Diabetic retinopathy in well-controlled type 2 diabetes: Role of glycaemic memory.

AIMS: As diabetic retinopathy (DR) can occur even in well-controlled patients with type 2 diabetes (T2D), our study sought to determine whether it might be related to 'glucose memory' by evaluating patients' HbA1c over previous years and their skin autofluorescence (SAF). METHODS: In 334 patients with T2D and HbA1c levels≤8%, their available values of HbA1c from previous years were collected, and their SAF measured by an advanced glycation end-product (AGE) reader. Binary logistic regression analysis was then used to correlate DR with previously recorded HbA1c levels and to SAF, with adjustment for DR risk factors [age, gender, BMI, duration of diabetes, arterial hypertension, diabetic kidney disease (DKD), blood lipid levels and statin treatment]. RESULTS: Our patients were mostly men (58.4%) aged 63±10years, with a duration of diabetes of 13±10years and HbA1c=7.1±0.7%. Of these patients, 84 (25.1%) had DR, which was associated with longer duration of diabetes and greater prevalence of DKD. A total of 605 HbA1c values from previous years were collected for time periods -4±3 months (n=255), -16±4months (n=152), -30±4months (n=93) and -62±26 months (n=105). After adjustment, the association between DR and having an HbA1c higher than the median was significant only for the oldest previous HbA1c values: OR=6.75, 95% CI: 1.90-23.90. Moreover, SAF values were higher in those with DR [2.95±0.67 arbitrary units (AU)] vs 2.65±0.65 AU with no DR (P<0.01) and were also associated with the oldest previous HbA1c values (P<0.01). CONCLUSION: Our study found that 25.1% of our well-controlled T2D patients had DR, which was related to both their HbA1c levels from 5years prior to study admission and their SAF values, a marker of glucose memory.

Relationship between renal capacity to reabsorb glucose and renal status in patients with diabetes.

AIMS: Interindividual variability in capacity to reabsorb glucose at the proximal renal tubule could contribute to risk of diabetic kidney disease. Our present study investigated, in patients with diabetes, the association between fractional reabsorption of glucose (FRGLU) and degree of renal disease as assessed by urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR). METHODS: FRGLU [1-(glucose clearance/creatinine clearance)] was assessed in 637 diabetes patients attending our tertiary referral centre, looking for correlations between FRGLU and UAE (normo-, micro-, macro-albuminuria) and Kidney Disease: Improving Global Outcomes (KDIGO) eGFR categories: >90 (G1); 90-60 (G2); 59-30 (G3); and<30-16 (G4) mL/min/1.73 m2. Patients were stratified by admission fasting plasma glucose (FPG) into three groups: low (<6mmol/L); intermediate (6-11mmol/L); and high (>11mmol/L). RESULTS: Median (interquartile range, IQR) FRGLU levels were blood glucose-dependent: 99.90% (0.05) for low (n=106); 99.90% (0.41) for intermediate (n=288); and 96.36% (12.57) for high (n=243) blood glucose categories (P<0.0001). Also, FRGLU increased with renal disease severity in patients in the high FPG group: normoalbuminuria, 93.50% (17.74) (n=135); microalbuminuria, 96.56% (5.94) (n=77); macroalbuminuria, 99.12% (5.44) (n=31; P<0.001); eGFR G1, 94.13% (16.24) (n=111); G2, 96.35% (11.94) (n=72); G3 98.88% (7.59) (n=46); and G4, 99.11% (2.20) (n=14; P<0.01). On multiple regression analyses, FRGLU remained significantly and independently associated with UAE and eGFR in patients in the high blood glucose group. CONCLUSION: High glucose reabsorption capacity in renal proximal tubules is associated with high UAE and low eGFR in patients with diabetes and blood glucose levels>11mmol/L.

Persistent cortisol response to desmopressin predicts recurrence of Cushing's disease in patients with post-operative corticotropic insufficiency.

OBJECTIVE: Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. DESIGN: Multicentre retrospective study. METHODS: Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. RESULTS: Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively). CONCLUSION: The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Serum fructosamine predicts macrosomia in well-controlled hyperglycaemic pregnant women: An observational cross-sectional study.

AIM: While serum fructosamine may be a good marker of glucose control in pregnant women with diabetes, its relationship with macrosomia is still uncertain. METHODS: In 130 hyperglycaemic women with singleton pregnancies (117 gestational diabetes mellitus, 13 pregestational diabetes), serum fructosamine and HbA1c levels were measured at 25±7 weeks of gestation. Levels in mothers of infants with and without macrosomic newborns (birth weight>4000g and/or large-for-gestational-age birth weight>90th percentile) were compared using logistic regression analysis adjusted for macrosomia risk factors. RESULTS: These 130 pregnant women were 33±5 years old; their BMI before pregnancy was 27.7±6.9kg/m2, and they gained 7.5±5.1kg during the first 6 months of gestation. Glucose control was good according to HbA1c levels (5.3±0.3%; 34±2mmol/mol), yet 17/130 (13%) newborns had macrosomia: 3900±227g vs 3057±512g (P<0.001) in the others. These mothers were older and had higher parity, whereas their BMI scores before pregnancy and gestational weight gains did not differ. Fructosamine levels were also higher at 221±40µmol/L vs 192±22µmol/l (P<0.001), respectively, and remained significant even after adjusting for maternal age, BMI, parity, type of diabetes, antecedents of macrosomia and excessive gestational weight gain. By contrast, HbA1c did not differ between the two groups. In fact, nearly two-thirds (64.7%) of the mothers of macrosomic newborns had fructosamine levels>200µmol/l vs 31.9% of mothers with non-macrosomic newborns (P<0.05). CONCLUSION: High fructosamine levels are associated with macrosomia in the newborns of well-controlled hyperglycaemic pregnant women.

Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.

BACKGROUND: Advanced glycation end-products play a role in diabetic vascular complications. Their optical properties allow to estimate their accumulation in tissues by measuring the skin autofluorescence (SAF). We searched for an association between SAF and major adverse cardiovascular events (MACE) incidence in subjects with Type 1 Diabetes (T1D) during a 7 year follow-up. METHODS: During year 2009, 232 subjects with T1D were included. SAF measurement, clinical [age, sex, body mass index (BMI), comorbidities] and biological data (HbA1C, blood lipids, renal parameters) were recorded. MACE (myocardial infarction, stroke, lower extremity amputation or a revascularization procedure) were registered at visits in the center or by phone call to general practitioners until 2016. RESULTS: The participants were mainly men (59.5%), 51.5 ± 16.7 years old, with BMI 25.0 ± 4.1 kg/m2, diabetes duration 21.5 ± 13.6 years, HbA1C 7.6 ± 1.1%. LDL cholesterol was 1.04 ± 0.29 g/L, estimated Glomerular Filtration Rates (CKD-EPI): 86.3 ± 26.6 ml/min/1.73 m2. Among these subjects, 25.1% were smokers, 45.3% had arterial hypertension, 15.9% had elevated AER (≥ 30 mg/24 h), and 9.9% subjects had a history of previous MACE. From 2009 to 2016, 22 patients had at least one new MACE: 6 myocardial infarctions, 1 lower limb amputation, 15 revascularization procedures. Their SAF was 2.63 ± 0.73 arbitrary units (AU) vs 2.08 ± 0.54 for other patients (p = 0.002). Using Cox-model, after adjustment for age (as the scale time), sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment and a previous history of MACE, higher baseline levels of SAF were significantly associated with an increased risk of MACE during follow-up (HR = 4.13 [1.30-13.07]; p = 0.02 for 1 AU of SAF) and Kaplan-Meier curve follow-up showed significantly more frequent MACE in group with SAF upper the median (p = 0.001). CONCLUSION: A high SAF predicts MACE in patients with T1D.

Sex-specific associations of variants in regulatory regions of NADPH oxidase-2 (CYBB) and glutathione peroxidase 4 (GPX4) genes with kidney disease in type 1 diabetes.

Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11-2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13-0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes.

Intensifying glycaemic control with insulin reduces adiponectin and its HMW isoform moderately in type 2, but not in type 1, diabetes.

INTRODUCTION: As the impact of diabetes control was not tested on adiponectin (ADPN) levels, this study was designed to assess whether or not controlling hyperglycaemia can affect ADPN. PATIENTS AND METHODS: A total of 15 T1D and 48 T2D patients with HbA(1c) greater than 10% were studied at the time of hospitalization for uncontrolled diabetes. Total, and high-, medium- and low-molecular-weight (HMW, MMW, LMW) ADPN were measured at the time of study inclusion, on days 1 and 8, and at 1, 3 and 6 months after insulin treatment. RESULTS: While diabetes control improved, total and HMW APDN decreased on days 1 and 8, but remained steady thereafter in T2D patients. In T1D patients, ADPN levels remained unchanged throughout the study. CONCLUSION: Glycaemic control with insulin reduces ADPN in T2D patients in the short-term, but was ineffective in T1D.

Use and utility of ankle brachial index in patients with diabetes.

Ankle brachial index (ABI) is a simple method to screen peripheral arterial disease (PAD) and to evaluate cardiovascular (CV) prognosis in the general population. Measuring it requires a hand-held Doppler probe but it can be done also with an automatic device. ABI is an effective tool for clinical practice or clinical studies. However, in diabetic patients, it has some specific caveats. Sensitivity of the standard threshold of 0.9 appears to be lower in diabetic patients with complications. Moreover, highly frequent arterial medial calcifications in diabetes increase ABI. It has been demonstrated that measurements >1.3 are well correlated with both an increased prevalence of PAD and CV risk. Therefore, ABI thresholds of less than 0.9 and more than 1.3 are highly suspicious for PAD and high CV risk in diabetic patients. However, when there is concomitant clinical peripheral neuropathy or high risk of arterial calcification, the efficiency of ABI seems to be limited. In this case, other methods should be applied, toe pressure, in particular. Thus, the ABI could be used in patients with diabetes, but values should be interpreted with precision, according to the clinical situation.

Concurrent Graves disease thyrotoxicosis and myasthenia gravis: the treatment of the former may dangerously reveal the latter.

Autoimmune thyroxicosis and myasthenia gravis are often associated. In both diseases, clinical features may include neuromuscular weakness, making their distinction challenging. We report a patient with known Graves disease who presented with generalised fatigue, initially attributed solely to thyrotoxicosis, and who experienced severe respiratory failure linked to associated myasthenia gravis that was unmasked by medication used in the perioperative management of his thyroxicosis. Anaesthetists should always consider myasthenia gravis in cases of hyperthyroidism presenting with neuromuscular features.

Distribution of HOX genes in the chicken genome reveals a new segment of conservation between human and chicken.

Homeobox genes play an important role in the regulation of early embryonic development. They represent a family of evolutionarily highly conserved transcription factors. In this work, several genes that belong to the four HOX gene clusters are assigned by in situ hybridization to four distinct chicken chromosomes. The four gene clusters are mapped to 2p2.1 (HOXA), 3q3.1 (HOXB), 1q3.1 (HOXC) and 7q1.3--> q1.4 (HOXD). We confirm partial homologies already detected by genetic mapping between chicken chromosomes 1, 2 and 7 and human chromosomes 12, 7 and 2 and we describe a new conserved segment between chicken chromosome 3 and human chromosome 17. These results represent the first data that confirm the physical linkage between chicken HOX genes and may improve our understanding of phylogenetic relationships and genome evolution.