaemic marker and birthweight predictor in pregnant women with type 1 diabetes, and compared its performance with HbA(1c). METHODS: 1,5-AG and HbA(1c) were measured in 82 pregnant women with type 1 diabetes. In addition, 58 continuous glucose monitoring system (CGMS) records were available. Macrosomia was defined as birthweight >90th centile. The data were analysed with Pearson's correlations, and linear and logistic regression models. Receiver operating characteristic (ROC) analysis was used to evaluate third trimester 1,5-AG as a predictor of macrosomia. RESULTS: Unlike HbA(1c), 1,5-AG strongly correlated with CGMS indices: the AUC above 7.8 mmol/l (r = -0.66; p < 0.001), average maximum glucose (r = -0.58; p < 0.001) and mean glucose (r = -0.54; p < 0.001). In the third trimester, 1,5-AG was the strongest predictor of macrosomia, with ROC AUC 0.81 (95% CI 0.70, 0.89). In contrast, HbA(1c) in the third trimester had a ROC AUC of 0.69 (95% CI 0.58, 0.81). The best discrimination was achieved when both markers were used jointly, yielding a ROC AUC of 0.84 (95% CI 0.76, 0.93). CONCLUSIONS/INTERPRETATION: In pregnant women with type 1 diabetes, 1,5-AG is a better glycaemic marker than HbA(1c), as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA(1c), is a strong predictor of macrosomia.
Diabetologia 02/2013; · 6.81 Impact Factor
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[hide abstract]
ABSTRACT: Mutations in the glucokinase (GCK) gene result in maturity-onset diabetes of the young (MODY). Pharmacotherapy is not effective in GCK MODY. Thus, nutritional intervention seems to be the only therapeutic option. This study evaluated the effect of the quantity of dietary carbohydrate on glucose levels in 10 GCK mutation carriers: seven with MODY and three with prediabetes. All patients were exposed to high-carbohydrate diets for 2 days and then switched to low-carbohydrate diets (60% versus 25% of the daily calorie intake) for another 2 days, after a 1-day washout. Glucose levels were assessed by continuous blood glucose monitoring. In patients with GCK MODY on high-carbohydrate diets, glucose levels were significantly higher, and more hyperglycaemic episodes occurred, compared with patients on low-carbohydrate diets. This short-term observational study suggested that diets with a modestly limited carbohydrate content may improve glycaemic control in patients with GCK MODY.
The Journal of international medical research 01/2011; 39(6):2296-301. · 0.90 Impact Factor
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I Kowalska,
M T Malecki,
M Straczkowski, J Skupien,
M Karczewska-Kupczewska,
A Nikolajuk,
M Szopa,
A Adamska,
N Wawrusiewicz-Kurylonek,
S Wołczynski,
J Sieradzki,
M Gorska
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies have shown that variation in the FTO gene predisposes to obesity and related traits that are common features of polycystic ovary syndrome (PCOS). The aim of the present study was to assess the effect of FTO variation on obesity, insulin sensitivity, and metabolic and hormonal profiles in PCOS.
We examined 136 PCOS women (mean body mass index [BMI]: 28.28+/-6.95kg/m(2), mean age: 25.36+/-5.48 years). Anthropometric measurement, euglycaemic-hyperinsulinaemic clamp and oral glucose tolerance tests and sex hormone assessments were performed. The study group was genotyped for the FTO rs9939609 polymorphism.
BMI (29.0+/-6.9kg/m(2) vs 26.1+/-6.8kg/m(2); P=0.023), body weight (80.1+/-20.7kg vs 72.6+/-20.2kg; P=0.048), fat mass (29.7+/-1 6.6kg vs 24.6+/-17.7kg; P=0.045) and waist circumference (89.8+/-16.7cm vs 83.2+/-17.1cm; P=0.028) were higher in carriers of at least one copy of the A allele. Differences in these parameters were more significant when comparing AA and TT homozygotes. Women with the AA genotype also had decreased insulin sensitivity (P=0.025) and follicle-stimulating hormone (P=0.036). In logistic-regression analyses, the association of the FTO gene polymorphism with insulin sensitivity was no longer significant when BMI was included in the model.
Variation in the FTO gene modifies weight, adiposity and other measures of obesity and insulin sensitivity in PCOS. The examined FTO gene variant appears to have a greater impact on obesity and related traits in PCOS than in other phenotypes. The effect on insulin sensitivity appears to be secondary to its influence on obesity and body fat.
Diabetes & Metabolism 08/2009; 35(4):328-31. · 2.41 Impact Factor
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Diabetic Medicine 07/2009; 26(6):663-4. · 2.90 Impact Factor
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ABSTRACT: Microangioathy and macroangiopathy in type 2 diabetes mellitus (T2DM) frequently coexist. Both types of vascular complications share traditional risk factors. It is not clear whether the presence of microangiopathy, such as diabetic retinopathy (DR), constitutes a predictor of atherosclerosis in T2DM. Here we described the search for the association between DR and intima-media thickness (IMT) in T2DM. We also compared endothelial function in subjects with and without DR.
We examined 182 consecutive patients with T2DM for at least 5 years (mean age at examination 56.3 +/- 6.52 years). We assessed (i) IMT of carotid artery by ultrasound and (ii) endothelial function by flow-mediated dilatation (FMD) method as well as by measurement of concentrations of von Willebrand factor (vWF) and s-ICAM-1. All patients underwent ophthalmological examination. Statistical analysis included Student's, Mann-Whitney, chi-square, Fisher tests and multiple regression.
DR was found in 71 (39.0%) subjects. IMT was higher in patients with DR than those without DR (0.87 mm vs. 0.79 mm, respectively, P = 0.0001). FMD was lower in the complication group than in subjects without DR (8.38% vs. 10.45%, respectively, P = 0.0023). Concentrations of s-ICAM-1 and vWF were not different between the groups. In multiple regression analysis, DR was among the predictors of increased IMT (P = 0.016) and decreased FMD (P = 0.002). We did not find a significant association of DR with vWF and s-ICAM-1 (P = 0.09 and P = 0.11, respectively).
DR is associated with increased IMT and endothelial dysfunction in T2DM. Impaired endothelial function may be a common denominator of pathogenesis of microvascular complications and atherosclerosis in T2DM.
European Journal of Clinical Investigation 01/2009; 38(12):925-30. · 3.02 Impact Factor
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[hide abstract]
ABSTRACT: Knowing the molecular background of monogenic diabetes in affected individuals influences the clinical practice. Mutations in the HNF1A gene are the most frequent cause of MODY. The aim of the present study was to identify the genetic and clinical characteristics of HNF1A MODY in a Polish population, and the prevalence of diabetic complications and renal malformations.
We identified 47 families with the early-onset, autosomal-dominant form of diabetes that met the criteria of MODY. Mutation screening involved direct sequencing of the HNF1A gene. Patients' characteristics included clinical data, anthropometric measurements and biochemical parameters. The search for renal malformations involved ultrasound examination of all HNF1A mutation carriers.
We identified 13 HNF1A MODY families and examined 56 mutation carriers, including 46 diabetic patients. The average HbA(1c) level among the diabetics was 7.5%. We identified diabetic retinopathy in 47.7% of the MODY patients, while diabetic nephropathy was present in 25%. In five HNF1A mutation carriers from three families, renal developmental malformations were identified, including one functioning kidney in two (3.6%) of them.
This first systematic search for HNF1A mutations in a Polish population revealed that they are a frequent cause of MODY. In this population, HNF1A mutation carriers were characterized by a high prevalence of diabetic complications. In addition, renal developmental abnormalities were found in some mutation carriers.
Diabetes & Metabolism 10/2008; 34(5):524-8. · 2.41 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Evidence exists that some clinical, metabolic and genetic risk factors are associated with the development of diabetic retinopathy (DR). The aim of the study was: (1) to define the prevalence of DR in the examined group of 267 patients with type 2 diabetes mellitus (T2DM) from a Polish population; (2) to identify in cross-sectional analysis, the clinical features associated with DR in the study group; and (3) to search for the association of 4 markers of vitamin D receptor (VDR), a candidate gene for vascular complications in diabetes, with DR. The examined group consisted of 146 female and 121 male T2DM patients (mean age at examination: 61.3+/-9.4 years; age at T2DM diagnosis: 50.0+/-9.2; T2DM duration: 11.3+/-7.8 years; body mass index (BMI): 30.5+/-5.5 kg/m(2); HbA1c: 7.8+/-1.5%). In all patients, the clinical and metabolic profile was determined. Diagnosis of DR was determined by a trained ophthalmologist by ophthalmoscopy after pupillary dilatation. Colour photographic documentation was made. The examined T2DM patients were genotyped for FokI, ApaI, BsmI and TaqI frequent VDR polymorphisms based on the restriction fragment length polymorphism method. The statistical analysis was performed using univariate and multivariate logistic regression (SAS) and haplotype analysis (Haplostat). DR was detected in 85 (31.8%) patients with T2DM. The multivariate analysis revealed that significant predictors of this complication were: never-smoking status (odds ratio 2.2, 95% confidence interval 1.2-4), urea serum level (1.3, 1.1-1.5), HbA1c level (1.4, 1.1-1.8) and insulin treatment (2.7, 1.4-5.1). Other features such as age of T2DM diagnosis, T2DM duration prior to ophthalmic exam, obesity (BMI>30), serum creatinine level, albumin/creatinine ratio and arterial hypertension were univariate predictors of DR, however they lost significance as independent predictors in multivariate analysis. Similarly, the alleles, genotypes, haplotype and haplotype combination of VDR were not associated with the examined complication. However, there was a suggestion of a possible slight association between the fbaT haplotype and DR (p=0.11). In conclusion, our study showed that DR in T2DM patients remains a frequent complication in Polish T2DM patients. We were able to confirm the role of some clinical risk factors, surprisingly including not-smoking status, as was previously shown in the UK Prospective Diabetes Study (UKPDS). VDR gene polymorphisms did not constitute a risk factor for this size of study group.
Acta Diabetologica 12/2006; 43(4):114-9. · 2.78 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Recently, several association studies of type 2 diabetes mellitus (T2DM) and the hepatocyte nuclear factor (HNF)-4alpha gene were reported with conflicting results. Our aim was to search for association between two polymorphisms of HNF-4alpha and T2DM in Polish Caucasians. The study groups comprised of 461 T2DM cases and 366 controls. Genotype-quantitative trait analyses were based on the oral glucose tolerance test (OGTT), glucose and insulin results, and comprised 310 glucose-tolerant subjects. All individuals were genotyped for two HNF-4alpha polymorphisms. The frequencies of the minor alleles were as follows: 19.2% in T2DM vs. 17.6% in controls for rs2144908; and 20.6% vs. 20.1% for rs4810424, respectively. The distributions of alleles, genotypes, and haplotypes of the HNF-4alpha polymorphisms did not differ between the study groups (lowest P = 0.41). None of the examined SNPs showed an association in control subjects with quantitative traits of fasting plasma glucose, fasting insulin, as well as plasma glucose and insulin 2 hours after glucose load in OGTT. We conclude that both examined polymorphisms in HNF-4alpha are not associated with T2DM and prediabetic phenotypes in Polish Caucasian study groups of this size.
Diabetes & Metabolism 03/2006; 32(1):86-8. · 2.41 Impact Factor
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N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
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N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
-
N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
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[show abstract]
[hide abstract]
ABSTRACT: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.
Rev Diabet Stud. 3(1):17-20.
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N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
-
N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
-
[show abstract]
[hide abstract]
ABSTRACT: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.
Rev Diabet Stud. 3(1):17-20.
-
N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
-
[show abstract]
[hide abstract]
ABSTRACT: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.
Rev Diabet Stud. 3(1):17-20.
-
N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
[show abstract]
[hide abstract]
ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
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ABSTRACT: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.
Rev Diabet Stud. 3(1):17-20.
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N. Nowak,
M. Szopa,
G. Thanabalasingham,
T. J. McDonald,
K. Colclough, J. Skupien,
T. J. James,
B. Kiec-Wilk,
E. Kozek,
W. Mlynarski,
A. T. Hattersley,
K. R. Owen,
M. T. Malecki
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ABSTRACT: Cystatin C is a marker of glomerular filtration rate (GFR). Its level is influenced, among the others, by CRP whose concentration is decreased in HNF1A-MODY. We hypothesized that cystatin C level might be altered in HNF1A-MODY. We aimed to evaluate cystatin C in HNF1A-MODY both as a diagnostic marker and as a method of assessing GFR. We initially examined 51 HNF1A-MODY patients, 56 subjects with type 1 diabetes (T1DM), 39 with type 2 diabetes (T2DM) and 43 non-diabetic individuals (ND) from Poland. Subjects from two UK centres were used as replication panels: including 215 HNF1A-MODY, 203 T2DM, 39 HNF4A-MODY, 170 GCK-MODY, 17 HNF1B-MODY and 58 T1DM patients. The data were analysed with additive models, adjusting for gender, age, BMI and estimated GFR (creatinine). In the Polish subjects, adjusted cystatin C level in HNF1A-MODY was lower compared with T1DM, T2DM and ND (p < 0.05). Additionally, cystatin C-based GFR was higher than that calculated from creatinine level (p < 0.0001) in HNF1A-MODY, while the two GFR estimates were similar or cystatin C-based lower in the other groups. In the UK subjects, there were no differences in cystatin C between HNF1A-MODY and the other diabetic subgroups, except HNF1B-MODY. In UK HNF1A-MODY, cystatin C-based GFR estimate was higher than the creatinine-based one (p < 0.0001). Concluding, we could not confirm our hypothesis (supported by the Polish results) that cystatin C level is altered by HNF1A mutations; thus, it cannot be used as a biomarker for HNF1A-MODY. In HNF1A-MODY, the cystatin C-based GFR estimate is higher than the creatinine-based one.
Acta Diabetol.
