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.

Skin autofluorescence and peripheral neuropathy four years later in type 1 diabetes.

OBJECTIVE: Advanced glycation end products (AGEs) are involved in diabetes complications. We aimed to investigate whether the accumulation of AGEs measured by skin autofluorescence (sAF) was associated with signs of diabetic peripheral neuropathy and to sensitivity, pain, motor and autonomic function 4 years later in patients with type 1 diabetes. METHODS: At baseline, 188 patients (age 51 years, diabetes duration 22 years) underwent skin autofluorescence measurement using the AGE Reader. Four years later, signs of diabetic peripheral neuropathy were defined as the presence of neuropathic pain and/or feet sensory loss or foot ulceration. Neurological tests were systematically performed: vibration perception threshold by neuroesthesiometry, neuropathic pain by the Douleur Neuropathique en 4 Questions score, muscle strength by dynamometry and electrochemical skin conductance. Multivariate analyses were adjusted by age, sex, height, body mass index, tobacco, HbA1c , diabetes duration, estimated glomerular filtration rate and albumin excretion rate. RESULTS: At the 4-year follow-up, 13.8% of patients had signs of diabetic peripheral neuropathy. The baseline sAF was higher in those with signs of diabetic peripheral neuropathy (2.5 ± 0.7 vs 2.1 ± 0.5 arbitrary units (AU), p < 0.0005). In the multivariate analysis, a 1 SD higher skin autofluorescence at baseline was associated with an increased risk of signs of neuropathy (OR = 2.68, p = 0.01). All of the neurological tests were significantly altered in the highest quartile of the baseline sAF (>2.4 AU) compared with the lowest quartiles after multivariate adjustment. CONCLUSION: This non-invasive measurement of skin autofluorescence may have a value for diabetic peripheral neuropathy in type 1 diabetes and a potential clinical utility for detection of diabetic peripheral neuropathy. Copyright © 2016 John Wiley & Sons, Ltd.

Is skin autofluorescence a marker of metabolic memory in pregnant women with diabetes?

AIM: To determine whether skin autofluorescence can help to detect those who have previously had abnormal glucose levels among women referred for diabetes during pregnancy. METHODS: Using an advanced glycation end product reader (AGE Reader(tm) (;) DiagnOptics BV, Groningen, the Netherlands), we measured forearm skin autofluorescence at 24-30 weeks of gestation in all women who were referred to our Nutrition Diabetology unit for diabetes during pregnancy. RESULTS: The study included 230 women (200 with gestational diabetes and 30 with pre-gestational diabetes, of whom 21 had Type 1 and nine had Type 2 diabetes) and a reference group of 22 normoglycaemic non-pregnant women. Skin autofluorescence was significantly higher in women with pre-gestational diabetes (1.97 ± 0.44 arbitary units) compared with gestational diabetes (1.77 ± 0.32 arbitary units; P = 0.003) and lower in the reference group (1.60 ± 0.32 arbitary units; P = 0.009 vs all pregnant women). Among women with gestational diabetes, 71 had a history of hyperglycaemia (i.e. gestational diabetes or macrosomia in a previous pregnancy or discovery of diabetes before 24th gestational week in the present pregnancy). These women had higher levels of skin autofluorescence (1.83 ± 0.35 arbitary units) than women with gestational diabetes without previous history of hyperglycaemia (1.73 ± 0.30 arbitary units; P = 0.04, non-significant, adjusted for age). Skin autofluorescence increased with the number of criteria present for previous hyperglycaemia (P for trend = 0.008) and was significantly associated with having two or three criteria for hyperglycaemia after adjusting for age (P = 0.02). CONCLUSIONS: Skin autofluorescence could reflect previous long-term hyperglycaemia in pregnant women, and could therefore be a marker of metabolic memory.

The influence of sex on renal function decline in people with Type 2 diabetes.

AIMS: Several reports have suggested a relationship between male sex and albuminuria in Type 2 diabetes, but impact on renal function decline has not been established. Our aim was to describe the influence of sex on renal function decline in Type 2 diabetes. METHODS: SURDIAGENE, an inception cohort, consisted in 1470 people with Type 2 diabetes. Patients without renal replacement therapy and with ≥ 3 serum creatinine determinations during follow-up prior to end-stage renal disease were included in the study. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Primary outcome was steep estimated glomerular filtration rate (eGFR) decline, defined as a yearly slope value lower than -3.5 ml min(-1) 1.73 m(-2). Secondary outcomes were estimated glomerular filtration rate trajectories according to sex and occurrence of end-stage renal disease. RESULTS: A total of 22 914 serum creatinine determinations were considered in 1146 participants (60% men), aged 65 ± 11 years, with a median follow-up duration of 5.7 years (range 0.1-10.2). Median yearly estimated glomerular filtration rate slope was -1.31 ml min(-1) 1.73 m(-2) in women and -1.77 ml min(-1) 1.73 m(-2) in men (P < 0.001). Men were more likely than women to develop end-stage renal disease (22 men vs. 7 women; P(log-rank) = 0.03). Male sex was an independent risk factor of steep estimated glomerular filtration rate decline [adjusted odds ratio = 1.33 (1.02-1.76), P = 0.04] after adjustment for age, time from diagnosis of Type 2 diabetes, glycated haemoglobin, systolic blood pressure and urinary albumin:creatinine ratio. A multivariable linear mixed-effects model showed a significant difference of estimated glomerular filtration rate trajectories between men and women (P < 0.001). CONCLUSION: Male sex is an important independent factor associated with renal function decline in Type 2 diabetes.

A long-term follow-up of weight changes in subthalamic nucleus stimulated Parkinson's disease patients.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) constitutes the mainstay treatment in advanced Parkinson's disease (PD) with motor fluctuations. Despite its efficacy on motor signs and quality of life, emergent adverse events have been recently reported. Among them, weight gain (WG) is a recognized adverse event of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Also, WG is poorly known at the long-term and predisposing factors have not yet been identified. We conducted a cross-sectional study of WG in 47 STN-DBS PD patients between 1999-2006. Data on disease history, motor status and dopaminergic drug treatment were retrospectively collected at surgery and 1 year post-surgery. Weight at disease diagnosis and at surgery, as well as the current weight and height were gathered by an autoquestionnaire. Moreover, the weight before surgery was obtained and verified in medical files in more than 90% of our patients. Sixty-six patients who underwent surgery between 1999-2006 were included, but six were deceased, four refused to participate and nine were lost for follow-up. So, 47 (71%) were retained in our analysis. A total of 78.7% of patients gained weight. On average 4.7 years follow up after surgery, the mean weight gain was +7.2±8.1kg compared to the preoperative assessment (p<0.001) and the mean BMI gain was +2.7±3.0kg/m(2) compared to pre-surgery values (p<0.001). The patients gained more weight after surgery than they had lost during disease evolution before surgery. Women and patients with a more severe UPDRS-III "off" drug score before surgery significantly gained more weight. Our study provides further evidence that the WG is a problem after STN-DBS and concerns a majority of patients at the long term. It may expose them to complications that should be considered for prevention and the patient's information before surgery.

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.

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.

Cystatin C improves the diagnosis and stratification of chronic kidney disease, and the estimation of glomerular filtration rate in diabetes.

AIMS: Estimation of glomerular filtration rate (GFR) is recommended to diagnose and stratify chronic kidney disease (CKD). Can cystatin-C (cysC) assay improve the results in diabetic patients? METHODS: In 124 diabetic patients with a wide range of GFR, as determined by 51Cr-EDTA clearance (i-GFR), we estimated 'e-GFR' by: the recommended Cockcroft-Gault (CG) formula and Modification of Diet in Renal Disease (MDRD) study equation; the new Mayo Clinic quadratic (MCQ) equation; the recently proposed composite estimation including both serum creatinine and cysC; and a simplified approach dividing the MDRD by cysC if less than 1.10mg/L. RESULTS: The highest diagnostic accuracy (receiver operating characteristic [ROC] curves) and the highest proportions of well-stratified patients were obtained by cysC and the MDRD which, however, underestimated i-GFR for patients without CKD (-17%, P<0.001). The CG overestimated GFR in KDOQI stages 1 and 2, ignored stage 5 and was the least accurate. The MCQ equation overrepresented stage 2, overestimating GFR at this stage (+23%, P<0.005). The composite estimation (54.7+/-27.0mL per minute 1.73m(2)) correlated best with i-GFR (56.1+/-35.3; r=0.90, P<0.001), and did not significantly differ from it across the entire population and within each Kidney Disease Outcome Quality Initiative (KDOQI) stage but was also biased (Bland-Altman procedure). Simply dividing the MDRD by cysC ifless than1.10mg/L produced a comparable performance and eliminated the bias. CONCLUSION: The recommended creatinine-based estimations of GFR need to be improved. CysC assay helps in the diagnosis and stratification of CKD and leads to better estimates of GFR in diabetic patients without any substantial increase in complexity.

Air displacement plethysmography can detect moderate changes in body composition.

OBJECTIVES: To determine the sensitivity of air displacement plethysmography (APD) for evaluation of changes in body composition in normal subjects. DESIGN: Comparison of measurements with and without oil or water loads. SUBJECTS AND METHODS: Ten healthy volunteers were analyzed, without and with 1 l and 2 l of oil or water. The measured and true changes in fat mass and fat-free mass were compared by paired t-tests. A correlation study and a Bland & Altman procedure was performed on the 60 measurements of adiposity changes in 30 subjects carrying 0.5 l (n=8 x 2), 1 l (n=10 x 2) and 2 l (n=12 x 2) oil and water loads. RESULTS: Fat-free mass increased when the 10 subjects were carrying water. When they carried oil, fat mass increased, however, a approximately 0.5 kg increase of fat-free mass was also detected. Two liters loads led to distinct changes: +1.49+/-0.59 kg fat and +0.50+/-0.60 kg fat-free with oil and +0.37+/-0.57 kg fat and +1.70+/-0.56 kg fat-free with water (both P<0.001). Mixed loads (+1 l oil and 1 l water) led to detect +0.85+/-0.48 kg fat and +1.09+/-0.45 kg fat-free (both P<0.005 vs without load). For the 30 subjects analyzed thrice, measured changes in fat and fat-free mass were slightly underestimated (-15%, NS) but correlated with the true changes. Measured changes in adiposity were correlated with the true changes, with no bias as indicated by the Bland & Altman procedure. CONCLUSION: APD detects approximately 2 kg changes in fat or fat-free mass in small populations.

How to better systematize the diagnosis of neuropathy?

Two attitudes can be proposed, one consisting of making a diagnosis of neuropathy, the other seeking to grade the stage that it has reached in order to give a prognosis and above all determine the right way in which to educate the patient. In order to do this, it is important for the diagnosis to be thorough. It should be based both on listening to what the patient has to say and examining him/her. It is vital to listen to the patient because the warning signs are discreet, yet very evocative, and they will be a great help in making a positive diagnosis. They should not be confused with signs of arterial damage. They should then be interpreted by means of clinical examination and the tools that are available, i.e. essentially monitoring the osteo-tendinous reflexes and sensory signs. The sensory signs can only be studied with high-quality instruments, i.e. either a monofilament of proven technical quality and that should be used with care in line with good clinical practice recommendations, or by using a graduated tuning fork, or a neuroesthesiometer which will make it possible to obtained graduated responses, not simply binary responses of the "yes/no" variety. A whole series of scores have been put forward combining both functional and physical signs, making it possible to try to quantify the stage reached and the extent of the neuropathy. It is only by using a thorough and regularly applied routine that we can progress to establishing a better prognosis and providing a better educational service for the patient.

A simplified Cockcroft-Gault formula to improve the prediction of the glomerular filtration rate in diabetic patients.

AIM: The National Kidney Foundation recommends stratification of renal failure into moderate (Glomerular Filtration Rate: GFR = 30-60 mL/min/1.73 m2), severe (15-30) or terminal (<15) using the Cockcroft-Gault (CG) or the Modification of Diet in Renal Disease (MDRD) equations. We studied the biases in these methods in an attempt to improve the standard CG (MCG) and devise a strategy for stratification. METHODS: GFR was measured by 51Cr-EDTA clearance in 200 diabetic patients: 100 (Group 1: study of concordance) before 2003 and 100 thereafter (Group 2: validation of MCG). The CG was modified by replacing body weight by its mean value: 76. RESULTS: In group 1, the recommended equations only correctly stratified 50 patients. The CG, not the MDRD, underestimated GFR if BMI was normal, and overestimated it in obese patients. In group 2, the MCG was well correlated with GFR and not biased by weight. Over the whole population, the MCG and MDRD were more accurate for the diagnosis of moderate and severe renal failure. The MDRD showed the lowest differences with GFR, except if GFR > 60, where the MCG performed better. All formulae overestimated low GFR, the MDRD also underestimated high GFR. The best stratification (147/200) was obtained using the MCG if creatininemia < 120 micromol/l and the MDRD if creatininemia > or =120 micromol/l. CONCLUSION: The CG is biased by weight, the MCG corrects this. The more accurate MDRD cannot be used in all patients as it underestimates high GFR. The best stratification was obtained using the MCG at low and the MDRD at high creatininemia.

Blood ketone monitoring: a comparison between gestational diabetes and non-diabetic pregnant women.

AIM: To measure ketonemia in a control population of pregnant women and in a population of women with gestational diabetes (GDM). To define a normal ketonemia threshold for the controls and to determine whether or not this value could play a role in the clinical management of women with GDM. METHOD: Fifty-six women with a normal OGTT and 49 women with GDM were included and monitored from the 25th to the 37th week of pregnancy. Control subjects agreed to perform glycaemia and ketonemia self-monitoring 3 times a day. In addition, women with GDM were asked to measure their postprandial glycaemia. Glycaemia and ketonemia measurements were performed using Optium meters. Subjects kept a 24-hour food record twice a week. RESULTS: The mean ketonemia was lower in the control group than in the GDM group (0.01+/-0.10 vs. 0.04+/-0.009 mmol/l; P<0.001). Ketonemia values measured before the midday meal and prior to the evening meal were lower for control subjects than for GDM patients (P=0.002 and P=0.005). Fasting ketonemia was unrelated to ketonuria in the GDM group, whereas there was a correlation in the control group (P=0.006). At least one chronic increase in ketonemia levels was observed in 47% of the women with GDM, compared with only 12% of controls. The lowest levels of evening glycaemia correlated with the highest levels of ketonemia; women with GDM reported lower food and carbohydrate intakes than controls (P<0.001). CONCLUSION: This work has enabled the establishment of ketonemia reference standards in non-diabetic pregnant women. If ketonemia does indeed indicate overly restrictive dietary behavior, this parameter could be employed for monitoring adherence to the nutritional recommendations for GDM.

In normal men, free fatty acids reduce peripheral but not splanchnic glucose uptake.

Raising plasma free fatty acid (FFA) levels reduces muscle glucose uptake, but the effect of FFAs on splanchnic glucose uptake, total glucose output, and glucose cycling may also be critical to producing lipid-induced glucose intolerance. In eight normal volunteers, we measured glucose turnover and cycling rates ([2H7]glucose infusion) during a moderately hyperglycemic (7.7 mmol/l) hyperinsulinemic clamp, before and after ingestion of a labeled (dideuterated) oral glucose load (700 mg/kg). Each test was performed twice, with either a lipid or a saline infusion; four subjects also had a third test with a glycerol infusion. As shown by similar rates of exogenous glucose appearance, the lipid infusion did not reduce first-pass splanchnic glucose uptake (saline 1.48+/-0.18, lipid 1.69+/-0.17, and glycerol 1.88+/-0.17 mmol/kg per 180 min; NS), but it reduced peripheral glucose uptake by 40% (P < 0.01 vs. both saline and glycerol infusions). Before oral ingestion of glucose, total glucose output was similarly increased by the lipid and glycerol infusions. Total glucose output was significantly increased by FFAs after oral ingestion of glucose (saline 3.68+/-1.15, glycerol 3.68+/-1.70, and lipid 7.92+/-0.88 micromol x kg(-1) x min(-1); P < 0.01 vs. saline and P < 0.05 vs. glycerol). The glucose cycling rate was approximately 2.7 micromol x kg(-1) x min(-1) with the three infusions and tended to decrease all along the lipid infusion, which argues against a stimulation of glucose-6-phosphatase by FFAs. It is concluded that in situations of moderate hyperinsulinemia-hyperglycemia, FFAs reduce peripheral but not splanchnic glucose uptake. Total glucose output is increased by FFAs, by a mechanism that does not seem to involve stimulation of glucose-6-phosphatase.