Publications by authors named "Jan Skupien"

75 Publications

Mortality Following Infection in Europe: A Retrospective Multicenter Case-Control Study.

Antibiotics (Basel) 2021 Mar 13;10(3). Epub 2021 Mar 13.

Department of Infectious and Tropical Diseases, Jagiellonian University Medical College, 30-688 Krakow, Poland.

We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were β-lactams; previous exposure to fluoroquinolones was significantly ( = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome.
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http://dx.doi.org/10.3390/antibiotics10030299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998379PMC
March 2021

Profibrotic Circulating Proteins and Risk of Early Progressive Renal Decline in Patients With Type 2 Diabetes With and Without Albuminuria.

Diabetes Care 2020 11 4;43(11):2760-2767. Epub 2020 Sep 4.

Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, MA

Objective: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and matrix metalloproteinase 7 (MMP-7; Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline.

Research Design And Methods: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m were monitored for 6-12 years to ascertain fast early progressive renal decline, defined as eGFR loss ≥5 mL/min/1.73 m/year.

Results: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and albumin-to-creatinine ratio (ACR) at baseline were 97 mL/min/1.73 m and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups, the risk of renal decline increased with increasing baseline levels of WFDC2 ( < 0.0001) and MMP-7 ( < 0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the fibrosis index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (odds ratio 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria.

Conclusions: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in the development of early renal decline.
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http://dx.doi.org/10.2337/dc20-0630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576423PMC
November 2020

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

Kidney Int 2021 03 25;99(3):725-736. Epub 2020 Jul 25.

Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed for seven-fifteen years to determine the slope of the estimate glomerular filtration rate and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PKD, determined as estimated glomerular filtration rate loss greater than or equal to three ml/min/1.73m/year, was associated with elevated circulating levels of 13 of 19 TNF receptors examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PKD. In contrast, none of the six measured TNF ligands showed association with risk of early PKD. Of significance, the disease process that underlies PKD leading to ESKD in Type 1 diabetes has a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PKD in Type 1 diabetes and must be investigated further. Thus, some of these receptors may be used as new risk predictors of ESKD.
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http://dx.doi.org/10.1016/j.kint.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891866PMC
March 2021

A Prospective Pilot Study on Use of Liquid Crystal Thermography to Detect Early Breast Cancer.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420915778

Jagiellonian University, Krakow, Poland.

Breast cancer is the most common cancer in women. While mammography is the standard for early detection in women older than 50 years of age, there is no standard for younger women. The aim of this prospective pilot study was to assess liquid crystal contact thermography, using the Braster device, as a means for the early detection of breast cancer. The device is intended to be used as a complementary tool to standard of care (sonography, mammography, etc). A total of 274 consecutive women presenting at Polish breast centers for prophylactic breast examination were enrolled to receive thermography; 19 were excluded for errors in thermographic image acquisition. The women were divided according to age (n = 135, <50 years; n = 120, ≥50 years). A control population was included (n = 40, <50 years; n = 23, ≥50 years). The primary endpoint, stratified by age group, was the -statistic for discrimination between breast cancer and noncancer. In women with abnormal breast ultrasound (n = 95, <50 years; n = 87, ≥50 years), the -statistic was 0.85 and 0.75, respectively ( = .20), for discrimination between breast cancer and noncancer. Sensitivity did not differ ( = .79) between the younger (82%) and older women (78%), while specificity was lower in the older women (60% vs 87%, = .025). The false-positive rate was similar in women with normal and abnormal breast ultrasound. Positive thermographic result in women with Breast Imaging Reporting and Data System (BIRADS) 4A on ultrasound increased the probability of breast cancer by over 2-fold. Conversely, a negative thermographic result decreased the probability of cancer more than 3-fold. Breast size and structure did not affect the thermography performance. No adverse events were observed. Thermography performed well in women <50 years of age, while its specificity in women ≥50 years was inadequate. These promising findings suggest that the Braster device deserves further investigation as a supporting tool for the early detection of breast cancer in women younger than 50 years of age.
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http://dx.doi.org/10.1177/1534735420915778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235966PMC
March 2021

Increased Incidence of Type 1 Diabetes in Children and No Change in the Age of Diagnosis and BMI-SDS at the Onset - is the Accelerator Hypothesis not Working?

J Clin Res Pediatr Endocrinol 2020 09 28;12(3):281-286. Epub 2020 Jan 28.

Department of Pediatric and Adolescent Endocrinology, Chair of Pediatrics, Pediatric Institute, Jagiellonian University, Medical College, Kraków, Poland

Objective: One of the hypothesized reasons for the observed increase in type 1 diabetes incidence in children is weight gain, causing accelerated disease development in predisposed individuals. This so-called accelerator hypothesis is, however, controversial. The aim was to analyze whether, in the ethnically homogeneous population of Lesser Poland, an increase in the number of cases of diabetes among children was associated with younger age and higher body mass index-standard deviation score (BMI-SDS) at the time of diagnosis.

Methods: Retrospective data analysis from medical records of all patients <14 years (n=559; 50.6% male), with newly diagnosed type 1 diabetes, in Lesser Poland between 1 January 2006 and 31 December 2017 (11 years).

Results: The incidence ratio ranged significantly (p<0.001) from the lowest in 2006 (11.2/100,000/year) to the highest in 2012 (21.9/100,000/year). The mean age of diagnosis was 8.2±3.5 years. There was no trend in decreasing diagnosis age (p=0.43). The mean BMI-SDS was -0.4±1.2. Almost all children (91.6%) presented with BMI-SDS within the normal range at the time of diagnosis, with only 2.7% of cases being obese and 5.7% underweight at the moment of diagnosis. There was no clear trend at all in BMI-SDS over the study period.

Conclusion: These results do not corroborate an increase of type 1 incidence in paediatric population being associated with younger age of diagnosis and higher BMI-SDS. This implies that the accelerator hypothesis does not hold true in the study population.
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http://dx.doi.org/10.4274/jcrpe.galenos.2020.2019.0133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499142PMC
September 2020

Randomized Clinical Trial of Surgical vs. Percutaneous vs. Hybrid Revascularization in Multivessel Coronary Artery Disease: Residual Myocardial Ischemia and Clinical Outcomes at One Year-Hybrid coronary REvascularization Versus Stenting or Surgery (HREVS).

J Interv Cardiol 2020 3;2020:5458064. Epub 2020 Jan 3.

Jagiellonian University School of Medicine, Krakow, Poland.

Aim: Optimal revascularization strategy in multivessel (MV) coronary artery disease (CAD) eligible for percutaneous management (PCI) and surgery remains unresolved. We evaluated, in a randomized clinical trial, residual myocardial ischemia (RI) and clinical outcomes of MV-CAD revascularization using coronary artery bypass grafting (CABG), hybrid coronary revascularization (HCR), or MV-PCI.

Methods: Consecutive MV-CAD patients ( = 155) were randomized (1 : 1 : 1) to conventional CABG (LIMA-LAD plus venous grafts) or HCR (MIDCAB LIMA-LAD followed by PCI for remaining vessels) or MV-PCI (everolimus-eluting CoCr stents) under Heart Team agreement on equal technical and clinical feasibility of each strategy. SPECT at 12 months (primary endpoint of RI that the trial was powered for; a measure of revascularization midterm efficacy and an independent predictor of long-term prognosis) preceded routine angiographic control.

Results: Data are given, respectively, for the CABG, HCR, and MV-PCI arms. Incomplete revascularization rate was 8.0% vs. 7.7% vs. 5.7% (=0.71). Hospital stay was 13.8 vs. 13.5 vs. 4.5 days ( < 0.001), and sick-leave duration was 23 vs. 16 vs. 8 weeks ( < 0.001). At 12 months, RI was 5 (2, 9)% vs. 5 (3, 7)% vs. 6 (3, 10)% (median; Q1, Q3) with noninferiority values of 0.0006 (HCR vs. CABG) and 0.016 (MV-PCI vs. CABG). Rates of angiographic graft stenosis/occlusion or in-segment restenosis were 20.4% vs. 8.2% vs. 5.9% (=0.05). Clinical target vessel/graft failure occurred in 12.0% vs. 11.5% vs. 11.3% (=0.62). Major adverse cardiac and cerebral event (MACCE) rate was similar (12% vs. 13.4% vs. 13.2%; =0.83).

Conclusion: In this first randomized controlled study comparing CABG, HCR, and MV-PCI, residual myocardial ischemia and MACCE were similar at 12 months. There was no midterm indication of any added value of HCR. Hospital stay and sick-leave duration were shortest with MV-PCI. While longer-term follow-up is warranted, these findings may impact patient and physician choices and healthcare resources utilization. This trial is registered with NCT01699048.
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http://dx.doi.org/10.1155/2020/5458064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961598PMC
September 2020

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol 2019 10 19;30(10):2000-2016. Epub 2019 Sep 19.

Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts;

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( or renal biology ( and ).

Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
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http://dx.doi.org/10.1681/ASN.2019030218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779358PMC
October 2019

Risk factors of hypoglycaemia in type 1 diabetes individuals during intensive sport exercise-Data from the SPORTGIVECHANCE event.

Int J Clin Pract 2019 Nov 4;73(11):e13411. Epub 2019 Sep 4.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Aims: Fear of hypoglycaemia seems to be one of the strongest barrier to physical activity for individuals with type 1 diabetes mellitus (T1DM).The aim of the study was to describe clinical characteristics of participants with T1DM in the intense sporting event of runs and bike rides"SPORTGIVECHANCE-Diabetic runners and cyclists for more sport for all in Europe", and investigate factors associated with self-reported hypoglycaemia episodes during the competition, in particular the use of continuous and flash glucose monitoring systems (CGM/FGM).

Methods: The sporting event took place in Spoleto, Italy from 30 August 2018 to 2 September 2018. An online survey was distributed among 150 participants with diabetes. Only T1DM patients were invited to complete the survey that included questions on baseline clinical characteristics as well as glucose control and meal related issues during the competition. Logistic regression was used to determine factors associated with reported hypoglycaemia.

Results: There were 35 T1DM individuals who completed the questionnaire: eight subjects were continuous glucose monitoring system (CGM) users, 10 used flash glucose monitoring systems (FGM), while the others performed self-measured blood glucose measurements (SMBG) on glucose meters. Mild hypoglycaemia episodes during the competition were reported by four CGM/FGM users and six non-users (OR: 0.73, CI: 0.34-1.53). No severe hypoglycaemic episode was reported. Body mass index (BMI) (OR: 1.47, CI: 1.01-2.13) and subjectively very hard or maximal intensity of the competition (OR: 4.90, CI: 1.51-15.89) were associated with a higher risk of hypoglycaemia.

Conclusions: Data obtained from the self-selected sample of T1DM patients suggests that T1DM individuals can participate in intense sport competitions with moderate risk of mild hypoglycaemia regardless of CGM/FGM or SMBG use.
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http://dx.doi.org/10.1111/ijcp.13411DOI Listing
November 2019

A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes.

Nat Med 2019 05 22;25(5):805-813. Epub 2019 Apr 22.

Research Division, Joslin Diabetes Center, Boston, MA, USA.

Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.
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http://dx.doi.org/10.1038/s41591-019-0415-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508971PMC
May 2019

A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations.

Endocrine 2019 04 18;64(1):75-81. Epub 2019 Feb 18.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.

Purpose: To investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY.

Methods: We examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation.

Results: Concentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients.

Conclusions: Plasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.
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http://dx.doi.org/10.1007/s12020-019-01863-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453873PMC
April 2019

Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy.

Diabetes Care 2019 01 19;42(1):93-101. Epub 2018 Nov 19.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts.

Research Design And Methods: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD.

Results: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, = 0.003) and lowest in Steno (HR 0.54, < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes.

Conclusions: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.
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http://dx.doi.org/10.2337/dc18-1369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300701PMC
January 2019

Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development.

Kidney Int 2018 05 2;93(5):1198-1206. Epub 2018 Feb 2.

Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.
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http://dx.doi.org/10.1016/j.kint.2017.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911430PMC
May 2018

Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease.

Kidney Int 2017 07 7;92(1):258-266. Epub 2017 Apr 7.

Section on Genetics and Epidemiology, Research Divisions, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Design of Phase III trials for diabetic nephropathy currently requires patients at a high risk of progression defined as within three years of a hard end point (end-stage renal disease, 40% loss of estimated glomerular filtration rate, or death). To improve the design of these trials, we used natural history data from the Joslin Kidney Studies of chronic kidney disease in patients with diabetes to develop an improved criterion to identify such patients. This included a training cohort of 279 patients with type 1 diabetes and 134 end points within three years, and a validation cohort of 221 patients with type 2 diabetes and 88 end points. Previous trials selected patients using clinical criteria for baseline urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Application of these criteria to our cohort data yielded sensitivities (detection of patients at risk) of 70-80% and prognostic values of only 52-63%. We applied classification and regression trees analysis to select from among all clinical characteristics and markers the optimal prognostic criterion that divided patients with type 1 diabetes according to risk. The optimal criterion was a serum tumor necrosis factor receptor 1 level over 4.3 ng/ml alone or 2.9-4.3 ng/ml with an albumin-to-creatinine ratio over 1900 mg/g. Remarkably, this criterion produced similar results in both type 1 and type 2 diabetic patients. Overall, sensitivity and prognostic value were high (72% and 81%, respectively). Thus, application of this criterion to enrollment in future clinical trials could reduce the sample size required to achieve adequate statistical power for detection of treatment benefits.
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http://dx.doi.org/10.1016/j.kint.2017.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796779PMC
July 2017

Fast renal decline to end-stage renal disease: an unrecognized feature of nephropathy in diabetes.

Kidney Int 2017 06 31;91(6):1300-1311. Epub 2017 Mar 31.

Research Division of Joslin Diabetes Center, Boston, Massachusetts, USA.

A new model of diabetic nephropathy in type 1 diabetes emerged from our studies of Joslin Clinic patients. The dominant feature is progressive renal decline, not albuminuria. This decline is a unidirectional process commencing while patients have normal renal function and, in the majority, progressing steadily (linearly) to end-stage renal disease (ESRD). While an individual's rate of renal decline is constant, the estimated glomerular filtration rate (eGFR) slope varies widely among individuals from -72 to -3.0 ml/min/year. Kidney Disease: Improving Global Outcomes guidelines define rapid progression as rate of eGFR declines > 5 ml/min/year, a value exceeded by 80% of patients in Joslin's type 1 diabetes ESRD cohort. The extraordinary range of slopes within the rapid progression category prompted us to partition it into "very fast," "fast" and "moderate" decline. We showed, for the first time, that very fast and fast decline from normal eGFR to ESRD within 2 to 10 years constitutes 50% of the Joslin cohort. In this review we present data about frequency of fast decliners in both diabetes types, survey some mechanisms underlying fast renal decline, discuss methods of identifying patients at risk and comment on the need for effective therapeutic interventions. Whether the initiating mechanism of fast renal decline affects glomerulus, tubule, interstitium or vasculature is unknown. Since no animal model mimics progressive renal decline, studies in humans are needed. Prospective studies searching for markers predictive of the rate of renal decline yield findings that may make detection of fast decliners feasible. Identifying such patients will be the foundation for developing effective individualized methods to prevent or delay onset of ESRD in diabetes.
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http://dx.doi.org/10.1016/j.kint.2016.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429989PMC
June 2017

[Hypoglycemia due to antibodies to exogenous insulin in a patient with type 2 diabetes – a case report of treatment with new generation oral hypoglycemic agents].

Przegl Lek 2017;74(1):41-3

Hypoglycemic syndromes associated with immune reactions against insulin are rare phenomena described predominantly in Asians. Steroid therapy, immunosuppression or plasmapheresis is often required.

Case Report: A 73-year-old White woman with a 20-year history of type 2 diabetes was admitted to hospital due to recurrent incidents of hypoglycemia that started several months after insulin initiation (lispro 75/25) and increased in severity over the next 5 years. They were accompanied by postprandial hyperglycemia up to 25 mmol/l. The patient’s glycated hemoglobin (HbA1c) was 70 mmol/ mol (8.6%). During hypoglycemic episodes recorded serum C-peptide was 0.57-0.73 nmol/l (1.7-2.2 ng/ml), while insulin concentration exceeded 7000 pmol/l (1000 mIU/l). Surreptitious insulin administration was ruled out as was, based on diagnostic imaging, the presence of an insulin secreting tumor. Anti-insulin antibody (AIA) level measured by 125I-insulin binding method was 92.5% (normal < 8.2%). Hypoglycemic episodes occurred for four days after discontinuation of insulin therapy and then resolved completely. Good glycemic control was maintained with metformin, acarbose and dapagliflozin. Three months later dapagliflozin was replaced with vildagliptine due to poor tolerance of a SGLT-2 inhibitor. Patient’s HbA1c was 54 mmol/mol (7.1%), total fasting insulin level 2577 pmol/l and AIA binding 85.9%. Over the next year the patient has not experienced hypoglycemia and maintained good glycemic control, as HbA1c level was 53 mmol/l (7.0%) and AIA binding 39.5%.

Conclusions: In this rare case of a patient with diabetes and hypoglycemic syndrome related to AIA, we achieved a rapid and stable remission of hypoglycemia without immunosuppression. Good glycemic control, despite 20-year history of diabetes was achieved with oral hypoglycemic agents.
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June 2018

Analysis of gene expression to predict dynamics of future hypertension incidence in type 2 diabetic patients.

BMC Proc 2016 18;10(Suppl 7):113-117. Epub 2016 Oct 18.

Center for Medical Genomics-OMICRON, Jagiellonian University Medical College, Kraków, Poland.

Background: The main focus of the Genetic Analysis Workshop 19 (GAW19) is identification of genes related to the occurrence of hypertension in the cohort of patients with type 2 diabetes mellitus (T2DM). The aim of our study was to predict dynamics of the future hypertension incidence, based on gene expression profiles, systolic and diastolic blood pressure changes in time, sex, baseline age, and cigarette smoking status. We analyzed data made available to GAW19 participants, which included gene expression profiles of peripheral blood mononuclear cells (PBMCs) from the diabetic members of 20 Mexican American families.

Methods: On the basis of mid blood pressure measurements at several time points, the coefficient of regression (slope) was calculated for each individual. We corrected the slope value in patients treated with antihypertensive medications. Feature preprocessing methods were used to remove highly correlated probes and linear dependencies between them. Subsequently, multiple linear regression model was used to associate gene expression with the regression coefficient calculated for each T2DM patient. Tenfold cross-validation was used to validate the model. We used linear mixed effects model and kinship coefficients to account for the family structure. All calculations were performed in R.

Results: This analysis allowed us to identify 6 well-annotated genes: and associated with dynamics of future hypertension incidence. Two of them, and were previously implicated in pathogenesis of hypertension.

Conclusions: There is no obvious mechanism that links all detected genes with dynamics of hypertension incidence. Identification of possible connection with hypertension needs further investigation.
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http://dx.doi.org/10.1186/s12919-016-0015-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133526PMC
October 2016

Risk of macrosomia remains glucose-dependent in a cohort of women with pregestational type 1 diabetes and good glycemic control.

Endocrine 2017 Feb 11;55(2):447-455. Epub 2016 Oct 11.

Department of Metabolic Diseases, University Hospital, Krakow, Poland.

Macrosomia risk remains high in type 1 diabetes (T1DM) complicated pregnancies. A linear relationship between macrosomia risk and glycated hemoglobin A (HbA) was described; however, low range of HbA has not been studied. We aimed to identify risk factors and examine the impact of HbA on the occurrence of macrosomia in newborns of T1DM women from a cohort with good glycemic control. In this observational retrospective one-center study we analyzed records of 510 consecutive T1DM pregnancies (1998-2012). The analyzed group consisted of 375 term singleton pregnancies. We used multiple regression models to examine the impact of HbA and self-monitored glucose in each trimester on the risk of macrosomia and birth weight. The median age of T1DM women was 28 years, median T1DM duration-11 years, median pregestational BMI-23.3 kg/m. Median birth weight reached 3520 g (1st and 3rd quartiles 3150 and 3960, respectively) at median 39 weeks of gestation. There were 85 (22.7 %) macrosomic (>4000 g) newborns. Median HbA levels in the 1st, 2nd, and 3rd trimester were 6.4, 5.7, and 5.6 %. Third trimester HbA, mean fasting self-monitored glucose and maternal age were independent predictors of birth weight and macrosomia. There was a linear relationship between 3rd trimester HbA and macrosomia risk in HbA range from 4.5 to 7.0 %. Macrosomia in children of T1DM mothers was common despite excellent metabolic control. Glycemia during the 3rd trimester was predominantly responsible for this condition.
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http://dx.doi.org/10.1007/s12020-016-1134-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272887PMC
February 2017

Patterns of Estimated Glomerular Filtration Rate Decline Leading to End-Stage Renal Disease in Type 1 Diabetes.

Diabetes Care 2016 Dec 19;39(12):2262-2269. Epub 2016 Sep 19.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: The patterns of estimated glomerular filtration rate (eGFR) decline to end-stage renal disease (ESRD) in patients with type 1 diabetes has not been conclusively described. Decline could be linearly progressive to ESRD but with a variable rate. Conversely, decline may be linear but interrupted by periods of plateaus or improvements.

Research Design And Methods: This observational study included 364 patients with type 1 diabetes attending the Joslin Clinic who developed ESRD between 1991 and 2013. We retrieved serum creatinine measurements from clinic visits or research examinations up to 24 years (median 6.7 years) preceding the onset of ESRD. Using serial measurements of serum creatinine to estimate renal function (eGFR), we used regression-based spline methods and a data smoothing approach to characterize individual trajectories of eGFR over time for the 257 patients with five or more data points.

Results: The rate of eGFR decline per year ranged widely, from -72 to -2 mL/min/1.73 m (median -8.5). The trajectories, as characterized with linear regression-based spline models, were linear or nearly so for 87% of patients, accelerating for 6%, and decelerating for 7%. Smoothed trajectories evaluated by a Bayesian approach did not significantly depart from a linear fit in 76%.

Conclusions: The decline of eGFR in type 1 diabetes is predominantly linear. Deviations from linearity are small, with little effect on the expected time of ESRD. A single disease process most likely underlies renal decline from its initiation and continues with the same intensity to ESRD. Linearity of renal decline suggests using slope reduction as the measure of effectiveness of interventions to postpone ESRD.
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http://dx.doi.org/10.2337/dc16-0950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127236PMC
December 2016

Changes in preconception treatment and glycemic control in women with type 1 diabetes mellitus: a 15‑year single‑center follow‑up.

Pol Arch Med Wewn 2016 Aug 29;126(10):739-745. Epub 2016 Aug 29.

INTRODUCTION    Pregnancy in women with type 1 diabetes mellitus (T1DM) is associated with higher risk of complications. Strict glycemic control before conception reduces the risk of unfavorable outcomes. OBJECTIVES    The aim of the study was to assess changes in clinical characteristics, preconception treatment, and glycemic control of women with T1DM at the first antinatal visit. PATIENTS AND METHODS    We analyzed the records from the first antenatal visit of 524 women with T1DM in the years 1998-2012. The follow‑up period was divided into 3 5‑year periods. RESULTS    Differences in the age of patients between the 3 follow‑up periods were observed (28.2 ±5.7 years for 1998-2002; 27.3 ±4.5 years for 2003-2007; and 29.4 ±4.8 years for 2008-2012; P <0.0001). The number of women planning pregnancy did not change and reached 32.1% in the first, 44.4% in the second, and 40.4% in the third period (P = 0.2). The use of rapid‑acting insulin analogues increased from 2.6% to 46.5% and then to 95.6% (P <0.001). The rate of therapy with personal insulin pumps before pregnancy increased from 4.6% in the first, through 23.5% in the second, to 33.3% in the third period (P <0.001). Over the subsequent periods, we observed a decrease in hemoglobin A1c (HbA1c) levels at the first antenatal visit (from 7.4% ±1.6%, through 6.9% ±1.4%, to 7.0% ±1.4%; P = 0.06), as well as a decrease in HbA1c levels between the subgroups of women planning pregnancy (6.8% ±1.4%, 6.6% ±1.2%, and 6.1% ±0.8%, P = 0.015). CONCLUSIONS    In the years 1998-2012, an increase in the use of insulin analogues and personal insulin pumps by women with T1DM before conception was observed, and these changes were accompanied by a slight improvement in glycemic control, particularly among women planning pregnancy. The percentage of women planning pregnancy did not change during the follow‑up.
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http://dx.doi.org/10.20452/pamw.3543DOI Listing
August 2016

Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.

Diabetes Care 2016 Nov 15;39(11):1915-1924. Epub 2016 Aug 15.

Research Division, Joslin Diabetes Center, Boston, MA

Objective: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

Research Design And Methods: A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality.

Results: Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10 and P = 2 × 10, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029).

Conclusions: Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.
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http://dx.doi.org/10.2337/dc16-0285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079609PMC
November 2016

Hypoglycemic episodes are associated with inflammatory status in patients with type 1 diabetes mellitus.

Atherosclerosis 2016 08 3;251:334-338. Epub 2016 May 3.

Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland; University Hospital, Krakow, Poland. Electronic address:

Backgroud: Glycemic control may be associated with inflammatory status in type 1 diabetes (T1DM). We examined the association between glucose control parameters and circulating inflammation markers in T1DM.

Methods: The study included 101 T1DM patients treated with personal insulin pumps (T1DM duration 15.2 + 7.3 years). The analysed glycemic parameters included HbA1c, mean glucose level, standard deviation and number of hypoglycemic episodes (glucose <55 mg/dL) from the last 7 days. Blood was collected for testing inflammatory markers (IL-6, VCAM, ICAM, E-selectin).

Results: The T1DM cohort had good glycemic control (HbA1c 7.1 ± 0.8%, mean daily glucose 141.5 ± 27.1 mg/dL and the mean number of hypoglycemic episodes was 5.6 ± 4.0/week). In a forward stepwise multiple linear regression analysis the number of hypoglycemic episodes predicted the levels of the investigated markers (sICAM p = 0.0019, sVCAM p = 0.021, sE-selectin p = 0.048, and IL-6 p = 0.049). None of the other glycemic parameters was shown to be an independent predictor.

Conclusions: For the first time, we report an association between the number of mild hypoglycemic episodes, recorded in a real life setting, and the level of inflammatory markers in T1DM patients with good glycemic control.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.002DOI Listing
August 2016

A family with the Arg103Pro mutation in the NEUROD1 gene detected by next-generation sequencing - Clinical characteristics of mutation carriers.

Eur J Med Genet 2016 Feb 8;59(2):75-9. Epub 2016 Jan 8.

Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland; University Hospital, Krakow, Poland. Electronic address:

Unlabelled: Until now only a few families with early onset autosomal diabetes due to the NEUROD1 gene mutations have been identified. Moreover, only some of them meet strict MODY (maturity-onset diabetes of the young) criteria. Next-generation sequencing (NGS) provides an opportunity to detect more pathogenic mutations in this gene. Here, we evaluated the segregation of the Arg103Pro mutation in the NEUROD1 gene in a pedigree in which it was detected, and described the clinical characteristics of the mutation carriers.

Methods: We included 156 diabetic probands of MODY families, among them 52 patients earlier tested for GCK-MODY and/or HNF1A-MODY by Sanger sequencing with negative results. Genetic testing was performed by targeted NGS sequencing using a panel of 28 monogenic diabetes genes.

Results: As detected by NGS, one patient had the missense Arg103Pro (CGC/CCC) mutation in the gene NEUROD1 changing the amino-acid structure of the DNA binding domain of this transcription factor. We confirmed this sequence difference by Sanger sequencing. This family had previously been tested with negative results for HNF1A gene mutations. 17 additional members of this family were invited for further testing. We confirmed the presence of the mutation in 11 subjects. Seven adult mutation carriers (all but one) from three generations had been already diagnosed with diabetes. There were 3 individuals with the Arg103Pro mutation diagnosed before the age of 30 years in the family. The range of age of the four unaffected mutation carriers (3 minors and 1 adult) was 3-48 years. Interestingly, one mutation carrier had a history of transient neonatal hypoglycemia, of which the clinical course resembled episodes typical for HNF4A-MODY.

Conclusions: We report a family with autosomal dominant diabetes related to a new NEUROD1 mutation, one of very few meeting MODY criteria. The use of the NGS method will facilitate identification of more families with rare forms of MODY.
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http://dx.doi.org/10.1016/j.ejmg.2016.01.002DOI Listing
February 2016

Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young.

Pol Arch Med Wewn 2015 9;125(11):845-51. Epub 2015 Nov 9.

Introduction: Molecular diagnosis of monogenic diabetes mellitus is important for individualized patient care. Next-generation sequencing (NGS) enables a simultaneous analysis of multiple genes in a single test.

Objectives: We aimed to assess the feasibility of using NGS for detecting mutations in a set of known monogenic diabetes gene mutations in a cohort of Polish patients with maturity-onset diabetes of the young (MODY) with earlier negative Sanger sequencing results for HNF1A-MODY or GCK-MODY.

Patients And Methods: We selected a panel of 28 chromosomal genes in which mutations have been reported to cause monogenic diabetes. The MiSeq platform was used for NGS. An exon-capture assay was designed to include coding regions and splice sites. A total of 54 patients with existing negative Sanger sequencing screening results for HNF1A or GCK gene mutations were selected for the study.

Results: NGS results were generated for all 54 patients and 9 positive controls with previously identified HNF1A or GCK gene mutation. All selected positive controls were confirmed by NGS. Among 28 genes, mutations were detected in 16. The type of the analyzed genetic changes was described in the NGS study as high (n = 3) or moderate (n = 76). Among the detected mutations, there were 4 known GCK gene mutations that had been previously missed in Sanger sequencing. So far, Sanger sequencing allowed us to confirm 21 gene mutations detected by NGS, and segregation with diabetes in 14 pedigrees.

Conclusions: Our pilot study using NGS for monogenic diabetes screening in the MODY cohort confirmed that it improves the detection of diabetes-related sequence differences. The screening with NGS should also include diabetic patients for whom Sanger-based screening for particular subtypes of MODY provided negative results.
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http://dx.doi.org/10.20452/pamw.3164DOI Listing
July 2016

Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes.

Kidney Int 2016 Feb;89(2):459-67

Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D.
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http://dx.doi.org/10.1038/ki.2015.314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848189PMC
February 2016

Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus.

Endocrine 2015 Dec 19;50(3):643-9. Epub 2015 May 19.

Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501, Krakow, Poland.

Ghrelin is a hormone that regulates appetite. It is likely to be involved in the pathophysiology of varying forms of diabetes. In animal studies, the ghrelin expression was regulated by the hepatocyte nuclear factor 1 alpha (HNF1A). Mutations of the HNF1A gene cause maturity onset diabetes of the young (MODY). We aimed to assess the circulating ghrelin levels in HNF1A-MODY and in other types of diabetes and to evaluate its association with HNF1A mutation status. Our cohort included 46 diabetic HNF1A gene mutation carriers, 55 type 2 diabetes (T2DM) subjects, 42 type 1 diabetes (T1DM) patients, and 31 glucokinase (GCK) gene mutation carriers with diabetes as well as 51 healthy controls. Plasma ghrelin concentration was measured using the immunoenzymatic assay with polyclonal antibody against the C-terminal fragment of its acylated and desacylated forms. Ghrelin concentrations were 0.75 ± 0.32, 0.70 ± 0.21, 0.50 ± 0.20, and 0.40 ± 0.16 ng/ml in patients with HNF1A-MODY, GCK-MODY, T1DM, and T2DM, respectively. The ghrelin levels were higher in HNF1A-MODY and GCK-MODY than in T1DM and T2DM (p < 0.001 for all comparisons) but lower than in non-diabetic controls (1.02 ± 0.29 ng/ml, p < 0.001 for both comparisons). In the multivariate linear model, the differences between both MODY groups and common diabetes types remained significant. Analysis by a HNF1A mutation type indicated that ghrelin concentration is similar in patients with different types of sequence differences. Plasma ghrelin level is higher in HNF1A-MODY and GCK-MODY than in the common polygenic forms of diabetes.
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http://dx.doi.org/10.1007/s12020-015-0627-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662709PMC
December 2015

Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients.

Eur J Endocrinol 2015 Mar 10;172(3):277-83. Epub 2014 Dec 10.

Department of Metabolic DiseasesJagiellonian University Medical College, 15 Kopernika Street, Krakow 31-501, PolandUniversity HospitalKrakow, PolandTranslational Medicine LaboratoryDepartment of Internal MedicineDepartment of Clinical BiochemistryJagiellonian University Medical College, Krakow, PolandDepartment of PediatricsOncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland Department of Metabolic DiseasesJagiellonian University Medical College, 15 Kopernika Street, Krakow 31-501, PolandUniversity HospitalKrakow, PolandTranslational Medicine LaboratoryDepartment of Internal MedicineDepartment of Clinical BiochemistryJagiellonian University Medical College, Krakow, PolandDepartment of PediatricsOncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland

Objective: Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects.

Design: To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY.

Methods: A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD.

Results: The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0±1.4 mm, whereas it reached 6.3±1.4 mm in GCK mutation carriers and 6.3±1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9±4.6%) and GCK-MODY (11.1±4.6%) patients in comparison with controls (13.9±4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls.

Conclusions: Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype.
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http://dx.doi.org/10.1530/EJE-14-0713DOI Listing
March 2015

SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes.

Diabetologia 2015 Mar 6;58(3):543-8. Epub 2014 Dec 6.

Sorbonne Université, UPMC Université Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.

Aims/hypothesis: The genetic determinants of diabetic nephropathy remain poorly understood. We aimed to identify novel susceptibility genes for diabetic nephropathy.

Methods: We performed a genome-wide association study using 1000 Genomes-based imputation to compare type 1 diabetic nephropathy cases with proteinuria and with or without renal failure with control patients who have had diabetes for more than 15 years and no evidence of renal disease.

Results: None of the single nucleotide polymorphisms (SNPs) tested in a discovery cohort composed of 683 cases and 779 controls reached genome-wide statistical significance. The 46 top hits (p < 10(-5)) were then sought for first-stage analysis in the Genetics of Kidneys in Diabetes US (US-GoKinD) study, an independent population of 820 cases and 885 controls. Two SNPs in strong linkage disequilibrium with each other and located in the SORBS1 gene were consistently and significantly (p < 10(-4)) associated with diabetic nephropathy. The minor rs1326934-C allele was less frequent in cases than in controls (0.34 vs 0.43) and was associated with a decreased risk for diabetic nephropathy (OR 0.70; 95% CI 0.60, 0.82). However, this association was not observed in a second stage with two additional diabetic nephropathy cohorts, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK and Republic of Ireland (UK-ROI; p = 0.15) and the Finnish Diabetic Nephropathy (FinnDiane; p = 0.44) studies, totalling 2,142 cases and 2,494 controls. Altogether, the random-effect meta-analysed rs1326934-C allele OR for diabetic nephropathy was 0.83 (95% CI 0.72, 0.96; p = 0.009).

Conclusions/interpretation: These data suggest that SORBS1 might be a gene involved in diabetic nephropathy.
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http://dx.doi.org/10.1007/s00125-014-3459-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438751PMC
March 2015

Diabetic pregnancy: an overview of current guidelines and clinical practice.

Curr Opin Obstet Gynecol 2014 Dec;26(6):431-7

aDepartment of Metabolic Diseases, Jagiellonian University, Medical College bUniversity Hospital, Krakow, Poland.

Purpose Of Review: We review the recent changes in diagnostic criteria of gestational diabetes mellitus (GDM), describe problems with maintaining and monitoring adequate blood glucose, especially in type 1 diabetes, and provide a brief overview of the currently approved glucose-lowering therapies in pregnancy.

Recent Findings: After the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, the definition of GDM was revised under the auspices of the International Association of Diabetes and Pregnancy Study Groups. The guidelines, with minor modifications, were endorsed by WHO in 2013. Intensive debate continues, focused on the expected large increase in prevalence of GDM and shortage of experimental evidence of clinical benefits from the new diagnostic criteria. Despite a very good glycaemic control, the prevalence of macrosomia remains high. This indicates a serious deficiency in current monitoring tools and the available therapies. So far, the only glucose-lowering medications approved for use during pregnancy are insulins.

Summary: The HAPO study provides a very suggestive evidence for a strong, continuous association of maternal glucose levels with an increased risk of excessive foetal weight gain. The new definition of GDM results in higher healthcare expenditure, but remains cost-effective. The current therapeutic goals require careful revision to further reduce the risk of adverse outcomes. New glucose-monitoring strategies and markers, and approval of new pharmacotherapies are needed.
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http://dx.doi.org/10.1097/GCO.0000000000000111DOI Listing
December 2014