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

AIMS: To examine the association between cardiac autonomic neuropathy and hypertension and the role of this association in diabetic complications. METHODS: We included 310 patients, 138 with Type 1 and 172 with Type 2 diabetes, 62 of them with hypertension. Cardiac autonomic neuropathy was assessed by analysing heart rate variations during three standard tests (deep breathing, lying to standing and Valsalva) and looking for postural hypotension. RESULTS: Cardiac autonomic neuropathy was present in 123 patients and 39 also had hypertension. The prevalence of a cardiac autonomic neuropathy/hypertension association was higher in Type 2 patients (P < 0.002). The prevalence of hypertension increased with the severity of cardiac autonomic neuropathy. In multiple logistic regression analysis, cardiac autonomic neuropathy was an independent risk factor for hypertension [odds ratio 2.86 (1.54-5.32); P < 0.001]. Only confirmed or severe cardiac autonomic neuropathy (two or more abnormal function tests, respectively) were independent risk factors for hypertension (P < 0.005 and < 0.0001). Cardiac autonomic neuropathy was found in most of the patients with macrovascular complications, retinopathy or nephropathy, but a large majority of the patients with these complications exhibited the cardiac autonomic neuropathy/hypertension profile. This profile was more prevalent among the patients with coronary or peripheral artery disease or antecedent stroke than among those free of these complications (P < 0.001). In logistic regression analyses, the cardiac autonomic neuropathy/hypertension profile associated significantly with macro- and microvascular complications. CONCLUSIONS: These data are strongly in favour of the role of cardiac autonomic neuropathy in hypertension in diabetic patients. The association of the cardiac autonomic neuropathy/hypertension profile with vascular complications is consistent with a deleterious effect on vascular hemodynamics and structure, additional to the effects of hypertension.

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients.

AIM: This randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes. METHODS: A total of 48 patients with poor glycaemic control (HbA(1c): 8-10.5%) underwent CGM for 48h using the GlucoDay((R)) system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA(1c) measurement and 48-h CGM were repeated 3 months later. RESULTS: Altogether, 34 patients with either T1D (n=9) or T2D (n=25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA(1c) levels decreased significantly in the CGM group (n=14, -0.63+/-0.27%; P=0.023), but not in the controls (n=20, -0.28+/-0.21%; P=0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA(1c) decreases (mean: -0.63+/-0.34%; P=0.05 vs -0.31+/-0.29%; P=0.18, respectively). However, HbA(1c) did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay system were reported. CONCLUSION: This is the first randomised study showing that CGM improves glycaemic control in patients with T2D.

Universal rather than selective screening for gestational diabetes mellitus may improve fetal outcomes.

AIM: The benefit of treating gestational diabetes mellitus (GDM) has recently been shown. The aim of this study was to compare offspring and maternal health benefits from selective or universal screening for GDM. METHODS: The incidence of outcomes was compared in three series of pregnant women: 1) the 159 consecutive women with GDM out of the 1909 women who delivered between October 2000 and September 2001: during this period screening for GDM was based on risk factors (risk factor-GDM); 2) the 265 consecutive women with GDM out of the 2111 women who delivered during the year 2002: during this period screening for GDM was universal (universal-GDM); 3) 1255 women with no GDM during year 2002 (controls). RESULTS: After adjustment for age, pregravid body mass index, parity, and ethnicity, the risk of large for gestational age (Odds ratio 2.19[95% confidence interval 1.36-3.54], P < 10(-3)), delivery before 37 weeks of gestation (OR 2.44 [95CI 1.32-4.51], P = 0.004), jaundice (OR 3.31[95CI 1.58-6.93], P = 0.002), hospitalization in the department of pediatrics (OR 2.35 [95CI 1.53-3.61], P < 10(-3)) was higher in the GDM-risk factor group than in the control group, whereas it was similar in the universal-GDM group and the control group. Compared with the control group, the risk of anticipated delivery and hospital stay > 4 days after delivery was increased in the GDM-risk factor group (OR 2.69[1.88-3.84], P < 10(-3); and OR 2.6 [1.82-3.71], P < 10(-3) respectively) and the universal-GDM group (OR 1.54 [1.15-2.07] P = 0.004; and OR 1.49 [1.13-1.97], P = 0.005 respectively). CONCLUSION: This observational study suggests that universal rather than selective screening for GDM may improve outcomes. Universal screening might reduce delay of diagnosis and care.

High prevalence and severity of cardiac autonomic neuropathy in Vietnamese diabetic patients.

AIMS: Malnutrition is frequent in Vietnamese people and may influence cardiac autonomic neuropathy (CAN). The aim of the present study was to investigate cardiac autonomic function in healthy subjects living in Vietnam and the prevalence of CAN in Vietnamese diabetic patients. METHODS: One hundred and five diabetic patients (BMI = 19.8 +/- 0.3 kg/m(2)), 50 Type 1 and 55 Type 2, living in Hué (Vietnam) were selected and compared with 60 non-diabetic healthy Vietnamese controls (BMI = 20.8 +/- 0.2 kg/m(2)) and also European controls. CAN function was evaluated by five standardized tests: three tests for heart rate variations (HRV) which depend mainly on parasympathetic activity, and two tests for blood pressure (BP) response which depend mainly on sympathetic activity. RESULTS: With age taken into account, 41 of the 60 Vietnamese controls had at least mild CAN, as defined by one abnormal test for HRV when compared with the European control series, and 11 of them had two or three abnormal tests. Among the Vietnamese control men, those with abnormal HRV had lower BMI than those without (P = 0.036). Seven Vietnamese controls had postural hypotension and 16 had an abnormal BP response to the handgrip test. Compared with the Vietnamese controls, 71 diabetic patients (67.6%), 40 Type 1 and 31 Type 2, had at least mild CAN, 37 of them had two or three abnormal HRV tests, and 56 diabetic patients (53.3%) had an abnormal BP response to the sympathetic tests. Abnormal HRV were associated with significantly lower BMI, waist and hip circumferences, longer diabetes duration and higher fasting blood glucose. In the logistic regression analyses, abnormal HRV were associated significantly with duration of diabetes and BMI in patients with Type 2 diabetes. CONCLUSIONS: Cardiac autonomic dysfunction is frequent in normal Vietnamese subjects. CAN appears to be a more frequent complication of diabetes in Vietnam than in Western countries and diabetic parasympathetic dysfunction is frequently associated with sympathetic disorders. This confirms the deleterious effect a poor nutritional state has on cardiac autonomic function.

Blood glucose changes and adjustments of diet and insulin doses in type 1 diabetic patients during scuba diving (for a change in French regulations).

OBJECTIVE: In France, diabetic subjects were not allowed to dive. The principal risk is hypoglycemia during immersion. However scuba diving is allowed in many countries. To follow blood glucose changes, food intake and insulin adjustments in type 1 diabetic patients when diving, and to propose specific guidelines for such patients willing to practice recreational scuba diving. METHODS: Fifteen well-controlled (mean HbA1c: 7.2%) type 1 diabetic patients without complications were volunteer to dive under strict medical monitoring. They dove 8 times in 4 days in autumn at a depth of 20 meters, in 12 degrees C to 16 degrees C water. A strict protocol based on blood glucose was implemented to prevent hypoglycaemia. RESULTS: No case of hypoglycemia was observed and no faintness was reported underwater. Mean blood glucose before diving was 200 mg/dl (11 mmol/l). There was a mean fall in blood glucose of 40 mg/dl (2.2 mmol/l) during dives, a mean decrease in daily insulin doses by 19.3% on the last day. Daily energy intake was 3,225 Kcal in average. A continuous glucose monitoring (CGMS) was performed in one patient and showed a rather stable glycemia during immersion but a decrease within the 8 hours after. CONCLUSION: When respecting a strict protocol to prevent hypoglycaemia, the risk of hypoglycaemia appears quite low. We recommend an ideal glycemic goal of 200-250 mg/dl (11-13.75 mmol/l) before immersion, a higher reduction of insulin doses (-30%) and taking carbohydrates on board in any case. The present data have recently led the French diving federation (FESSM) to allow type 1 diabetic patients to dive with some restrictive qualification requirements: dives within the "safety curve" (no decompression curve), in above 14 degrees C water, depth limited to the median space range (6 to 20 meters), plus mandatory guidance by a diving instructor.

Markers for silent myocardial ischemia in diabetes. Are they helpful?

Silent myocardial ischemia (SMI) and silent coronary stenoses (CS) are two to seven times more frequent in diabetic patients than in non-diabetic patients. In addition to this, they have a higher predictive value for cardiovascular events than the classical cardiovascular risk factors, either taken alone or combined. Coronary arterial disease is the leading cause of mortality and morbidity in the diabetic population. Altogether, these data suggest that screening for SMI and silent CS is an important issue. We assume that detecting SMI and silent CS improves patient management, and leads to optimised follow-up, action taken on nutrition, exercise and lifestyle, management of the cardiovascular risk factors, and revascularisation procedures whenever possible. However, screening for SMI and silent CS is expensive and may induce morbidity. Selecting the patients with a high a priori risk of SMI and silent CS is therefore of major concern. Carotid or lower limb peripheral arterial disease, proteinuria, male gender, an age greater than 60 years, and two or more cardiovascular risk factors among smoking, microalbuminuria, dyslipidemia, hypertension, a family history of premature cardiac disease, and cardiac autonomic neuropathy have been demonstrated to be the best current predictors of SMI and silent CS. New markers, such as adhesion molecules, Lp(a), inflammation parameters or homocysteine, and endothelium function assessment might be of further help in the future.

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

OBJECTIVES: In 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. METHODS: (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. RESULTS: (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. CONCLUSION: Fas-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.

[Role of vagosympathetic balance in obesity-induced hypertension]. / Rôle de la balance vagosympathique dans l'hypertension associée à l'obésité.

A sympathetic hyperactivity is a common feature in hypertension, type 2 diabetes (T2D), ageing and obesity-induced hypertension. This increase in sympathetic activity may lead to an elevation of arterial rigidity. By contrast, cardiac parasympathetic impairment is observed in these pathologies. Recently we showed in a model of rats with massive obesity (ventromedial hypothalamic lesions) that an enhanced vagal activity may be protective against hypertension. The aim of the present study was to evaluate the influence of an increase in sympathetic activity and a change in vagal activity on arterial rigidity and hypertension in T2D patients. Fourteen hypertensive T2D patients aged 54 +/- 2 years were compared to 22 elderly normotensive subjects (75 +/- 1 years: 11 controls and 11 T2D) and 34 middle aged normotensive subjects (43 +/- 1 years; 17 controls and 17 T2D). Cardiovascular vagosympathetic activity was investigated by spectral analysis of heart rate (HR) and blood pressure (BP) (Finapres) during 6 min at a controlled breathing rate (12 cycles/min). BP and the low frequencies of systolic BP (LF-SBP) were significantly (p<0.01) higher in hypertensive T2D and elderly patients. Pulse pressure (PP) and the high frequencies of HR (HF-HR) were lower in hypertensive T2D patients. PP was positively correlated to LF-SBP (r=0.58; p=0.03) only in hypertensive T2D patients. Diastolic BP was negatively correlated to HF-HR in elderly control subjects (r=-0.63; p=0.03) but not in hypertensive T2D patients. The present results suggest that: sympathetic nervous system activity is enhanced in subjects over 70 years without any aggravating effect of T2D and in middle-aged hypertensive patients with type 2 diabetes; the increase in pulse pressure, an index of arterial rigidity, in elderly subjects may result from sympathetic override; the decrease in the cardiac sympathovagal balance, mainly due to a high vagal activity, may be protective against the occurrence of hypertension in patients with type 2 diabetes.

Detecting silent coronary stenoses and stratifying cardiac risk in patients with diabetes: ECG stress test or exercise myocardial scintigraphy?

AIMS: To determine whether performing a myocardial scintigraphy immediately after a maximal electrocardiogram (ECG) stress test is effective in detecting silent coronary stenoses and predicting cardiovascular events. METHODS: Asymptomatic patients (n = 262) aged 57.6 +/- 8.8 years, with diabetes for 12.0 years (5-39) [median (range)] and no history of a cardiac event, underwent a maximal ECG stress test followed by a myocardial scintigraphy. The patients with an abnormal ECG stress test or abnormal imaging underwent a coronary angiography. Cardiac events were assessed in 250 (95.4%) patients followed for 37.8 months (3-101). RESULTS: The ECG stress test was abnormal in 54 patients. Among them, 18 had coronary stenoses and seven had a cardiac event. Despite a normal ECG stress test, the myocardial scintigraphy was abnormal in 42 additional patients, including 16 patients with coronary stenoses. Four of these 42 patients experienced a cardiac event. Follow-up showed a poor prognosis in subjects who were abnormal on the two tests. Univariate predictors of the 15 cardiac events were the ECG stress test [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.3, 11.4, P = 0.008], myocardial scintigraphy (OR 3.8, 95% CI 1.3, 11.0, P = 0.009), coronary stenoses (OR 26.6, 95% CI 7.6, 90.7, P < 0.001), and peripheral or carotid occlusive arterial disease (OR 9.5, 95% CI 2.1, 42.5, P < 0.001). CONCLUSIONS: In the asymptomatic patients with diabetes, combining a myocardial scintigraphy with a maximal ECG stress test is effective in detecting more patients with coronary stenoses and predicting cardiovascular events. However, the ECG stress test has a good negative predictive value for cardiac events (97%), is cheaper, and should therefore be proposed first.

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

OBJECTIVES: We 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. METHODS: 362 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. RESULTS: 121 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. CONCLUSION: Silent 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.

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.

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.

Weight reduction and long-term maintenance after 18 months treatment with orlistat for obesity.

OBJECTIVE: To determine the effect of orlistat on weight reduction and the long-term maintenance of this weight loss when associated with a continuous mildly reduced energy diet. DESIGN: A multicenter, 18-month, double-blind study conducted in 81 hospital centers. Patients were randomized to orlistat 120 mg or placebo three times daily in conjunction with a mildly reduced-energy diet maintained throughout the study. SUBJECTS: In total, 696 otherwise healthy, overweight patients aged 18-65 y (BMI >or=28 kg/m(2)) were randomized to treatment with orlistat (n=346) or placebo (n=350). MEASUREMENTS: Body weight, anthropometry, lipid and glycemic control parameters and blood pressure. RESULTS: After 18 months, patients treated with orlistat lost significantly more body weight compared with placebo (-6.5+/-0.8 vs -3.0+/-0.8%; P=0.0005). After 12 months, 32.9% of orlistat vs 24.5% of placebo patients lost >or=10% of their initial weight (P=0.04). A significantly greater number of patients receiving orlistat treatment maintained this >or=10% weight loss compared to those receiving placebo (28.1 vs 13.8%; P<0.0001). Compared with placebo, orlistat was associated with a greater decrease in fasting blood glucose (-0.86+/-0.12 vs -0.29+/-0.18 mmol/l; P<0.05) and LDL-cholesterol (-13.0+/-1.3 vs -7.0+/-1.3%; P<0.001). CONCLUSION: A clinically meaningful reduction in body weight and the maintenance of this weight loss is achievable with orlistat treatment and dietary restriction over a period of 18 months. This weight loss resulted in an improvement in risk factors for coronary heart disease.

In vivo kinetics of 123 iodine-labelled insulin in skeletal muscle of patients with type 2 diabetes. Effect of metformin.

BACKGROUND: The capillary filtration of albumin (CFA) is often increased in diabetic patients. However, the transcapillary transfer of insulin is considered to be a key stage in insulin action. The aim was to study the in vivo kinetics of 123I-labelled human insulin in the skeletal muscle of type 2 diabetic patients with an increase in CFA and to evaluate the effect of metformin, using a noninvasive method. METHODS: Ten type 2 diabetic patients and 6 healthy control subjects were investigated. After an i.v injection of 123I-labelled insulin, venous samples were drawn during 75 minutes and radioactivity was counted externally by a gammacamera on the contralateral forearm before, during and after venous compression. The changes in the serum percentages of bound and free 123I were followed during the entire test and the forearm iodine bound to insulin was estimated by multiplying the forearm counted radioactivity by the serum percentage of bound iodine at the same time. RESULTS: In the diabetic patients the maximal increase in the forearm iodine bound to insulin during venous compression was lower (p=0.06), and 10 minutes after removal of venous compression the forearm retention of labelled insulin was significantly lower (p<0.0005) than in controls. After one month of metformin treatment, retention of labelled insulin significantly increased (p<0.001) but was still significantly lower than in the controls (p<0.001). CONCLUSION: The in vivo kinetics of (123) I-labelled insulin procedure allows the study of skeletal muscle metabolism provided venous compression is exerted. In type 2 diabetic patients a reduction of insulin transfer from capillary to tissue despite an increase in CFA, and a reduction of the time spent by insulin in the tissues contribute to insulin resistance. The latter disorder may be improved by metformin.

[Relationship between vasosympathetic activity and insulin resistance in normotensive and mildly hypertensive obese patients]. / Relations entre activité vagosympathique et insulinorésistance chez les obèses normotendus et modérément hypertendus.

Several studies have well demonstrated that obesity is associated with changes in cardiovascular vagosympathetic activity. The aim of the present work was to evaluate this activity in normotensive and in mildly hypertensive obese patients, and to correlate this activity with clinical and biological indexes of insulin resistance. Heart rate (HR) and systolic blood pressure (sBP) were examined by spectral analysis in 70 normotensive obese patients (group 1), 32 mildly hypertensive obese patients (group 2), and 21 controls. The high frequency peak of HR variations at a controlled breathing rate (vagal activity) was significantly reduced in both groups (p < 0.001). The mid frequency peak of sBP in the standing position (sympathetic activity) was similar in both groups and in the control group. In groups 1 and 2, the high frequency peak correlated negatively with age (p = 0.005 and 0.034 respectively). In group 1, the mid frequency peak correlated positively with fat mass, fasting plasma insulin and triglyceride levels, and insulin resistance index (p < or = 0.03). In group 2, the mid frequency peak correlated positively with fasting insulin and insulin resistance index (p = 0.006 and 0.007 respectively). This study shows that, in obese patients: 1. cardiac vagal activity is reduced in normotensive and mildly hypertensive subjects; 2. vascular sympathetic activity is unchanged in means but may be increased as a consequence of adiposity, hyperinsulinemia and insulin resistance, and this increase is likely to be involved in the increase of blood pressure.

[Arterial rigidity and cardiovascular vagosympathetic activity in normotensive and hypertensive obese patients and type 2 diabetics]. / Rigidité artérielle et activité vagosympathique cardiovasculaire chez les obèses et les diabétiques de type 2 normotendus et hypertendus.

An increase in arterial rigidity is associated with a poor cardiovascular prognosis. Several studies have suggested that an increase in sympathetic activity may be involved in essential hypertension. We have recently shown that vagal control of heart rate (HR) variations during standardised tests is altered in normotensive obese and diabetic patients. The aim of the present study was to compare cardiovascular vagosympathetic activity in obese and type 2 diabetic patients, either normotensive or hypertensive, and to investigate the relationship between pulse pressure (an index of arterial rigidity) and sympathetic activity in this population. Seventy normotensive obese and 32 mildly hypertensive obese patients, 18 normotensive type 2 diabetic patients and 14 mildly hypertensive type 2 diabetic patients were compared with 21 control subjects. Finapres studied HR and blood pressure variations. In the four groups, during a 6-min period at a controlled breathing rate, the high frequency peak of HR variations was significantly reduced (p < 0.001). The mid-frequency peak of systolic BP variations in the standing position, which depends on sympathetic activity, did not differ significantly between the four groups and control subjects. In obese and diabetic hypertensive patients, this peak correlated significantly with pulse pressure measured in the lying position (r = 0.379; p = 0.043 and r = 0.81; p < 0.0001, respectively). This study 1, confirms that vagal control of HR variations is reduced to a similar extent in obese and diabetic patients; and 2, suggests that cardiovascular sympathetic activity is relatively increased in these patients without significant difference between normotensive and hypertensive patients, but interestingly that the increase in arterial rigidity is associated with a higher sympathetic activity.

Lower-limb vascularization in diabetic patients. Assessment by thallium-201 scanning coupled with exercise myocardial scintigraphy.

OBJECTIVE: To investigate, by thallium-201 scanning, circulation in the muscles of the lower limb (LL) in diabetic patients without clinical peripheral vascular disease but with a high cardiovascular risk profile. RESEARCH DESIGN AND METHODS: A total of 80 diabetic patients (76 patients with type 2 diabetes, mean age 57.3 years, duration of diabetes 13.0 +/- 7.5 years) with more than one additional cardiovascular risk factor but no claudication were investigated. After stress testing, 1.5 MBq/kg thallium-201 was administered to perform myocardial single-photon emission computed tomography followed by LL scanning. Muscle blood flow was considered abnormal if the asymmetry in thallium-201 uptake between the two buttocks and/or thighs and/or calves was > 10%. RESULTS: Muscle perfusion defects were found in 42% of the patients, mainly in the calves. These defects correlated with retinopathy (P = 0.042) and the HbA1c level (P = 0.044). In patients with defects in the buttock and/or thigh, the prevalence of nephropathy and retinopathy was higher than in those with isolated defects in the calf (P = 0.032 and 0.023, respectively). CONCLUSIONS: This study suggests that LL scanning coupled with myocardial scintigraphy is a convenient method of investigating peripheral muscle circulation. Proximal perfusion defects in patients without clinical arterial disease are associated with increased prevalence of retinopathy and nephropathy and, therefore, may be due to microvascular disease of LL muscle. Distal defects may indicate silent macrovascular disease of the LL.

Impairment of coronary microvascular dilation in response to cold pressor--induced sympathetic stimulation in type 2 diabetic patients with abnormal stress thallium imaging.

Coronary microcirculation dysfunction may be associated with myocardial perfusion defects on thallium imaging in diabetic patients without coronary artery stenosis. Microvascular coronary adaptation to increased myocardial oxygen demand in response to sympathetic stimulation evoked by the cold pressor test was examined in 22 type 2 diabetic patients with thallium imaging defects and in 15 control subjects. Both the diabetic patients and control subjects had angiographically normal coronary arteries and no other risk factors. Despite a similar increase in the rate-pressure product in the two groups (22.6 +/- 12.4% in diabetic patients and 31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in the left anterior descending artery (mean flow velocity measured by intracoronary Doppler multiplied by the cross-sectional area measured by digital angiography) was significantly lower in diabetic patients than in control subjects (14.7 +/- 19.8 vs. 75.5 +/- 13.5%, respectively; P = 0.0001). In addition, when there was a positive correlation between the two parameters in control subjects (r = 0.651, P < 0.01), there was no relationship in diabetic patients (r = 0.054). In conclusion, vasodilation of the coronary microcirculation in response to sympathetic stimulation evoked by the cold pressor test is impaired in type 2 diabetic patients without epicardial artery lesions. This microvascular impairment during sympathetic stimulation may explain exercise-induced myocardial perfusion abnormalities observed in these patients and may impair microcirculatory coronary vasodilation during current life stress episodes such as exercise, mental stress, or cold exposition.

Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia.

OBJECTIVE: The aim of this study was to determine the predictive value of silent myocardial ischemia (SMI) and cardiac autonomic neuropathy (CAN) in asymptomatic diabetic patients. RESEARCH DESIGN AND METHODS: We recruited 120 diabetic patients with no history of myocardial infarction or angina, a normal 12-lead electrocardiogram (ECG), and two or more additional risk factors. SMI assessment was carried out by means of an ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring. CAN was searched for by standardized tests evaluating heart rate variations. Accurate follow-up information for 3-7 years (mean 4.5) was obtained in 107 patients. RESULTS: There was evidence of SMI in 33 patients (30.7%). CAN was detected in 33 of the 75 patients (38.9%) who were tested, and a major cardiac event occurred in 11 of them. Among these 75 patients, the proportion of major cardiac events in the SMI+ patients was not significantly higher than that in the SMI- patients (6 of 25 vs. 5 of 50 patients), whereas it was significantly higher in the CAN+ patients than in the CAN- patients (8 of 33 vs. 3 of 42 patients; P = 0.04), with a relative risk of 4.16 (95% CI 1.01-17.19) and was the highest in the patients with both SMI and CAN (5 of 10 patients). After adjusting for SMI, there was a significant association between CAN and major cardiac events (P = 0.04). CONCLUSIONS: In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than SMI. The risk linked to CAN appears to be independent of SMI and is the highest when CAN is associated with SMI.