Estimating COVID-19 recovery time in a cohort of Italian healthcare workers who underwent surveillance swab testing.

OBJECTIVES: The COVID-19 pandemic is putting a huge strain on the provision and continuity of care. The length of sickness absence of the healthcare workers as a result of SARS-CoV-2 infection plays a pivotal role in hospital staff management. Therefore, the aim of this study was to explore the timing of COVID-19 recovery and viral clearance, and its predictive factors, in a large sample of healthcare workers. STUDY DESIGN: This is a retrospective cohort study. METHODS: The analysis was conducted on data collected during the hospital health surveillance programme for healthcare staff at the University Hospital of Verona; healthcare workers were tested for SARS-CoV-2 through RT-PCR with oronasopharyngeal swab samples. The health surveillance programme targeted healthcare workers who either had close contact with SARS-CoV-2-infected patients or were tested as part of the screening-based strategy implemented according to national and regional requirements. Recovery time was estimated from the first positive swab to two consecutive negative swabs, collected 24 h apart, using survival analysis for both right-censored and interval-censored data. Cox proportional hazard was used for multivariate analysis. RESULTS: During the health surveillance programme, 6455 healthcare workers were tested for SARS-CoV-2 and 248 (3.8%, 95% confidence interval [CI]: 3.4-4.3) reported positive results; among those who tested positive, 49% were asymptomatic, with a median age of 39.8 years, which is significantly younger than symptomatic healthcare workers (48.2 years, P < 0.001). Screening tests as part of the health surveillance programme identified 31 (12.5%) of the positive cases. Median recovery time was 24 days (95% CI: 23-26) and 21.5 days (95% CI: 15.5-30.5) in right- and interval-censoring analysis, respectively, with no association with age, sex or presence of symptoms. Overall, 63% of participants required >20 days to test negative on two consecutive swabs. Hospitalised healthcare workers (4.8%) were older and had a significantly longer recovery time compared with non-hospitalised healthcare workers in both analyses (33.5 vs 24 days, P = 0.005). CONCLUSIONS: Recovery from COVID-19 and viral clearance may take a long time, especially in individuals who are hospitalised. To detect asymptomatic cases, screening programmes for healthcare workers is recommended.

COVID-19 pandemic: an Italian single institution's experience and lessons learned by public health residents' workforce.

Methods: We hereby provide a systematic description of the response actions in which the public health residents' workforce was pivotal, in a large tertiary hospital. Background: The Coronavirus Disease 2019 pandemic has posed incredible challenges to healthcare workers worldwide. The residents have been affected by an almost complete upheaval of the previous setting of activities, with a near total focus on service during the peak of the emergency. In our Institution, residents in public health were extensively involved in leading activities in the management of Coronavirus Disease 2019 pandemic. Results: The key role played by residents in the response to Coronavirus Disease 2019 pandemic is highlighted by the diversity of contributions provided, from cooperation in the rearrangement of hospital paths for continuity of care, to establishing and running new services to support healthcare professionals. Overall, they constituted a workforce that turned essential in governing efficiently such a complex scenario. Conclusions: Despite the difficulties posed by the contingency and the sacrifice of many training activities, Coronavirus Disease 2019 pandemic turned out to be a unique opportunity of learning and measuring one's capabilities and limits in a context of absolute novelty and uncertainty.

Effects of ACE inhibition on spontaneous and insulin-stimulated endothelin-1 secretion: in vitro and in vivo studies.

To evaluate the effect of angiotensin-converting enzyme inhibition on spontaneous and insulin-stimulated endothelin-1 (ET-1) secretion in vitro and in vivo, human endothelial cells derived from umbilical cord veins were cultured onto acellular collagen-coated permeable membrane, thus mimicking in vivo conditions with a luminal and abluminal side. Insulin (10(-6,-8,-9) mol/l) significantly stimulated ET-1 secretion by cultured cells (P < 0.05 starting from 2-h incubation). Captopril (10(-7,-8,-9) mol/l) significantly reduced both spontaneous and insulin-stimulated ET-1 secretion, while increasing nitric oxide production. Considering each cell side, captopril significantly inhibited the apical secretion of ET-1, while its effect on the basolateral compartment was modest. In the presence of D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin (10(-6) mol/l), a bradykinin B2 receptor antagonist, captopril had no effects on ET-1 and nitric oxide production and also when insulin was added to the culture media. With regard to in vivo experiments, oral captopril therapy (25 mg twice daily for 1 week) was given to normotensive (n = 5) and hypertensive (n = 6) subjects and significantly decreased plasma ET-1 concentration (normotensive subjects, before: 0.98 +/- 0.09 pg/ml; after: 0.55 +/- 0.08 pg/ml, P < 0.0001; hypertensive subjects, before: 1.05 +/- 0.03 pg/ml; after: 0.56 +/- 0.05 pg/ml, P < 0.0001). Transient hyperinsulinemia was accompanied by a significant rise in plasma ET-1 concentrations in both groups (P < 0.0001 at 180 and 210 min) before but not after captopril treatment. In conclusion, captopril inhibits both spontaneous and insulin-stimulated ET-1 secretion by endothelial cells, acting on angiotensin-converting enzyme bound to the luminal cell side. In vivo, captopril significantly reduces plasma ET-1 levels in both basal and insulin-stimulated conditions.

Plasma endothelin-1 levels in obese hypertensive and normotensive men.

Plasma endothelin-1 (ET-1) levels were studied in 15 obese hypertensive (mean age 48.5 +/- 3.9 years) and 15 obese normotensive men (mean age 49.5 +/- 3.6 years) before and after weight loss due to an 800 kcal/day diet lasting 12 weeks. Circulating peptide concentrations were also assessed in nonobese hypertensive (n = 11) and normotensive men (n = 12). Baseline plasma ET-1 levels were similar in obese hypertensive (0.87 +/- 0.22 pg/ml) and obese normotensive men (0.91 +/- 0.30 pg/ml). In seven obese hypertensive men, caloric restriction normalized blood pressure levels (systolic: from 166.6 +/- 8.1 to 145.0 +/- 6.3 mmHg, P < 0.0001; diastolic: from 106.6 +/- 5.1 to 89.1 +/- 2.0 mmHg, P < 0.0001) and decreased body mass index (BMI) (from 33.4 +/- 1.6 to 29.6 +/- 2.1 kg/m2, P < 0.002) and plasma ET-1 levels (from 0.93 +/- 0.21 to 0.64 +/- 0.26 pg/ml, P < 0.05). In the remaining obese hypertensive men (n = 8), blood pressure levels were not normalized by caloric restriction despite a significant decrease of BMI and plasma ET-1 levels (from 0.83 +/- 0.23 to 0.60 +/- 0.16 pg/ml, P < 0.04). Weight loss also significantly decreased BMI and ET-1 (from 0.91 +/- 0.30 to 0.65 +/- 0.19 pg/ml, P < 0.01) in obese normotensive men. Baseline ET-1 and fasting insulin levels were significantly correlated in obese hypertensive (r = 0.518, P < 0.05) and obese normotensive men (r = 0.535, P < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between insulin resistance and nonmodulating hypertension: linkage of metabolic abnormalities and cardiovascular risk.

Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.

Endogenous insulin modulates circulating endothelin-1 concentrations in humans.

OBJECTIVE: To assess the effect of oral glucose loading on plasma endothelin-1 (ET-1) levels in humans. RESEARCH DESIGN AND METHODS: A total of 75 g D-glucose was given orally to 14 nonobese nondiabetic essential hypertensive subjects (eight men and six women, mean age 43.1 +/- 3.0 years) and eight normotensive subjects (four men and four women, mean age 45.2 +/- 4.1 years). Blood samples for plasma ET-1 measurement were drawn every 30 min for 2 h and then at 180 and 240 min. RESULTS: After glucose load, insulin increased more significantly in hypertensive subjects than in normotensive subjects at times 60 (P = 0.004) and 90 (P = 0.001) min. Glucose loading was followed by a mild but significant increase in circulating ET-1 levels in both groups (hypertensive subjects, from 0.87 +/- 0.25 pg/ml at time 0 to 1.64 +/- 0.33 pg/ml at 120 min and 1.74 +/- 0.38 pg/ml at 180 min, P < 0.05; normotensive subjects, from 0.82 +/- 0.38 pg/ml at time 0 to 1.42 +/- 0.18 pg/ml at 180 min, P < 0.05). Whereas baseline ET-1 levels were similar between the two groups, postload ET-1 levels were higher in hypertensive subjects than in normotensive subjects (P = 0.003 at 120 min; P = 0.04 at 180 min). CONCLUSIONS: This study indicates that significant changes in circulating ET-1 levels occur after oral glucose loading, probably due to a glucose-induced increment in endogenous insulin concentration.

Circulating catecholamines and metabolic effects of captopril in NIDDM patients.

OBJECTIVE: To evaluate the effects of captopril on circulating catecholamine levels in NIDDM patients and the possible relationship between captopril-related changes in circulating catecholamine levels and insulin sensitivity. RESEARCH DESIGN AND METHODS: Fourteen nonobese normotensive NIDDM men (aged 44.5 +/- 5.1 years) underwent a 2-h euglycemic-hyperinsulinemic clamp (40 mU.m-2.min-1). Baseline evaluation of insulin sensitivity was followed by the random assignment of each patient to either captopril or placebo treatment, according to a crossover double-blind design. Euglycemic-hyperinsulinemic clamp studies were then repeated for all patients after both placebo and captopril treatments. Plasma norepinephrine (NE) and epinephrine (E) levels were assessed before, during, and after each clamp. RESULTS: Resulting data showed that plasma catecholamine levels increased during baseline euglycemic-hyperinsulinemic clamp (NE: +23.6% time 0 vs. time 120 min, P < 0.05; E: +24.8% time 0 vs. time 120 min, P < 0.05). Captopril treatment significantly increased total glucose uptake (from 19.0 +/- 9.0 to 26.8 +/- 10.1 mmol.kg-1.min-1, P < 0.05) and reduced baseline plasma NE (P < 0.001) and E (P < 0.05) levels. However, the magnitude of the NE (+25.7% time 0 vs. time 120 min, P < 0.001) and E (+27.2% time 0 vs. time 120 min, P < 0.05) increments during euglycemic hyperinsulinemia were not affected by the drug. Percentage changes in the ratio of total body glucose uptake to circulating insulin levels and corresponding decrements of baseline plasma E levels after captopril therapy were negatively correlated (r = -0.57, P < 0.05). CONCLUSIONS: The reduction of circulating catecholamines could contribute, at least in part, to the captopril-related amelioration of insulin sensitivity.

Atrial natriuretic factor in hypertensive and normotensive diabetic patients.

OBJECTIVE: To evaluate plasma atrial natriuretic factor (ANF) behavior in hypertensive patients with either insulin-dependent (type I) or non-insulin-dependent (type II) diabetes. RESEARCH DESIGN AND METHODS: Plasma ANF levels were measured in euglycemic normotensive patients (n = 18) and hypertensive patients (n = 18), in diabetic normotensive patients (type I diabetes, n = 12; type II diabetes, n = 12), and in diabetic hypertensive patients (type I diabetes, n = 12; type II diabetes, n = 22). In all groups, plasma ANF levels were determined at the end of a normal NaCl diet period (120 mmol NaCl per day for 10 days) in both the supine and the upright positions. RESULTS: Plasma ANF levels were significantly higher (P < 0.05) in hypertensive euglycemic patients (supine vs. upright: 13.4 +/- 6.7 vs. 8.5 +/- 4.3 fmol/ml) than in normotensive type I diabetic patients (supine vs. upright: 8.6 +/- 2.2 vs. 5.9 +/- 2.9 fmol/ml) but not in euglycemic normotensive subjects (supine vs. upright: 11.4 +/- 5.1 vs. 7.6 +/- 5.8 fmol/ml) and normotensive type II diabetic patients (supine vs. upright: 10.1 +/- 4.1 vs. 7.9 +/- 4.1 fmol/ml). Moreover, in the normotensive groups plasma ANF levels did not significantly differ among euglycemic type I and type II diabetic patients. However, the highest levels of plasma ANF were observed in hypertensive type II diabetic patients (supine vs. upright: 16.9 +/- 7.4 fmol/ml [P < 0.01 vs. euglycemic normotensive subjects, P < 0.0001 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients and normotensive type II diabetic patients] vs. 11.6 +/- 2.9 fmol/ml [P < 0.005 vs. normotensive type I diabetic patients, P < 0.01 vs. hypertensive type I diabetic patients]). On the contrary, plasma ANF levels were higher (P < 0.05) in hypertensive type I diabetic patients (supine vs. upright: 10.8 +/- 1.9 vs. 6.4 +/- 2.2 fmol/ml) compared with normotensive type I diabetic patients, but not with any other patient group. A significant correlation between supine ANF and insulin levels was found in both type II diabetic (r = 0.457; P < 0.05) and nondiabetic hypertensive patients (r = 0.716; P < 0.0001). CONCLUSIONS: These findings indicate that circulating ANF levels are markedly elevated in type II diabetic patients affected by essential hypertension. On the contrary, plasma ANF levels are in the range of normality in normotensive type I and type II diabetic patients.

Circulating endothelin-1 levels increase during euglycemic hyperinsulinemic clamp in lean NIDDM men.

OBJECTIVE: To evaluate whether or not insulin stimulates endothelin (ET)-1 secretion in vivo. RESEARCH DESIGN AND METHODS: Plasma ET-1 levels were evaluated in 16 lean normotensive men with non-insulin-dependent diabetes mellitus (NIDDM) (mean age 50.3 +/- 4.1 years) during either a 2-h euglycemic hyperinsulinemic clamp (40 mU insulin.m-2.min-1) or placebo infusion (50 ml isotonic saline) according to a single-blind randomized crossover protocol. RESULTS: Circulating ET-1 levels increased during the euglycemic hyperinsulinemic clamp (from 0.88 +/- 0.38 pg/ml at time 0 to 1.66 +/- 0.22 pg/ml and 1.89 +/- 0.99 pg/ml at 60 and 120 min, respectively [P < 0.05 vs. time 0]) and returned to baseline levels after the discontinuation of insulin infusion (0.71 +/- 0.22 pg/ml after a 30-min period of recovery [NS]). Compared with placebo, the euglycemic hyperinsulinemic clamp induced a significant increase in plasma ET-1 levels at 60 min (P < 0.0001) and 120 min (P < 0.0001). Changes in basal insulin levels and corresponding changes in circulating ET-1 levels after a 2-h euglycemic hyperinsulinemic clamp were significantly correlated (r = 0.771, P < 0.0001). A possible unfavorable effect of ET-1 on the tissue sensitivity to insulin-stimulated glucose uptake was suggested by the presence of a negative correlation between total glucose uptake and baseline ET-1 levels (r = -0.498, P < 0.05). CONCLUSIONS: Our findings indicate that circulating ET-1 levels significantly increase during euglycemic hyperinsulinemic clamp in men with NIDDM. The negative correlation between total glucose uptake and circulating ET-1 levels suggests that the peptide might exert negative effects on the insulin sensitivity of target tissues. The consequent increase in insulin secretion as well as the insulin-related ET-1 release from endothelial cells could favor the development of diabetes-related vascular lesions.

Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.

OBJECTIVE: To determine the isotypes and clonality of antibodies to GAD (GADA) and IA-2 (IA-2A) in patients with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and IA-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed prospectively. RESULTS: GADA or IA-2A were detected in 37 (71%) type 1 diabetic patients compared with only 10 (5%) type 2 diabetic patients (P<0.0001). Both GAD and IA-2 antibodies, regardless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less prevalent than IgG1 (P<0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. CONCLUSIONS: These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.

Early upregulation of endothelial adhesion molecules in obese hypertensive men.

Upregulation of endothelial adhesion molecules is the earliest step of atherogenesis. Whether obesity induces endothelial adhesin upregulation is unknown. To address this topic, circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor (vWF) concentrations were evaluated in 22 obese hypertensive (51.4+/-4.6 years [mean+/-SD age]), 19 obese normotensive (50.6+/-3.8 years), 18 nonobese hypertensive (52.3+/-3.9 years), and 16 nonobese normotensive (52. 4+/-3.5 years) men without other risk factors or overt atherosclerosis. All measurements were repeated in the obese subgroups after weight loss induced by 12 weeks of caloric restriction. Basal circulating VCAM-1 levels were similar between the 2 obese groups but were higher (P<0.0001) than in the 2 nonobese groups. No differences were found between nonobese hypertensives and normotensives. Serum low density lipoprotein cholesterol was weakly correlated with plasma soluble VCAM-1 levels in pooled, obese subjects (r=0.362, P=0.02). Plasma soluble adhesin and vWF concentrations decreased significantly after weight loss in obese hypertensives (VCAM-1 P=0.03, ICAM-1 P=0.004, E-selectin P<0.0001, and vWF P=0.003) and normotensives (VCAM-1 P=0.04, ICAM-1 P=0.003, E-selectin P<0.0001, and vWF P<0.0001). Body mass index was correlated with plasma E-selectin concentrations at baseline and after weight loss in obese hypertensives (r=0.501, P=0.018 and r=0. 466, P=0.03, respectively) and obese normotensives (r=0.523, P=0.021 and r=0.460, P=0.05, respectively). In conclusion, our data show that obesity per se induces early endothelial activation in hypertensive and normotensive men. Weight loss counteracted endothelial activation in both obese hypertensive and normotensive men.

Insulin stimulates endothelin-1 secretion from human endothelial cells and modulates its circulating levels in vivo.

Endothelin-1 (ET-1) is a potent vasoactive and mitogenic peptide produced by the vascular endothelium. In this study, we evaluated whether insulin stimulates ET-1 secretion by human endothelial cells derived from umbilical cord veins and by human permanent endothelial hybrid cells Ea.hy 926. Moreover, to provide evidence that insulin may stimulate ET-1 secretion in vivo, plasma ET-1 levels were evaluated in 7 type II diabetic normotensive males (mean age, 54.3 +/- 4.0 yr) during 2-h hyperinsulinemic euglycemic clamps (287 pmol insulin/m2.min-1) as well as in 12 obese hypertensive males (mean age, 44.2 +/- 4.6 yr) before and after a 12-week period of caloric restriction. Our results showed that insulin stimulated ET-1 release from cultured endothelial cells in a dose-dependent fashion. ET-1 release persisted for 24 h and was also observed at physiological insulin concentrations (10(-9) mol/L). The insulin-induced ET-1 secretion was inhibited by genistein, a tyrosine kinase inhibitor, and by cycloheximide, a protein synthesis inhibitor, suggesting that it requires de novo protein synthesis rather than ET-1 release from intracellular stores. In the in vivo experiments, plasma ET-1 levels rapidly increased during euglycemic hyperinsulinemic clamps (from 0.76 +/- 0.18 pg/mL at time zero to 1.65 +/- 0.21 pg/mL at 60 min; P < 0.05) and persisted elevated until the end of insulin infusion (1.37 +/- 0.37 pg/mL at 120 min; P < 0.05 vs. time zero). In obese hypertensives, plasma ET-1 levels significantly decreased after 12 weeks of caloric restriction (from 0.85 +/- 0.51 to 0.48 +/- 0.28 pg/mL; P < 0.04). The decrease in body weight induced by caloric restriction was accompanied by a significant reduction in fasting insulin levels (from 167.2 +/- 94.0 to 98.9 +/- 44.9 pmol/L; P < 0.05) which correlated with the reduction in plasma ET-1 levels (r = 0.78; P < 0.003). In conclusion, our data show that insulin stimulates both in vitro and in vivo ET-1 secretion. Such interaction could play a significant role in the development of atherosclerotic lesions in hyperinsulinemic conditions.

Salicylate hydroxylation as an early marker of in vivo oxidative stress in diabetic patients.

In vivo metabolism of salicylic acid produces two main hydroxylated derivatives (2,5- and 2,3-dihydroxybenzoic acid). The former can be produced by enzymatic pathways through the cytochrome P-450 system, while the latter is reported to be solely formed by direct hydroxyl radical attack. Therefore, measurement of 2,3-dihydroxybenzoate, following oral administration of salicylate in its acetylated form (aspirin), has been proposed for assessment of oxidative stress. In this article we report plasma levels of 2,3- and 2,5-dihydroxybenzoates following the administration of 1 g aspirin and plasma levels of thiobarbituric acid-reactive material (TBARM) in well-controlled diabetic patients and in healthy subjects. 2,3-Dihydroxybenzoate levels were significantly higher (23%) in diabetic patients than in controls (63.4 +/- 20.1 versus 49.0 +/- 6.8 nM; p < .05). On the other hand, TBARM values were not significantly different between groups. These results suggest that the method is useful to reveal in vivo oxidative stress independently from the peroxidation of lipids, and they support the hypothesis that oxygen radicals are involved in the pathogenesis of chronic complications of diabetes.

Changes of the intralymphocytic sodium concentration after acute and chronic captopril administration.

The effect of captopril on intralymphocytic sodium concentration in hypertensive subjects was studied. After acute and chronic treatment the intralymphocytic sodium content decreased. The possibility is discussed that a similar decrease might also occur in smooth muscle cells, thus enhancing the hypotensive effect of captopril.

Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study)

OBJECTIVE: Protection of residual beta cell function at the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) by intensive insulin therapy and the addition of nicotinamide (NA) has been established. The objective of this study was to evaluate the effect of a free oxygen radical scavenger such as vitamin E (Vit E) on residual beta cell function and parameters of metabolic control in patients with recent onset IDDM undergoing intensive insulin therapy. DESIGN: The effect of Vit E was compared with that of NA (control group) in a randomized multicentre trial. METHODS: Eighty-four IDDM patients between 5 and 35 years of age (mean age 15.8 +/- 8.4 (s.d.) years) entered a one year prospective study. One group of patients (n = 42) was treated with Vit E (15 mg/kg body weight/day) for one year; the other group (n = 42) received NA for one year (25 mg/kg body weight/day). All patients were under intensive insulin therapy with three to four injections a day. Basal and stimulated (1 mg i.v. glucagon) C-peptide secretion, glycosylated haemoglobin and insulin dose were evaluated at diagnosis and at three-monthly intervals up to one year. RESULTS: Preservation and slight increase of C-peptide levels at one year compared with diagnosis were obtained in the two treated patient groups. No statistically significant differences were observed in basal or stimulated C-peptide levels between the two groups of patients for up to one year after diagnosis. Glycosylated haemoglobin and insulin dose were also similar between the two groups; however patients receiving Vit E under the age of 15 years required significantly more insulin than NA-treated patients one year after diagnosis (P < 0.04). CONCLUSIONS: Our data indicate that Vit E and NA possess similar effects in protecting residual beta cell function in patients with recent onset IDDM. Since their putative mechanism of protection on beta cell cytotoxicity is different, combination of these two vitamins may be envisaged for future trials of intervention at IDDM onset.

Circulating endothelin-1 levels in lean non-insulin-dependent diabetic patients. Influence of ACE inhibition.

To evaluate the effect of captopril on plasma endothelin-1 (ET-1) levels and insulin sensitivity, 15 lean normotensive men (51.6 +/- 3.8 years) affected by non-insulin-dependent diabetes mellitus (NIDDM) underwent 2-h euglycemic hyperinsulinemic clamp. Each patient was then assigned to receive either captopril (25 mg twice daily for 1 week) or placebo, in a double-blind randomized fashion, before repeating clamp. At baseline, plasma ET-1 levels were 0.77 +/- 0.25 pg/mL in captopril (n = 10) and 0.83 +/- 0.3 pg/mL in placebo patients (n = 5). A twofold increase in plasma ET-1 levels occurred during the 2-h insulin infusion in both groups (P < .05 after 60 and 120 min), with a rapid return to baseline after 30 min from insulin withdrawal. After 1 week of therapy, total glucose uptake significantly increased in captopril (from 3.71 +/- 1.70 mg/kg/min to 4.24 +/- 1.72 mg/kg/min, P < .03) but not in placebo patients. Plasma ET-1 levels significantly decreased after captopril therapy (0.48 +/- 0.25 pg/mL at time 0, P < .03 v pretreatment levels), but were unaffected by placebo. Moreover, captopril slightly reduced the magnitude of ET-1 increment during insulin infusion (0.65 +/- 0.28 pg/mL and 0.88 +/- 0.48 pg/mL at 60 and 120 min, respectively, P < .05 v time 0). As a consequence, during the second insulin infusion circulating ET-1 levels were significantly lower in captopril- than in placebo-treated patients at time 0 (P < .02), 60 (P < .002), 120 (P < .004), and 150 min (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Octreotide, a somatostatin analog, reduces insulin secretion and increases renal Na+ excretion in lean essential hypertensive patients.

The influence of insulin on renal Na+ excretion is still subject to debate. In order to evaluate the effect of insulin suppression on Na+ excretion, 20 never-treated essential hypertensive men and 8 normotensive men were studied. All subjects had a body mass index < 27 kg/m2. Both the glucose and the lipid metabolisms were normal. After 2 weeks under normal NaCl intake (120 mEq NaCl daily), either octreotide, a somatostatin analog, or vehicle were infused in a forearm vein during acute volume expansion (0.30 mL/kg/min isotonic saline given intravenously over a period of 30 min). A double-blind randomized cross-over design was followed, and each subject was given both infusions at a 1 week interval. Blood and urine samples were taken at times--60, 0, 30, 60, 90, 120, 180, 240, and 300 min. Our data showed that octreotide significantly lowered insulin levels in both hypertensives (from 12.2 +/- 2.4 microU/mL at time 0 to undetectable values at time 30 and 60 min) and normotensives (from 11.5 +/- 2.8 microU/mL at time 0, to undetectable values at time 30 and 60 min). Compared to saline infusion alone, octreotide significantly increased Na+ excretion in both hypertensives and normotensives (saline + octreotide v saline alone = P < .05 at time 60 and 90 min). In conclusion, octreotide enhanced the natriuretic response to intravenous Na+ load in both hypertensives and normotensives. The increase in urinary Na+ was accompanied by a significant decrease in plasma insulin levels.

Plasma insulin levels do not change during atrial natriuretic factor infusion in human essential hypertensives.

In order to evaluate the effects of atrial natriuretic factor (ANF) infusion on plasma insulin (IRI) in hypertension, 32 essential hypertensives (aged 40 to 62 years) were studied. After 1 week of pharmacologic washout under normal sodium intake (120 mEq of Na+/day), patients were randomly assigned to receive either ANF (0.04 micrograms/kg/min) or its vehicle (50 mL of isotonic saline) over a 60-min period in supine position. Plasma IRI and glucose were measured at -60, 0, 20, 40, 60, 120, 180, and 240 min (infusion time: from 0 to 60 min). Plasma levels of IRI and glucose did not change significantly during ANF infusion. On the contrary, after ANF discontinuation plasma IRI rose from levels of 13.5 +/- 6.4 microU/mL at 60 min to values of 20.1 +/- 11.3 microU/mL at 240 min (P less than .0001 v time 0). Plasma glucose showed a similar behavior, increasing from values of 100.4 +/- 5.0 mg/dL at 60 min to values of 120.0 +/- 5.1 mg/dL at 240 min (P less than .02 v time 0). Our findings suggest that ANF did not influence insulin release in hypertensives. The increase of plasma glucose and IRI observed after ANF discontinuation could be due to the relapse of sympathetic activity, suppressed during ANF infusion.

Does mild autonomic neuropathy affect atrial natriuretic factor regulation in diabetic hypertensive patients?

The effect of postural changes on plasma atrial natriuretic factor (ANF) levels was investigated in 16 diabetic hypertensives (eight with and eight without mild autonomic neuropathy) and in 10 hypertensives. The presence of renal damage or secondary hypertension was excluded. All diabetic patients were in good metabolic control. In upright position, the mean levels of plasma ANF were of 23.1 +/- 7.6 pg/mL in neuropathic diabetic hypertensives, 24.2 +/- 8.3 pg/mL in diabetic hypertensives, and 21.6 +/- 6.7 in essential hypertensives. Percentage decrease observed after the assumption of supine position was 47 +/- 18, 50 +/- 10, and 46 +/- 13, respectively. No significant difference was found between hypertensives and diabetic hypertensives, even in the presence of mild autonomic neuropathy. Plasma ANF response to postural changes was similar in all groups.

Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy.

To evaluate the role of circulating and renal endothelin-1 (ET-1) in early diabetic nephropathy, plasma ET-1 levels and urinary ET-1 excretion were evaluated in lean, normotensive patients affected by non-insulin-dependent diabetes (NIDDM) either with (n = 9, NIDDM+) or without microalbuminuria (n = 18, NIDDM-); in never-treated, lean, essential hypertensive patients with (n = 12, EH+) or without microalbuminuria (n = 10, EH-); and in healthy volunteers (n = 12). Results showed higher plasma ET-1 levels in NIDDM+ (1.97 +/- 0.58 pg/mL) than in NIDDM- (1.59 +/- 0.14 pg/mL, P = .013), EH+ (1.40 +/- 0.21 pg/mL, P = .005), EH- (0.91 +/- 0.19 pg/mL, P < .0001), and controls (0.60 +/- 0.10 pg/mL, P < .0001). The circulating ET-1 concentration was also higher in EH+ than EH- and controls (P < .0001). Urinary ET-1 excretion did not differ (P = .387, NS) between NIDDM+ (48.5 +/- 20.1 pg/min) and NIDDM- (40.9 +/- 21.6 pg/min), but was significantly reduced (P < .0001) in both groups compared with controls (70.0 +/- 15.5 pg/min). Similar findings were observed in hypertensive subgroups. No correlations were found between urinary ET-1 and other variables, including plasma ET-1 levels, in all groups. In conclusion, NIDDM+ is accompanied by a significant increase in plasma ET-1 levels. A significant elevation of circulating ET-1 concentration was evident also in NIDDM-, suggesting that early abnormalities of ET-1 production might precede the microalbuminuric phase of diabetes-related renal damage.