Recent studies have reported a high incidence of postoperative unfavorable cardiac-related events in patients with diabetes who underwent coronary artery bypass grafting (CABG). Structural and functional characteristics of CABG conduits, which have been shown to play an important role in patient outcome after myocardial revascularization, have not been fully investigated in diabetic subjects. Therefore, we sought to determine the influence of adult-onset diabetes on vasoreactivity and morphological profile of venous and arterial grafts. Of the 160 consecutive patients enrolled in the study, 90 were diagnosed with type 2 diabetes and 70 did not have diabetes (control group). All patients underwent evaluation of glucose control before surgery. Tissue specimens were collected from left internal thoracic artery (LITA) and saphenous vein (SV) grafts harvested during elective CABG. Functional tests were performed to assess contractile and vasodilative responses of bypass conduits. Histological evaluation was carried out to examine vessel wall structure. Univariate and multivariate analyses were performed to correlate the preoperative factors related to the control of the endocrine disorder with histological findings. Patient medical history and demographics did not differ between the groups. Diabetic patients showed significant microalbuminuria and higher plasma levels of C-peptide and GHb as compared with nondiabetic subjects. Functional tests of the LITA segments revealed no difference between groups with regard to contractile and vasodilative responses. In contrast, significant impairment in the endothelium-related vasodilation of the SV grafts was observed in diabetic subjects. Histological studies showed structural preservation of the arterial conduits in both groups. However, marked intimal abnormalities (also atherosclerotic calcified plaques) were detected in SV grafts harvested from diabetic patients. Logistic regression analysis showed that high levels of proteinuria and GHb were independent predictors of advanced structural degeneration of SV conduits. Treatment modality, duration of diabetes, and other demographic or metabolic factors were found to have no influence on the morphological characteristics of SV conduits. In conclusion, biological properties of LITA conduits for CABG were preserved in diabetic patients. However, these patients frequently showed impairment of the endothelium-dependent vasorelaxation and intimal degeneration of SV grafts. The extent of structural abnormalities of SV grafts was inversely correlated with the efficacy of the metabolic control of the endocrine disorder. Further studies are required to conclusively correlate preoperative SV graft abnormalities with postoperative conduit patency rate and the occurrence of adverse cardiac-related events in diabetic subjects.

Objective: Spontaneous parathyroid hormone (PTH) secretory dynamics include tonic and pulsatile components. It is not known how glucocorticoids might alter these secretory dynamics. Design: The aim of our study was to evaluate spontaneous fluctuations in serum PTH levels in six adult male patients (aged 31-64 years) receiving chronic ( . 6 months) therapy with glucocorticoids (daily dosage . 7.5 mg of prednisone or dose equivalent of other corticosteroid) as compared with a control group of 10 age-and sex-matched normal subjects. Methods: Peripheral venous blood sampling was performed every 3 min for 6 h from 0900 to 1500 h. Plasma PTH release profiles were subjected to deconvolution analysis, a method that resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, that in turn provides an integrated measure of the serial regularity or orderliness of the release process. Results: In the glucocorticoid-treated group, the PTH tonic secretory rate was reduced (4.3^0.74 vs 8.8^1.4 pg/ml per min in controls, P ¼ 0.017). There was, however, an increase in the fractional pulsatile PTH secretion (42^8.2 vs 18.3^3.9 pg/ml per min, P ¼ 0.006) in glucocorticoid-treated vs normal subjects. Mean overall PTH concentration, as well as mean integrated area, was similar among normal and glucocorticoid-treated subjects.Conclusions: These results demonstrate, for the first time, that chronic glucocorticoid treatment induces a redistribution of spontaneous PTH secretory dynamics by reducing the amount released in tonic fashion and increasing the amount released as pulses.

The aim of this study was to examine the effect of recombinant human leptin on growth hormone (GH) secretion in perifused anterior pituitary slices from adult pigs. Anterior pituitary slices from sows were perifused and treated with recombinant human leptin (10 nM) and GH-releasing hormone (GHRH; 1 nM). In some experiments, pituitary slices were coincubated with stalk median eminence (SME). In a subset of the coincubation experiments, immunoneutralization of endogenous GHRH and somatostatin (SRIH) release was performed with antisera to GHRH and SRIH. Leptin increased GH secretion in pituitary slices alone (up to 100% vs. control at 40 min) as well as in pituitary slices coincubated with SME (up to 122% vs. control at 40 min). A significant difference was observed in GH secretion from pituitary slices when the tissue was coincubated with leptin and GHRH at a low concentration (0.1 nM), but not when GHRH was used at 1 and 10 nM. Furthermore, anti-SRIH antiserum increased GH release from pituitary slices in coincubation experiments with SME. Finally, SRIH secretion was significantly reduced by leptin (down by 35% vs. control from 0 to 30 min of treatment) in cultured SME. These data show that leptin is effective in stimulating GH secretion by acting at two different levels: (1) it stimulates GH secretion directly from pituitary slices, and (2) it reduces SRIH tone from the median eminence and, indirectly, increases GH secretion from the pituitary. These results support the hypothesis that leptin may be an interesting hormonal mediator of growth and related metabolic effects by acting directly on the hypothalamic-pituitary axis.

Abstract-Structural alterations of small resistance arteries in patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. However, we have observed the presence of hypertrophic remodeling in patients with renovascular hypertension, as well as in patients with noninsulin-dependent diabetes mellitus, suggesting a relevant effect of humoral growth factors on vascular structure. Growth hormone may stimulate in vitro proliferation of vascular smooth muscle cells. However, no data are presently available about small artery structure in acromegalic patients. Therefore, we have investigated the structure of subcutaneous small arteries in 12 normotensive (NT) subjects, in 12 EH subjects, and in 9 acromegalic patients (APs). All subjects underwent biopsy of the subcutaneous fat; then, small resistance arteries were dissected and mounted on a micromyograph. The normalized internal diameter, media thickness, media-to-lumen ratio, the media cross-sectional area together with remodeling, and growth indices were calculated. Demographic variables were similar in the three groups, except for blood pressure. The media-to-lumen ratio was significantly greater in EH and AP, compared with NT. No difference was observed between EH and AP. The media cross-sectional area was significantly greater in AP compared with EH and with NT. The calculation of remodeling and growth index suggests the presence of eutrophic remodeling in EH (growth index 0%) and of hypertrophic remodeling in AP (growth index 40%). In conclusion, our data suggest the presence of hypertrophic remodeling of subcutaneous small resistance arteries of AP, probably as a consequence of growth-stimulator properties of IGF-1. Key Words: arteries Ⅲ hypertrophy Ⅲ remodeling Ⅲ growth hormone S tructural alterations of small resistance arteries (lumen diameter: 100 to 300 m) 1 of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling (rearrangement of the same wall material around a narrowed lumen). 2,3 At variance, we have observed the presence of hypertrophic remodeling (vascular smooth muscle cell hypertrophy or hyperplasia) in subcutaneous small arteries of patients with renovascular hypertension. 4 Neurohumoral factors are probably involved in the genesis of vascular structural alterations, and growth factors, such as angiotensin II, seem to be able to induce smooth muscle cell hypertrophy. 5,6 Also, patients with noninsulin-dependent diabetes mellitus showed the presence of hypertrophic remodeling of subcutaneous small arteries, 7 suggesting, again, a relevant effect of humoral growth factors on vascular structure. In fact, insulin and insulin-like growth factor-1 (IGF-1) seem to be able to stimulate cardiac and vascular smooth muscle cell growth. 8 A weak but statistically significant correlation between mediato-lumen ratio of subcutaneous small arteries and levels of circulating insulin was observed in patients with diabetes mellitus. 7 It was previously demonstrated that growth hormone ...

The aim of this article is to briefly review the physiology of growth hormone-releasing hormone (GHRH) and the diagnosis and treatment of GHRH-mediated acromegaly. Moreover, the role of GHRH and its antagonists in the pathogenesis and treatment of cancer will be reviewed. Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. GHRH-producing neurons have been well characterized in the hypothalamus by immunostaining techniques. Hypothalamic tumors, including hamartomas. choristomas, gliomas. and gangliocitomas. may produce excessive GHRH with subsequent GH hypersecretion and resultant acromegaly. GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation and increased GH secretion. The structure of hypothalamic GHRH was infact elucidated from material extracted from pancreatic GHRH-secreting tumors in two patients with acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small-cell lung cancers, adrenal adenomas, and pheochromocitomas which have been reported to secrete GHRH. Acromegaly in these patients. however, is uncommon. In a retrospective survey of 177 acromegalic patients only a single patient was identified with elevated plasma GHRH levels. Measuring GHRH plasma levels therefore provides a precise and cost-effective test for the diagnosis of ectopic acromegaly. Peripheral GHRH levels are not elevated in patients with hypothalamic GHRH- secreting tumors, supporting the notion that excess eutopic hypothalamic GHRH secretion into the hypophyseal portal system does not appreciably enter the systemic circulation. Elevated circulating GHRH levels, a normal or small-size pituitary gland, or clinical and biochemical features of other tumors known to be associated with extrapituitary acromegaly, are all indications for extrapituitary imaging. An enlarged pituitary is, however, often found on MRI of patients with peripheral GHRH-secreting tumors, and the radiologic diagnosis of a pituitary adenoma may be difficult to exclude. Surgical resection of the tumor secreting ectopic GHRH should reverse the hypersecretion of GH, and pituitary surgery should not be necessary in these patients. Nonresectable, disseminated or reccurrent carcinoid syndrome with ectopic GHRH secretion can also be managed medically with long-acting somatostatin analogs (octreotide and lanreotide). The presence of GHRH and its receptors in several extrahypothalamic tissues, including ovary, testis and the digestive tract, suggests that GHRH may have a regulatory role in these tissues. As previously mentioned, biologically or immunologically active GHRH and mRNA encoding GHRH have been found in several human malignant tumors. including cancers of the breast, endometrium and ovary and their cell lines. The s...

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