Better Cardiorespiratory Fitness Defined as VO2max Increases the Chance of Partial Clinical Remission and Prolongs Remission Duration in People with Newly Diagnosed Type 1 Diabetes.

Introduction: An essential process affecting the course of type 1 diabetes (DM1) is the appearance and duration of clinical remission. One of the most important factors promoting the occurrence of remission is physical activity, due to increased activity of antioxidants, reduces insulin resistance and improves glucose transport. Maximal oxygen capacity (VO2max) is an objective measure of the body's aerobic capacity. To assess VO2max, oxygen uptake should be measured directly during the exercise test. The aim of the study was to evaluate the physical capacity in adults with DM1 and its relationship with the occurrence of partial clinical remission (pCR) during 2 years follow-up. Methods: The pCR was assessed by the following mathematical formula: A1c (%) + [4 × insulin dose (U/kg/d)]. The result ⩽9 indicates pCR. VO2max was assessed between 6th and 24th month of diabetes duration using an ergospirometer (COSMED K5 System), during an exercise test carried out on a cycloergometer (RAMP incremental exercise test). Results: The study group consisted of 32 adults with DM1. People with pCR were proved to have higher VO2max level [36.0 (33.0-41.5) vs 30.9 (26.5-34.4) ml/min/kg, P = .009. Univariate and multivariate regression confirmed a significant association between VO2max and presence of pCR [AOR 1.26 (1.05-1.52), P = .015]. Duration of remission was longer among group with higher VO2max results [15 (9-24) vs 9 (0-12) months, P = .043]. The positive relationship was observed between diabetes duration and VO2max (rs = 0.484, P = .005). Multivariate linear regression confirms a significant association between remission duration and VO2max (ml/min/kg) (ß = 0.595, P = .002). Conclusion: The higher VO2max, the better chance of partial clinical remission at 2 years of DM1 and longer duration of remission.

Better cardiorespiratory fitness increases the chance of partial clinical remission and prolongs remission duration in people with newly diagnosed type 1 diabetes. Introduction An essential process affecting the course of type 1 diabetes (DM1) is the appearance and duration of clinical remission. One of the most important factors promoting the occurrence of remission is physical activity, due to increased activity of antioxidants, reduces insulin resistance and improves glucose transport. Maximal oxygen capacity (VO₂max) is an objective measure of the body's aerobic capacity. To assess VO₂max, oxygen uptake should be measured directly during the exercise test. The aim of the study was to evaluate the physical capacity in adults with DM1 and its relationship with the occurrence of partial clinical remission (pCR) during 2 years follow-up. Methods The pCR was assessed by the following mathematical formula: A1c (%) + [4 × insulin dose (U/kg/d)]. The result ⩽9 indicates pCR. VO₂max was assessed between 6th and 24th month of diabetes duration using an ergospirometer (COSMED K5 System), during an exercise test carried out on a cycloergometer (RAMP incremental exercise test). Results The study group consisted of 32 adults with DM1. People with pCR were proved to have higher VO₂max level [36.0 (33.0-41.5) vs 30.9 (26.5-34.4) ml/min/kg, P = .009. Univariate and multivariate regression confirmed a significant association between VO₂max and presence of pCR [AOR 1.26 (1.05-1.52), P = .015]. Duration of remission was longer among group with higher VO₂max results [15 (9-24) vs 9 (0-12) months, P = .043]. The positive relationship was observed between diabetes duration and VO₂max (rs = 0.484, P = .005). Multivariate linear regression confirms a significant association between remission duration and VO₂max (ml/min/kg) (ß = 0.595, P = .002). Conclusions The higher VO₂max, the better chance of partial clinical remission at 2 years of DM1 and longer duration of remission.

Interactive calculator to estimate insulin sensitivity in type 1 diabetes.

The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic-euglycemic clamp, a time, costly, and labor-intensive research tool. A low insulin sensitivity is associated with a complication-risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated-GDR), enabling comparison of IS and its probability of IS <4.45 mg/kg/min (low) or >6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005-0.87 with agreement in detecting low and high glucose disposal rates in the range 49-93% and 89-100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user-friendly tool for individual IS calculations and also offers efficient batch processing of data for research.

Independent euglycaemic hyperinsulinaemic clamp studies validate clinically applicable formulae to estimate insulin sensitivity in people with type 1 diabetes.

BACKGROUND AND AIM: Low insulin sensitivity (IS) increases Type 1 diabetes (T1D) complication risk and can be estimated by simple formulae developed from complex euglycemic hyperinsulinaemic clamp studies. We aimed to validate these formulae using independent clamp data. METHODS: Clamps were performed in 104 T1D adults. Measured glucose disposal rate (GDR) was correlated with eGDR and eLog10 M/I calculated by five IS formulae. RESULTS: Correlations ranged between 0.23-0.40. Two IS formulae (by the authors), using age, sex, HDL-C, HbA1c, pulse pressure, BMI, and waist-hip-ratio had the highest correlation with measured GDR and the best performance in detecting low IS.

Is it time to change the goals of lipid management in type 1 diabetes mellitus? Changes in apolipoprotein levels during the first year of type 1 diabetes mellitus. Prospective InLipoDiab1 study.

Introduction: Apolipoprotein complement is a critical determinant of lipoprotein function and metabolism. The relation between exogenous insulin and apolipoproteins (apos) in newly diagnosed type 1 diabetes mellitus (T1DM) has not yet been studied extensively. The aim of this study was to prospectively observe the changes in serum apos AI (apo AI) and AII (apo AII) in patients with newly diagnosed T1DM and their association with the daily insulin requirement. Material and methods: Thirty-four participants of the InLipoDiab1 study aged 26 (IQR: 22-32) were enrolled in this analysis. Apolipoprotein AI and AII concentrations were assessed at diagnosis and at follow-up after 3 weeks, 6 months, and 1 year of insulin treatment. The daily dose of insulin (DDI) was calculated as the amount of short- and long-acting insulin at discharge from the hospital and at follow-up visits. Results: The changes in apo AI concentration were observed after 3 weeks of insulin treatment (p = 0.04), with the largest increase between 3 weeks and 6 months of observation (p < 0.001). Apolipoprotein AII level did not change significantly after 3 weeks, while a significant increase was observed between 3 weeks and 6 months of treatment (p < 0.001). The correlations between DDI and apo concentration were not statistically significant. Conclusions: In the first year of T1DM, there is a significant increase in apos concentration. Due to the significant deviation of apos concentration from accepted norms, changes in the recommendations of lipid control criteria in T1DM may be considered.

Suppression of serum lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism by intensive insulin therapy in the first year of type 1 diabetes mellitus: Prospective InLipoDiab1 study.

BACKGROUND AND AIMS: Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are crucial proteins in reverse cholesterol transport. There are insufficient data on regulating these proteins by insulin therapy in type 1 diabetes mellitus (T1DM). We aimed to assess prospectively the impact of insulin therapy initiation on transfer proteins serum levels in adults with newly diagnosed T1DM. METHODS AND RESULTS: 57 adults with newly diagnosed T1DM were enrolled in the InLipoDiab1 Study. All participants were treated with subcutaneous insulin in the model of intensive insulin therapy since the diagnosis of diabetes. Serum PLTP and CETP concentrations were measured at diagnosis, after three weeks, six months, and after one year of insulin treatment, using the immunoenzymatic method ELISA. A significant decrease in PLTP and CETP concentrations were demonstrated during twelve months of insulin therapy in newly diagnosed T1DM. The dynamics of changes in the level of these proteins varied depending on the occurrence of remission after a year of the disease. In the group without remission, a significant decrease in PLTP and CETP levels appeared after six months of follow-up. The remission group was characterized by a decrease in proteins concentration only after one year of treatment. In the non-remission group, significant negative correlations were found between the daily dose of insulin and levels of PLTP and CETP. CONCLUSION: Exogenous insulin is an inhibitor of lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism in the first year of treatment.

Insulin Resistance in Adults with Type 1 Diabetes is Associated with Lower Vitamin D Serum Concentration.

AIM: Type 1 diabetes mellitus (T1DM) is a disease characterized by an absolute deficiency of endogenous insulin secretion. Insulin resistance (IR) may develop among patients with T1DM. Vitamin D deficiency was reported to be a risk factor in the development of IR. The aim of the study was to assess the relationship between serum concentrations of 25-hydroxyvitamin D (25(OH)D) and IR among patients with T1DM. METHODS: The test group consisted of 110 adult patients [males=65 (59%)] with T1DM. Participants were recruited in Poland between 1st October and 30th April in 2015/2016 and 2016/2017. VD serum level was assessed by ELISA array. IR was assessed by estimated Glucose Disposal Rate (eGDR). RESULTS: In the study group 21 (19%) patients were recognized as IR according to eGDR cut-offs (<7.5 mg/kg/min), 52 (47.3%) patients had VD deficiency (25(OH)D<20 ng/ml), 16 (14.5%) patients had 25(OH)D<10 ng/ml. Only 6 (5%) participants reported VD supplementation. Patients with IR, according to eGDR cut-off revealed significantly lower 25(OH)D serum level 15.7 (9.2-28.4) vs. 22.1 (13.0-38.4) ng/ml; p=0.04 as compared to patients without IR. R Spearman analysis found a positive relationship between VD and eGDR (Rs=0.27; p<0.01). Logistic regression analysis revealed significant relationship between the presence of IR and VD serum level/presence of 25(OH)D serum level below 10 ng/ml, both models adjusted to sex, age, BMI, LDL and triglycerides, accordingly (OR=0.95, CI: 0.90-0.99; p=0.04) and (OR=4.19, CI: 1.04-16.93; p=0.04). CONCLUSION: The serum concentration of Vitamin D is negatively associated with insulin resistance in patients with T1DM and may have clinical implications.

Excess body fat increases the accumulation of advanced glycation end products in the skin of patients with type 1 diabetes.

BACKGROUND: The process of protein glycation described by Brownlee et al. is a crucial pathogenic mechanism in the development of chronic complications of diabetes. OBJECTIVES: To assess advanced glycation end products (AGEs) in the skin of patients with type 1 diabetes (DM1) and excess body fat (EBF) accumulation. MATERIAL AND METHODS: The study group consisted of 227 DM1 patients (121 women and 106 men) whose mean age was 31 ±9.2 years; the mean duration of diabetes was 12 ±7.7 years; and the mean HbA1c was 8.9 ±1.8%. The inclusion criteria were as follows: age 18-65 years, DM1, and lack of acute inflammations and uncontrolled chronic diseases. The exclusion criteria were: anemia (hemoglobin (Hb) <11 g/dL), chronic kidney disease (CKD) (glomerular filtration rate (eGFR) <30 mL/min/1.73 m2) and elevated aminotransferase levels (more than twice the upper normal limits). Total adipose tissue content was assessed using the electrical bioimpedance method, with the Tanita BC-418 MA analyzer (Tanita Corp., Tokyo, Japan). The Tanita ViScan AB 140 (Tanita Corp.) was used to evaluate visceral fat tissue (VTF). The content of glycation end products in the skin was assessed using a DiagnOptics AGE Reader device (type 214D00102; DiagnOptics, Groningen, the Netherlands). RESULTS: The group with normal body fat (NBF) consisted of 123 subjects, whereas 104 subjects had EBF. No significant statistical differences were found between the NBF and EBF groups with regard to age, duration of diabetes, current HbA1C value, and tobacco use. A significantly higher AGE score was observed in the EBF group. CONCLUSIONS: Increased body fat affects the amount of AGE in the skin, which correlates with a higher risk of developing chronic diabetes complications.

Clinical Remission of Type 1 Diabetes Predicts Higher Insulin Sensitivity at 7 Years from Diagnosis of the Disease.

Background: Clinical remission of type 1 diabetes is not only associated with regeneration of beta cells and preserved insulin secretion but also with increased insulin sensitivity. The aim of the study was to determine the association between presence of remission in the first year of type 1 diabetes and insulin resistance at 7 years from diagnosis of the disease. Material and Methods: A total of 108 consecutive patients with newly diagnosed type 1 diabetes were followed prospectively. During the follow-up time, the onset and duration of clinical remission were registered. Seventy-four patients were included in the final analysis. Insulin sensitivity was assessed by the glucose disposal rate (GDR), determined using the hyperinsulinemic-euglycemic clamp, performed at 7 years from diagnosis of diabetes. Patients were divided into groups with GDR <4.5 mg/(kg·min) (G1-lower insulin sensitivity group) and GDR ≥4.5 mg/(kg·min) (G2-higher insulin sensitivity group). Results: Higher insulin sensitivity was observed in the remission group [GDR 6.2 interquartile range (IQR) 4.2-7.0 mg/(kg·min) vs. 3.8 (IQR 3.0-4.8) mg/(kg·min); P = 0.01]. Furthermore, in G2 group, the duration of remission was longer than in G1 group: (351 [IQR 206-561] days vs. 70 [IQR 0-289] days; P = 0.002). Also, the GDR value correlated positively with duration of remission (r = 0.42; P = 0.002). In the multivariate logistic regression model, including age, sex, body mass index at diagnosis, and presence of remission, the remission period was independently associated with a higher GDR value (odds ratio 10.88; 95% confidence interval: 1.70-69.50; P = 0.009]. Conclusions: Patients with type 1 diabetes who entered remission at the beginning of the disease, despite its ending, have higher insulin sensitivity at 7 years after diagnosis of diabetes than nonremitters.

Changes in high-density lipoprotein cholesterol (HDL-C) level and the ratio of triglycerides to HDL-C during the first year of type 1 diabetes.

INTRODUCTION: Patients in an insulin­deficient state show reduced high­density lipoprotein cholesterol (HDL­C) levels. Insulin treatment affects lipid metabolism in this population. There have been no prospective studies evaluating changes in lipid profile after the diagnosis of type 1 diabetes (T1D). OBJECTIVES: We investigated the effect of subcutaneous insulin therapy initiation on quantitative changes in HDL­C levels and other components of lipid profile in patients with newly diagnosed T1D. PATIENTS AND METHODS: A total of 127 patients with newly diagnosed T1D aged 28 years (interquartile range, 23-34 years) were enrolled in the InLipoDiab1 study. The lipid profile was assessed before the first injection of insulin (baseline) and after 3 and 12 months of insulin therapy. The daily dose of insulin (DDI) was defined as the requirement for insulin per kilogram body weight per day. The DDI was calculated at hospital discharge and during visits in an outpatient clinic at 3 and 12 months. RESULTS: We observed a persistent increase in HDL­C levels at 3 and 12 months versus baseline (P <0.001) in men and women. Moreover, a reduction was observed in triglyceride levels (P <0.001) and the ratio of triglycerides to HDL­C (P <0.001) in men and women. In contrast, a decrease was observed in low­density lipoprotein cholesterol and non­HDL­C levels (P <0.001), but only in men. CONCLUSIONS: Subcutaneous insulin therapy reverses the impaired phenotype of lipoproteins during the first year of treatment. Changes in lipoprotein levels in newly diagnosed T1D differ depending on sex.

Nonadherence to potassium replacement protocol leads to prolonged management of diabetic ketoacidosis.

Introduction Diabetic ketoacidosis is a life-threatening condition that requires prompt management. Objectives We aimed to assess the impact of adherence to potassium replacement protocol according to the guidelines of Diabetes Poland on the duration of diabetic ketoacidosis (DKA) treatment. Patients and methods This retrospective analysis included 242 adults (median age, 27 years; range, 21-38 years). Nonadherence to potassium replacement protocol was assessed, along with the relationship between nonadherence and duration of DKA management. Nonadherence to the protocol was defined as too low or too high doses of potassium compared with the recommended potassium replacement protocol. Results The median duration of DKA treatment was longer in the nonadherent group than in the adherent group: 37 hours (interquartile range [IQR], 27-48) and 30 hours (IQR, 17-43), respectively (P = 0.005). Treatment duration correlated positively with nonadherence to potassium replacement protocol (r = 0.18; P = 0.005) and severity of DKA (r = 0.52; P <0.0001). Stepwise multivariate linear regression analysis indicated nonadherence to the protocol (ß = 0.14; P = 0.02) and severity of DKA (ß = 0.43; P <0.0001) as predictors of treatment duration, after adjustment for body mass index and age (R2 = 0.28; P <0.0001). Conclusions Nonadherence to potassium replacement protocol leads to prolongation of DKA management. Medical staff should be educated about the benefits of potassium replacement and precision in potassium administration and dosing in patients with DKA.

Metformin added to intensive insulin therapy improves metabolic control in patients with type 1 diabetes and excess body fat.

INTRODUCTION Bad nutritional habits and administration of insulin in supraphysiological doses lead to the development of insulin resistance and poor metabolic control in patients with type 1 diabetes. Accumulation of visceral fat is the main cause of the decrease in insulin sensitivity. OBJECTIVES We aimed to evaluate changes in anthropometric parameters, indirect measures of insulin resistance, and safety of treatment with metformin added to intensive insulin therapy in patients with type 1 diabetes and excess body fat. PATIENTS AND METHODS We analyzed 114 patients (60 women and 54 men; median age, 31 years [range, 18-60 years]), with a median diabetes duration of 14 years (range, 10-20 years). Metformin was administered for at least 6 months in 74 patients, while 40 patients did not receive metformin. The study group was randomized in a 2:1 ratio. Total body fat assessment and laboratory tests were performed before the study and at 6-month follow-up. RESULTS At 6 months, in the metformin group, compared with the non-metformin group, an improvement was noted for adiposity parameters (reduction in body mass index, -0.4 kg/m2 vs 0.6 kg/m2, P = 0.006; waist circumference, -5 cm vs 3.5 cm, P = 0.02; and total body fat, -1.7 kg vs 1.4 kg; P <0.001; glycated hemoglobin A1c: -0.6% vs 0.2%, P <0.001), as well as for lipid parameters and blood pressure. An increase in the estimated glomerular filtration rate was greater in the metformin compared with the non-metformin group: 0.9 mg/kg/min vs -0.2 mg/kg/min, P <0.001). CONCLUSIONS In patients with type 1 diabetes and excess body fat, treated with intensive functional insulin therapy, the addition of metformin improves metabolic control of diabetes at 6 months. Metformin added to insulin therapy in patients with type 1 diabetes and excess body fat appears to be safe.

TG/HDL-C ratio and visceral adiposity index may be useful in assessment of insulin resistance in adults with type 1 diabetes in clinical practice.

BACKGROUND: Insulin resistance (IR) is an important clinical issue in patients with type 1 diabetes due to worse metabolic control and risk of development of chronic complications. OBJECTIVE: The aim of the study was to evaluate simple and easily available parameters as indirect markers of IR in adults with type 1 diabetes and correlate it with the results of hyperinsulinemic-euglycemic clamp. METHODS: The study included 88 patients (62 men), aged 34.1 ± 6.5 years, with type 1 diabetes with a median disease duration of 8 (7-13) years and mean HbA1c of 7.6 ± 1.5%. Tissue sensitivity to insulin was assessed on the basis of glucose distribution rate (GDR) obtained in the course of hyperinsulinemic-euglycemic clamp. In addition, indirect markers of IR, such as estimated GDR, presence of features of metabolic syndrome, visceral adiposity index (VAI), and the triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio, were evaluated. RESULTS: In the study group, IR defined as GDR <4 mg/kg/min was observed in 33 (37.5%) patients. Group with IR had significantly higher postprandial glycemia (9.1 ± 2.0 vs 8.4 ± 1.1 mmol/L, P = .04), serum TG level (1.11 [0.75-1.92] vs 0.85 [0.60-1.08] mmol/L, P = .001), lower HDL-C level (1.59 ± 0.38 vs 1.8 ± 0.5 mmol/L, P = .02), higher TG/HDL-C ratio (1.60 [1.00-3.13] vs 1.05 [0.62-1.53], P = .001), and higher VAI (2.61 [1.31-4.25] vs 1.56 [0.96-2.25], P = .002). Significant relationship between GDR and TG/HDL-C ratio and VAI, adjusted for age, sex, HbA1c, and duration of diabetes was revealed (respectively, odds ratio 1.90 [95% confidence interval 1.15-3.15], P = .01 and odds ratio 1.47 [95% confidence interval 1.06-2.04], P = .01). CONCLUSIONS: TG/HDL-C ratio and VAI appear to be clinically useful tools to assess IR in adults with type 1 diabetes.

The Higher the Insulin Resistance the Lower the Cardiac Output in Men with Type 1 Diabetes During the Maximal Exercise Test.

BACKGROUND: The aim of this study was to assess the hemodynamic parameters analyzed in bioimpedance cardiography during maximal exercise in patients with type 1 diabetes differing in insulin resistance. METHODS: The study group consisted of 40 men with type 1 diabetes. Tissue sensitivity to insulin was assessed on the basis of the glucose disposal rate (GDR) analyzed during hyperinsulinemic-euglycemic clamp. Patients were divided into groups with GDR <4.5 mg/kg/min (G1 group-lower insulin sensitivity) and GDR ≥4.5 mg/kg/min (G2 group-higher insulin sensitivity). During the exercise test, the heart rate, systolic volume, cardiac output, cardiac index were measured by the impedance meter (PhysioFlow). RESULTS: Compared with the G2 group, the G1 group had a lower cardiac output (CO): during exercise 8.6 (IQR 7.7-10.0) versus 12.8 (IQR 10.8-13.7) L/min; P < 0.0001, at the maximal effort 13.1 (IQR 12.2-16.7) versus 18.6 (IQR 16.9-20.2) L/min; P = 0.001, and during observation after exercise 8.4 (IQR 6.3-9.6) versus 11.9 (IQR 10.1-13.1) L/min; P < 0.0001. We noticed a positive correlation of GDR and cardiac output: during the exercise test (r = 0.63, P = 0.0002), at the maximal effort (Rs 0.56, P = 0.001), and during observation after the exercise test (r = 0.72, P < 0.0001). In multivariate logistic regression, cardiac output during exercise and during observation was associated with high GDR, regardless of the age and duration of diabetes [OR: 1.98 (95% CI 1.10-3.56), P = 0.02 and OR: 1.91 (95% CI 1.05-3.48), P = 0.03; respectively]. CONCLUSION: In nonobese subjects with type 1 diabetes, with good metabolic control, insulin resistance is associated with cardiac hemodynamic parameters assessed during and after exercise. The higher the insulin resistance the lower the cardiac output during maximal exercise in men with type 1 diabetes.

High-intensity Exercise in Men with Type 1 Diabetes and Mode of Insulin Therapy.

The purpose of this study was to evaluate the impact of high intensity exercise on glucose levels and risk of metabolic decompensation in males with type 1 diabetes (T1D), depending on the method of insulin administration. The study comprised 29 males (aged 25.3±5.1 years; duration of diabetes 10.3±3.2 years) treated with continuous subcutaneous insulin infusion (CSII) or multiple daily insulin injections (MDI). Treadmill exercise test was performed twice in each patient until subjective exhaustion as maximum according to the Borg scale. All the patients achieved ≥85% of the maximal heart rate. Distance during the test was 4 500±1 400 m and 4 473±1 559 m in the MDI and CSII groups, respectively, which was achieved in 31±8 min. During the test and in the 6 h after, no clinically significant episodes of hypoglycemia occurred. Mean glucose levels did not exceed 10 mmol/L in most patients. The risk of the composite endpoint (hypoglycemia<3.8 mmol/L, hyperglycemia≥16.6 mmol/L, ketones≥0.6 mmol/L, and lactate>2.2 mmol/L) was higher in patients treated with MDI than CSII (OR3.75, 95%CI:1.22-11.52, p=0.02). In conclusion, planned high intensity physical effort in men with well-controlled T1D is metabolically safe. CSII shows greater metabolic advantage over MDI during and after high intensity exercise in men with T1D.

Influence of remission and its duration on development of early microvascular complications in young adults with type 1 diabetes.

INTRODUCTION: Prevalence of partial remission ranges between 20% and 80% in the initial course of type 1 diabetes. In this phase of the disease, a substantial insulin secretion contributes to good metabolic control. The aim of the study was to determine the association between presence of partial remission and occurrence of microangiopathy complications in type 1 diabetes. MATERIAL AND METHODS: Ninety-eight consecutive patients with newly diagnosed type 1 diabetes were asked to participate in a cohort study. Partial remission was defined as the time in which all of the following criteria were met: HbA1c below 6.5% (48mmol/mol), daily insulin requirement below 0.3 U/kg body weight and serum Cpeptide concentration above 0.5ng/ml. Patients were divided into those who were in remission at any time during follow-up (remitters) and non-remitters. After 7years of follow-up, the occurrence of microangiopathy complications was analyzed. In statistical analysis, Mann-Whitney test, chi(2) test and Fisher test were used for analysis between groups. We applied a Cox's multivariate regression model and univariate regression method. P<0.05 was considered statistically significant. RESULTS: In univariate logistic regression, a significant association was found between absence of remission and occurrence of at least one microvascular complication. In the Cox proportional hazards regression model that included clinically significant parameters at diagnosis (presence of ketoacidosis, cigarette smoking and HbA1c value) as covariates, absence of remission was associated with occurrence of chronic complications of diabetes at 7years [HR: 3.65 (95% CI 1.23-4.56), p=0.04]. In non-remitters, higher incidence of at least one microvascular complication (46.4% vs. 7.6%), higher incidence of retinopathy (42.8% vs. 5.7%), and neuropathy (21.4% vs. 1.9%) was found. CONCLUSIONS: Occurrence of partial remission of diabetes is associated with a reduced risk of chronic microvascular complications at 7-year follow-up.

In diabetic Charcot neuroarthropathy impaired microvascular function is related to long lasting metabolic control and low grade inflammatory process.

AIMS: The aim of this study was to assess microvascular function associated with the occurrence of Charcot neuroarthropathy (CN) in patients with diabetes. METHODS: We evaluated 70 diabetic patients (54 men) with Charcot neuroarthropathy (CN-DM), median age 59 (IQR: 51-62), mean disease duration 16±8years. The control group were 70 subjects with diabetes and without Charcot neuroarthropathy (DM), 54 men, median age 60 (54-62), mean diabetes duration 15±7years. We assessed metabolic control of diabetes, serum C-reactive protein concentration (CRP) and cardiovascular autonomic neuropathy (CAN). We used AGE-Reader to measure skin autofluorescence (AF) associated with accumulation of advanced glycation end products that reflects long lasting metabolic control. Microvascular function was examined by laser Doppler flowmetry (PERIFLUX 5000) with thermal hyperemia (TH) and postocclusive reactive hyperemia (PORH). RESULTS: CN-DM patients as compared to DM subjects had lower HbA1c level [7.6 (6.6-8.4) vs 8.4 (7.3-9.7)%, p<0.001], lower eGFR [75.9±24.1 vs 86.6±17.8ml/min/1.73m(2), p=0.003], higher CRP serum concentration [3.8 (2.3-10.1) vs 1.9 (0.8-4.4)mg/l, p<0.001] and higher skin autofluorescence [2.8 (2.5-3.1) vs 2.6 (2.3-2.9)AU, p=0.03]. The cardiovascular autonomic neuropathy (CAN) was more frequently diagnosed in CN-DM subjects [59 vs 27%, p<0.001]. The peak flow during thermal hyperemia (THmax) was lower in CN-DM subjects as compared to DM group [156 (93-240) vs 235 (155-300)PU, p=0.001]. We found negative correlation between THmax and CRP concentration (Rs=-0.34, p=0.003), TG concentration (Rs=-0.37, p=0.002) and skin AF (Rs=-0.32, p=0.04) and positive correlation between THmax and HDL cholesterol level (Rs=0.42, p<0.001) in CN-DM patients. There was also a positive correlation between PORHpeak and HDL cholesterol level (Rs=-0.23, p=0.04). CONCLUSION: Deterioration of microvascular function and autonomic system dysfunction are present in Charcot neuroarthropathy. Impaired microvascular reactivity is associated with worse long lasting metabolic control of diabetes and low grade inflammatory process.

Are zinc transporter type 8 antibodies a marker of autoimmune thyroiditis in non-obese adults with new-onset diabetes?

OBJECTIVE: The diagnosis of autoimmune diabetes in non-obese adults is based on the detection of glutamic acid decarboxylase autoantibodies (GADA), islet cell antibodies (ICA) and antibodies to tyrosine phosphatase (IA-2A). Zinc transporter 8 (ZnT8) has been identified as a new autoantigen in patients with type 1 diabetes mellitus. The coincidence of autoimmune thyroiditis (AITD) with diabetes is common; therefore, screening of TSH and thyroid peroxidase antibodies (ATPO) is recommended during the diagnosis of diabetes. In this study, we determined whether the occurrence of islet autoantibodies is associated with a positive titre of ATPO in newly diagnosed adult-onset autoimmune diabetic patients. DESIGN AND METHODS: THE STUDY INVOLVED 80 NON-OBESE ADULTS AGED 44 (INTERQUARTILE RANGE (IQR): 37-51) years with a BMI of 24.0 (IQR: 22.2-26.0) kg/m(2) and new-onset diabetes. The markers of autoimmune diabetes (GADA, ICA, IA-2A and ZnT8A), TSH and thyroid peroxidase antibodies (ATPO) were evaluated. RESULTS: IN THE STUDY POPULATION, 70% (N=56) OF THE SUBJECTS WERE POSITIVE FOR AT LEAST ONE OF THE FOUR ASSESSED MARKERS OF AUTOIMMUNE DIABETES (83.9% GADA, 62.5% ICA, 42.8% IA-2A AND 33% ZNT8A) AND 37.5% OF THE SUBJECTS WERE POSITIVE FOR ATPO. THE ZNT8A-POSITIVE SUBJECTS HAD HIGHER ATPO TITRES THAN THE ZNT8A-NEGATIVE SUBJECTS (172.7 (IQR: 0.36-410.4) vs 92.4 (IQR: 0-23.7) IU/ml, P=0.001). Based on the assessed islet autoantibodies, the occurrence of positive ZnT8A and GADA was found to be related to a positive titre of ATPO using logistic regression (OR=5.48, 95% CI: 1.65-18.14, P=0.006 and OR=3.42, 95% CI: 1.09-10.71, P=0.03 respectively). CONCLUSIONS: In non-obese adults with new-onset diabetes, the presence of GADA and especially ZnT8 autoantibodies increases the risk of AITD.

Increased accumulation of skin advanced glycation end products is associated with microvascular complications in type 1 diabetes.

BACKGROUND: Skin autofluorescence (AF) measured with an AF reader device is a noninvasive tool to measure the tissue accumulation of advanced glycation end products (AGEs). The aim of the study was to assess the association between AF and microvascular complications in type 1 diabetes mellitus (DM1). METHODS: The study population consisted of 140 DM1 patients, 28 years old (interquartile range [IQR], 23-35), 76 of whom were women, with disease duration of 13 years (IQR, 8-19). We used the AGE Reader (DiagnOptics, Groningen, The Netherlands) to measure the AF phenomenon, which occurs because of fluorescent properties of AGEs. The patients were divided according to the presence or absence of diabetes-associated microvascular complications: retinopathy, nephropathy, and neuropathy and any microangiopathy. RESULTS: The median AF was 2.0 (IQR, 1.7-2.4). In the univariate logistic regression AF was significantly associated with retinopathy (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.26-4.84, P = 0.008), nephropathy (OR 3.15, 95% CI 1.34-7.39, P = 0.008), neuropathy (OR 3.17, 95% CI 1.46-6.90, P = 0.003), and any microvascular complication (OR 2.94, 95% CI 1.46-5.92, P = 0.002). Multivariate logistic regression showed that skin AF was independently associated only with diabetic neuropathy (OR 2.98, 95% CI 0.99-8.90, P = 0.05). CONCLUSIONS: The tissue accumulation of AGE is significantly associated with microvascular complications in DM1.

Assessment of skin autofluorescence as a marker of advanced glycation end product accumulation in type 1 diabetes.

INTRODUCTION: Advanced glycation end products (AGEs) are important in the pathogenesis of atherosclerosis and reflect the risk of cardiovascular mortality. AGE levels are significantly higher in patients with diabetes. OBJECTIVES: The aim of the study was to compare AGE accumulation in the skin of patients with type 1 diabetes and nondiabetic population as well as to assess its association with disease duration and metabolic control. We also aimed to assess the potential usefulness of this method in the monitoring of diabetes control, especially in a long-term follow-up. PATIENTS AND METHODS: The study included 140 type 1 diabetes patients (mean age 30.4 ± 9.7 years; mean disease duration 13.6 ± 8.5 years) and 57 nondiabetic subjects. AGE accumulation in the skin was assessed noninvasively with the AGE Reader device, which measures autofluorescence (AF) that occurs because some AGEs have fluorescent properties. RESULTS: Mean AF in the diabetes group was 2.13 ± 0.55 and it was significantly higher than in controls (AF 1.70 ± 0.27, P <0.05). A significant positive correlation between AF and the age of patients was found for the whole study population (P <0.05). In diabetic subjects, we observed a significant positive correlation between AF and diabetes duration (P <0.05), and between AF and glycated hemoglobin (HbA1c) (P <0.05). CONCLUSIONS: AF measurement is a simple and noninvasive method of assessing AGE accumulation in the skin. It may be useful as a secondary method of assessing metabolic control, as it reflects glycemic control over a longer period of time than that reflected by HbA1c levels.