Impact of COVID-19 in immunosuppressive drug-naïve autoimmune disorders: Autoimmune gastritis, celiac disease, type 1 diabetes, and autoimmune thyroid disease.

Few conflicting data are currently available on the risk of SARS-CoV-2 infection in patients with autoimmune disorders. The studies performed so far are influenced, in most cases, by the treatment with immunosuppressive drugs, making it difficult to ascertain the burden of autoimmunity per se. For this reason, herein we assessed the susceptibility to COVID-19 in immunosuppressive drug-naïve patients with autoimmune diseases, such as autoimmune gastritis (AIG), celiac disease (CD), type 1 diabetes (T1D), and autoimmune thyroid disease (AITD). Telephone interviews were conducted on 400 patients-100 for each group-in May 2021 by looking at the positivity of molecular nasopharyngeal swabs and/or serology for SARS-CoV-2, the need for hospitalization, the outcome, and the vaccination status. Overall, a positive COVID-19 test was reported in 33 patients (8.2%), comparable with that of the Lombardy general population (8.2%). In particular, seven patients with AIG, 9 with CD, 8 with T1D, and 9 with AITD experienced COVID-19. Only three patients required hospitalization, none died, and 235 (58.7%) were vaccinated, 43 with AIG, 47 with CD, 91 with T1D, and 54 with AITD. These results seem to suggest that autoimmunity per se does not increase the susceptibility to COVID-19. Also, COVID-19 seems to be mild in these patients, as indicated by the low hospitalization rates and adverse outcomes, although further studies are needed to better clarify this issue.

A Case of Ischemic Pituitary Apoplexy Secondary to ACTH-Secreting Macroadenoma.

Background: Pituitary apoplexy (PA) represents a rare but extremely serious complication of pituitary adenoma. It is characterized by the rapid onset of headache, nausea and vomiting, changes in vision, paralysis of the oculomotor nerves and alteration of the sensory. Due to the rarity of this complication and the non-specificity of symptoms, the patient's clinical presentation may not be interpreted correctly, leading to a diagnostic delay and a worsening of prognosis. Case Description: This case report relates to a 73-year-old man with ACTH-secreting macroadenoma infiltrating the cavernous sinuses bilaterally and causing the rapid onset of headache, bilateral eyelid ptosis, complete bilaterally ophthalmoplegia and bitemporal hemianopia. The patient underwent urgent surgery to remove the lesion by transsphenoidal route and subsequent monitoring of pituitary function by endocrinologist specialist obtaining a near-total recovery from illness. Conclusions: PA is often characterized by the appearance of unilateral ocular or neurological deficits, while a clinical presentation given by ophthalmoplegia and bilateral ptosis is a very rare condition, difficult to find in the literature. Therefore, similar symptoms should not be underestimated and should raise the diagnostic suspicion of PA. In this case, in fact, a prompt treatment and multidisciplinary management of the patient allowed to markedly improve the prognosis. Furthermore, the instrumental findings supported a picture of ischemic pituitary apoplexy without signs of haemorrhage, a condition reported only sporadically in the literature.

Evaluation of endocrinological sequelae following particle therapy performed on anterior skull base lesions in the adult population.

Background: Radiotherapy has increasingly assumed a central role in the multidisciplinary treatment of skull base lesions. Unfortunately, it is often burdened by relevant radio-induced damage to the pituitary function and the surrounding structures and systems. Patients who were treated with radiotherapy around the sellar region especially have a high risk of developing radio-induced hypopituitarism. Particle therapy has the potential advantage of delivering a higher radiation dose to the target while potentially sparing the sellar region and pituitary function. The aim of this study is to evaluate the pituitary function in adult patients who have undergone hadron therapy for anterior skull base lesions involving or surrounding the pituitary gland. Methods: This is a retrospective, observational, and noncontrolled study. We evaluated pituitary and peripheral hormone levels in all patients referring to National Center for Oncological Hadrontherapy, Pavia, Italy for anterior skull base tumors. Furthermore, we performed a magnetic resonance imaging for every follow-up to evaluate potential tumoral growth. Results: We evaluated 32 patients with different tumoral lesions with a mean follow-up of 27.9 months. The mean hadron therapy (HT) dose was 60 ± 14 Gray, with a mean dose per fraction of 2.3 ± 2.1 Gray. Six patients were treated with carbon ions and 26 with protons. Pituitary hormone alteration of some kind was reported for six patients. No patient experienced unexpected severe adverse events related to particle therapy. Conclusion: Particle radiotherapy performed on anterior skull base lesions has proved to cause limited damage to pituitary function in the adult population.

Abnormal post-prandial glucagon-like peptide release in patients with Crohn's disease.

BACKGROUND AND AIMS: Glucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn's disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients. METHODS: Fifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded. RESULTS: Basal GLP-1 levels were up-regulated in CD, however, as compared to HC, stimulated GLP-1 secretion was significantly reduced in CD (-31 %, p < 0.05) as in MS (-52 %, p < 0.003). Similarly, basal GLP-2 levels were comparable to that of HC, while response to MTT in CD was virtually absent (p < 0.05). Similar fasting insulin sensitivity, estimated 1st and 2nd phase insulin secretion and insulinogenic index were found in CD and in HC. Post-prandial GLP secretion was positively correlated to insulin secretion indices, both in CD and MS. In CD, high-sensitive C reactive protein levels (hsCRP) and extra-cellular to intra-cellular water ratio (ECW/ICW), an index of cellular inflammation, were inversely correlated with stimulated GLP-1 (p < 0.05 and p < 0.01, respectively) levels. CONCLUSION: CD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.

Fasting hyperinsulinemia associates with increased sub-clinical inflammation in first-degree relatives normal glucose tolerant women independently of the metabolic syndrome.

BACKGROUND: To evaluate the influence of gender on the relationship between inflammation and hyperinsulinemia in first-degree relatives of type 2 diabetic patients independently of metabolic syndrome. METHODS: Study group consisted in 217 first-degree relatives with normal glucose tolerance after an oral glucose tolerance test. A logistic analysis, adjusted for age, sex and all the components of the metabolic syndrome, was used to determine the relationship between interleukin-6 (IL-6) and leptin and tertiles of fasting insulin, and to take into account the influence of gender. RESULTS: In the whole cohort, IL-6 and leptin were significantly higher and adiponectin significantly lower in the III tertile when corrected for age, body mass index (BMI) and metabolic syndrome components. In women, but not in men, IL-6 and leptin remained significantly higher when corrected for metabolic syndrome. In the whole cohort and in women, univariate correlations between IL-6 concentrations and the parameters under evaluation showed that IL-6 and leptin were positively correlated with age, BMI, waist, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, fasting insulin, Delta AUC insulin area, triglyceride (TG), free fatty acids (FFA) and monocyte chemoattractant protein-1 (MCP-1) and inversely correlated with HDL cholesterol (HDL-C) and adiponectin. In women a forward stepwise linear regression analysis in a model including age, BMI, features of metabolic syndrome, fasting insulin, Delta AUC insulin and insulin sensitivity index (ISI) index revealed that only IL-6 and leptin were independently associated with fasting insulin levels. CONCLUSIONS: In first-degree relatives normal glucose tolerant women, fasting hyperinsulinemia, independently of the presence of metabolic syndrome, is associated with elevated IL-6 and leptin levels, suggesting an increased cardiovascular risk.

ACTH-dependent Cushing's Syndrome: Diagnostic Pitfalls in Concomitant Non-secreting Pituitary Adenomas.

OBJECTIVES: To describe the possible pitfalls in correctly interpreting clinical, radiological and biochemical findings in ACTH-dependent Cushing's syndrome. METHODS: We describe a case of a pituitary adenoma visualized at MRI not correlated with an ACTH-dependent Cushing's syndrome. RESULTS: Radiological imaging and hormonal testing can be misleading in suspected pituitary ACTH-related Cushing's syndrome. CONCLUSION: Correct interpretation of the initial clinical presentation can help in the proper diagnosis and treatment of ACTH-dependent Cushing's syndrome. LEARNING POINTS: Occult neoplasia should always be excluded in cases of severe ACTH-dependent Cushing's syndrome.A positive MRI result can be misleading. Ectopic ACTH-dependent syndrome is generally associated with a peculiar phenotype.

Systemic Sarcoidosis Unmasked by Cushing's Disease Surgical Treatment.

Diseases responsive to glucocorticoids, like sarcoidosis, are rarely masked by Cushing's syndrome. An ACTH secreting pituitary adenoma is a possible cause of Cushing's syndrome and its resection can make a subclinical sarcoidosis clear. Only few cases of sarcoidosis following the treatment of hypercortisolism are reported in literature. We report a case of sarcoidosis after the resection of an ACTH secreting pituitary adenoma.

Acute intravenous L-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms: correlation with asymmetric dimethylarginine levels.

BACKGROUND: We tested the hypothesis that asymmetric dimethylarginine (ADMA) levels could be elevated and influence endothelin-1 and nitric oxide release and action in patients with cardiac syndrome X (CSX). In addition, we evaluated whether an intravenous infusion of L-arginine would improve endothelial function in these subjects. METHODS AND RESULTS: Nine patients with CSX and 14 control subjects underwent a continuous infusion of L-arginine (0.125 g/min) or saline for 120 minutes. Sixty minutes after L-arginine or saline infusions, an intravenous insulin bolus (0.1 U/kg) combined with a euglycemic clamp was performed. Basal ADMA and endothelin-1 levels were higher in patients with CSX than in controls. At the end of the first hour of infusion, compared with saline, L-arginine infusion increased basal forearm blood flow, nitrite and nitrate (NOx), and forearm cGMP release and decreased endothelin-1. After insulin bolus, during saline, insulin-induced NOx, endothelin-1, and forearm cGMP release was almost abolished. Conversely, L-arginine restored a physiological profile of all endothelial variables compared with control subjects. In control subjects, compared with saline infusion, L-arginine infusion did not modify any parameter. ADMA levels were positively correlated with basal endothelin-1 levels and negatively correlated with insulin-induced incremental levels of NOx and forearm cGMP release. CONCLUSIONS: Plasma ADMA levels are increased in patients with CSX, and they are correlated with increases in endothelin-1 and reductions in insulin-induced increments in plasma NOx and cGMP, effects that are reversed by intravenous L-arginine. These data suggest that increased ADMA levels play a role in the abnormal vascular reactivity that is observed in patients with CSX.

Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting.

BACKGROUND: Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting. METHODS AND RESULTS: Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up. CONCLUSIONS: We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome.

Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 + 27A-->C), and intron 23 (IVS23 + 10G-->T) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 + 27C alleles, but not the IVS23 + 10G-->T variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two- and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 + 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes.

Insulin resistance and endothelial function are improved after folate and vitamin B12 therapy in patients with metabolic syndrome: relationship between homocysteine levels and hyperinsulinemia.

OBJECTIVE: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. DESIGN AND METHODS: A double-blind, parallel, identical placebo-drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 microg/day) for another month. RESULTS: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2+/-1.2 vs 8.8+/-0.7 micromol/l; P<0.01). A significant decrement was observed for insulin levels (19.9+/-1.7 vs 14.8+/-1.6 microU/ml; P<0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r=0.60; P<0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. CONCLUSIONS: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors.

Haemorrhagic presentation of a craniopharyngioma in a pregnant woman.

Objective. Craniopharyngioma is a rare tumour, and, consequently, acute clinical presentation and diagnosis, during pregnancy, of this pathology are quite difficult to find. Only few cases are reported in the literature, and no one describes these two conditions in association. Methods. We report a particular case of craniopharyngioma presenting both of the above conditions. Results. The patient was successfully operated with endoscopic technique. Conclusions. Rare and difficult cases, created by the superposition of different clinical conditions, need multidisciplinary management, with collaboration, integration, and cooperation between different medical specialists.

Effect of normalization of fasting glucose by intensified insulin therapy and influence of eNOS polymorphisms on the incidence of restenosis after peripheral angioplasty in patients with type 2 diabetes: a randomized, open-label clinical trial.

Primary objective was to evaluate whether an intensified insulin therapy (IIT) incorporating the target of normal fasting glucose and HbA1c levels could halve the incidence of restenosis/amputation/SCA/death at 6 months after peripheral angioplasty compared with standard care (SC) in patients with type 2 diabetes (DMT2) affected by critical limb ischemia (CLI). Forty-six consecutive patients with DMT2 and CLI were randomly assigned to a parallel, open-label study with IIT (basal-bolus glulisine + glargine administrations) or SC (glargine administration + oral antidiabetic drugs). A SNP of eNOS (rs753482-A>C) and circulating CD34(+) and CD34(+)KDR(+) progenitor cells were determined. At the end of the study, although HbA1c levels were lower in IIT than in SC (6.9 ± 1.3 % vs. 7.6 ± 1.2 %, p < 0.05), IIT did not reduce the cumulative incidence of restenosis/amputation/SCA/death (52 and 65 %, respectively, odd ratio 0.59; CI 95 %: 0.21-1.62, p = 0.59). rs753482AC+CC as compared with rs753482AA increased the cumulative incidence of restenosis/amputation/SCA/death (79 and 42 %; odd ratio 5.3; CI 95 %: 1.41-19.5, p < 0.02). Baseline CD34(+)KDR(+) were higher in rs753482AA (166.2 ± 154.0 × 10(6) events) than in rs753482AC+CC (63.1 ± 26.9 × 10(6) events, p < 0.01). At the end of the study, the highest circulating CD34(+)KDR(+) were found in IIT rs753482AA (246.9 ± 194.0 × 10(6) events) while the lowest levels were found in SC rs753482AC+CC (70.9 ± 45.0 × 10(6) events). IIT did not decrease the cumulative incidence of restenosis/amputation/SCA/death in DMT2 and CLI patients. These patients correspond to a class of fragile subjects at high risk of cardiovascular events, and new predictors of restenosis should be contemplated, such as of eNOS polymorphism, (rs753482-A>C SNP) and circulating endothelial progenitor cells.

Aerobic and resistance training effects compared to aerobic training alone in obese type 2 diabetic patients on diet treatment.

AIMS: The study was designed to compare a combined aerobic and resistance training (ART) with an aerobic training (AT) over hemodynamic, glucose metabolism and endothelial factors, adipokines and pro-inflammatory marker release in a population of obese type 2 diabetic patients. METHODS: Forty-seven patients were randomly assigned to aerobic (27 patients) or aerobic plus resistance (20 patients) exercise trainings, on the top of a diet regime. Anthropometric, metabolic, hormonal and inflammatory variables were measured at hospitalization and discharge. RESULTS: Both exercise programs equally improved body weight and fructosamine levels however ART only partially decreased HOMA index compared with AT (ART: -25% vs AT: -54%, p<0.01). Mean blood pressure (AT: -3.6 mmHg vs ART: +0.6 mmHg, p<0.05) and endothelin-1 (ET-1) incremental areas during walking test (AT: -11% vs ART: +30%, p<0.001) decreased after AT while increased after ART. Adiponectin levels increased by 54% after AT while decreased by 13% after ART (p<0.0001) and matrix metalloproteinase-2 (MMP-2), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractan protein-1 (MCP-1) levels significantly decreased in AT while increased in ART group. CONCLUSIONS: Compared with AT, ART similarly enhanced body weight loss but exerted less positive effects on insulin sensitivity and endothelial factors, adipokines and pro-inflammatory marker release.

Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass.

It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.

Incretin-based therapies in type 2 diabetes: a review of clinical results.

GLP-1 analogues (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) represent new classes of anti-diabetic agents for the treatment of type 2 diabetes. The efficacy and safety of the incretin mimetic exenatide and of the DPP-4 inhibitors, sitagliptin and vildagliptin, have been clearly demonstrated by a very large number of clinical trials. Efficacy was demonstrated in terms of reduction of HbA1c, fasting and postprandial glucose. Moreover, exenatide showed a favourable effect on weight, while DPP-4 inhibitors were neutral with respect to this outcome. The low rate of hypoglycemic events seen in all studies confirms the glucose dependent action of incretins.

Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis.

Little is known about the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms and the presence of insulin resistance and the early evolution of atherosclerosis in nondiabetic subjects with cardiovascular disease (CAD) and stent implantation. The present study was performed in an attempt to better understand whether metabolic, endothelial, and angiographic findings characteristic of subjects with cardiovascular disease and in-stent restenosis are related to NOS3 variants. This is a case-control study performed from 2002 to 2006. All subjects admitted to the study were recruited in the Nord-Centre of Italy, most from Milan and its surrounding towns. Measures of glucose tolerance, insulin sensitivity, markers of endothelial dysfunction, forearm vasodilation, and adipokine levels were determined and associated to the frequency of two single-nucleotide polymorphisms of NOS3, i.e., Glu298Asp (rs1799983, G/T) and rs753482 (intron 18 A/C). A total of 747 subjects, not known to have diabetes, were evaluated: 333 subjects had asymptomatic CAD, 106 subjects had unstable angina and were evaluated for in-stent restenosis 6 mo after stent placement, and 308 were control subjects. The presence of TT and CC minor alleles was significantly greater in case groups compared with control subjects. At phenotypic level, subjects with the polymorphisms were characterized by hyperinsulinemia and reduced reactive hyperemia, whereas increased leptin and decreased adiponectin levels were present in subjects with restenosis in the presence of reduced minimal lumen diameter and length of stenosis almost doubled. Hyperinsulinemia, endothelial dysfunction, and a more atherogenic profile seem to be peculiar features of subjects with asymptomatic CAD and restenosis carrying NOS3 gene variants.

Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency.

Patients with growth hormone deficiency (GHD) are known to have reduced life expectancy due to increased cardiovascular and cerebrovascular events. An increase in asymmetric dimethylarginine (ADMA) levels previously found in GHD patients could promote premature atherosclerosis. The aim of this study was to determine whether 6-month growth hormone (GH) replacement therapy was able to decrease ADMA levels and ameliorate endothelial dysfunction. Thirty-one GHD patients were studied before and after 6 months of GH (4 microg/[kg d], daily) replacement therapy. Reduced pretreatment levels of serum insulin-like growth factor (IGF) 1 were normalized during GH treatment (88.2 +/- 62.5 to 191.7 +/- 80.3 ng/mL, P < .0001). After 6 months of GH replacement, plasma cyclic guanosine monophosphate levels significantly increased (2.14 +/- 0.52 to 3.54 +/- 1.2 ng/mL, P < .0001), serum ADMA levels were significantly decreased (0.65 +/- 0.1 vs 0.59 +/- 0.11 mumol/L, P < .05), and arganine (Arg) to ADMA ratio was significantly higher (155 +/- 53 vs 193 +/- 61, P < .01). No changes were observed for plasma nitric oxide end products (nitrite and nitrate) levels after GH treatment (21.9 +/- 14.9 vs 24.1 +/- 19.0 mumol/L, not significant). Basal forearm blood flow remained unchanged, whereas reactive hyperemia increased from 7.30 +/- 5.31 mL/100 mL forearm per minute before GH therapy to 13.18 +/- 7.30 mL/100 mL forearm per minute after 6 months of therapy (P < .001). There was a positive correlation between IGF-1 and cyclic guanosine monophosphate (r = 0.73, P < .0001), IGF-1 and reactive hyperemia (r = 0.63, P < .0001), and IGF-1 and Arg/ADMA ratio (r = 0.44, P < .01). Conversely, a negative correlation was found between IGF-1 and ADMA levels (r = -0.41, P < .02). At the end of the study period, fat-free mass, plasma glucose, and hemoglobin A(1c) levels significantly increased, even if they were still in the reference range, suggesting moderate alteration of glucose metabolism. In conclusion, in GHD patients, GH replacement contributes to decreased, to some extent, cardiovascular risk, reducing ADMA levels and improving Arg/ADMA ratio and endothelial dysfunction.

Increased insulin-stimulated endothelin-1 release is a distinct vascular phenotype distinguishing Cushing's disease from metabolic syndrome.

OBJECTIVE: Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD). PATIENTS AND METHODS: We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers. RESULTS: Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area. CONCLUSIONS: In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.