Vittorio Cacciatori

Comparative Assessment of Peripheral Sympathetic Function by Postural Vasoconstriction Arteriolar Reflex and Sympathetic Skin Response in NIDDM Patients

PURPOSE The aim of the study was to compare peripheral sympathetic adrenergic and cholinergic nerve function in NIDDM (non-insulin-dependent diabetes mellitus) patients with various degrees of diabetic neuropathy and neuropathic foot ulceration. The parameters used were postural vasoconstriction arteriolar reflex (VAR) and sympathetic skin response (SSR), respectively. PATIENTS AND METHODS Forty-seven NIDDM patients were studied. No patients had clinically significant peripheral vascular disease. They were divided according to peripheral somatic neuropathy, assessed by clinical score and vibration perception threshold (VPT). Twenty-two patients showed no significant evidence of peripheral neuropathy and normal VPT (DN-); 15 had signs and symptoms of neuropathy and VPT alteration (DN+); 10 had diabetic neuropathy and foot ulceration (DNU). Twenty-two normal subjects were also examined as a control group. Resting arteriovenous shunt skin blood flow, measured using laser-Doppler flowmetry, and the VAR of the big toe on lowering the foot were studied. Sympathetic skin response was assessed by an EMG apparatus. Autonomic function was also investigated by using standard cardiovascular reflex tests. RESULTS Resting blood flow values were similar in the three NIDDM groups and in the control group. VAR to foot lowering was significantly impaired in all NIDDM groups by comparison with controls (72.8 +/- 2.1%, mean +/- SEM), this impairment being progressively more pronounced in DN- (58.8 +/- 2.3%, P < 0.001), DN+ (33.3 +/- 3.0%, P < 0.001 versus DN-) and DNU (8.6 +/- 2.7%, P < 0.001 versus DN+). Sympathetic skin response was assessed in 28 patients and was significantly impaired in DN-compared with the control group (2.53 +/- 0.04 versus 2.71 +/- 0.04 log mcV, P < 0.01). This impairment was severe in the DNU compared with the DN+ group (1.36 +/- 0.05 versus 2.26 +/- 0.04 log mcV, P < 0.005). A positive correlation was found between VAR values and SSR (P < 0.001), and these measurements were also closely correlated with several parameters of central autonomic and somatic neuropathy. CONCLUSION These results indicate that peripheral sympathetic adrenergic and cholinergic fibers simultaneously undergo early alterations in diabetic patients, even when there is no clinical neuropathy. Our data also show almost complete abolition of peripheral sympathetic activity in NIDDM patients with foot ulceration.

Acute Effect of Insulin on Autonomic Regulation of the Cardiovascular System: A Study by Heart Rate Spectral Analysis

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2‐h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 ± 1.3 years), at two different insulin infusion rates: 80 mU m−2 and 400 mU m−2 min−1, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90–120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 ± 0.12 vs 2.09 ± 0.16 log ms2, p < 0.005), as at both low and high infusion rates (2.46 ± 0.13 to 2.14 ± 0.23 log ms2, p < 0.05, and 2.92 ± 0.18 to 1.98 ± 0.06 log ms2, p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 ± 0.10 vs 0.63 ± 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.

Glycated haemoglobin is inversely related to serum vitamin D levels in type 2 diabetic patients.

Objective A correlation between glucose control and 25(OH)D metabolism has been suggested by previous studies. However, this correlation has not yet been evaluated considering the impact of chronic complications of type 2 diabetes, especially the presence of nephropathy. Thus, the aim of this study was to determine the correlation between A1C and 25(OH)D in a well characterized cohort of type 2 diabetic patients. Research Design and Methods We cross-sectionally examined the association between A1C and serum 25(OH) D in 715 type 2 diabetic patients attending our clinic during the years 2011–2012. The average age was 68±12 years (range 26–94 years). The relation between A1C and serum 25(OH)D levels was modelled by multiple linear regression analyses. Results Serum 25(OH)D levels were inversely associated with A1C levels (r = −0.116, p = .003). This relation maintains its independence in the multivariate analysis after adjusting for age, sex, A1C, BMI, treatment and duration of diabetes and nephropathy. Conclusions In type 2 diabetic patients, high A1C levels are associated with low concentrations of serum 25(OH)D independently of duration of diabetes, diabetic treatment and nephropathy. Future studies are needed to clarify the biological relation between glucose control and vitamin D metabolism in type 2 diabetes.

Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program

AIMS Somatic neuropathy is a chronic complication of diabetes. The purpose of our study was to determine prevalence and clinical variables associated with somatic neuropathy applying a simple screening method. METHODS All outpatients with type 2 diabetes attending our diabetic clinic were offered to participate into a diabetic foot screening program, in the period January 2004-December 2012. A total of 3,591 diabetic patients (55.5% men, age 68±10years) underwent detection of somatic neuropathy using the Michigan Neuropathy Screening Instrument in its parts of symptoms (administering a questionnaire) and clinical assessment slightly modified (evaluating foot inspection, vibration sensation by biothesiometer, ankle reflexes). RESULTS The prevalence of somatic neuropathy was 2.2% in men and 5.5% in women (p<0.001) when assessed by symptom questionnaire, whereas it was 30.5% in men and 30.8% (p=NS) in women when identified by clinical assessment. In subjects with somatic neuropathy macro- and microvascular complications of diabetes were significantly more common. In multivariate logistic regression analyses BMI, HbA1c and ankle/brachial index independently predicted the presence of neuropathy. CONCLUSION The prevalence of somatic neuropathy in type 2 diabetes is nearly 30% when searched with clinical examination. Poor metabolic control, excess body weight and peripheral arteriopathy are independent markers of somatic neuropathy.

Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes

Objective Low levels of serum 25-hydroxyvitamin D [25(OH)D] are commonly found in type 2 diabetes. We examined whether there is an association between circulating 25(OH)D concentrations and the presence of microvascular complications in people with type 2 diabetes. Research design and methods We studied 715 outpatients with type 2 diabetes who regularly attended our clinic. Participants were evaluated for the presence of microvascular complications (namely retinopathy and/or nephropathy) by clinical evaluation, fundus examination, urine examination and biochemical tests. Serum 25(OH)D levels were also measured for each participant. Results Hypovitaminosis D (ie, a serum 25(OH)D level <30 ng/mL) was found in 75.4%, while deficiency (ie, a 25(OH)D level <20 ng/mL) was found in 36.6% of these patients. Serum 25(OH)D levels decreased significantly in relation to the severity of either retinopathy or nephropathy or both. In multivariate logistic regression analysis, lower 25(OH)D levels were independently associated with the presence of microvascular complications (considered as a composite end point; OR 0.758; 95% CI 0.607 to 0.947, p=0.015). Notably, this association remained significant even after excluding those with an estimated glomerular filtration rate <60 mL/min/1.73 m2. Conclusions We found an inverse and independent relationship between circulating 25(OH)D levels and the prevalence of microvascular complications in patients with type 2 diabetes. However, vitamin D may be simply a marker and causality cannot be implied from our cross-sectional study. Whether vitamin D supplementation in patients with type 2 diabetes may have beneficial effects on the risk of microvascular complications remains to be investigated.

Relationship between fasting insulin and cardiovascular risk factors is already present in young men : the Verona Young Men Atherosclerosis Risk Factors Study

The associations between fasting plasma insulin concentration and risk factors for cardiovascular diseases were examined in 979 18‐year‐old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross‐sectional population‐based study. Body mass index (BMI), waist‐to‐hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high‐density lipoprotein (HDL)–total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low‐density lipoprotein cholesterol concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F =7.1; P <0.001). However, systolic blood pressure and uric acid were close to statistical significance (P =0.06–0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e. three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F =4.0; P <0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides.

Prevalence of Cardiovascular Autonomic Neuropathy in a Cohort of Patients With Newly Diagnosed Type 2 Diabetes: The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).

OBJECTIVE Cardiovascular autonomic diabetic neuropathy (CAN) is a serious complication of diabetes. No reliable data on the prevalence of CAN among patients with newly diagnosed type 2 diabetes are available. Therefore, the aim of this study was to estimate the prevalence of CAN among patients with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS A cohort of 557 patients with newly diagnosed type 2 diabetes with cardiovascular autonomic test results available was selected. Early and confirmed neuropathy were assessed using a standardized methodology and their prevalences determined. A multivariate logistic regression analysis was modeled to study the factors associated with CAN. RESULTS In the entire cohort, the prevalence of confirmed CAN was 1.8%, whereas that of early CAN was 15.3%. Prevalence did not differ between men and women. In the multivariate analyses BMI results were independently and significantly associated with CAN after adjusting for age, sex, hemoglobin A1c, pulse pressure, triglyceride-to-HDL cholesterol ratio, kidney function parameters, and antihypertensive treatment. CONCLUSIONS CAN could be detected very early in type 2 diabetes. This study may suggest the importance of performing standardized cardiovascular autonomic tests after diagnosis of type 2 diabetes.

Studies on the mechanism of action of sulphonylureas in type II diabetic subjects: gliquidone.

The mechanism of action of sulphonylureas is not completely understood. In the present study we evaluated the effects of gliquidone, a second-generation compound, on several metabolic parameters in 22 patients with untreated newly-diagnosed type II (noninsulin-dependent) diabetes mellitus. After either 1 or 6 months of treatment with gliquidone plus isocaloric diet we observed: 1) a significant decrease in fasting plasma glucose and glycemic profile after oral glucose load; 2) unchanged fasting and postglucose plasma insulin levels; 3) no change in fasting C-peptide levels but a significant increase in C-peptide concentrations after glucose challenge; 4) a significant increase in glucose disappearance rate from plasma following iv insulin injection; 5) an increase in the insulin-induced reduction of plasma levels of free-fatty acids; 6) no change in plasma C-peptide levels following iv insulin injection; 7) a significant increase in specific insulin binding to monocytes. After 6 but not 1 month of gliquidone therapy we also found an increase in the activity of hexokinase in circulating mononuclear leukocytes. These results suggest that the hypoglycemic effect of gliquidone occurs through either an increased beta cell response to glucose stimulus or an enhanced insulin sensitivity. The latter effect seems to depend on both receptor and postreceptor mechanisms.

Plasma concentrations of glucagon during hyperglycemic clamp with or without somatostatin infusion in obese subjects

SummaryThe aim of the present study was to evaluate whether the inhibitory effect on pancreatic A-cell exerted by hyperglycemic hyperinsulinemia and/or by somatostatin administration is impaired in human obesity. For this purpose plasma glucagon concentrations were measured in 8 obese and 8 nonobese nondiabetic subjects during a 4-h hyperglycemic clamp. Synthetic cyclic somatostatin-14 was infused at the rate of 2.5 nmol/min during the third hour of the study. Fasting plasma glucagon was higher in obese than in nonobese subjects (242±32vs 163±15 pg/ml, p<0.05) (mean±SEM). In the last 20 min of the glucose infusion period preceding somatostatin administration (100–120 min of the study) plasma glucagon averaged 195±26 pg/ml in obese and 122±13 pg/ml in nonobese subjects (p<0.05), with a reduction of 19±3% in the former and 28±4% in the latter (p=n.s.). In both groups somatostatin infusion did not result in a further decrease in plasma glucagon, which averaged 192±27 pg/ml in obese and 123±16 pg/ml in nonobese subjects (p<0.05) in the 160–180 min period of the study. Also after discontinuing somatostatin infusion plasma glucagon levels did not change. These results suggest that in human obesity hyperglycemic hyperinsulinemia has a normal inhibitory effect on pancreatic A-cell and that somatostatin administration has no additive effect on hyperglycemia and hyperinsulinemia in either obese or nonobese nondiabetic subjects.

The aspartate aminotransferase-to-alanine aminotransferase ratio predicts all-cause and cardiovascular mortality in patients with type 2 diabetes.

Abstract An increased aspartate aminotransferase-to-alanine aminotransferase ratio (AAR) has been widely used as a marker of advanced hepatic fibrosis. Increased AAR was also shown to be significantly associated with the risk of developing cardiovascular (CV) disease. The aim of this study was to assess the relationship between the AAR and mortality risk in a well-characterized cohort of patients with type 2 diabetes. A cohort of 2529 type 2 diabetic outpatients was followed-up for 6 years to collect cause-specific mortality. Cox regression analyses were modeled to estimate the independent association between AAR and the risk of all-cause and CV mortality. Over the 6-year follow-up period, 12.1% of patients died, 47.5% of whom from CV causes. An increased AAR, but not its individual components, was significantly associated with an increased risk of all-cause (adjusted-hazard risk 1.83, confidence interval [CI] 95% 1.14–2.93, P = 0.012) and CV (adjusted-hazard risk 2.60, CI 95% 1.38–4.90, P < 0.003) mortality after adjustment for multiple clinical risk factors and potential confounding variables. The AAR was independently associated with an increased risk of both all-cause and CV mortality in patients with type 2 diabetes. These findings suggest that an increased AAR may reflect more systemic derangements that are not simply limited to liver damage. Further studies are needed to elucidate the pathophysiological implications of an increased AAR.