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Objective: We studied the serum concentration of tumor necrosis factor receptor 2 (TNFR2) and the rate of renal decline, a measure of the intensity of the disease process leading to end-stage renal disease (ESRD)., Research Design and Methods: A cohort of 349 type 1 diabetic patients with proteinuria was followed for 5-18 years. Serum TNFR2, glycated hemoglobin A1c (HbA1c), and other characteristics were measured at enrollment. We used a novel analytic approach, a joint longitudinal-survival model, fitted to serial estimates of glomerular filtration rate (eGFR) based on serum creatinine (median seven per patient) and time to onset of ESRD (112 patients) to estimate the rate of renal decline (eGFR loss)., Results: At enrollment, all patients had chronic kidney disease stage 1-3. The mean (±SD) rate of eGFR loss during 5-18 years of follow-up was -5.2 (±4.9) mL/min/1.73 m(2)/year. Serum TNFR2 was the strongest determinant of renal decline and ESRD risk (C-index 0.79). The rate of eGFR loss became steeper with rising concentration of TNFR2, and elevated HbA1c augmented the strength of this association (P = 0.030 for interaction). In patients with HbA1c ≥10.1% (87 mmol/mol), the difference in the rate of eGFR loss between the first and fourth quartiles of TNFR2 was 5.4 mL/min/1.73 m(2)/year, whereas it was only 1.9 in those with HbA1c <7.9% (63 mmol/mol)., Conclusions: Circulating TNFR2 is a major determinant of renal decline in patients with type 1 diabetes and proteinuria. Elevated HbA1c magnifies its effect. Although the mechanisms of this synergism are unknown, our findings allow us to stratify patients according to risk of ESRD., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Patients with diabetes caused by single-gene mutations generally exhibit an altered course of diabetes. Those with mutations of the glucokinase gene (GCK-MODY) show good metabolic control and low risk of cardiovascular complications despite paradoxically lowered high-density lipoprotein (HDL) cholesterol levels. In order to investigate the matter, we analyzed the composition of low-density lipoprotein (LDL) and HDL subpopulations in such individuals. The LipoPrint(©) system (Quantimetrix, USA) based on non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL and HDL subclasses in fresh-frozen serum samples from patients with mutations of glucokinase or HNF1A, type 1 diabetes (T1DM) and healthy controls. Fresh serum samples from a total of 37 monogenic diabetes patients (21 from GCK-MODY and 16 from HNF1A-MODY), 22 T1DM patients and 15 healthy individuals were measured in this study. Concentrations of the small, highly atherogenic LDL subpopulation were similar among the compared groups. Large HDL percentage was significantly higher in GCK-MODY than in control (p = 0.0003), T1DM (p = 0.0006) and HNF1A-MODY groups (p = 0.0246). Patients with GCK-MODY were characterized by significantly lower intermediate HDL levels than controls (p = 0.0003) and T1DM (p = 0.0005). Small, potentially atherogenic HDL content differed significantly with the GCK-MODY group showing concentrations of that subfraction from control (p = 0.0096), T1DM (p = 0.0193) and HNF1A-MODY (p = 0.0057) groups. Within-group heterogeneity suggested the existence of potential gene-gene or gene-environment interactions. GCK-MODY is characterized by a strongly protective profile of HDL cholesterol subpopulations. A degree of heterogeneity within the groups suggests the existence of interactions with other genetic or clinical factors.

Aims/hypothesis: Most pregnant women with type 1 diabetes mellitus achieve HbA1c 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 HbA1c., Methods: 1,5-AG and HbA1c 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 HbA1c, 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, HbA1c 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 HbA1c, as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA1c, is a strong predictor of macrosomia.

Aims: Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA., Methods: ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated., Results: Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68)., Conclusions: We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

Background: Insulin aspart (IAsp) is one of the three rapid-acting insulin analogues (RAAs) registered for the treatment of diabetes. However, there is an ongoing debate concerning the efficacy and safety of RAAs. For this reason, a systematic review-based study was performed to compare clinical outcomes of treatment with IAsp and regular human insulin (RHI) as well as biphasic insulin aspart and premixed human insulin in type 1 and type 2 diabetes (T1DM, T2DM) patients., Methods: Relevant articles were identified by a systematic search through the electronic medical databases (MEDLINE, EMBASE, CENTRAL) up to July 2009., Results: A total of 28 trials fulfilled the inclusion criteria, including 17 studies of T1DM, 10 of T2DM and one study of both. For T1DM, pooled data for HbA(1c) (13 studies) demonstrated lower levels with IAsp than with RHI (WMD=-0.11%; 95% CI: -0.16 to -0.06). In addition, meta-analysis revealed statistically significant differences in favour of IAsp for postprandial glucose (PPG) after breakfast, lunch and dinner, but not for fasting glucose (FG). The Diabetes Treatment Satisfaction Questionnaire evaluating treatment flexibility showed IAsp benefits compared with RHI (WMD=0.31; 95% CI: 0.15 to 0.47). Safety analyses (three studies) showed a significant reduction in nocturnal hypoglycaemia risk with IAsp (RR=0.67; 95% CI: 0.54 to 0.83), and no difference in severe hypoglycaemias and a slight increase in any hypoglycaemic episodes with RAAs (RR=1.06; 95% CI: 1.01 to 1.10). For T2DM, a meta-analysis of nine studies revealed no significant differences between IAsp and RHI in HbA(1c) (WMD=-0.04%; 95% CI: -0.10 to 0.03), whereas PPG was significantly lower in the IAsp group (WMD=-1.18 mmol/L; 95% CI: -1.88 to -0.47). No studies of treatment satisfaction or quality of life were identified., Conclusion: Analyses based on a systematic review showed that treatment with IAsp in T1DM patients resulted in moderately better metabolic control and treatment satisfaction than RHI. In T2DM patients, meta-analysis showed improvement in PPG, but not in any other outcomes., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

This observational study assessed metabolic control in young, active professionals with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) with or without the use of a bolus calculator. Eighteen patients aged 19 - 51 years with diabetes duration of 6 - 22 years were included; eight patients used a bolus calculator and 10 did not. Metabolic control was assessed by glycosylated haemoglobin (Hb(A1c)) measurements and blood glucose profiles. A continuous glucose monitoring system (CGMS) was also used by three patients from each group. Mean Hb(A1c) and fasting blood glucose levels were not significantly different between the two groups, but mean post-prandial blood glucose was significantly lower in bolus calculator users than non-users. The CGMS showed more blood glucose levels within the target range in bolus calculator users than non-users, but statistical significance was not achieved. In conclusion, a bolus calculator may help to improve postprandial blood glucose levels in active professional type 1 diabetes patients treated with CSII, but does not have a major impact on Hb(A1c) levels.

Objective: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood., Research Design and Methods: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes., Results: We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant., Conclusions: We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.

It has recently been shown that mutations in BETA2/NeuroD1 are responsible for the development of type 2 diabetes mellitus (T2DM) in Caucasians. This gene is located near the IDDM7 region and one of its amino acid polymorphisms, Ala45Thr, has been associated with type 1 diabetes (T1DM) in Japanese and Danish populations. The aim of our study is to examine Ala45Thr for its role in T1DM in Caucasians. We used both population-based case-control analysis and family-based transmission/disequilibrium testing (TDT). Genotyping was carried out by the dot-blotting method using P32. Study subjects comprised 202 type 1 diabetes cases (mean age at diagnosis: 11.1 years, mean age at examination: 36.4 years) and 139 controls with normal fasting glucose. For the TDT study, allelic transmission was evaluated in 209 case family trios. The frequency of the Ala45 allele was 70.3 % in cases and 62.9 % in controls (p=0.04), and 47.5 % of cases were Ala45 homozygotes compared to 36.0 % of controls (p=0.03). The TDT component of the study did not achieve statistical significance. However, given the high frequency of this variant even among controls, exceptionally large data sets are needed to provide adequate power for this approach. Our case-control study suggests that the Ala45 variant of BETA2/NeuroD1 may be associated with T1DM in Caucasians (or in linkage disequilibrium with a causative variant). However, this finding should be confirmed by a much larger family-based study.

Background: Genetic variants of vitamin D-binding protein (DBP) have been reported to be associated, not only with diabetes, but also with prediabetic traits, in several populations. There are two known polymorphisms in exon 11 of the DBP gene that result in amino acid variants: at codons 416 GAT-->GAG (Asp-->Glu) and 420 ACG-->AAG (Thr-->Lys)., Objective: To examine the association of these polymorphisms with diabetes in white Americans of European origin., Methods: We studied unrelated individuals: 181 with type 1 diabetes, 215 with type 2 diabetes, and 163 healthy controls. Exon 11 was amplified using polymerase chain reaction and the two alleles were determined by digestion with specific endonucleases: HaeIII and StyI, respectively., Results: At codon 416, Asp/Glu allele frequencies were 45%/55% in patients with type 1 diabetes, 43%/57% in patients with type 2 diabetes, and 46%/54% in controls (chi(2)=0.69, 2 d.f., P<0.71). At codon 420, corresponding Lys/Thr frequencies were 27%/73%, 30%/70%, and 30%/70% (chi(2)=1.25, 2 d.f., P=0.53). Distributions of genotypes at both loci, and the haplotypes defined by the two loci, were also very similar in all groups., Conclusion: DNA polymorphisms in the DBP gene are not associated with diabetes in white Americans of European origin.