Prevalence of neuropathy in IDDM patients in Piemonte, Italy. The Neuropathy Study Group of the Italian Society for the Study of Diabetes, Piemonte Affiliate.

OBJECTIVE: In view of the scarce data available in Italy, to assess the prevalence of neuropathy in various subgroups of IDDM patients living in the Piemonte region of Italy and to develop, based on existing guidelines, and test the practicality of a standardized assessment of diabetic neuropathy. RESEARCH DESIGN AND METHODS: All IDDM patients (766) attending 23 outpatient clinics, evenly distributed in the region, were stratified into 3 age-groups (15-29, 30-44, and 45-59 yr) and into 3 groups of diabetes duration (1-7, 8-14, and > or = 15 yr). A random sample of 467 patients was selected; 81% of whom participated in the studies (196 men and 183 women). The following data were collected: personal and clinical data, structured questionnaire (SQ), neurological examination (NE), vibration sensation (tuning fork) (VS), and two cardiovascular tests (CTs). Patients were classified as follows: stage 0, (no neuropathy) < 2 abnormalities among SQ, NE, VS, and CT; stage 1, (asymptomatic neuropathy) > 1 abnormality among NE, VS, and CT; stage 2, (symptomatic neuropathy) abnormalities in SQ and in NE, and/or VS, and/or CT. RESULTS: The prevalence rates were as follows: stage 0 = 71.5%, stage 1 = 7.2%, and stage 2 = 21.3% and all had a 95% CI. No difference was found between men and women. The prevalence of neuropathy (stages 1 and 2) was higher (P < 0.01) in groups of longer diabetes duration or older age. CONCLUSIONS: Polyneuropathy is a frequent complication in a north Italian IDDM population. Our results suggest that IDDM patients > 30 yr of age, with diabetes of > 15 yr duration, and who complain of symptoms suggestive of neuropathy, should be promptly assessed for the presence of diabetic polyneuropathy.

QT interval prolongation and mortality in type 1 diabetic patients: a 5-year cohort prospective study. Neuropathy Study Group of the Italian Society of the Study of Diabetes, Piemonte Affiliate.

OBJECTIVE: The aim of the study was to assess the relationship between QT interval prolongation and mortality in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Data on survival after 5 years were obtained from 316 of 379 patients (83.3%) who took part in a study on the prevalence of diabetic neuropathy and QT interval prolongation. RESULTS: Mortality at 5 years was 6.32%. Patients who survived were significantly younger (P = 0.04), had a shorter duration of diabetes (P = 0.01), had lower systolic (P = 0.004) and diastolic (P = 0.03) blood pressure levels, and had a shorter QT interval corrected for the previous cardiac cycle length (QTc) (P = 0.000005) than subjects who died. In univariate analysis, patients had a higher risk of dying if they had a prolonged QTc (odds ratio [OR] 20.14 [95% CI 5.7-70.81) or if they were affected by autonomic neuropathy (3.55 [1.4-8.9]). QTc prolongation was the only variable that showed a significant mortality OR in multivariate analysis (24.6 [6.51-92.85]; P = 0.0000004). CONCLUSIONS: This is the first cohort-based prospective study indicating that QTc prolongation is predictive of increased mortality in type 1 diabetic patients.

Clinical, immunological, and genetic heterogeneity of diabetes in an Italian population-based cohort of lean newly diagnosed patients aged 30-54 years. Piedmont Study Group for Diabetes Epidemiology.

OBJECTIVE: In lean diabetic patients, the presentation of the disease does not allow one to easily distinguish between type 1 and type 2. Aims of this study were to describe clinical, immunological, and genetic features of lean newly diagnosed diabetic patients. RESEARCH DESIGN AND METHODS: A population-based cohort of 130 lean (BMI < 25 kg/m2) newly diagnosed patients, aged 30-54 years, was identified among residents of the province of Turin. Islet cell antibodies (ICAs), anti-GAD, fasting and glucagon-stimulated C-peptide values, and HLA DQA1-DQB1 susceptibility genotypes were assessed within 2 months of the diagnosis. RESULTS: A total of 45 (34.6%) and 29 (22.3%) patients were, respectively, ICA+ and anti-GAD+, with 15 (11.5%) having both antibodies. In 59 patients, ICAs and/or anti-GAD antibodies were detected, giving a high prevalence of autoimmunity (45.4%, 95% Cl 36.8-54.0); relative to patients without markers (n = 71), they were younger (40.8 +/- 7.5 vs. 45.0 +/- 6.5 years, P < 0.001) and showed lower values of fasting C-peptide (0.56 +/- 0.33 vs. 0.79 +/- 0.41 nmol/l, P < 0.001) and stimulated C-peptide (1.03 +/- 0.56 vs. 1.42 +/- 0.69 nmol/l, P < 0.001). The lowest stimulated C-peptide values were found in patients with both ICA and anti-GAD antibodies. Frequencies of adult-onset type 1 and type 2 diabetes were, respectively, 49.2 and 50.8%. Clinical and genetic features were not useful in the classification of patients. CONCLUSIONS: Almost 50% of lean young and middle-aged patients were ICA+ and/or anti-GAD+, suggesting a high prevalence of a slowly evolving form of type 1 diabetes. The evaluation at diagnosis of both beta-cell secretory capacity and markers of autoimmunity is recommended to provide a pathogenetic classification of the disease.

Cardiovascular risk profile of type 2 diabetic patients cared for by general practitioners or at a diabetes clinic: a population-based study.

The aims of this study were to compare the cardiovascular risk profiles of patients with type 2 diabetes mellitus cared for by general practitioners and those regularly attending a diabetes center. Out of an Italian population-based cohort of 1967 diabetic patients, 1574 (80%) were investigated. Patients exclusively cared for by general practitioners (23.8%) were older and showed lower prevalence of hypertension (79.0% vs 85.9%, P < 0.001), poor blood glucose control (HbA1c >8.0, 33.4% vs 47.9%, P < 0.001) and coronary heart disease (18.1% vs 22.3%, P = 0.003), and lower plasma fibrinogen (3.5 +/- 0.8 vs 3.7 +/- 0.9 g/L, P < 0.001). In logistic regression analysis, they had significantly lower ORs for HbA1c >8.8% (OR 0.67, 95% CI 0.45-0.99), hypertension (OR 0.53, 95% CI 0.36-0.78), fibrinogen >4.1 g/L (OR 0.50, 95% CI 0.32-0.77), smoking (OR 0.60, 95% Cl 0.36-1.00), and coronary heart disease (OR 0.65, 95% CI 0.45-0.93), after adjustment for age, sex, duration of diabetes, BMI, and antidiabetic treatment. Patients regularly cared for at a diabetes clinic had a higher cardiovascular risk profile, suggesting selective referral to the clinics of patients with more difficult management and/or severity of the disease. These findings have implications in the interpretation of morbidity and mortality clinic-based studies.

Physiological inhibitors of blood coagulation and prothrombin fragment F 1 + 2 in type 2 diabetic patients with normoalbuminuria and incipient nephropathy.

Microalbuminuria and haemostasis derangements have been considered as independent risk factors for cardiovascular death in type 2 (non-insulin-dependent) diabetic patients. Few studies have assessed coagulation inhibitors in type 2 diabetic patients with normoalbuminuria and microalbuminuria. Therefore, 32 type 2 diabetic patients with normoalbuminuria (albumin excretion rate, AER < 20 mg/min, mean 7 +/- 1) and 28 type 2 diabetic patients with microalbuminuria (AER 20-200 mg/min, mean 84 +/- 11) were studied. The patients were matched for age, sex, disease duration and treatment, body mass index (BMI), blood pressure and glycohaemoglobin. Protein C and S activity, antithrombin III, thrombomodulin and prothrombin fragments 1 + 2 (F 1 + 2) were assessed together with fibrinogen, triglycerides, total and high density lipoprotein (HDL)-cholesterol concentrations. Fibrinogen, total and low density lipoprotein (LDL) concentrations were similar in the two groups, while a significant difference was observed for triglycerides (normoalbuminuric group: 128 +/- 10 mg/dl, microalbuminuric group: 184.1 +/- 17 mg/dl; P < 0.007) and HDL-cholesterol (normoalbuminuric group: 45 +/- 2 mg/dl, microalbuminuric group: 39 +/- 2 mg/dl; P < 0.05). The coagulation parameters were as follows: normoalbuminuric group: protein C activity 109% +/- 5%, protein S 95.4% +/- 5%, thrombomodulin 49.3 +/- 3 ng/ml, antithrombin III 93.3% +/- 3%, F 1 + 2 1.05 +/- 0.04 nmol/l; microalbuminuric group: protein C activity 107% +/- 4%, protein S 98.4% +/- 4%, thrombomodulin 64.4 +/- 4 ng/ml, antithrombin III 93.3% +/- 3%, F 1 + 2 1.03 +/- 0.05 nmol/l. The difference was significant for thrombomodulin (P < 0.007). A significant direct correlation was observed in the microalbuminuric group between AER and thrombomodulin (r = 0.38, P < 0.05). In conclusion, our data do not support the hypothesis that a reduction in the activity of anticoagulant physiological inhibitors (protein C, protein S, antithrombin III) could contribute to explain the higher cardiovascular risk in type 2 diabetic patients with microalbuminuria. The elevation of plasma thrombomodulin concentration in type 2 diabetic patients could be the consequence of widespread vascular damage in diabetic patients with incipient nephropathy.

Anticoagulant protein C activity in non-insulin-dependent diabetic patients with normoalbuminuria and microalbuminuria.

Microalbuminuria in diabetic patients is associated with an increased cardiovascular risk which is not completely explained by an excess of conventional cardiovascular risk factors. A depression of physiologic inhibitors of blood coagulation could contribute to a thrombophilic state and to cardiovascular complications: data on protein C in diabetic patients are controversial, and no information exists about protein C activity in non-insulin-dependent diabetic patients or its relation to the microalbuminuric state. The aim of this study was to assess protein C activity in non-insulin-dependent diabetic patients with and without microalbuminuria. Protein C activity was determined (Protein C Reagent, Boehringer Mannheim, Germany) in 29 non-insulin-dependent diabetic patients with microalbuminuria (group A, > 20 micrograms/min), 33 non-insulin-dependent diabetic patients with normoalbuminuria (group B), and in 36 non-diabetic healthy blood donors as a control group (group C). The groups were matched for sex, and no difference in age, body mass index, blood pressure, glycated haemoglobin or known duration of diabetes was observed between groups A and B. Protein C activity was similar in the three groups (mean +/- SD): group A, 106.9% +/- 25.2%; group B, 109.3% +/- 27.6%; group C, 103.1% +/- 18.9%; F value 0.58, NS. Protein C activity did not correlate significantly with body mass index, glycated haemoglobin, known duration of diabetes, age or albumin excretion rate in any of the groups or in the diabetic patients as a whole. No significant difference in protein C activity was observed in patients taking other therapy (diet, oral agents, insulin).(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic nervous activity in obese subjects before and after caloric restriction.

The heart rate response to deep breathing (DB test) and standing (30:15 r test) and the blood pressure response to standing (LS test) and sustained handgrip (HG test) were assessed in 19 obese subjects and 15 age matched lean controls. The results of DB, 30:15 r and LS tests were not significantly different in both groups. The diastolic blood pressure increase during handgrip was significantly higher in obese than in control subjects. After a period of caloric restriction the tests were repeated in 9 patients who had obtained a weight loss of at least 5 kg: a significant decrease in heart rate, diastolic blood pressure and 30:15 r results was observed, whereas the caloric restriction did not cause significant variations in the results of DB, LS and HG tests. Our results suggest that in obese patients some autonomic nervous changes can occur before and after weight loss.

The clinical utility of QT interval assessment in diabetes.

A prolonged (QT) interval is considered an indicator of an increased risk of malignant ventricular arrhythmias and/or sudden death. It has been proposed that autonomic neuropathy in diabetes is related to QT interval prolongation and higher mortality rates. More recently, the interlead difference in QT interval duration has been referred to as QT interval dispersion, which has proven to be predictive of ventricular arrhythmias and mortality in different groups of patients. QT interval duration and dispersion are significantly related, but are not concordant in a substantial number of cases in identifying patients at risk. The prevalence of QT prolongation in Type 1 and Type 2 diabetic (T1 and T2DM) patients is higher than 20%. Several studies in T1 and T2DM patients have confirmed the independent relation between prolonged QT interval duration and increased QT interval dispersion and chronic ischemic heart disease. It has been consistently shown that autonomic neuropathy is related to QT interval duration, while more controversies exist on the association with QT interval dispersion. In recent years 5 studies have been published which confirm the value of QT interval as a predictor of total mortality in diabetic as well as in non-diabetic subjects. Surprisingly, no data exist on the relation between the risk of sudden death and QT interval prolongation in diabetic patients. As corrected QT interval is significantly related to mortality, it could be used to stratify the death risk in diabetic patients, particularly those who are candidates for surgery or kidney and/or pancreas transplantation. We still do not know why QT interval is prolonged and how this abnormality leads to death: however, a simple, low-cost measurement, which is easily obtainable without the need of the patient's compliance, could help select patients who need second level diagnostic procedures and strict observation.

Does abnormal QT interval prolongation reflect autonomic dysfunction in diabetic patients? QTc interval measure versus standardized tests in diabetic autonomic neuropathy.

The question as to whether the QTc interval correlates with five cardiovascular tests (deep breathing test, 30/15 ratio test, lying to standing test, cough test, and postural blood pressure test) for the diagnosis of diabetic autonomic neuropathy (DAN) was investigated in 168 (38 Type 1, 130 Type 2) consecutive outpatients (mean age 54.9 +/- 11.2 years). QT interval was measured on an ECG recorded at rest and QTc calculated according to Bazett's formula. The percentage of patients with a QTc greater than 0.440 s was: absent DAN = 11% (n = 7), probable DAN = 7% (n = 4), definite DAN = 23% (n = 12) (p < 0.05), and the mean (+/- SD) QTc values were 0.403 +/- 0.028 s, 0.405 +/- 0.023 s, and 0.421 +/- 0.026 s, respectively. A significant correlation between QTc duration and DAN score of autonomic cardiovascular test results (r = 0.34, p < 0.0001) was observed. The calculated specificity, sensitivity, positive and negative predictive values were 89%, 15%, 70% and 37%, respectively. In conclusion, QTc can be considered as an additional specific test in the assessment of diabetic autonomic neuropathy, but cannot replace the standard battery of cardiovascular tests.

QT interval, cardiovascular risk factors and risk of death in diabetes.

A prolonged QT interval is considered an indicator of increased risk of malignant ventricular arrhythmias and/or sudden death. It has been proposed that autonomic neuropathy in diabetes is related to QT interval prolongation and increased mortality rates. Several studies in Type 1 and Type 2 diabetic patients have confirmed the independent relation between prolonged QT interval duration or increased QT interval dispersion and chronic ischemic heart disease. It has been consistently shown that autonomic neuropathy is related to QT interval duration while more controversies exist on the association with QT interval dispersion. In recent years, studies have confirmed the value of QT interval as a predictor of total mortality in both diabetic and non-diabetic subjects. Moreover, several studies have shown a significant relation between QT interval prolongation and cardiovascular disease risk factors. QT interval could be used to stratify the cardiovascular risk in diabetic patients. We still do not know why QT interval is prolonged and how this abnormality leads to death. Nevertheless, QT interval is a simple, low-cost measure, easily obtainable without the need of the patient's compliance and which could help to select patients who need second level diagnostic procedures and strict observation.

Kappa/lambda ratio on peripheral blood lymphocytes and bone marrow plasma cell labeling index in monoclonal gammopathies.

Bone marrow plasma cell labeling index (L.I.), kappa/lambda ratio, CD4+ and CD8+ subpopulations were studied in patients with smoldering multiple myeloma (SMM), active myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). The loss of the light chain isotype suppression (LCIS) and a high labeling index (L.I.) allowed us to distinguish all MM patients from SMM patients. On the contrary, a low L.I. and a normal kappa/lambda ratio were found in most kappa and lambda MGUS. A significant difference in the kappa/lambda ratio was noted between MGUS and K-SMM. A significant decrease in CD4+ and a significant increase in CD8+ were not observed in patients with LCIS. The kappa/lambda ratio together with the plasma cell L.I. could be useful parameters for distinguishing active MM from SMM, especially in the cases with a border line L.I.

The discriminating analysis in the differential diagnosis of monoclonal gammopathies.

The clinical diagnosis is not always easy in monoclonal gammopathies. Therefore we used discriminating analysis to obtain diagnosis statistically sure. The parameters considered were kappa-lambda ratio, marrow plasma cells percentage and labeling index, CD3, CD4, CD8 lymphocytic absolute values. The plasma cells percentage and their labeling index make the differential diagnosis between MM and MGUS or SMM and MGUS feasible and quite correct. Additional immunological parameters should be used for the diagnosis between SMM and MM.

Prevalence of QT prolongation in a type 1 diabetic population and its association with autonomic neuropathy. The Neuropathy Study Group of the Italian Society for the Study of Diabetes.

The prevalence of QT prolongation in a large random sample of Type 1 diabetic patients in Piemonte, Italy and its association with autonomic neuropathy were assessed. Three hundred and seventy-nine Type 1 diabetic patients (age 15-59) with (94, DAN+) and without (280, DAN-) autonomic neuropathy and 118 non-diabetic control subjects participated in the study. QT interval was measured on an ECG recorded at rest and QTc calculated according to Bazett's formula. QTc was greater than 0.440 s in 7.6% (95% CI 2.9-12.3) of control subjects, 25.6% (21.0-30.0) of diabetic patients, 30.8% (21.5-40.1) of DAN+, 23.9% (18.9-28.9) of DAN-. QTc was greater than 0.460 s (mean + 2SD of QTc in control subjects) in 11.7% (8.5-14.9) of diabetic patients, 18.1% (10.3-25.9) of DAN+, 9.6% (6.2-13.0) of DAN-. QT was above the 95% upper limit for the control subjects in the plot of measured QT against RR interval in 21.4% (17.3-25.5) of diabetic patients, 26.6% (17.7-35.5) of DAN+, 19.3% (14.7-23.9) of DAN-. No correlation was found between QT interval and age or disease duration. The prevalence of QT prolongation was higher in diabetic patients than in control subjects and in DAN+ than in DAN-.

The effects of exposure to moderate altitude on cardiovascular autonomic function in normal subjects.

Cardiovascular responses to altitude have been studied on well-trained young subjects, generally at high altitudes (>4000 m). Less known are the effects of exposure to lower altitudes, easily reached by the general population. The aim of the study was to evaluate the effects of exposure to a moderate altitude (2950 m) on heart rate (HR), blood pressure (BP) profile, and cardiovascular autonomic function, and their correlation with hemoglobin oxygen saturation (HbO2S), in untrained subjects of a wide age range. Twenty-seven healthy normotensive subjects (age range 6-83; 8 children, 9 adults, and 10 elderly subjects) underwent a battery of noninvasive cardiovascular reflex tests and 24-h ambulatory BP monitoring. Corrected QT interval was also calculated. HbO2S was measured with a transcutaneous oxymeter. All measurements were performed at about 200 m (s.l.) and repeated at 2950 m. 24-h HR and systolic/diastolic BP mean values increased at 2950 m in children (% change respectively: 6.4 +/- 6.4, p<0.05; 6.5 +/- 4.0/13.5 +/- 6.9, p < 0.05), adults (4.9 +/- 8.1, NS; 6.0 +/- 5.1/8.1 +/- 5.8, p < 0.05), and elderly subjects (7.2 +/- 4.8, p < 0.05; 5.1 +/- 2.3/2.8 +/- 4.1, p < 0.05 for systolic BP only). Standard deviation of BP mean values increased during night-time in the adult group (p < 0.05). All subjects scored normal cardiovascular test results and no differences were observed after exposure to 2950m, at both 1 hour and 24 hours from arrival. After exposure to altitude, HbO2S decreased significantly in the three groups, both on arrival and after 24 hours. No correlation was found between changes in HbO2S and BP/HR responses, and cardiovascular test results. In conclusion, exposure to moderate altitudes, easily and often reached by the general population, causes a small but significant increase in BP and HR in healthy untrained subjects of a wide age range (6-83 years). Some physiological factors (eg, lower environmental temperature and lifestyle modification) together with hypoxia, possibly more than altered cardiovascular reactivity, seem responsible for this cardiovascular change. In terms of end-organ damage, the clinical relevance of this increase in BP and BP variability for repeated exposure is not known.

The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group.

The prevalence of QT interval prolongation is higher in people with diabetes and its complications. Sudden death has been reported as a common cause of death in insulin-dependent diabetic patients affected by autonomic neuropathy. It has been postulated that QT prolongation predisposes to cardiac arrhythmias and sudden death. In this analysis the prevalence of QT interval prolongation and its relation with diabetic complications were evaluated in the EURODIAB IDDM Complications Study (3250 insulin-dependent diabetic patients attending 31 centres in 16 European countries). Five consecutive RR and QT intervals were measured with a ruler on the V5 lead of the resting ECG tracing and the QT interval corrected for the previous cardiac cycle length was calculated according to the Bazett's formula. The prevalence of an abnormally prolonged corrected QT was 16% in the whole population, 11% in males and 21 % in females (p < 0.001). The mean corrected QT was 0.412 s in males and 0.422 s in females (p < 0.001). Corrected QT duration was independently associated with age, HbA1c and blood pressure. Corrected QT was also correlated with ischaemic heart disease and nephropathy but this relation appeared to be stronger in males than in females. Male patients with neuropathy or impaired heart rate variability or both showed a higher mean adjusted corrected QT compared with male patients without this complication. The relation between corrected QT prolongation and autonomic neuropathy was not observed among females. In conclusion we have shown that corrected QT in insulin-dependent diabetic female patients is longer than in male patients, even in the absence of diabetic complications known to increase the risk of corrected QT prolongation.