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.

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.

Glucagon secretion induced by natural and artificial amino acids in the perfused rat pancreas.

The glucagon-secreting potency of 22 amino acids was investigated in the rat isolated perfused pancreas. Arginine and the structurally related amino acids were the most potent A2-cell stimulators that induced a biphasic and sustained glucagon release. Dose-response curver were different for L(+) and D(+)arginine, and the suppressor effect of glucose on the response to L(+) arginine was not detected in the presence of D(+) arginine or homoarginine. Citrulline was the only exception among the arginine-related amino acids; it displayed neither stimulatory nor inhibitory potency on glucagon release. The A2-cell response to D(+) amino acids and artificial analogues of arginine is a strong case for the theory of amino acid receptors' triggering the release of the hormone before (or in the absence of) further metabolism. The prominent rank of arginine and ornithine amont stimulatory amino acids and some other physiologic evidence suggest that A2-cell may play a regulatory role in the metabolsm of ammonia by the liver.

Phenformin-induced lactic acidosis in diabetic patients.

Eighteen diabetic patients with lactic acidosis (L.A.) were analyzed for possible causal factors, metabolic changes, and efficacy of treatment. An antecedent phenformin therapy was performed in fifteen cases and was associated with renal insufficiency in ten cases and liver disease in eight cases. Tissular anoxia of primary hemodynamic or respiratory origin was absent in all cases. The severe metabolic acidosis (pH m.93 +/- 0,03; HCO3-= 6 +/- 1 MM; PaCO2 = 18 +/- 2 MM. Hg) and hyperlactatemia (14.2 +/- 0.3 mM) were associated with high lactate/pyruvate ration (70 +/- 22). High alanine levels (up to 4.6 mM) were measured in some of these patients. High beta-hydroxybutrate levels were sometimes measured (up to 7.6 mM), and substantial amounts of acetoacetate were also detected in twelve cases. Glucagon level was always increased (1,050 +/- 240 pg./ml.), and insulin/glucagon ratio was low. Cortisol (49 +/- 10 mug./100 ml.) and HGH (10.8 +/- 0.6 ng./ml.) were also elevated. Increased plasma levels of phenformin were measured in five L.A. diabetic subjects (50 +/- 5 mug./ml.) by comparison with other phenformin-treated diabetic subjects. The specificity of the assay was investigated, and phenformin metabolites were characterized by thin-layer chromatography. Por the treatment of L.A., adjunction of dialysis and furosemide improved the efficacy of early and massive sodium bicarbonate infusion. It is suggested that accumulation of phenformin via renal insufficiency plays a determinant role in causing L.A. through an impairment of lactate metabolism in the liver. An accelerated epuration of the drug may be helpful in therapy of L.A. Phenformin treatment should be avoided in case of renal and/or liver insufficiency.

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.

Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with angiographically normal coronary arteries and normal left ventricular systolic function.

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)

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.

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.

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.

Soluble L-selectin level is a marker for coronary artery disease in type 2 diabetic patients.

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.

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.

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.

Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment.

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.

Evidence of direct thyroid-stimulating action of thyrotropin-releasing hormone by perifusion of rat thyroid fragments.

The possibility that TRH has a direct thyroid-stimulating action has never been reported. A number of studies have shown a rise in serum concentrations of thyroid hormone after stimulation with TRH, without a rise in TSH secretion. This has led us to test TRH with rat thyroid fragment perifusion. Significant T4 release was observed for TRH concentrations as low as 1.7 X 10(-11) M. A dose-response curve was determined. The response was immediate, reaching a peak after the sixth minute and continuing for 15 min after the stimulation had ceased. This kinetic pattern is different from the one observed with TSH and with theophylline and suggests that a different mechanism may be involved. TRH seems to be capable of directly stimulating both the secretion of the pituitary hormone (TSH) and the corresponding peripheral gland, like LHRH, which also acts directly on the Leydig cells of the testis.

Gonadal and adrenal catheterization during adrenal suppression and gonadal stimulation in a patient with bilateral testicular tumors and congenital adrenal hyperplasia.

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.

Use of the perifusion technique on rat thyroid fragments in the study of thyroid hormone secretion: short-term effects of thyrotrophin, theophylline and glucagon.

Perifusion of rat thyroid fragments was performed to study short-term effects of TSH, theophylline and glucagon on thyroid hormone secretion. This technique proved to be relatively convenient and sensitive, and gave reproducible results for at least 3 h, permitting precise kinetic studies of response to hormonal and pharmacological agents without any interference. There was a significant (P less than 0.001) linear correlation between the log TSH concentrations over the range 20-150 mu./ml and thyroid response. A second stimulation, using the same concentration of TSH, did not differ from the first stimulation if they were separated by an active 'washing' period of only 15 min. Theophylline also had a stimulating effect and like TSH induced an early release of the hormone fraction with a peak between 2 and 4 min, but it did not potentiate the TSH effect. Perifusion of rat thyroid fragments was found to be a useful tool for analysing dynamic effects of various substances. These effects were significant for periods of time as short as 20 min. Each thyroid preparation could be used a second time for another pharmacological or hormonal test. Our preliminary results also suggested that there was a direct glucagon effect on thyroid hormone secretion with a dose-response correlation.

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.

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

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

Glucagon and noradrenaline reduce erythrocyte deformability.

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.

Erythrocyte deformability in diabetes and erythrocyte membrane lipid composition.

Erythrocyte deformability was assessed in 40 diabetic patients, 24 insulin-dependent (IDD) and 16 non-insulin-dependent (NIDD), by measuring the initial filtration flow rate of whole blood, isolated red blood cells (RBC), and isolated RBC membranes with the Hanss hemorheometer, and its relationship to the plasma and ghost membrane lipid composition was investigated. RBC deformability was significantly reduced, whereas the deformability of the isolated RBC membranes did not differ significantly from the controls. In the plasma, the triglycerides were high, the high-density lipoprotein (HDL) cholesterol was reduced, and the ratio of total cholesterol over HDL cholesterol was high as compared with the controls. The RBC lipid composition expressed in mumol lipids/10(10) RBC showed significantly lower levels of free cholesterol, sphingomyelines, and phosphatidylcholine, which are the lipids principally located on the outer layer of the RBC membranes. These data suggest that in both IDD and NIDD patients, there may be a relation between these modifications in the RBC lipid composition and rheological impairment of the RBC.