Jacques Pariès

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.

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.

Are silent coronary stenoses predictable in diabetic patients and predictive of cardiovascular events

OBJECTIVESnWe have previously shown that silent coronary stenoses (CS) were predictors of subsequent major cardiac events in diabetic patients with silent myocardial ischemia (SMI). The aim of this study was to determine their correlates and their prognostic value for other cardiovascular events.nnnMETHODSn362 asymptomatic diabetic patients, without prior myocardial infarction, with > or =1 additional risk factor and a normal resting electrocardiogram underwent a myocardial scintigraphy to detect SMI. The patients with SMI subsequently underwent a coronary angiography to detect CS. A total of 345 (95.3%) patients were followed up for 41 +/- 24 months with regard to the occurrence of stroke, gangrene or a peripheral revascularization procedure, exercise occurrence of angina, and nonfatal arrhythmia.nnnRESULTSn121 patients had SMI and 44 had CS. The univariate correlates of CS were age > 65 years (Odds Ratio 2.1 [CI 95%: 1.1-4.0]; p=0.021), male gender (OR 3.1 [1.5-6.3]; p=0.001), smoking (OR 2.8 [1.4-5.6]; p=0.004), > or =2 risk factors (OR 2.1 [1.09-4.09]; p=0.024) and peripheral arterial disease (OR 3.2 [1.2-8.7]; p=0.018). Logistic regression showed that age > 65 years (p=0.034), male gender (p=0.001) and > or =2 risk factors (p=0.013) were independently associated with the presence of CS. The univariate predictors of the 16 minor events were peripheral arterial disease (OR 8.8 [2.7-28.5]; p<0.001), CS (OR 4.9 [1.7-14.2]; p=0.002), SMI (OR 3.7, [1.3-10.5]; p=0.009) and smoking (OR 3.2 [1.1-9.2]; p=0.024). In the multivariate analysis, arterial occlusive disease (p<0.001), smoking (p<0.036) and CS (p=0.044) were independent predictors of events.nnnCONCLUSIONnSilent CS predict major cardiac events but also other cardiovascular events and are more common in diabetic patients > 65 years-old, of male gender and with > or =2 risk factors.

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.

Fas/Fas-Ligand pathway is impaired in patients with type 2 diabetes. Influence of hypertension and insulin resistance

OBJECTIVESnIn type 2 diabetic patients with no cardiac history or symptoms, 1) to evaluate whether the soluble forms of Fas (sFas) and Fas-ligand (sFasL), involved in apoptosis, may be markers of silent coronary disease or related to hypertension or microangiopathic complications; 2) to examine the effect of short-term glycemic control on sFas and sFasL.nnnMETHODSn(1) sFas and sFasL were measured with the ELISA method in 44 asymptomatic diabetic patients, 33 with hypertension, and with a normal myocardial scintigraphy (n=14), with silent myocardial ischemia (SMI) and without (n=15) or with (n=15) significant coronary stenoses; and in 14 controls; (2) sFas and sFasL were measured in 15 poorly controlled diabetic patients before and after 7 days of CSII treatment.nnnRESULTSn(1) sFas and sFasL differed in the four groups of patients (p=0.003 each). sFas was significantly higher in the patients with SMI without (p=0.035) and with coronary stenoses (p=0.002) than in the control group. sFasL was lower in the three groups of diabetic patients (p<0.05 each) than in control group. In the diabetic population, sFas correlated positively with hypertension (p=0.021), and sFasL negatively with hypertension (p=0.027) and HOMA index in the non-insulin treated patients (p=0.049); (2) sFas did not differ before or after CSII, and there was a marginal decrease in sFasL.nnnCONCLUSIONnFas-mediated apoptosis is involved in type 2 diabetes and might be associated with hypertension and/or its vascular consequences. sFasL might be affected by insulin resistance. sFas and sFasL are not effective markers of SMI.

Peripheral vasoconstrictor responses to sympathetic activation in diabetic patients: Relationship with rheological disorders

The sympathetic nervous system regulates peripheral blood flow. This study investigated sympathetic vascular control in diabetic patients by measuring cutaneous blood flow (CBF) with a laser Doppler device at rest and during three sympathetic activation tests: deep-breathing, changing positions from sitting to standing, and using the Valsalva maneuver. The influence of various factors, particularly rheological changes, was also assessed. Forty-two type II diabetes mellitus (non-insulin-dependent [NIDDM]) patients and 14 control subjects were studied. The mean value and standard deviation (SD) of basal CBF at rest were not significantly different in the two groups. In 12 NIDDM patients, the SD was less than the lowest limit found in the controls. During the three tests, the reduction in CBF and its downward slope were lower in NIDDM patients than in controls, with the greatest difference occurring during the deep-breathing test. During this test, the downward slope of CBF was less than the lowest control level in 14 NIDDM patients. The log SD of basal CBF correlated with the decrease in CBF during the sitting-to-standing and Valsalva tests in control subjects and during all three tests in NIDDM patients. In NIDDM patients, log mean basal CBF correlated negatively with the log erythrocyte filtration index ([FI] an index of rigidity) and positively with hemoglobin A1c (HbA1c). The log downward slope of CBF during the deep-breathing test correlated negatively with log erythrocyte Fl. The log downward slope of CBF during the sitting-to-standing and Valsalva tests correlated positively with total cholesterol and triglycerides, respectively. Basal CBF and the CBF response to these tests did not correlate with retinopathy, nephropathy, peripheral neuropathy, or heart rate variations during these tests. This study suggests that CBF assessment by laser Doppler flowmetry affords an attractive noninvasive way to investigate sympathetic nervous function in diabetic patients. The amplitude of changes in basal CBF and the decrease in CBF during the deep-breathing test show that this is a simple and sensitive procedure for detecting sympathetic nerve dysfunction. Moreover, theological blood properties and metabolic factors seem to strongly influence resting CBF and vasomotor reflexes.

Anthropometric markers for detection of the metabolic syndrome in adolescents

OBJECTIVESnThis study aimed to estimate, in a large group of Algerian adolescents, the prevalence of the metabolic syndrome (MetS), using four definitions (by Cook, De Ferranti, Viner and the IDF), and to test the validity of unique thresholds of waist circumference, waist/height ratio and BMI in screening for the MetS regardless of the definition used.nnnSUBJECTS AND METHODSnA total of 1100 adolescent students, aged 12-18 y, were randomly selected from schools and classrooms in the city of Constantine; all had anthropometric measurements taken and 989 had blood tests.nnnRESULTSnPrevalences of the MetS were: 2.6% for boys and 0.6% for girls by the Cook definition; 4.0% for boys and 2.0% for girls by the De Ferranti definition; 0.7% for boys and 0% for girls by the Viner definition; and 1.3% for boys and 0.5% for girls by the 2007 IDF definition. Prevalences ranged from 3.7% to 13.0% in obese adolescents. Unique thresholds, independent of gender, age and height, of 80cm for waist circumference, 0.50 for waist/height ratio and 25kg/m(2) for BMI had sensitivities of 72-100%, 67-100% and 72-100%, respectively, and specificities of 74-78%, 74-86% and 74-78%, respectively, depending on the MetS definition used.nnnCONCLUSIONnThe MetS is present in Algerian adolescents and the prevalence is especially high in obese young people. Our thresholds for waist circumference, waist/height ratio and BMI for screening for the MetS should now be tested in other adolescent populations.