ABSTRACT
BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.
Subject(s)
Blood Glucose/metabolism , Glucose Metabolism Disorders/epidemiology , Prader-Willi Syndrome/epidemiology , Adolescent , Adult , Age Distribution , Biomarkers/blood , Chi-Square Distribution , Child , Female , Glucose Metabolism Disorders/blood , Glucose Metabolism Disorders/diagnosis , Human Growth Hormone/therapeutic use , Humans , Insulin Resistance , Italy/epidemiology , Linear Models , Male , Metabolic Syndrome/epidemiology , Middle Aged , Multivariate Analysis , Obesity/epidemiology , Prader-Willi Syndrome/blood , Prader-Willi Syndrome/diagnosis , Prader-Willi Syndrome/drug therapy , Prevalence , Retrospective Studies , Risk Factors , Young AdultABSTRACT
We found that in obese youth, plasma glucose above 155mg/dl (8.6mmol/l) at 60min of an OGTT, a predictor of type 2 diabetes (T2D) in adults, was present in 12% with normal glucose tolerance and 57% with impaired glucose tolerance. Performance of elevated 1-h glucose in predicting T2D in overweight youngsters should be tested.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/epidemiology , Glucose Tolerance Test/methods , Obesity/blood , Adolescent , Adult , Female , Humans , PrevalenceABSTRACT
We tested the hypothesis that patients with Prader-Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P < 0.05), whereas G2 stage was significantly more frequent in control patients (P < 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children.
Subject(s)
Non-alcoholic Fatty Liver Disease/epidemiology , Prader-Willi Syndrome/physiopathology , Adolescent , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Blood Glucose/analysis , Body Composition , Body Mass Index , Child , Cross-Sectional Studies , Fasting , Female , Growth Hormone/therapeutic use , Humans , Insulin Resistance , Male , Non-alcoholic Fatty Liver Disease/blood , Waist CircumferenceSubject(s)
Infant, Small for Gestational Age , Physical Fitness , Case-Control Studies , Child , Exercise Test , Female , Humans , Infant, Newborn , Male , Prospective StudiesABSTRACT
BACKGROUND: Benefit of fitness on children with type 1 diabetes mellitus (T1DM) is still debated. AIM: To evaluate the influence of physical activity on metabolic balance and exercise tolerance in prepubertal children affected by T1DM. METHODS: We analyzed 35 pre-/peripubertal T1DM children and 31 matched controls using an activity monitor (SenseWear Armbad) and physical activity questionnaire (PAQ) to assess energy expenditure (EE), total and active, sedentary and physical activities (h/day and Mets = metabolic equivalents). The maximal cardiopulmonary exercise test (CPET) was also performed. RESULTS: Total physical activities and total and active EE (>3 Mets) resulted higher in controls than in T1DM patients and self-reported perception of physical and sedentary activities was altered in T1DM children as well in controls and were different from the measured data. No differences were found in CPET parameters with the exception of a higher maximal blood pressure in T1DM children. In multivariate analysis HbA1c negatively correlated with VO(2). CONCLUSION: Prepubertal T1DM children seem to have a lower level of physical activity and EE and a probable altered feeling of physical and sedentary activities. On the other hand, T1DM children do not show any alteration of cardiovascular performance, although glycemic control (HbA1c) may play a role in cardiovascular performance.
Subject(s)
Cardiovascular System , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/physiopathology , Energy Metabolism/physiology , Exercise Tolerance/physiology , Actigraphy/instrumentation , Actigraphy/methods , Body Mass Index , Cardiovascular System/physiopathology , Child , Exercise Test , Female , Humans , Male , Physical Fitness/physiology , Surveys and QuestionnairesABSTRACT
Adults with normal glucose tolerance (NGT) but exaggerated plasma glucose excursion at 1 h (1HPG) following the oral glucose tolerance test (OGTT) have significantly higher risk of developing impaired glucose tolerance (IGT) or diabetes. Aim of the study will be to characterize the metabolic phenotype of NGT obese youth according to values of 1HPG. To accomplish this aim, obese patients (N = 1,454; 761 men; 79 IGT; BMI z-score 2.56 ± 0.16 SDS; age 11 ± 0.7 years) from two data sets were analyzed. In all patients, empirical parameters of insulin metabolism were calculated in fasting condition and following an OGTT (1.75 mg of glucose per kilogram/body weight). Receiver-operating characteristic (ROC) analysis was performed in the first group (training set, N = 920) to establish the cutoff value of 1HPG best identifying IGT. The second set (validation set, N = 534) served to verify the goodness of the model and the identified cutoff values. 1HPG ≥ 132.5 mg/dl identified IGT with 80.8% sensitivity and 74.3% specificity in the training set (AUC 0.855, 95% CI 0.808-0.902, p < 0.0001), and 70.3% sensitivity and 80% specificity in the validation set (AUC 0.81, 95% CI 0.713-0.907, p < 0.0001), respectively. NGT patients with 1HPG ≥ 132.5 mg/dl had a metabolic phenotype (triglycerides, insulin action, and secretion) that was in between those of NGT patients with 1HPG below the threshold and IGT patients (p < 0.0001 for all the comparisons). 1HPG ≥ 132.5 mg/dl seems to be associated with increased metabolic risk in obese youth, identifying patients with lower insulin sensitivity, early secretion, and higher total insulin secretion than in obese mates with lower 1HPG.
Subject(s)
Blood Glucose/analysis , Obesity/blood , Adolescent , Age Factors , Blood Glucose/metabolism , Child , Child, Preschool , Female , Glucose Intolerance/blood , Glucose Intolerance/diagnosis , Glucose Intolerance/epidemiology , Glucose Tolerance Test , Humans , Insulin/blood , Insulin/metabolism , Insulin Resistance , Insulin Secretion , Male , Obesity/epidemiology , Sensitivity and Specificity , Time FactorsABSTRACT
OBJECTIVES: The aim of our study was to evaluate the physical and sedentary activities and energy expenditure (EE) in a group of children affected by non-alcoholic fatty liver disease (NAFLD), compared with normal and obese subjects, using a physical activity questionnaire (PAQ) and a SenseWear armband (SWA). METHODS: Forty NAFLD (10 females), 41 lean (NRM; 11 females) and 30 obese (OB; 10 females), age- and pubertal stage-matched, children were included. RESULTS: Sedentary activity (PAQ) was similar in NAFLD and NRM but less in OB, while SWA showed that NAFLD spent less time in physical activity and more in sedentary activities compared with NRM, but not with OB. Insulin sensitivity index result is related to active EE (cal kg(-1) d(-1) ) in NAFLD, while homeostatic model assessment index result was negatively related to total EE in OB. CONCLUSIONS: Regular physical activity must be encouraged in all obese children affected by NAFLD or not, and SWA might be a possible valid tool for evaluating actual EE.
Subject(s)
Energy Metabolism/physiology , Fatty Liver/metabolism , Insulin Resistance/physiology , Motor Activity/physiology , Obesity/metabolism , Adolescent , Body Mass Index , Child , Energy Intake/physiology , Fatty Liver/diagnosis , Fatty Liver/epidemiology , Female , Humans , Male , Non-alcoholic Fatty Liver Disease , Obesity/diagnosis , Obesity/epidemiology , Physical Fitness/physiology , Prevalence , Risk Factors , Sedentary Behavior , Surveys and QuestionnairesABSTRACT
BACKGROUND AND AIM: Metabolic characteristics and rate of progression to overt Type 2 diabetes (T2D) in low-risk European obese children are not well documented. Aim of the study was to investigate differences in insulin sensitivity and secretion in Italian obese children and youngsters with pre-diabetes. METHODS: Ninety-six obese children and youngsters with pre-diabetes, pair-matched with individuals with normal glucose tolerance (NGT) were included in the present study. Participants were screened by oral glucose tolerance. Pre-diabetes was classified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined IFG-IGT. Homeostasis model assessment of insulin resistance (HOMA-IR), 2-h insulin, insulin sensitivity index (ISI) and disposition index (DI) were calculated to estimate fasting, peripheral and whole body insulin sensitivity and capacity of pancreatic islets to compensate for lower insulin sensitivity, respectively. One-way analysis of variance was used to compare groups. RESULTS: Eleven subjects had IFG (11.5%), 79 IGT (82.3%), 6 combined IFG-IGT (6.3%). Individuals with IFG showed the highest HOMA-IR (p=0.0007), those with IGT the highest 2-h insulin (p<0.0001), those with IFG-IGT the lowest ISI (p<0.0001), with severely reduced DI (p=0.0003). Compared with NGT, DI was 60% lower in those with IFG-IGT. CONCLUSION: IFG is linked primarily to fasting insulin resistance, IGT to peripheral insulin resistance. IFG-IGT is hallmarked by reduced whole body insulin sensitivity and an additional severe defect in DI. Further longitudinal studies are needed to understand whether the different categories of pre-diabetes in European obese adolescents represent real pre-diabetic alterations.
Subject(s)
Obesity/physiopathology , Prediabetic State/physiopathology , Adolescent , Blood Glucose/metabolism , Child , Diabetes Mellitus, Type 2/physiopathology , Disease Progression , Fasting , Female , Glucose Intolerance/physiopathology , Glucose Tolerance Test , Homeostasis , Humans , Insulin Resistance/physiology , Male , Obesity/complications , Prediabetic State/etiology , Risk Factors , Young AdultABSTRACT
OBJECTIVE: To investigate whether body mass index (BMI) and body composition can affect peak bone mass in a population of obese (OB) (BMI SDS>2.0) and normal weight (NORM) (BMI-SD score <2.0) pubertal subjects (Tanner stage T3 to T5). PATIENTS AND METHODS: 151 subjects (81 OB, age 14.5±2.4 yr) were analyzed using dual-X-ray absorbiometry technique to study Lumbar and whole body bone mineral density (BMD) (areal, normalized for height) and Z-score, lean mass (LM) and lean/fat ratio. RESULTS: As a whole group, OB males did not show any significant difference in bone parameters vs NORM, while OB females showed higher bone density parameters (p<0.05). When grouped according to T, while OB males showed higher bone density at T3-4 stage (p<0.01), and lower at T5 (p<0.01) compared to NORM, OB females showed a tendency through increased BMD at T3-4 and T5 although statistically different only at T5. BMD was independently correlated to LM, lean/fat ratio, and testosterone in NORM males and, at lower level, in OB males, while to LM in NORM females and only to age in OB females. CONCLUSION: Our data seem to confirm the possible negative influence of obesity on bone density in boys, a possible explanation could be an unfavorable body composition during sexual maturation that seems not to affect bone development in adolescents girls.
Subject(s)
Body Composition , Body Mass Index , Bone Density , Obesity , Puberty/physiology , Sex Characteristics , Absorptiometry, Photon , Adolescent , Bone Development/physiology , Estradiol/blood , Female , Humans , Male , Testosterone/bloodABSTRACT
AIMS/HYPOTHESIS: The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis. METHODS: Three samples of Europeans with fasting glucose <7.0 mmol/l were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination. RESULTS: R84 carriers were at higher risk of IGR: OR for the additive model 1.54, p=0.004, and 1.63, p=0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8+/-17.7, 33.8+/-14.4, and 31.6+/-13.3 micromol min(-1)kg(-1), p=0.022, in QQ, QR and RR individuals, respectively. CONCLUSIONS/INTERPRETATION: Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion.
Subject(s)
Cell Cycle Proteins/genetics , Glucose/metabolism , Homeostasis/genetics , Insulin Resistance/genetics , Insulin/metabolism , Protein Serine-Threonine Kinases/genetics , Repressor Proteins/genetics , Adolescent , Adult , Aged , Female , Genetic Predisposition to Disease/genetics , Humans , Insulin Secretion , Male , Middle Aged , Polymorphism, Genetic/genetics , Young AdultABSTRACT
Estrogen deficiency in females and androgen deficiency in males may harm periosteal and endosteal apposition, reduce bone size and both cortical and trabecular thickness, modifying in this way the bone structure later in life. To date, few systematic studies on bone mineral density (BMD) and hypogonadism in adolescents are available. Therefore we aimed to determine if sexual hormone deficiency during pubertal age might have an impact on peak bone mass and body composition. We compared areal BMD (L-aBMD), volumetric lumbar spine BMD (L-vBMD), lumbar spine Z-score (L-Z-score), lumbar spine bone mineral content (L-BMC), whole body (wbBMD), normalized whole body (n-wbBMD) BMD, and whole body BMC (wb-BMC) of 25 male children with hypogonadism (HYPO) with 37 sex-, age-, and body mass index-matched healthy subjects (CNT) using dual-energy X-ray absorptiometry. Furthermore we analyzed whether a difference in lean (lean%) and fat (fat%) mass as percentage of body weight and as a lean/fat ratio is present in the two groups of children. HYPO demonstrated a statistically lower L-aBMD, LvBMD, L-BMC, Z score, wbBMD, n-wbBMD, and wb-BMC compared to CNT. CNT showed a higher lean% and lower fat% and a higher lean/fat ratio when compared with HYPO group. Lean mass correlated positively with L-aBMD, L-BMC, and wb-BMC. Our study seems to confirm previous observations that sex hormone deficiency during puberty reduces bone mass accrual. Body composition alterations may play a role in bone parameters during development in healthy as such as in hypogonadal children during developmental age.
Subject(s)
Body Composition , Bone Density , Hypogonadism , Puberty/physiology , Absorptiometry, Photon , Adolescent , Body Mass Index , Child , Female , Humans , Hypogonadism/diagnostic imaging , Hypogonadism/pathology , Lumbar Vertebrae/diagnostic imaging , MaleABSTRACT
Acute exercise is a well-known stimulus for GH secretion but the effect of chronic training on GH secretion still remains equivocal. The aim of our study was to analyse spontaneous pulsatile GH secretion (during a period of 2 hours in the morning) in a group of young elite athletes (EA) compared with non-elite athletes (NEA), and sedentary subjects (SS). Mean and peak GH levels proved significantly higher in EA than in NEA and SS (p=0.0004 and p<0.0001, respectively). The same differences in mean and peak GH levels were also demonstrated in males and females when considered separately (males: p=0.0062 and p=0.0025; females: p=0.0056 and p=0.0032). In addition, GH levels (mean and peak) were higher in females than in males in SS while no differences were demonstrated between the 2 sexes in the EA and NEA groups. IGF-I levels were within the normal range for age in all the subjects with no difference between the 3 groups. Body mass index (BMI) exhibited no difference between groups, while EA showed higher lean mass (p=0.0063) and lower fat mass (p=0.0139) than NEA and SS measured by dual-energy x-ray absorptiometry. A strong positive correlation between GH levels (mean and peak) and hours of training a week was demonstrated (p=0.0101; r2=0.1184; p=0.0022; r2=0.1640, respectively). In conclusion, GH levels were higher in EA than NEA and SS without any modification of IGF-I levels; a strong positive correlation was present between GH levels and intensity of training. An increase in the knowledge of the effect of chronic training on GH secretion could improve the training programme to elicit the greatest exercise- induced GH response.
Subject(s)
Exercise/physiology , Human Growth Hormone/metabolism , Pulsatile Flow , Sports/physiology , Adolescent , Adult , Age Factors , Body Mass Index , Female , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/analysis , Male , Physical Fitness/physiology , Sex CharacteristicsABSTRACT
BACKGROUND: Craniopharyngiomas account for 2-5% of all primary intracranial tumours. Despite their benign histological appearance, they are often associated with an unfavourable prognosis and their optimal treatment remains controversial. AIM: To analyse the natural history and treatment outcome of children and adults presenting to the Departments of Paediatrics and Endocrinology with craniopharyngioma between 1964 and 2003. PATIENTS AND METHODS: The records of 121 patients (age range 2.5-83 years, 42 aged < 16 and 79 aged > or = 16) were identified. The mean follow-up period since presentation was 103 months (8.6 years) (range 0.3-468 months). Sixteen patients underwent gross total removal (A), 3 gross total removal + radiotherapy (B), 51 partial removal (C), 33 partial removal + radiotherapy (D), 6 cyst evacuation alone (E) and 3 cyst evacuation + radiotherapy (F). The clinical, imaging and endocrinological data at presentation and during follow-up were analysed. RESULTS: Headache and visual field defects were the most common presenting clinical features (64% and 55%, respectively). Ninety-four per cent of the tumours had an extrasellar component and 23% of them were associated with hydrocephalus. There was a significant difference in the recurrence-free survival rates between groups A-D [at 10 years: 100% (A), 100% (B), 38% (C) and 77% (D), P < 0.01], which persisted even when analysing patients operated after 1980. The median time of first recurrence was 2.5 years (range 0.5-36). The peri-operative mortality of the patients who had any type of neurosurgical intervention due to recurrence was higher than that observed after primary surgery (24%vs. 1.8%) (P < 0.01). The rate of re-accumulation of the cyst fluid was 58% during the first year in patients of group E, whereas none of the subjects of group F experienced such an event during their follow-up period. There was no reversal of pre-existing pituitary hormone deficits after any surgical intervention. The probabilities of GH, FSH/LH, ACTH, TSH deficiency and diabetes insipidus at the 10-year follow-up were 88%, 90%, 86%, 80% and 65%, respectively. After excluding the non-tumour-related deaths, the 10-year survival rate following presentation was 90%. Patients with recurrence had a significantly lower probability for survival compared with those without it (at 10 years: 70%vs. 99%, P < 0.01). At the 10-year follow-up the probability of the presence of major visual field defects was 48%, hyperphagia/obesity 39%, epilepsy 12% and hemi-/monoparesis 11%. In this large series no substantial differences in the outcome of tumours diagnosed during childhood or adult life were found. CONCLUSIONS: Craniopharyngiomas remain tumours associated with significant morbidity. Gross total removal provides favourable results in terms of recurrences. If this cannot be achieved safely, adjuvant radiotherapy is beneficial in preventing tumour re-growth. Childhood- and adult-onset lesions generally behave similarly.
Subject(s)
Craniopharyngioma , Neoplasm Recurrence, Local , Pituitary Neoplasms , Adolescent , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Child , Child, Preschool , Craniopharyngioma/diagnosis , Craniopharyngioma/mortality , Craniopharyngioma/surgery , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/surgery , Pituitary Neoplasms/diagnosis , Pituitary Neoplasms/mortality , Pituitary Neoplasms/surgery , Statistics, Nonparametric , Survival RateABSTRACT
BACKGROUND: Patients with type 2 diabetes mellitus are usually treated with oral antidiabetic agents but it is still not known whether these drugs have antioxidant effects in humans. METHODS: We studied 60 patients with type 2 diabetes mellitus, divided into three groups on the basis of hypoglycaemic treatment (Group A: metformin, Group B: glibenclamide, Group C: diet). All patients were followed for at least 1 year. The three subgroups had similar clinical characteristics. Twenty healthy subjects, of comparable sex and age, were enrolled as controls. In each subject, platelet production of superoxide anion (O(2)(-)) elicited by collagen, was determined by lucigenin assay. RESULTS: Patients with diabetes had higher platelet O(2)(-) production than controls; no correlation was observed between blood glucose and platelet O(2)(-) production. Group A patients had platelet O(2)(-) production similar to that of healthy subjects but lower than Group B and Group C patients. CONCLUSION: The present findings suggest an in vivo antioxidant activity of metformin and warrant prospective studies to further explore this hypothesis.
Subject(s)
Blood Platelets/physiology , Diabetes Mellitus, Type 2/drug therapy , Metformin/therapeutic use , Superoxides/blood , Antioxidants/therapeutic use , Blood Platelets/drug effects , Diabetes Mellitus, Type 2/blood , Female , Glyburide/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Reference Values , Superoxides/antagonists & inhibitorsABSTRACT
AIMS: To investigate whether diabetic retinopathy (DR), already associated with microvascular alterations, ischaemia, and endothelial dysfunction, was also characterised by abnormal modulation of coagulation pathways. METHODS: Plasma samples, collected from 67 type 1 diabetics comparable for age, duration of disease (DD), and metabolic control (MC), were processed for prothrombin degradation products (F1+2) and factor VII coagulant activity (FVII:c). 50 normal subjects served as a control group. The ETDRS-Airlie House Classification of DR was used. RESULTS: A significant correlation between FVII:c and F1+2 plasma concentrations was observed (p <0.05). FVII:c (p <0.005) and F1+2 (p <0.0001) levels were higher in diabetics than in controls, especially in patients with proliferative DR (FVII:c p <0.0001; F1+2 p<0.005). However, cases without retinal lesions and healthy subjects did not differ significantly (FVII:c and F1+2 p >0.05). CONCLUSIONS: These findings pointed out the presence of a hypercoagulable state associated with endothelial dysfunction in patients with insulin dependent diabetes mellitus (IDDM), demonstrated both by increased FVII:c and F1+2 plasma levels. Moreover, the observation of different DR related degrees of procoagulant activity, despite comparable DD and MC, strengthens the hypothesis of multiple risk factors in the pathogenesis of DR.