Jr Attali

Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications—the french multicenter study

The current study sought to examine in a large series of diabetic patients the prevalence of symptoms of autonomic neuropathy and subclinical cardiac autonomic neuropathy (CAN) and their determinants, particularly the influence of diabetes duration, obesity, and microangiopathic complications. Three hundred ninety-six patients, 245 type 1 and 151 type 2, were recruited in 7 French departments of diabetology. CAN was detected by measuring heart rate variability during 3 standardized tests: deep-breathing, Valsalva, and lying-to-standing tests. At least 24.5% of the patients had one or more symptoms suggesting overt autonomic neuropathy. They were older than those free of dysautonomic symptom (P<.001). The deep-breathing test correlated negatively with body mass index (BMI) in type 2 diabetic patients (P<.0001). In the whole population, the deep-breathing and Valsalva tests correlated negatively with diabetes duration (P=.0004 and.019, respectively) and the log urinary albumin/creatinine ratio (P<.002 and.001, respectively). The prevalence of CAN (51%) was higher than the prevalence of other diabetic complications. The rate of moderate and severe CAN (defined by 2 or 3 abnormal CAN function tests) was higher in type 1 than in type 2 diabetic patients (P=.031). It correlated with diabetes duration (P=.026) and was higher in the patients with retinopathy than in those without (P=.035). Among type 2 diabetic patients, the prevalence of CAN was higher in the obese ones (P=.033); in a logistic regression taking age, diabetes duration, and obesity as independent variables, CAN was associated independently with obesity (P=.034). Mild or moderate CAN was found in 33.8% and 13.0% of the 80 patients with diabetes duration less than 18 months. We conclude that CAN is found early in the course of diabetes and should be considered as a prognostic marker of microangiopathic complications. Obesity could be involved in the impairment of CAN function in type 2 diabetics and body weight control could provide an approach to reducing neuropathic complications.

Factors Involved in Cardiac Autonomic Neuropathy in Diabetic Patients

The role cardiac autonomic neuropathy (CAN) plays in diabetes is not well known. The aim of this study was to identify the factors involved in CAN in diabetic patients. One hundred patients, 44 insulin-dependent (IDDM) and 56 non-insulin-dependent (NIDDM), were investigated, using five standard tests. Three of these tests were for parasympathetic control (cardiac response to the lying-to-standing, deep breathing, and Valsalva tests), and the other two measured sympathetic control (testing for orthostatic hypotension and evaluating heart and blood pressure response to the handgrip test). Results were compared to those found in a series of 40 healthy volunteers. An age-adjusted comparison with the controls, showed that 34 patients had one abnormal parasympathetic test, 23 had two, and 6 patients had three. Cardiac parasympathetic neuropathy was thus present in 63% of the patients. The handgrip test was completed by 84 diabetic patients. There was evidence of orthostatic hypotension and/or an abnormal cardiac response to the handgrip in 15 of these patients, who all had a parasympathetic abnormality as well. There was no significant association between the type of diabetes and the presence of CAN. The duration of diabetes was significantly longer in patients with CAN (9.3 +/- 0.9 years) (p < 0.01) than in those with all three parasympathetic tests normal (5.8 +/- 0.9 years) (p < 0.01). The HbA1c level was also higher in patients with CAN than in those with three normal parasympathetic tests (9.95 +/- 0.35% versus 8.17 +/- 0.42%, p < 0.005). There was a significant association between the presence of retinopathy, observed by angiofluorography, and the presence of peripheral neuropathy confirmed by the electrophysiological investigation and the presence of CAN (p < 0.001). However, more than half the patients without retinopathy or nephropathy had CAN, and 11 of the 31 patients with a normal electrophysiological investigation also had CAN. Eighteen patients (6 IDDM) without retinopathy and nephropathy, who had been diabetic for less than 2 years, also had CAN. This study shows that CAN occurs early and is frequently found in a population of unselected diabetic patients. Metabolic factors may play an important role in its occurrence. CAN is significantly associated with the presence of retinopathy, which suggests that an impairment of autonomic peripheral blood flow control might be a contributing factor in the formation of microvascular lesions.

Diabetic peripheral neuropathy: Effects of age, duration of diabetes, glycemic control, and vascular factors

The aim of this study was to determine the factors associated with diabetic peripheral neuropathy and more particularly its relation to precisely assessed microangiopathy. Peripheral neuropathy was assessed in 135 diabetic patients: 28 insulin-dependent diabetes mellitus (IDDM), 85 non-insulin-dependent diabetes mellitus (NIDDM), and 22 insulin-treated NIDDM patients, on the basis of both clinical findings and extensive electrophysiological testing (four motor nerves and four sensory nerves, and right and left Hoffmanns reflex), using a total of 20 parameters. The percentage of women with severe clinical neuropathy was significantly higher than that of men, and the clinical neurological stage correlated significantly with age and duration of diabetes. According to multivariate analysis the clinical stage correlated only with gender and duration of diabetes. Several electrophysiological parameters were significantly more abnormal in women and correlated with age, type and duration of diabetes, and recent glycemic control. The multivariate analysis showed that 17 electrophysiological parameters correlated with duration of diabetes, nine correlated with age, seven with glycemic control, and only one with gender. The presence of clinical neuropathy also correlated with presence of retinopathy, arterial hypertension, macroangiopathy, and biological signs of nephropathy. All the electrophysiological parameters were significantly more abnormal in patients with retinopathy or macroangiopathy than in patients without these complications. Separate parameter analysis showed that at least one abnormal electrophysiological parameter was almost always found in patients with retinopathy, macroangiopathy, or incipient nephropathy, but abnormalities were also found to a slightly lesser extent in patients without these complications. Multivariate analysis showed that when duration of diabetes, retinopathy, macroangiopathy, and biological signs of nephropathy were introduced into the model, 11 electrophysiological parameters correlated with duration of diabetes, 11 with retinopathy, seven with macroangiopathy, and five with a sign of nephropathy. This study demonstrates that age and glycemic control have an effect, and diabetes duration a major effect on peripheral nerve function. It suggests that vascular factors may participate in the development of nerve lesions.

Impairment of lymphatic function in women with gynoid adiposity and swelling syndrome.

The current study sought to investigate the factors, in particular anthropometric parameters, associated with an impairment of capillary permeability and lymphatic function in a large series of women complaining of a swelling syndrome. One hundred ninety-seven women with a swelling syndrome were investigated, 43 of whom were obese (body mass index [BMI]>30 kg/m2), 77 overweight (BMI=25 to 30 kg/m2). Thirty-five of the 197 women had abdominal adiposity (waist-to-hip ratio [WHR]>0.85). Capillary filtration of albumin and lymphatic function were studied by means of an isotopic test using 99mtechnetium-labeled albumin and venous compression. This test allowed measurement of interstitial albumin retention (AR) and the evaluation of lymphatic function by analyzing the radioactivity disappearance curve after removal of venous compression with the fast Fourier transform (low frequency/high frequency [LF/HF]). Body composition was studied by the bioelectrical impedance method. WHR correlated with fasting blood glucose (P=.03), serum triglyceride (P<.0001), and apoprotein B (P=.008) levels. AR was increased (> or =8 %) in 117 women (59.4%) and LF/HF (> or =1 %) in 149 cases (75.6%). Extracellular water (ECW) was increased (>107% of the theoretical value) in 144 cases (73.1%). LF/HF correlated negatively with age (P=.001), BMI (P=.006), WHR (P<.0001), and fat mass (P=.002). In the multivariate analysis taking age, BMI, and WHR as independent variables, LF/HF correlated significantly with WHR (P<.005). There was a trend to a higher prevalence of an increase in AR in the women with an increase in ECW (61.8 %) as compared with those without an increase in ECW (52.8%). We conclude that abdominal adiposity is associated with metabolic disorders secondary to insulin resistance as previously demonstrated, whereas lymphatic dysfunction is mainly associated with gynoid adiposity. Besides microcirculatory disorders, changes in the secretory regulation of hormones involved in salt and water retention are likely to play an important role in ECW excess.

Hyperinsulinemia and hypofibrinolysis: Effects of short-term optimized glycemic control with continuous insulin infusion in type II diabetic patients

A defect in the fibrinolytic system results from an increase in type 1 plasminogen activator inhibitor (PAI-1) in diabetes. It can be considered an independent risk factor for the development of cardiovascular disease. In obese and type II diabetic patients, plasma PAI-1 level correlates with fasting insulinemia. However, during the euglycemic clamp, acute hyperinsulinemia does not increase PAI-1 production. The present study was undertaken to investigate the effect of optimized glycemic control by continuous subcutaneous insulin infusion (CSII) on the hypofibrinolytic state for 14 days in 16 type II diabetic patients with poor metabolic control despite maximal oral antidiabetic treatment. Plasma PAI-1 activity levels decreased from 13.38 +/- 2.85 IU/mL to 6.77 +/- 1.81 IU/mL (P = .002) during CSII, along with a concurrent improvement in insulin sensitivity (index obtained by basal glycemia-nadir glycemia/basal glycemia) during the insulin sensitivity test (0.121 +/- 0.03 v 0.057 +/- 0.02, P = .02). These results suggest that insulin resistance rather than hyperinsulinism may be involved in the hypofibrinolytic state in type II diabetic patients. The positive correlation between the changes in triglycerides and in PAI-1 activity (r = .589, P = .026) strongly suggests a role for triglycerides in the impairment of fibrinolysis, which could be a link between insulin resistance and hypofibrinolysis.

Association between cardiac autonomic neuropathy and hypertension and its potential influence on diabetic complications

Diabet. Med. 27, 804–811 (2010)

Influence of parasympatheitc dysfunction and hyperinsulinemia on the hemodynamic response to an isometric exercise in non—insulin-dependent diabetic patients

The handgrip test has long been used as a test for investigating cardiac autonomic neuropathy in diabetic patients. However, the factors involved in the hemodynamic response to the handgrip test have not been thoroughly studied. The aim of this study was to investigate blood pressure (BP) and heart rate (HR) responses to an isometric test in non-insulin-dependent diabetics (NIDDs) and to correlate the results with vagal function evaluated by three standardized tests and with plasma insulin levels. Fifty-five NIDDs, 35 of whom had one to three abnormal parasympathetic tests (PS+), were compared with 10 healthy control subjects. Fasting and postprandial plasma insulin levels were significantly higher in the PS+ than in the PS- patients. Resting HR correlated significantly with log fasting and postprandial insulin. In PS+ NIDDs, resting HR was significantly higher than in PS- patients. Age-matched comparisons also showed that resting systolic BP was significantly higher in PS+ patients than in controls. In PS- patients, the mean acceleration of HR was significantly higher than in the control group from the second to the fifth minute, and the BP response was also higher than in controls. These data suggest that (1) sympathetic response to an isometric exercise is increased in PS- NIDDs; (2) cardiac parasympathetic dysfunction is associated with a more severe insulin resistance; and (3) the subsequent higher plasma insulin level may contribute to the increase in resting HR and BP through sympathetic activation while limiting the hemodynamic response to an isometric exercise through its vasodilative effect.

Increased capillary filtration of albumin in diabetic patients—relation with gender, hypertension, microangiopathy, and neuropathy

The aim of this study was to investigate the factors associated with an increase in capillary filtration of albumin (CFA) in a large series of diabetic patients and its relationship with gender, hypertension, microangiopathy, and neuropathy. One hundred sixty-three unselected diabetic patients, 74 type I and 89 type II, were included. An isotopic test of CFA was performed with 99m technetium-labeled albumin injected intravenously. Radioactivity was counted externally at the forearm with a gamma camera before, during, and after venous compression. After removal of venous compression, interstitial albumin retention (AR) was calculated and the radioactivity disappearance curve was analyzed by the Fast Fourier transform, which provides an index for lymphatic uptake of interstitial albumin (low-frequency to high-frequency amplitude peak ratio [LF/HF]). An increase in AR and LF/HF was found in 65 (39.9%) and 117 (71.7%) patients, respectively. Increased AR was significantly more frequent in women than in men (P=.018) and in patients without microangiopathic complications than in those with them (P=.028). In men, it was significantly more frequent in type I versus type II diabetic patients (P=.004), and AR was significantly higher in patients with peripheral neuropathy than in those without (P=.004). The LF/HF was also significantly higher in men with peripheral neuropathy (P=.045). In women, the AR level correlated negatively with postprandial glycemia (P=.006) and was significantly higher in patients without microangiopathic complications (P=.003). These data suggest the role of hormonal factors, both sex steroids and insulin, and the major role of peripheral neuropathy in the increase in CFA. The highly prevalent increase in CFA before the onset of microangiopathic complications is consistent with the presence of a functional microcirculatory disorder that might contribute to the occurrence of microangiopathic lesions.

Impairment of skin vasoconstrictive response to sympathetic activation in obese patients: influence of rheological disorders.

Alterations of cardiac vagosympathetic activity have been suggested in obesity. We have previously shown that the skin vasoconstrictive response to sympathetic activation is reduced in non-insulin-dependent diabetic patients. The present study investigates the skin vasoconstrictive response to sympathetic activation in nondiabetic obese patients and the influence of clinical and rheological factors. Fifty-seven obese and 18 healthy women were investigated. The resting cutaneous blood flow (CBF) and CBF response to three tests that activate the sympathetic nervous system (deep breathing, Valsalva maneuver, and sitting to standing) were measured by a laser Doppler device. The red blood cell (RBC) filtration index (FI) and RBC aggregation were measured using a Hanss hemorrheometer and a Myrenne aggregometer (Myrenne, Roetgen, Germany), respectively. Resting CBF was not significantly different in obese and control subjects. The vasoconstrictive response to the deep-breathing and sitting-to-standing tests expressed as the decrease in CBF was significantly lower in obese patients versus controls (43.9% +/- 3.1% v 73.7% +/- 17.9%, P = .01, and 67.1% +/- 3.8% v 89.8% +/- 12.0%, P = .02, respectively). The spontaneous basal CBF variations and the downward slope of the CBF reduction during the Valsalva and sitting-to-standing tests correlated negatively with age in obese patients (P = .042, .022, and .008, respectively). During the sitting-to-standing test, the percent change in CBF correlated positively with RBC aggregation at a shear rate of 0 and 3 s(-1) (P = .011 and .017, respectively). In conclusion, (1) CBF assessment by laser Doppler flowmetry is an effective noninvasive method to investigate sympathetic nervous function in obese patients; (2) obesity is associated with a significant reduction in the vasoconstrictive response to two tests for sympathetic activation, the deep-breathing and sitting-to-standing tests; (3) the severity of this reduction increases with age; and (4) RBC aggregation may contribute to the increase in the vasoconstrictive response and may thus increase the risk of widespread cardiovascular disease.

Isotopic test of capillary permeability to albumin in diabetic patients: effects of hypertension, microangiopathy, and duration of diabetes

Capillary permeability to albumin (CPA) was studied by performing an isotopic noninvasive test with venous compression on 87 nonselected diabetics with no edema, no cardiac failure, and no peripheral vascular disease. Excessive albumin retention (AR greater than or equal to 8%) ten minutes after removal of the compression was found in 27 patients (31%). The radioactivity disappearance curve was then analyzed using the Fast Fourier Transform (FFT). An abnormal isotopic CPA test was thus found in at least 45 out of the 87 patients. The prevalence of an abnormal test was not different in type 1 and type 2 diabetics. We studied the independent effects of hypertension, presence of specific clinical signs of microangiopathy (retinopathy and/or significant proteinuria), and duration of diabetes. Among diabetics free of specific clinical signs of microangiopathy, the prevalence of an AR greater than or equal to 8% was significantly higher in those with hypertension (11/19) than in those with normal blood pressure (2/28) and in nondiabetic hypertensive patients (0/16). Among normotensive diabetics, the prevalence of an abnormal test was higher, but not significantly, in patients with specific clinical signs of microangiopathy (8/11) than in those free of them (7/18). Seven normotensive diabetics without specific clinical signs of microangiopathy had an abnormal test; five of them had had diabetes for more than five years. The prevalence of diabetes of more than five years duration was significantly higher in patients with an abnormal test (35/45) than in normotensive diabetics free of specific clinical signs of microangiopathy with a normal test (4/11).(ABSTRACT TRUNCATED AT 250 WORDS)