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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.

Objective: To improve the quality of diabetes care in general practice by the use of audit., Material and Methods: A prospective multicenter pilot study. Thirty-five groups of ten general practitioners (GPs) have been set up throughout France on a voluntary basis. These groups were led by a steering committee that includes a diabetologist and a GP. Each group established a consensus on healthcare standards and carried out 2 data collections over a 12-month period, with adoption of corrective measures between these 2 collections., Results: 309 (90.4%) of the 342 practitioners completed the first data collection, assessing the management of 3,125 patients over a year. Less than half the groups have reached the 80% reference threshold for quality of care with regard to foot examination, microalbuminuria, ECG, fundoscopy and assessment of diet. The audit also found no intervention within one year in case of poor glucose control for 47% of patients, unsatisfactory quality of HbA(1c) measurement and insufficient resources for diet and education. 226 (66.1%) practitioners completed the second data collection assessing the management of 2,248 patients. Comparison between the two phases of the audit showed significant improvements for all the indicators of the process of care (p<0.001). Quality of HbA(1c) measurement and diet assessment by GPs progressed (p<0.01). Outcomes of care also improved with respect to the proportion of patients with HbA(1c)<=8% (p=0.007), fasting glycaemia<1.40 g/l (p=0.05) and SBP<140 mmHg (p=0.02)., Conclusions: This pilot study confirms the feasibility of using clinical audit at the national level. It seems to be an effective measure to improve the management of patients with type 2 diabetes in primary care. It is intended that the large-scale DIABEST study will address this issue.

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.

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.

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.

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.

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.

A failure of coronary blood flow to increase during cold pressor test has been shown in patients with coronary atherosclerosis and impaired metabolic coronary vasodilatation in response to atrial pacing has been demonstrated in diabetic patients without significant epicardial artery stenoses. This study was designed to evaluate coronary microvascular adaptation to increased myocardial oxygen demand in response to sympathetic stimulation in diabetic patients with angiographically normal coronary arteries. Microvascular coronary adaptation to increased myocardial oxygen demand due to sympathetic stimulation evoked by the cold pressor test has been examined in 22 type 2 diabetic patients and in 15 control subjects with angiographically normal coronary arteries and no other risk factors. Coronary blood flow was calculated by measuring mean flow velocity in left anterior descending coronary artery by intracoronary Doppler and cross sectional area of the artery by digital angiography. Results show that despite a similar increase in rate-pressure product in the 2 groups (+22.6 +/- 12.4% in diabetic patients and +31.8 +/- 8.2% in control subjects, NS), coronary blood flow increase in left anterior descending artery 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 2 parameters in control subjects (R = 0.651, p < 0.01), there was no relationship in diabetic patients (R = 0.054). In conclusion, this study demonstrates that vasodilatation of coronary microcirculation in response to sympathetic stimulation evoked by 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 vasodilatation during current life stress episodes such as exercise, mental stress or cold exposure.

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.

Objective: To investigate whether the fall in soluble L-selectin (sL-selectin) level constitutes a marker for myocardial ischemia., Research Design and Methods: The levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), P-selectin (sP-selectin), and L-selectin (sL-selectin), were compared in type 2 diabetic patients without inflammatory syndrome but with symptomatic coronary artery disease (CAD) (group 1, n = 11), with silent ischemic disorders and proven coronary stenoses (group 2, n = 11), with silent myocardial ischemia (SMI) and normal coronary angiography (group 3, n = 10), and without proven SMI (group 4, n = 13). These levels were compared with those of 22 control subjects., Results: The sL-selectin level was significantly lower in groups 1, 2, or 3 with symptomatic CAD or with SMI as compared with the control group (P = 0.0004). Group 4 without myocardial ischemia did not significantly differ from the control subjects (P = 0.6). In type 2 diabetic patients, after controlling for HbA1c, a partial correlation between sL-selectin and the CAD status was significant (P = 0.001). sICAM-1 and sP- or sE-selectin did not differ significantly between type 2 diabetic patients and control subjects or among the different groups of patients. The sVCAM-1 level in type 2 diabetic patients was significantly higher than in the control subjects (P = 0.001), but there were no significant intergroup differences (P = 0.4)., Conclusions: In type 2 diabetic patients, sVCAM-1 is increased with regard to glycemic control, whatever the CAD status. In type 2 diabetic patients with symptomatic CAD or SMI associated with coronary stenoses, sL-selectin is significantly decreased. A marked fall in sL-selectin might constitute a marker for silent CAD in type 2 diabetic patients.

Bone localisations of amyloidosis are rare, usually diffuse and associated with myeloma. We report the case of a patient with massive obesity complicated by diabetes, hypertension, sleep apnea and liver steatosis, who complained of rapidly worsening bilateral polyradiculalgia of the lower limbs. After sufficient weight loss made nuclear magnetic resonance imaging feasible, a spinal tumour was visualised on the 5th lumbar vertebra, extending to soft tissues. Total excision was performed, and pathological studies revealed an amyloid bone tumour with no evidence of myeloma.

We have previously shown that alterations of vagal control of heart rate variations are found in more than half of non diabetic obese subjects (Int J Obes 1995) and are associated with a more severe insulin resistance in noninsulin dependent diabetic patients (Metabolism 1998). The aim of this study was to examine whether parasympathetic alterations are also associated with a more severe insulin resistance in non diabetic obese subjects. 245 obese subjects (BMI = 34.2 +/- 0.4 kg/m2) aged 38.6 +/- 0.8 years, with a normal oral glucose tolerance test were included. Parasympathetic activity was evaluated by heart rate variations during three standardised tests: Valsalva, deep-breathing and active lying-to-standing, with age being taken into account. The Valsalva maneuver was abnormal in 17.5%, the deep-breathing test in 18% and the lying-to-standing test in 30.3% of the cases. One hundred and thirty subjects (52.1%) had at least one abnormal test. Compared with those with three normal tests, the obese subjects with parasympathetic alterations had very similar BMI and blood pressure, but significantly higher values of heart rate (75.5 +/- 1.4 vs 71.3 +/- 1.1 beats/min, p = 0.02), fasting blood glucose (5.0 +/- 0.1 vs 4.8 +/- 0.1 mmol/L, p = 0.03) and plasma insulin (98 +/- 6 vs 82 +/- 4 pmol/L, p = 0.03). In the whole series of obese subjects, heart rate variations during the deep-breathing and lying-to-standing tests correlated negatively with blood glucose (p = 0.001 and p = 0.03 respectively), and during the deep-breathing test they correlated negatively with the waist/hip ratio (p = 0.004). This data suggests that cardiac parasympathetic alterations should take part in the insulin-resistance syndrome and might account for the poor cardiovascular prognosis linked to this syndrome.

Left ventricular hypertrophy (LVH) is a recognized independent risk factor for cardiovascular morbidity and mortality. The purpose of this study was to assess the determinants of left ventricular mass index (LVMI), according to the presence or absence of silent myocardial ischaemia (SMI), in diabetic patients with at least two additional risk factors but with no known coronary artery disease. Eighty diabetic patients (14 Type 1 and 66 Type 2) were studied, and LVMI was measured echocardiographically. Three non-invasive tests (the ECG stress test, thallium-201 myocardial scintigraphy with intravenous dipyridamole infusion, and ambulatory 48-h ECG monitoring) were performed on all patients. Forty-five percent of patients had LVH (LVMI > or = 110 g/m2 in men and > or = 106 g/m2 in women). Twenty-six patients (37%) had SMI assessed on at least one of the non-invasive tests, 7 of whom had significant coronary stenoses on angiography. LVMI was significantly higher in patients with coronary stenoses on angiography than in those with SMI but without coronary stenoses or in those without SMI (p < 0.05), and was correlated with systolic blood pressure. In patients free of SMI, LVMI correlated with creatininemia. In patients with SMI and normal coronary arteries on angiography, LVMI correlated with the waist/hip girth ratio, the log urinary albumin excretion rate and the red blood cell filtration index (a rigidity index). This study suggests that LVH is very frequent in diabetic patients and that the main factor contributing to the increase of LVMI differs according to the presence or absence of SMI and coronary stenoses: volume load in patients free of SMI, microcirculatory disorders in those with SMI but with normal coronary arteries, and blood pressure in those with coronary stenoses.

Evidence-based therapeutic decisions in type 2 diabetes are considered here in terms of both the individual and public health policy. They lead to the recommendation which has proved to be the most effective: early, intensive, global care, first for glycemic control, then, according to the case, for the other risk factors of atheromatosis.

Objective: The aim of this study was to look for a relationship between autonomic dysfunction and alterations in glucose- induced thermogenesis (GIT) and lipid oxidation rate in obese non-diabetic women., Subjects: 37 obese women, 20 with impaired cardiac autonomic function tests (group 1) were matched with 17 women with normal tests (group 2) according to age, weight, body mass index (BMI), waist-to-hip ratio (WHR), fat mass (FM) and fat free mass (FFM)., Measurements: A series of five standardized tests was carried out, three of which were based mainly on cardiac parasympathetic control (heart rate response to Valsalva, deep breathing and lying-to-standing) and two on cardiovascular sympathetic function (blood pressure response to standing and to handgrip). Energy expenditure (EE), lipid and glucose oxidation rate were determined by indirect calorimetry at fasting and after an oral glucose load (75 g). Blood glucose, insulin and catecholamines responses to glucose were examined., Results: There was no significant difference in plasma glucose, insulin, catecholamines, metabolic rate, glucose and lipid oxidation rate at fasting and plasma glucose, insulin and catecholamine responses to glucose. GIT was slightly but not significantly lower in group 1 (24.7+/-10.4 kJ) than in group 2 (46.8+/-9.0 kJ). The cumulative glucose oxidation rate did not differ significantly in the two groups. The cumulative lipid oxidation rate was significantly lower in group 1 than in group 2 (-49.4+/-4.1 vs -30.8+/-8.0, respectively, P = 0.033). It correlated negatively with the area under the curve of insulin response (r=-0.37, P=0.04). In the multivariate analysis, both autonomic dysfunction and the area under the curve of insulin response correlated significantly with the cumulative lipid oxidation rate., Conclusion: This study suggests that 1) the glucose-induced inhibition of the lipid oxidation rate in obese women is greater in the patients with autonomic dysfunction; 2) a decrease in sympathetic activity is likely to be involved in this phenomenon.

Objective: To evaluate the effects of a 14-day intensive insulin therapy and short-term improvement of glycemic control on serum levels of soluble forms of adhesion molecules, i.e., intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in NIDDM patients with poor glycemic control., Research Design and Methods: A total of 16 NIDDM patients were compared with 23 healthy subjects (control group) and investigated before and after intensive insulin treatment., Results: On day 0, sE-selectin and sVCAM-1 levels were significantly higher in NIDDM patients than in nondiabetic control subjects (median 87, range 63-115; median 544, range 408-797 vs. 58, 43-80; 443, 395-573 ng/ml, respectively) (P < 0.008 in both cases). On day 15, the fall in sE-selectin levels was significant (P < 0.0001) and at a lesser extent in sVCAM-1 levels (64, 48-85; 506, 417-678 ng/ml, respectively); these levels reached values that no longer differed from those of control subjects (P = 0.23 and 0.15, respectively). Moreover, the fall in sE-selectin was positively associated with the change in LDL cholesterol and the improvement of glycemia., Conclusions: In poorly controlled NIDDM patients, sE-selectin levels are increased and significantly fall to normal after short-term improvement of glycemic control. This suggests that assaying sE-selectin makes it possible to detect endothelium activation and to follow its reversal with euglycemia.

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.

Background: Acetylcholine produces coronary artery (CA) constriction in diabetic patients, suggesting an impairment of endothelium-dependent dilation. In diabetes, multiple metabolic abnormalities may inactivate nitric oxide through oxygen free radical production., Methods and Results: To examine the mechanism of this abnormal response, two physiological tests (ie, a cold pressor test [CPT] and coronary flow increase induced by an injection of 10 mg papaverine [PAP] in the distal left anterior descending CA) were performed before and after either intravenous L-arginine (625 mg/min x 10 minutes) or intravenous deferoxamine (50 mg/min x 10 minutes) in 22 normotensive nonsmoking diabetic patients with angiographically normal CAs and normal cholesterol. Coronary surface areas were measured with quantitative angiography. Before the administration of L-arginine or deferoxamine, CPT induced CA constriction in both groups (-14 +/- 10% and -15 +/- 11%, respectively; each P<.001), and PAP injection in distal LAD did not modify significantly proximal LAD dimensions. In the 10 diabetic patients receiving L-arginine, responses to CPT and PAP were not modified. Conversely, in the 12 patients receiving deferoxamine, CA dilated in response to the two tests (+10 +/- 9% after CPT and +22 +/- 7% after PAP, each P<.001). Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the two groups (+47 +/- 19% and +41 +/- 15%, respectively; each P<.001)., Conclusions: This study shows that (1) responses of angiographically normal CAs to CPT and to flow increase are impaired in diabetic patients; (2) abnormal responses are not improved by L-arginine, suggesting that a deficit in substrate for nitric oxide synthesis is not involved; and (3) deferoxamine restores a vasodilator response to the two tests, suggesting that inactivation of NO by oxygen species might be partly responsible for the impairment of CA dilation in diabetic patients.

The "short Achilles tendon" syndrome, characterised by limited dorsiflexion of the tibiotarsal joint, is not well-known but could be a disposing factor for trophic disorders and plantar ulcer related to hypersupport in the diabetic subject. We report two cases of multicomplicated diabetic patients treated during several months for plantar ulcer superinfected with underlying osteoarthrits, whose course became rapidly favourable after tenotomy of the Achilles tendon. This simple surgical act can be performed in ambulatory conditions under local anaesthesia. Functional disability is negligible. The benefit of this treatment as part of the curative or preventive therapeutic arsenal for care of the diabetic foot remains to be evaluated.

The purpose of this study was to evaluate the ability of three noninvasive techniques to detect silent myocardial ischaemia and analyse the factors associated with this condition, particularly left ventricular hypertrophy, in diabetic patients. An ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole intravenous infusion, ambulatory 48 h ECG monitoring and an echocardiographic study were performed in 92 diabetic patients without cardiac symptoms but with > or = 2 additional cardiovascular risk factors. At least one of these tests was positive in 28 patients (30.4%), suggesting silent myocardial ischaemia. Twenty-four of these patients had a coronary angiography which showed significant coronary stenosis in only 9 cases. An accurate echocardiographic tracing was obtained in 79 patients, particularly in 7 of the 9 with coronary stenosis. Left ventricular hypertrophy was detected in 34 patients, 6 of whom had coronary stenosis. In patients with left ventricular hypertrophy, the positive predictive values of myocardial scintigraphy and the ECG stress test were respectively 50% and 100%, as compared to only 33% and 11% in those without hypertrophy. In summary, coronary stenoses were found in < 10% of asymptomatic diabetic patients with > or = 2 cardiovascular risk factors, but more frequently in individuals with left ventricular hypertrophy. Thus, silent myocardial ischaemia should be searched for first in diabetic patients with hypertrophy, for which the stress test was the most accurate detection method in this study.

Microangiopathic disorders, characterized by capillary vasodilation and increases in capillary blood flow and permeability, are common in diabetes and can occur before the development of microangiopathic complications. In a study of 163 diabetic patients, capillary permeability, measured by albumin retention (AR), was increased in 39% of patients. AR was increased more frequently in women than in men, and in patients without microangiopathic complications than in patients with complications. Increased AR was significantly associated with insulin-dependent diabetes in male patients. Lymphatic function was abnormal in 72% of patients; this abnormality was often present before AR increased. The pathophysiology of microangiopathy is complex and involves metabolic, haemodynamic, neurological and hormonal factors. Improved control of glycaemia and blood pressure can reduce capillary permeability. In addition, studies with a flavonoid fraction and n-3 polyunsaturated fatty acids suggest that these agents may also be beneficial.

Several studies suggest alterations of parasympathetic and sympathetic control in obesity. We have already shown that more than 40% of non diabetic obese subjects have alterations of parasympathetic control of heart rate (HR) variations. The present study aimed to investigate parasympathetic and sympathetic cardiovascular control by using spectral analysis. Sixty-two non diabetic obese subjects were compared to 38 sex-matched healthy controls. Spectral analysis was performed by Anapres system and identified two particular peaks: the one of high frequency (0.20-0.25 Hz) for heart rate variations during controlled breathing which depends on parasympathetic activity, the other of low frequency (around 0.10 Hz) for systolic BP variations in the standing position which mainly depend on sympathetic activity. In control subjects the amplitude of the high frequency peak (r = -0.556, p < 0.0001) but not the amplitude of the low frequency peak correlated negatively with age. In the obese subjects both the high and low frequency peaks correlated negatively with age (r = -0.249; p = 0.05 and r = -0.289, p = 0.036 respectively) and did not correlate with body mass index. The high frequency peak was significantly lower than in controls (4.80 +/- 3.37 (SD) vs 8.38 +/- 4.14; p < 0.0001). In the 25 obese subjects over 40 years the low frequency peak was also significantly lower than in controls (10.00 +/- 3.10 vs 11.95 +/- 4.25; p < 0.05). This study suggests that 1) age must be taken into account when interpreting the cardiovascular parameters under vagosympathetic control; 2) in non diabetic obese subjects vagal activity is decreased and in those over 40 years sympathetic activity is also decreased.

Unlabelled: Acetylcholine produces coronary artery (CA) constriction in diabetic patients suggesting an impairment of endothelium-dependent dilation. To examine the mechanism of this abnormal response. 2 physiological tests, i.e. cold pressor test (CPT) and coronary flow-increase induced by 10 mg papaverine (PAP) injection in the distal left anterior descending CA (dLAD), were performed before (1) and after (2) either i.v. L-arginine (L-arg, 625 mg/min x 10 min) or i.v. desferrioxamine (DFX, 50 mg/min x 10 min) in 15 normotensive nonsmoker diabetic patients with angiographically normal CA and normal cholesterol. Dimensions of the proximal LAD (pLAD) were measured by quantitative angiography. [table: see text] Before administration of L-arg or DFX, CPT induced a decrease of pLAD diameter, and PAP injection in dLAD dit not modify pLAD diameter. In the 7 diabetic patients receiving L-arg, responses to CPT and PAP were not modified. Conversely in the 10 patients receiving DFX, pLAD dilated in response to the 2 tests. Intracoronary isosorbide dinitrate, an endothelium-independent dilator, produced similar dilation in the 2 groups (+20 +/- 8% and +16 +/- 6%, respectively)., Conclusions: 1) responses of angiography normal CA to CPT and to flow increase are impaired in diabetic patients; 2) abnormal responses are not improved by L-arg suggesting that a deficit in substrate for NO synthesis is not involved; 3) DFX restores a vasodilator response to the 2 tests suggesting that inactivation of NO by superoxide radicals might be partly responsible of the impairment of CA dilatation 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.

We report here the extremely rare case of a twenty-eight year-old woman with a metastatic ACTH-secreting pituitary carcinoma. This is the thirteenth case to be described in the literature. Ten years ago Cushing's disease was diagnosed. After pituitary surgery, then bilateral adrenalectomy, a Nelson's syndrome appeared. The particularly extensive pituitary secondary development led to several pituitary surgical procedures, radiotherapy, and octreotide treatment. Eight years after Cushing's disease was diagnosed, liver tumors were discovered. Pathological examination and ACTH immunostaining demonstrated the secretory nature of these metastases. The lack of ectopic tumor, the LPH/ACTH equimolar ratio and a study of the plasma proopiomelanocortin derivatives by HPLC showed that the ACTH secretion originated in pituitary tissues (in situ and liver metastases). The processing of POMC seems thus to be normal in this kind of tumor and metastases. Intact POMC levels were very high, indicating an aggressive tumor, and ACTH/LPH production was paradoxically stimulated by octreotide. This case is also exceptional because of the slow development of the disease, which may be due to the complementary hepatic chemoembolization treatment.

It is difficult to treat obese non-insulin-dependent diabetic patients (NIDDs) whose glycaemic control remains poor despite maximal oral antidiabetic therapy. We studied the effect of a continuous subcutaneous insulin infusion (CSII) associated with a low-calorie diet and metformin 1,700 mg/day on glycaemic control and basal and stimulated insulin secretion in a series of 82 overweight NIDD before (T1), during CSII (T2), and after CSII withdrawal (T3). Patients were treated for 8 to 23 days with a mean amount of 0.50 +/- 0.02 IU/kg/day. Glycaemic control was very good after 3-5 days of CSII and remained good at T3. At T2, fasting and postprandial plasma C peptide levels decreased significantly. At T3, fasting C peptide was very similar to T1, and postprandial C peptide was significantly higher than at T1. The molar fasting and postprandial plasma C peptide/glycaemia ratios increased significantly at T3. After glucagon injection, the molar delta C peptide/glycaemia ratio was significantly increased at T2 and even higher at T3. At T2, as at T1 and T3, there were significant correlations between fasting and postprandial C peptide levels and between the glucagon-induced C peptide peak and fasting and postprandial C peptide levels. Between T1 and T3 weight changes correlated significantly with the molar fasting C peptide/glycaemia ratio at T1. Twenty-nine of the 30 patients for whom this ratio was > 6.6 x 10(-8) lost weight. The length of CSII treatment did not correlate with weight changes or other biological parameters. This study shows that CSII with moderate amounts of insulin associated with a low-calorie diet and metformin provided rapid glycaemic control, led to weight loss, maintained regulation of insulin secretion and seemed to improve insulin secretion and sensitivity. These results were obtained in only 8 to 10 days.

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 Hoffmann's 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.

The objective of the present study was to investigate the effects of a purified micronized flavonoid fraction (Daflon 500 mg) on the increased capillary filtration of albumin (CFA) which is an early change in the microcirculation of patients with diabetes. A placebo controlled trial lasting 30 to 42 days including two equal groups of 20 patients, following a 15-day initial placebo run-in phase. The CFA test employed consisted of injecting albumin labelled with technetium (99mTc) intravenously, applying a venous tourniquet to one arm, and counting the radioactivity on the ipselateral forearm using an external gamma camera. The disappearance of radioactivity was analysed by means of two parameters after the tourniquet had been released, i.e. albumin retention (AR) and the LF/HF index which indicates lymphatic function in interstitial protein clearance. All patients included exhibited an increase in these two indices before the initial placebo run-in phase and at the end of the run-in period. At the end of the treatment phase, AR had significantly decreased in the group treated by the flavonoid fraction (FF) by comparison with the placebo group, and had normalized in 65% of patients in the FF group, compared with 25% of patients in the placebo group (p = 0.010). The LF/HF index normalized in 55% of cases in the FF group, compared with no patients on placebo (p = 0.00001). This study suggests that the flavonoid fraction tested here can improve and even normalize capillary filtration of albumin in diabetic patients.

Objective: To investigate the rheological properties of RBC in obese subjects and the factors associated with their changes., Subjects: Two consecutive studies of non diabetic obese subjects., Measurements: Filtration index of RBC using the Hanss hemorheometer, RBC filterability using a cell transit time analyser and RBC aggregation measured on the Myrenne aggregometer., Results: In both studies an increase in the filtration index of RBC, namely a reduction in their deformability, was found. In the first study the filtration index correlated negatively with hematocrit and positively with plasma C peptide levels. In the second study RBC filterability was also studied by the cell transit time analyzer in which there is no aggregate formation. The RBC transit time was not found to be different in the obese patients and in the controls, but RBC aggregation was increased and correlated significantly with body weight and BMI. RBC aggregation worsened after four days of hypocaloric diet., Conclusion: (1) obesity, independently of the other cardiovascular risk factors, is associated with significant changes in RBC rheology; (2) these changes are probably related for the most part to plasma factors, possibly via hyperinsulinemia, even if changes in the chemical composition of the RBC membrane are not excluded, (3) RBC aggregation worsens during the first days of a hypocaloric diet; (4) rheological changes in RBC seem to be another component of the insulin resistance syndrome.

Objective: To evaluate the prevalence in obese patients of an increased urinary albumin excretion rate (UAER) and the factors involved in this parameter., Subjects: Two hundred and seven nondiabetic obese patients with BMI = 34.7 +/- 5.7 (SD) kg/m2. None had proteinuria or a history of nephropathy or uropathy. Fifty-two had moderate hypertension. A control group of 22 lean healthy subjects was also studied., Measurements: The UAER was determined from 24-h urine samples by means of immunonephelemetry laser method. Creatinine clearance was calculated. Glycemia and plasma C peptide at fasting and 120 mine after glucose oral administration, HbA1c, serum fructosamine, plasma total cholesterol and triglycerides, HDL and LDL cholesterol were measured. Food intakes were determined by dietary history., Results: Compared with the control group, the UAER was significantly higher in the obese patients (18.0 +/- 20.1 mg/24 h vs 3.2 +/- 2.8 mg/24 h, P < 0.0001). It was elevated (> 30 mg/24 h) in 25 obese patients (12.1%) and in particular, in 19.2% of the obese patients with hypertension. It was significantly higher in the patients with android or mixed (both android and gynoid) obesity than in those with gynoid obesity (p = 0.050). Log UAER correlated negatively with the duration of hypertension (p = 0.038) and was higher in the patients with familial hypertension than in those without (p = 0.002). Log UAER correlated strongly with log creatinine clearance (p < 0.0001) and fractional albumin clearance (p < 0.0001). It correlated significantly with fasting and 120 min after glucose plasma C peptide concentrations (p = 0.018 and p = 0.046, respectively). Creatinine clearance was significantly higher in the patients with android or mixed obesity than in those with gynoid obesity (p = 0.001). Log creatinine clearance correlated negatively with age (p = 0.046), and log LDL cholesterol (p = 0.025) and positively with log lipid caloric intake (p = 0.014)., Conclusion: These results show the high prevalence of microalbuminuria in nondiabetic obese patients and suggest the involvement of renal hyperfiltration. Microalbuminuria may be an indicator of familial hypertension in obese subjects. Insulin resistance may be involved in the increase in the UAER. Nutritional factors, particularly lipid intake, may contribute to this increase in the UAER via an increase in glomerular hyperfiltration.

The aim of this study was to investigate TSH and PRL response to TRH and domperidone, an antidopaminergic drug which does not cross the blood-brain barrier, in 16 patients with primary empty sella (PES) and either normal or elevated plasma PRL level and to compare it with the response observed in 8 patients with prolactinoma. In the patients with PES and hyperprolactinemia, the PRL response to TRH was significantly lower than in the controls and the patients with PES and normal PRL, which suggests there is impaired PRL synthesis and release in cases of PES with hyperprolactinemia. The TSH response to domperidone was significantly elevated in patients with PES and either normal or elevated PRL, as in patients with prolactinoma. The PRL response to domperidone was significantly reduced in patients with PES and hyperprolactinemia as in patients with prolactionoma. These results suggestthat in PES with prolactinoma the inhibiting dopaminergic tone is increased on the thyrotropic cells and reduced on the lactotropic cells in PES with elevated PRL and that some patients with PES might bear a microprolactinoma in the bottom of the sella which remained undetected by the CT scan.

The bioavailability of rapid-acting insulin administered as a nasal spray was studied in 6 type 1 (insulin-dependent) diabetic patients. They received long-acting bovine insulin (Ultratardum 40 U/ml, Organon) as basal treatment at 8 a.m. Rapid-acting insulin was also administered at 8 a.m., then at noon and 6 p.m, subcutaneously on day 1 as a 100 U/ml solution and intranasally by aerosol spray as a 100 U/ml and 500 U/ml with 1% (w/v) 9 lauryl ether solution on day 2 and day 3 respectively. On days 2 and 3, the dose of insulin was at least nine times higher than the subcutaneous dose on day 1. Free and total plasma insulin concentrations were assayed after the noon insulin administration. The peaks of the free and total plasma insulin levels were reached earlier and the return to basal levels was obtained earlier after nasal insulin administration than after insulin injected subcutaneously. The bioavailability of nasal spray insulin versus subcutaneous insulin with a 100 U/ml insulin solution was similar to that with a 500 U/ml insulin solution: 5.14 +/- 0.38% (m +/- SEM) and 4.64 +/- 0.46% according to the total plasma insulin level. This study suggests that the bioavailability of nasal spray insulin is not increased by increasing insulin concentration in our experimental conditions.

Parasympathetic as well as cardiovascular sympathetic activity is perturbed in the heart of diabetic and obese subjects. The aim of this work was to assess the effect of sympathetic control on variations in skin blood flow in 14 controls, 42 subjects with non-insulin-dependent diabetes and 57 obese subjects without diabetes. All subjects had normal blood pressure and had no other disease state which might modify skin blood flow. Laser-Doppler measurement of skin blood flow on the palmar aspect of the right first finger was performed at rest and during three tests which activate sympathetic tone: deep respiration (R), active orthostatism (O) and Valsalva's manoeuvre (V). In all 113 subjects, there was a negative correlation between age and the standard deviation of blood skin flow at rest (p = 0.001) and rate of blood skin flow decline during R (p = 0.002), O (p < 0.0001) and V (p = 0.005). The standard deviation and slope of decline in blood skin flow during R was lower than the initial levels in controls in 11 diabetes patients and 6 obese subjects and in 15 diabetic patients and 12 obese subjects respectively. The slope of decline in skin blood flow during O was positively correlated with plasma cholesterol (p = 0.002), red cell aggregation index (p = 0.013) and negatively with hematocrit, glucose control and creatininemia. The respective effects of these factors were analyzed in each of the three groups of subjects. These preliminary results suggest that 1) the variation in skin blood flow at rest is regulated by the sympathetic system and the drop in skin blood flow during the three tests activating the sympathetic system decreases with age, 2) sympathetic control of peripheral vasoconstriction is reduced in many diabetic and obese subjects, 3) red cell aggregability and different metabolic parameters and renal function have an effect.

The purpose of this study was to evaluate the efficacy of a traditional Chinese treatment (TCT) based on three plants in association with a sulfonylurea, glibenclamide (2.5 mg X 3/d). A 2 X 2 factorial design was adopted for this multicentre randomized double-blind trial involving 4 groups [A = placebo (P) TCT + P glibenclamide; B = P TCT + verum glibenclamide; C = verum TCT + P glibenclamide; D = verum TCT + verum glibenclamide]. Patients included were type 2 diabetic outpatients, 40-70 years of age, treated by diet alone or oral anti-diabetic drugs. Endpoint criteria evaluated were HbA1, blood glucose and plasma insulin (at fasting, and 1 and 2 h after a test meal). At each visit, a clinical examination was performed, and a questionnaire on side effects and associated symptoms was completed. The dose was reduced by half in the case of hypoglycaemia. The 216 patients were recruited in 5 centres [Shanghai (1) = 48, Shanghai (2) = 40, Beijing = 40, Canton = 42, Chengdu = 46 and randomized into treatment groups A, B, C, D (56, 56, 50 and 54 respectively). Eleven patients were withdrawn for administrative reasons. In patients treated with glibenclamide, a significant increase in weight and insulinaemia was observed, together with a significant decrease in blood glucose values; in those receiving TCT, blood glucose values were significantly decreased only 2 h after the test meal. A synergistic effect on blood glucose was observed when both treatments were given. Hypoglycaemia occurred in 19 patients (all in the two verum glibenclamide groups). This first multicentre controlled trial showed that the 3 Chinese plants tested were well-tolerated and effective in Type 2 diabetes as indicated by a significant synergistic effect in association with a sulfonylurea.

An experimental work has suggested the efficacy of metformin, an oral antidiabetic agent, on capillary permeability. This agent has been tested in 10 women patients with cyclic edema, 7 of them being obese. The capillary permeability to albumin studied by an isotope test derived from Landis's method was initially increased. After a mean of six-weeks of treatment the albumin retention and an index demonstrating the interstitial protein elimination through the lymph route were significantly improved. Concomitantly, the swelling feelings were reduced in 8 cases and the lower limb edema had decreased or disappeared in 8 of 9 patients who initially presented these symptoms. The effects of metformin are beneficial and have been observed to be independent of glycemic change. The results suggest a special effect of this agent on the microcirculation. Nevertheless, a controlled study is required.

Objective: The aim of this work was to determine the presence and prevalence of alterations in cardiac autonomic function in obese, non-diabetic subjects., Subjects: These were 121 obese people, 15 with glucose intolerance and none with diabetes, and a group of 40 healthy people., Measurements: A series of five standardized tests was carried out, three of which were based mainly on parasympathetic control (heart rate response to Valsalva, deep breathing and lying-to-standing) and two on cardiovascular sympathetic function (blood pressure response to standing and to handgrip)., Results: The response to the deep breathing test correlated negatively with age, as it did in control subjects. At least one parasympathetic test, age-adjusted, was abnormal in 49 patients (40.5%). Five other patients had an abnormal handgrip test, and no patient had orthostatic hypotension. No correlation was found between the parasympathetic test results and sex or body mass index. Prevalence of cardiac autonomic dysfunction, considered to be present when at least one parasympathetic test was abnormal, did not differ according to a gynoid or android type of obesity. A significant negative correlation was found between heart rate response to deep breathing and fasting glycemia., Conclusion: It was concluded that cardiac autonomic dysfunction evidenced by means of simple, reliable, reproducible tests is frequent in the non-diabetic obese subject. This disorder could explain the poor cardiovascular prognosis associated with obesity. Whether it is a complication of obesity or a marker associated with certain kinds of obesity (of hypothalamic origin) remains to be clarified.

Anti-thyroid hormone autoantibodies are occasionally found in Hashimoto's disease. They can interfere with thyroid hormone assays. The authors report the case of a 35-year-old hypothyroid (TSH between 29 and 46 microIU/ml) female patient with Hashimoto's disease and surprisingly high free and total levels of plasma T4 and T3 assayed with different solid phase radio-immunologic kits. Two immunoenzymologic assay kits gave a T4 level close to the one expected. The presence of circulating anti-T4, T3 and reverse T3 autoantibodies was demonstrated by precipitating the corresponding tracers with the patient's serum in the presence of polyethylene glycol without heterologous antibodies. The replacement treatment of 150 micrograms l-thyroxine allowed normalization of TSH at 3.4 microIU/ml, but the patient remained tired and anxious, with headaches and tachycardia. After discontinuing treatment for one month a series of four plasma exchanges was carried out in six days. After the first exchange the binding percentages were already much lower and went even lower after the other exchanges. After the fourth one, the free T4 and T3 levels were closer to the expected levels:7.3 pmol/l (N:10-30 pmol/l) and 4.3 pmol/l (N:3-9 pmol/l). Treatment by prednisone made it possible to maintain the percentages of binding to the three tracers for two weeks at the levels reached after the fourth plasma exchange. Two months after discontinuing corticosteroid treatment they returned to the initial levels and were again interfering with the free T4 and T3 assays. This finding suggests that usefulness of the thyroid hormone immuno-enzymologic assay, which apparently is not affected by the anti-thyroid hormone autoantibody interference.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a patient with bilateral testicular tumors and congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Catheterization of the left testicular and adrenal veins was performed. The presence of 11 beta-hydroxylated steroids in the spermatic veins confirmed the presence of testicular tumor secondary to adrenal rest cells. After adrenal suppression by dexamethasone combined with gonadal stimulation with hCG, a dramatic decrease in androgens and adrenal steroids was observed in the peripheral blood. Compared to the periphery, 21-deoxycortisol and 11 beta-hydroxy-delta 4-androstenedione levels remained higher than that of 21-deoxycorticosterone in the gonadal vein, but not in the adrenal vein, which seems to indicate that the nature of this ectopic tissue is unusual and that its sensitivity to dexamethasone depends on the adrenocortical zones. No rise in estradiol or testosterone was obtained after hCG stimulation, suggesting that all of the testicular tissue was inactive or destroyed. This finding was confirmed by histological examination.

Objectives: Thyroid disorders, particularly euthyroid goiters and hyperthyroidism, can be observed in sarcoidosis. The aim of this study was to analyze the presence of thyroid stimulating antibodies (TSAb) in 21 patients with sarcoidosis. 12 patients out of 21 had simultaneous euthyroid goiter. The others were euthyroid and free of goiter., Methods: The TSAb testing was carried out using the rat thyroid fragment perifusion technique. Thyroid response to IgG was determined by the mean rate of T4 release (R) during a 30-min perifusion and the secretion peak (Imax). Antibodies inhibiting TSH binding to its receptors were also looked for., Results: Ten patients were TSAb+ and eleven were TSAb-. There was no difference between the TSAb+ and TSAb- groups in the clinical parameters for sarcoidosis, nor in the number of goiters found (n = 6 for both groups). In 5 out of the 6 cases where goiter was present in the TSAb+ group it was homogeneous and diagnosed at the same time as or after the first signs of sarcoidosis, whereas in 5 out of the 6 cases of goiter in TSAb- patients, it was nodular, diagnosed before sarcoidosis in 3 of them, endemic in one of them, and familial in another. The search for antibodies inhibiting TSH binding to its receptors was negative in 10 out of 21 patients tested., Conclusion: Although the presence of thyroid-stimulating antibodies in the serum of patients with sarcoidosis, found here for the first time, remains to be explained, it pleads in favor of the immunologic nature of the association of sarcoidosis with thyroid disorders.

The St-Vincent declaration supported by WHO/IDF Europe is a vast european program for the improvement of health care and a new strategic approach to the treatment of diabetes. The DiabCare project is to serve as a tool for verification and assessment. Continuous improvement in diabetic patient care could be facilitated by: making comparison between centres, like "looking into a mirror where one can see oneself and the others at the same time"; setting up health care networks (local, regional and national) for all the professionals involved in treating diabetes; promoting and using advanced computer techniques ("smart" health care card). DiabCare-France, created by the "Conseil Supérieur du Diabète", has completed its first task, an "inventory questionnaire", sent to 150 diabetes centres located throughout France.

This study evaluated the reproducibility of nerve function assessment in a group of 132 diabetic patients with moderate peripheral polyneuropathy. Patients were investigated at the beginning and the end of the run-in period (a 1-month placebo period) of a multicentre trial of an aldose-reductase inhibitor (Ponalrestat). Reproducibility was evaluated by performing four types of tests: quantitative visual scales of symptoms, quantitative sensory assessment (vibration perception thresholds in medial malleolus and great toe, foot thermal perception threshold to hot and cold), electrophysiological investigations on the dominant side (conduction velocities and potential amplitudes of sensory and median motor nerve, sural and peroneal nerves, amplitudes of F waves of median motor and peroneal nerves) and cardiac autonomic tests (Valsalva, deep-breathing, lying-to-standing). Reproducibility was poor for symptoms, thermal sensitivity, and potential amplitudes. It was satisfactory (total coefficient of variation < 50%) for all the other parameters and even very good (total variation coefficient < 26%, intra-subject variation factors corresponding to < 56% of total variance) for velocities of sensory and median motor and peroneal nerves, the amplitudes of F waves and the three autonomic tests. For most of the parameters total variance was mainly related to inter-subject variability. However, inter-subject variability for the three cardiac autonomic tests was very low and at least one cardiac autonomic test was altered in all the patients. Inter-centre variability was low for all the parameters, except for action potential amplitudes and for F wave velocity of the median motor nerve. This study suggests those parameters that are appropriate for the assessment of diabetic neuropathy and for therapeutic trials.(ABSTRACT TRUNCATED AT 250 WORDS)

An impairment in red blood cell (RBC) deformability has been reported in several diseases and might be involved in the pathogenesis of atherosclerosis. The aim of the present study was to test in vitro the effect of two "stress hormones," norepinephrine and glucagon, on the filterability of RBCs from healthy subjects. Measurements were performed with the Hanss hemorrheometer, and results were expressed as the rigidity index (RI). All concentrations of norepinephrine from 10(-7) to 10(-4) mol/L induced a significant increase in RI compared with Hanks buffer, with the maximal effect being reached using 10(-6) mol/L. All concentrations of glucagon from 0.01 to 5 ng/mL also induced a significant increase in RI, with the maximal effect being achieved using 1 ng/mL. These data suggest that these two stress hormones could be involved in the rheologic impairments found in several diseases and therefore in the pathogenesis of atherosclerosis.

Evidence is increasing for small-vessel disease and disturbance of endothelium-dependent vasodilation in diabetic patients. The aim of this study was to compare coronary circulation in 11 diabetic patients (6 type I and 5 type II) and 7 control subjects. All patients had normal left ventricular systolic function and angiographically normal coronary arteries. To evaluate the maximal area of coronary microcirculation, coronary vascular reserve was determined by intracoronary Doppler and a maximally vasodilating dose of intracoronary papaverine (peak-to-resting coronary flow velocity ratio). To assess coronary endothelial function responses to stepwise intracoronary infusion of acetylcholine (10(-8) to 10(-5) M coronary estimated concentrations) were analyzed on four different segments in each patient by quantitative angiography. Peak-to-resting coronary flow velocity ratio was lower in diabetic patients than in control subjects (3.9 +/- 0.9 and 5.0 +/- 0.7, respectively, P < 0.02). Acetylcholine did not produce any diameter change at 10(-8) and 10(-7) M, but a progressive diameter reduction was observed at 10(-6) and 10(-5) M (-8.0 +/- 15.2%, P < 0.02 and -24.0 +/- 13.6%, P < 0.001, respectively). In control subjects, a progressive diameter dilation was produced from 10(-8) to 10(-6) M acetylcholine (5.1 +/- 3.4, 12.1 +/- 7.0, and 16.4 +/- 7.3%, respectively, all P < 0.001), and a moderate reduction was observed at 10(-5) M (-4.9 +/- 7.5%, P < 0.02). In the two groups, all segments dilated similarly after intracoronary isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)