Osteosarcopenia in acromegaly: reduced muscle quality and increased vertebral fat deposition.

PURPOSE: Musculoskeletal disorders are among the most disabling comorbidities in patients with acromegaly. This study examined muscle and bone quality in patients with acromegaly. METHODS: Thirty-three patients with acromegaly and nineteen age- and body mass index-matched healthy controls were included in the study. Body composition was determined using dual-energy X-ray absorptiometry. The participants underwent abdominal magnetic resonance imaging (MRI) for cross-sectional evaluation of muscle area and vertebral MRI proton density fat fraction (MRI-PDFF). Muscular strength was measured using hand grip strength (HGS). Skeletal muscle quality (SMQ) was classified as weak, low, or normal, according to HGS/ASM (appendicular skeletal muscle mass) ratio. RESULTS: Groups had similar lean tissues, total body fat ratios, and total abdominal muscle areas. Acromegalic patients had lower pelvic BMD (p = 0.012) and higher vertebral MRI-PDFF (p = 0.014), while total and spine bone mineral densities (BMD) were similar between the groups. The SMQ score rate was normal only 57.5% in the acromegaly group, and 94.7% of the controls had a normal SMQ score (p = 0.01). Subgroup analysis showed that patients with active acromegaly (AA) had higher lean tissue and lower body fat ratios than controlled acromegaly (CA) and control groups. Vertebral MRI-PDFF was higher in the CA group than that in the AA and control groups (p = 0.022 and p = 0.001, respectively). The proportion of participants with normal SMQ was lower in the AA and CA groups than that in the control group (p = 0.012 and p = 0.013, respectively). CONCLUSION: Acromegalic patients had reduced SMQ and pelvic BMD, but greater vertebral MRI-PDFF. Although lean tissue increases in AA, this does not affect SMQ. Therefore, increased vertebral MRI-PDFF in controlled acromegalic patients may be due to ectopic adiposity.

Changing clinical characteristics of thyroid carcinoma at a single center from Turkey: before and after the Chernobyl disaster.

AIM: The aim of the study was to determine the possible role of Chernobyl disaster on changing clinical features of thyroid carcinoma (TC) in a moderately iodine deficient region. METHODS: We retrospectively reviewed demographical features, presenting symptoms, tumor size, histopathological diagnosis and distant metastates in 160 patients with TC diagnosed between 1990-2007. We compared our findings with the database of 118 TC patients diagnosed between 1970-1990 in the same center. RESULTS: There were 123 female (76.9%) and 37 (23.1%) male patients with a mean age of 44.89±14.84. Sex distribution and age at diagnosis were similar between 1970-1990 and 1990-2007 (P=0.77 and P=0.42, respectively). Histopathological diagnoses were papillary in 114 (73.1%), follicular in 22 (14.1%), medullary in 9 (5.8%), hurthle cell in 7 (4.5%) and anaplastic TC in 4 (2.6%) patients. We observed a marked increase in papillary TC (P<0.001) and marked decreases in follicular (P<0.001) and anaplastic TC (P=0.01) compared to the period between 1970-1990. Thyroid microcarcinomas accounted for 27.1% and 37.1% of carcinomas in 1970-1990 and 1990-2007, respectively (P<0.05). CONCLUSION: We showed that incidence of papillary TC increased and incidences of follicular and anaplastic TC decreased in a period that might be affected by Chernobyl fallout in a moderately iodine deficient area. Presenting symptoms of TC have changed and microcarcinomas are diagnosed more frequently compared to past. Further large scale trials are needed to find out whether Chernobyl disaster has role on changing characteristic of TC in countries that are not very near but also not very far from Chernobyl such as Turkey.

Follow-up of pregnancy in acromegalic women: different presentations and outcomes.

Pregnancy in acromegaly is a rather rare event since the fertility is reduced in acromegalic women. Besides, metabolic complications of acromegaly are harmful to both mother and fetus. Little is known about the outcome of pregnancy in acromegalic women. Here, we report seven cases of pregnancy out of 48 acromegalic women followed for 16 years. At diagnosis, five patients had macroadenoma, one patient had microadenoma and the size of the tumor was not documented in one patient. In one patient, acromegaly was initially diagnosed during pregnancy at 29 weeks. When she was 33 weeks, she developed pituitary apoplexy and had an emergency transsphenoidal resection of her macroadenoma during which she also had a cesarian section and delivered a healthy baby girl. In the remaining six patients, pregnancy occurred 6 to 64.5 months after the adenoma resection. Three patients received radiotherapy before getting pregnant. In three patients, pregnancy occurred during bromocriptine treatment and the drug was withdrawn. In one patient, pregnancy occurred during chronic octreotide treatment and therapeutic abortion was performed. In another patient, therapeutic abortion was performed because of uncontrolled disease. In the remaining four patients, there were neither worsening of symptoms nor tumor growth. All four patients gave birth to full-term healthy infants. Out of our seven patients, two developed gestational diabetes mellitus which was controlled with diet. None of the patients had coronary artery disease, hypertension or dyslipidemia. These cases show that pregnancy might be uneventful in acromegalic women when the disease is controlled with prior surgery and radiotherapy.

Genetic Alterations in Differentiated Thyroid Cancer Patients with Acromegaly.

AIM: Acromegaly is associated with increased thyroid cancer risk. We aimed to analyze the frequency of point mutations of BRAF and RAS genes, and RET/PTC, PAX8/PPARγ gene rearrangements in patients with acromegaly having differentiated thyroid cancers (DTC) and their relation with clinical and histological features. MATERIALS AND METHODS: 14 acromegalic patients (8 male, 6 female) with DTC were included. BRAF V600E and NRAS codon 61 point mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ gene rearrangements were analyzed in thyroidectomy specimens. We selected 14 non-acromegalic patients with DTC as a control group. RESULTS: 2 patients (14.3%) were detected to have positive BRAF V600E and 3 patients (21.4%) were detected to have NRAS codon 61 mutation. NRAS codon 61 was the most frequent genetic alteration. Patients with positive mutation had aggressive histologic features more frequently than patients without mutations. Comparison of the acromegalic and non-acromegalic patients with DTC revealed that BRAF V600E mutation was more frequent in non-acromegalic patients with DTC (14.2% vs. 64.3%, p=0.02). RET/PTC 1/ 3, PAX8/PPARγ gene rearrangements were not detected in any patient. None of the patients including the patients with positive point mutations had recurrence, and local and/or distant metastasis. CONCLUSION: NRAS codon 61 is the most frequent genetic alteration in this acromegaly series with DTC. Since acromegalic patients have lower prevalance of BRAF V600E mutation, BRAF V600E mutation may not be a causative factor in development of DTC in acromegaly. Despite the relation of BRAF V600E and NRAS codon 61 mutations with aggresive histopathologic features, their impact on tumor prognosis remains to be defined in acromegaly in further studies.

Lipoatrophy induced by subcutaneous administration of octreotide in the treatment of acromegaly.

Octreotide is the first somatostatin analogue to become available for clinical use in the treatment of acromegaly. To our knowledge, there are no reports describing lipoatrophy in patients treated with octreotide. Here, we report three patients who developed lipoatrophy after treatment with subcutaneous octreotide. Three patients (all women; 36, 43, and 50 years of age) with diagnosis of acromegaly due to pituitary macroadenoma who had undergone transsphenoidal surgery and radiotherapy received subcutaneos octreotide because of uncontrolled disease. The dose of octreotide was increased gradually in all patients. Lipoatrophy was noticed around the injection sites after about 6 years, 30 months, and 4 years of subcutaneous octreotide treatment in all patients. Thereafter, subcutaneous octreotide treatment was changed to intramuscular octreotide-LAR injection in all patients. In two of them, lipoatrophy around all injection sites did not regress after about 8 and 12 months of octreotide-LAR treatment, respectively. In the third patient, lipoatrophy around the injection sites regressed after 12 months of octreotide-LAR treatment. These cases highlight a potential for subcutaneous octreotide to induce lipoatrophy. The underlying mechanism is unknown but an immunological mechanism which is seen in lipoatrophy induced by insulin may be involved in the pathogenesis. Besides; simple trauma, personal susceptibility, mistakes in the administration of the drug, a problem in drug pH, or an idiosyncratic reaction of adipocytes to octreotide or additives in the drug may have caused lipoatrophy in our patients. Lipoatrophy in these cases was observed on long-term subcutaneous octreotide administration. Although intramuscular octreotide-LAR has largely replaced subcutaneous octreotide, we suggest close clinical follow-up for lipoatrophy in patients who are still on subcutaneous octreotide.

Comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis.

OBJECTIVE: To compare the effects of erythromycin and metoclopramide on gastric emptying and symptoms of gastroparesis in diabetic patients with delayed gastric emptying. RESEARCH DESIGN AND METHODS: The study group consisted of 13 patients with symptoms of severe gastroparesis and delayed gastric emptying. Gastric emptying was evaluated using a radionuclide method, and gastrointestinal symptoms were scored. The patients were given either erythromycin (250 mg 3 times/day) or metoclopramide (10 mg 3 times/day) in random order for 3 wk, and after a washout period of 3 wk they were crossed-over to the other medication for another 3 wk. Parameters of gastric emptying were assessed before treatment and after both erythromycin and metoclopramide administration. RESULTS: The half-time of gastric emptying in diabetic subjects was 110 (77-120) min before treatment. At 60 and 90 min, the median value of residual isotope activity was 66.5 (55-83.5) and 55% (43-74.3), respectively. The half-time decreased to 55 min (28.6-115) after 3 wk of treatment with erythromycin and percentages of meal retention in the stomach at 60 and 90 min were 49.9 (38.4-70) and 40.5% (29.7-60), respectively. After taking metoclopramide, the median value of half-time was 67 min (15-115) and percentages of meal retention at 60 and 90 min were 51 (34.5-93.9) and 42% (24-71.2), respectively. When compared with baseline values a significant difference in gastric emptying parameters was found after both erythromycin and metoclopramide. A significant improvement of the total score for gastrointestinal symptoms was observed with both drugs, but this improvement was more pronounced with erythromycin. CONCLUSIONS: Erythromycin, a macrolide antibiotic and a motilin receptor agonist, appears to stimulate intestinal motility and seems to be an alternative agent for the treatment of gastroparesis caused by diabetic autonomic neuropathy.

Platelet dysfunction in type 2 diabetes.

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events.

Dermal neurovascular dysfunction in type 2 diabetes.

OBJECTIVE: To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes. RESEARCH DESIGN AND METHODS: We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques. RESULTS: Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension. CONCLUSIONS: These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes.

Radiotherapy in the management of giant pituitary adenomas.

BACKGROUND AND PURPOSE: The description of giant pituitary adenoma is not clear yet. In this study we tried to identify which adenomas can be defined as giant pituitary adenomas when tumor control and progression free survival (PFS) are taken as end points and we also tried to evaluate prognostic factors other than tumor size. MATERIALS AND METHODS: Between January 1981 and December 1997, 74 patients with pituitary macroadenomas more than 2 cm in size were treated. Of these 30 had tumors of more than 4 cm, while 44 patients were with tumors of 2-4 cm. Two patients received primary radiotherapy, while 72 were treated postoperatively. In the postoperative group, 52 patients underwent immediate radiotherapy after surgery and 20 were treated with irradiation after regrowth or progression of the tumor after initial surgery. The mean and median tumor doses were 5518 and 5425 cGy, respectively. RESULTS: Overall primary tumor control rate was 84%. The local control rates among patients with tumors more than 4 cm and among patients with tumors 2-4 cm after radiotherapy were 73 and 91%, respectively. PFS was 65% for patients who had a tumor size of more than 4 cm and 87% for the patients with tumor size of 2-4 cm (P = 0.09). Young age (<20) and tumors of unclassified histology were the bad prognostic factors. Six months after radiotherapy normalisation or improvement in hormonal hypersecretion and visual field and acuity deficits were 82 and 63%, respectively. CONCLUSION: Tumors more than 4 cm in size may be more convenient for the definition of 'giant pituitary adenoma' when tumor control and PFS are taken as the end points.

Serum levels of interleukin 6 and tumor necrosis factor-alpha in hyperthyroid patients before and after propylthiouracil treatment.

Contrary to the usual inhibitory role of tumor necrosis factor-alpha (TNF-alpha) in thyroid metabolism, it also has specific stimulatory effects in autoimmune thyroid disorders, including induction of HLA class II antigen-presenting cell-T cell interaction. Despite high intrathyroidal concentrations, various studies were not able to demonstrate high serum levels of TNF-alpha in patients with Graves' disease. To investigate this discrepancy we determined TNF-alpha and interleukin 6 (IL-6) levels in 25 hyperthyroid patients who responded to propylthiouracil treatment (16 with Graves' disease and nine with toxic multinodular goiter) and compared them with the levels found in euthyroid patients with simple diffuse goiter (n = 15) and normal healthy controls (n = 15). Median IL-6 levels were high in both Graves' disease and toxic multinodular goiter patients before propylthiouracil treatment (23 and 26.5 pg/ml, respectively). After restoring euthyroidism there was a statistically significant decline to near-normal levels (3 and 10 pg/ml, respectively). On the other hand, median serum TNF-alpha levels were high only in Graves' disease patients (20 pg/ml) and could not be normalized with antithyroid medication (20 pg/ml) compared to that of controls (5 pg/ml). Tumor necrosis factor-alpha, but not IL-6, was found to be high in the sera of Graves' disease patients when euthyroid, which may be due to an ongoing antigen-antibody interaction, a feature of autoimmune attack. It remains to be determined whether the degree of TNF-alpha and/or IL-6 elevation will be a predictor of disease recurrence.

Methods for evaluation of peripheral neurovascular dysfunction.

Measurement of skin blood flow is a sensitive marker of C-fiber neurovascular dysfunction. It precedes development of abnormalities in diabetes mellitus, correlates with in vivo indices of the metabolic syndrome, and may be a "benchmark" for future studies on agents to improve microvascular dysfunction in diabetes mellitus. Skin blood flow can be measured under basal and stimulated conditions. There are different methods of evaluation. Iontophoresis and microdialysis are novel methods of drug delivery and the latter may be used as a means of extracting analytes in the skin. Theses methods are not invasive (iontophoresis) or minimally invasive (microdialysis). They can be performed repeatedly and safely in most patients. The use of microdialysis may be limited by sampling only water-soluble molecules. An alternative to microdialysis is iontophoresis, which works better with polar molecules. A combination of microdialysis and iontophoresis techniques can be useful in assessment of the pharmacokinetics of polar and nonpolar agents and the physiology and pathophysiology of the skin neurovascular system.

Factors associated with bone metabolism in acromegalic patients: hypogonadism and female gender.

The purpose of the study was to determine the factors associated with bone metabolism in acromegalic patients. Thirty three patients with acromegaly who had been followed on a regular basis in the endocrinology clinic were enrolled for the study. Among the factors acting upon bone metabolism, age, gender, body mass index (BMI), duration and activity of the disease, length of remission, treatment modalities and functional status of the pituitary were evaluated. Their influences on the determinants of bone remodelling and bone mineral density (BMD) were tried to be elucidated. The median age of the 33 acromegalics (19 females, 14 males) was 39.73 +/- 10.1 years. Twenty-three patients (9 males and 14 females) were eugonadal. Ten patients had been diagnosed with history of at least one year of untreated hypogonadism (5 males and 5 females; for 1 - 10 years). The BMD values of the lumbar vertebrae, the femur and the radius were correlated with each other. Patients were grouped according to their T-scores as decreased, normal, and increased BMD. Groups were similar with regard to age, BMI, gender, duration of disease, and remission, GH, IGF-1, IGFBP-3 levels, markers of bone turnover. Presence of hypogonadism and duration of hypogonadism revealed statistically significant difference among the 3 groups (p = 0.005 and p = 0.035, respectively). Hypogonadal acromegalic patients had decreased BMD compared to eugonadal acromegalics and healthy population while the eugonadal female acromegalic patients revealed increased BMD of lumbar vertebrae, femur, and distal radius compared to the sex-matched healthy population.

Frequency of severe hypoglycaemia in type 1 and type 2 diabetes during conventional insulin therapy.

To determine the frequency of severe hypoglycaemia during conventional insulin therapy in juvenile-onset and adult-onset type 1 and in type 2 diabetes mellitus (DM), we retrospectively analysed the medical records of 165 Turkish diabetic patients who have been treated with conventional insulin. Patients were divided into 3 subgroups with respect to the type of diabetes: 33 had juvenile-onset Type 1 DM, 18 had adult-onset type 1 DM, and 114 had type 2 DM. The diabetic subgroups were found to be comparable with regard to mean frequency of severe hypoglycaemia (juvenile-onset type 1 DM: 0.20 episode x patient(-1) x year-1, adult-onset type 1 DM: 0.10 episode x patient(-1) x year(-1), type 2 DM: 0.15 episode x patient(-1) x year(-1)). Frequency of severe hypoglycaemia necessitating in-hospital treatment was 0.05 episode x patient(-1) x year(-1) for all diabetic subgroups. The data clearly indicate that the extent of the problem of severe hypoglycaemia during conventional insulin therapy in type 2 DM is comparable with both juvenile and adult-onset forms of type 1 DM in Turkish diabetic population.

The effect of clozapine on glucose metabolism.

Although there have been several reports that clozapine precipitated hyperglycemia and diabetic ketoacidosis in some patients, the mechanism by which clozapine impairs glucose metabolism is not known. This study investigated the effect of clozapine on glucose metabolism in six schizophrenic patients while they were free of medication and receiving 200 mg/d and 450 mg/d of clozapine. Clozapine increased mean levels of blood glucose, insulin and C-peptide. It is possible, based on these findings, that the glucose intolerance was due to increased insulin resistance.

Small fiber neuropathy and neurovascular disturbances in diabetes mellitus.

Functional and organic abnormalities in small unmyelinated C fibers are the hallmark of type 2 diabetes. These may be silent clinically or present with burning feet, neurovascular abnormalities, wherein warm, cold, and heat pain thresholds are disturbed in association with impairment in skin blood flow and loss of PGP 9.5 immunostaining nerves in the skin. There is a dysfunctional phase preceding organic structural damage to the neurovascular unit. It coexists with elements of the metabolic syndrome, particularly insulin resistance (IR), elevated systolic blood pressure, and diabetic dyslipidemia i.e. dysfunction of the neurovascular unit may contribute to IR due to compromised blood flow with decreased delivery of fuels to their target tissues. If this proves to be the case, it will become important to re-focus energies on the defective neuropeptidergic regulation of blood flow as an approach to ameliorating diabetes. Because there is a functional phase that precedes structural damage, reversibility of the defect is achievable.

Metabolic syndrome.

The metabolic syndrome is characterized by diabetes mellitus, obesity, hypertension, hyperlipidaemia and polycystic ovary syndrome. The lipid profiles of patient with metabolic syndrome is often characterized by the appearance of hypertrygliceridaemia and small, dense LDL-cholesterol, together with low HDL-cholesterol. Patients with these abnormalities are at an increased risk for premature coronary artery disease. Treatment is a multifactorial process and includes modification of lifestyle factors such as diet and physical activity, weight reduction, correction of dyslipidemia, meticulous blood pressure and glycemic control. The case of a 36-year-old woman who develops metabolic syndrome is discussed.

Frequency of insulin-dependent diabetes mellitus in Turkish adult-onset diabetic population.

The frequency of insulin-dependent diabetes mellitus in the Turkish adult-onset diabetic population has not been assessed previously. In the present study, we retrospectively evaluated the medical records of 801 Turkish patients with adult-onset (> or = 30 years) diabetes to determine the frequency of cases diagnosed as insulin-dependent diabetes. Fifty-two (6.5%) patients met our criteria of adult-onset insulin-dependent diabetes mellitus. At disease onset, 20 patients presented with ketoacidosis (38.5%), while 32 patients (61.5%) were non-ketotic. In the insulin-dependent diabetic group, islet cell antibodies were positive in 10 out of 16 (62.5%) patients studied. In contrast, none of the 16 patients had positive reactions with respect to insulin autoantibodies. Twelve out of 20 patients (60%) had glucagon-stimulated C-peptide levels above 0.6 nmol/l, suggesting a sufficient insulin secretory reserve. In view of these observations, we conclude that insulin-dependent diabetes mellitus is not rare among patients with adult-onset diabetes in the Turkish population. In a majority of cases, the disease onset is non-ketotic. Beta-cell function is relatively preserved, and insulin autoantibodies do not develop at diagnosis. In contrast, islet cell antibodies are frequently present at the onset of clinical insulin-dependent diabetes, possibly indicating continuing beta-cell destruction.

Multifocal idiopathic fibrosclerosis manifesting with Riedel's thyroiditis.

OBJECTIVE: To discuss our experience with a case of Riedel's thyroiditis manifesting in conjunction with several other fibrosclerotic lesions. METHODS: We describe a case of multifocal fibrosclerosis and its response to glucocorticoid therapy. RESULTS: A 46-year-old man with dyspnea, dysphagia, and hoarseness was found to have Riedel's thyroiditis, sclerosing cholangitis, retroperitoneal fibrosis, and renal cortical fibrosis. Treatment with high-dose glucocorticoids in the early stages of the disease and maintenance therapy with low-dose glucocorticoids in later stages of the disease had a beneficial effect. Serial follow-up assessments with determination of the erythrocyte sedimentation rate and computed tomographic imaging of the abdomen and thorax are recommended for monitoring of disease activity. CONCLUSION: Glucocorticoids are currently the treatment of choice for progressive multifocal fibrosclerosis. Accumulation of further clinical data is needed to determine more precise treatment strategies.

Cerebellar ataxia associated with hypogonadotropic hypogonadism and chorioretinopathy: a poorly recognized association.

We report a male with cerebellar ataxia, hypogonadism and chorioretinopathy. The age of onset was 12. The parents were first cousins. Endocrinologic studies demonstrated hypogonadotropic hypogonadism due to pituitary dysfunction. The ocular disorder involved the choriocapillaris and the retina. The association may represent a separate syndrome, seldom recognized in the past.

Plasma big-endothelin levels, cardiac autonomic neuropathy, and cardiac functions in patients with insulin-dependent diabetes mellitus.

BACKGROUND: The alteration of endothelin (ET) levels in diabetic patients with cardiac autonomic neuropathy (CAN) has not been studied extensively and its correlation with cardiac function parameters has not been discussed. HYPOTHESIS: The aim of the present study was to discuss the correlation between the degree of cardiac autonomic neuropathy, plasma big-ET levels, and cardiac functions in diabetic patients who were clinically free of cardiovascular disease. METHODS: Twenty subjects (32.1 +/- 7.8 years, 11 men, 9 women) with insulin-dependent diabetes mellitus (IDDM) were studied to evaluate the relationship between circulating big-endothelin (big-ET1) levels, CAN, and cardiac functions. The severity of CAN was scored according to Ewing's criteria. Cardiac functions were assessed using Doppler echocardiography. RESULTS: Left ventricular systolic function in the patient group was within normal limits and comparable with the values of the control group (n = 10). The mean E/A values of diabetics with CAN (1.15 +/- 0.33, p = 0.004) and without CAN (1.34 +/- 0.17) were significantly lower than those of controls (1.57 +/- 0.27). Diabetics with CAN had significantly higher big-ET1 values (81.1 +/- 94 pg/ml) compared with others (12.4 +/- 5.9 and 21.1 +/- 17.7 pg/ml, p = 0.04). Circulating big-ET1 levels showed a significant correlation with E/A values in the control group (p = 0.01, r = -0.7) and with peak A values (p = 0.003, r = 0.64) in diabetics. The CAN score correlated negatively with E/A values (p = 0.01, r = 0.54). CONCLUSIONS: High big-ET levels might have an important role in the pathogenesis or consequences of diastolic dysfunction in diabetics with CAN. Their role in cardiac autonomic neuropathy and diastolic dysfunction should be investigated further.