Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the majority of patients suffering from chronic pancreatitis an endocrine pancreatic insufficiency is correlated with exocrine dysfunction. The prevalence of impaired or diabetic glucose tolerance is 40-70%, half of these patients suffer from an insulin-dependent diabetes mellitus. In general the probability of endocrine insufficiency progressively increases within the ten years following diagnosis of chronic pancreatitis. Onset and severity of the endocrine dysfunction depend on parenchymal destruction of the pancreas but are also influenced by ongoing alcohol consumption. Pathological findings in the endocrine pancreas are a loss of B-cells with decrease in secretion of insulin but also a loss of B-cell responsiveness to glucose by impaired perisinusoidal diffusion. Disturbances of the enteroinsulinar axis with diminished levels of incretins due to an exocrine insufficiency are also discussed. In addition, an impaired A-cell function may be important, that is characterized by diminished levels of stimulated glucagon. Increased plasma levels of somatostatin were found, the source of which is unknown. The susceptibility to severe hypoglycemia in patients with diabetes mellitus secondary to chronic pancreatitis is higher than in Type I diabetics. This is mainly caused by the impaired glucagon secretion but also influenced by malnutrition and concomitant hepatic dysfunction due to the toxic affect of alcohol. Diagnostic procedures are the measurement of C-peptide-concentrations and profiles of blood glucose after fasting and stimulation with L-arginine or glucose. Especially in the beginning of the endocrine insufficiency the determination of basal levels of blood glucose or C-peptide are not useful. Unless treatment by diet is effective, the therapy of diabetes secondary to chronic pancreatitis should be done by insulin replacement. A certain degree of hyperglycemia may be tolerated due to the risk of hypoglycemia and the persistent alcohol consumption in these patients. Intensified insulin therapy should only be done in selected patients with good compliance. Long-term complications in patients with pancreatogenic diabetes are comparable to diabetes Type I and largely depend on the duration of the diabetes. Life expectancy is reduced, death in these patients is mainly due to persistent alcohol and nicotine abuse (cardiovascular disease, malignant tumors, etc.), in only a minority pancreatitis or diabetes (mainly hypoglycaemia) are relevant risk factors.
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PMID:[Secondary diabetes in chronic pancreatitis]. 1044 9

Cardiovascular disease is the most severe complication of acromegaly accounting for the increased mortality of these patients. Recently, the slow-release form of octreotide (OCT; Sandostatin LAR, OCT-LAR), for im injection every 28 days, was reported to induce suppression of GH levels below 7.5 mU/L (2.5 microg/L) in 39-75% of patients, and normalization of insulin-like growth factor (IGF)-I levels for age in 64-88% of patients, with an excellent patients' compliance. The aim of the present study was to investigate the early effect of OCT-LAR treatment on the left ventricular (LV) structure and performance in 15 somatostatin analog-naive patients with acromegaly (GH, 94.8 +/- 24.9 mU/L; IGF-I, 757.9 +/- 66.6 microg/L), focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy, before and after 3 and 6 months of treatment with OCT-LAR. OCT-LAR was initially administered im, at a dose of 20 mg every 28 days, for 3 months. In six patients, the dose was then increased to 30 mg every 28 days to achieve disease control, which was considered when fasting and/or glucose-suppressed GH values were below 7.5 and 3.0 mU/L, respectively, together with IGF-I values within the normal range for age. The treatment with OCT-LAR for 6 months induced a significant decrease of GH (to 12.9 +/- 3.0 mU/L) and IGF-I levels (to 340.3 +/- 40.2 microg/L) in all 15 patients. After 6 months of treatment, the percent IGF-I suppression was 52.8 +/- 4.4%, and serum GH/IGF-I levels were normalized in 9 patients. A significant decrease of LV mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness was observed in all 15 patients after 3 and 6 months of OCT-LAR treatment: LVMi was decreased by 19.1 +/- 2.0% without any difference in patients with (19.9 +/- 2.7%) or without disease control (17.8 +/- 3.3%). Among the 11 patients with LV hypertrophy, 6 normalized their LVMi after treatment. At study entry, an inadequate LV ejection fraction (LVEF) at rest (<50%) was found in 5 patients (33.3%), whereas an impaired response of LVEF at peak exercise (<5% increase of basal value) was found in 9 patients (60%). A significant increase in LVEF, both at rest (from 51.6 +/- 2.6 to 58.1 +/- 1.7%, P < 0.01) and at peak exercise (from 51.6 +/- 2.3 to 60.2 +/- 2.4%, P < 0.001) was found in patients with (as compared with those without) disease control (from 55.2 +/- 3.8 to 58.0 +/- 4% and from 61.8 +/- 4.6 to 61.8 +/- 3.4%, respectively). Among the 5 patients with inadequate LVEF at rest, all but 1 regained a normal LVEF after 6 months of treatment; whereas, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 patients normalized, 4 improved, and 2 impaired their responses after treatment. The percent of IGF-I suppression was significantly correlated with the percent increase of resting LVEF (r = 0.644, P < 0.01). Exercise duration (from 6.0 +/- 0.7 to 7.3 +/- 0.7 min) and capacity (from 69.0 +/- 8.2 to 80 +/- 7.8 watts) were increased in the 15 patients considered as a whole, but the improvement in the exercise response was significant only in patients with disease control (P < 0.01 and P < 0.05, respectively) who also had an increase in the peak ejection rate (P = 0.03). No change in hemodynamic parameters, either at rest or at peak exercise, was found after treatment with OCT-LAR in the 15 patients. In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induces a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. (ABSTRACT TRUN
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PMID:Cardiovascular effects of depot long-acting somatostatin analog Sandostatin LAR in acromegaly. 1099 98

Cardiovascular disease is a major cause of mortality and morbidity in patients with acromegaly. We describe the case of a 43-year-old man with acromegaly who presented with severe congestive heart failure. Treatment with the somatostatin analog octreotide improved cardiac function with an increase in left ventricular ejection fraction (LVEF) from 11% to 27%. LVEF further increased to 43% after trans-sphenoidal surgery. Recovery was uneventful. We emphasize the need for early diagnosis and effective treatment of acromegaly to prevent cardiovascular complications. Octreotide therapy or trans-sphenoidal surgery, if possible, should be considered to control cardiac function even in acromegalic patients with severe congestive heart failure.
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PMID:Improvement of cardiac function after treatment with octreotide followed by trans-sphenoidal surgery in an acromegalic patient who presented with congestive heart failure. 1204 92

Obese individuals tend to be both insulin resistant and at increased risk to develop cardiovascular disease (CVD). Given the increased prevalence of obesity in the US population, we thought it important to define the relationship between degree of obesity and insulin-mediated glucose disposal in the population at large, as well as the relationship between obesity, insulin resistance, and CVD risk in these individuals. To do this we quantified insulin-mediated glucose disposal in 465 healthy volunteers by determining the steady-state plasma glucose (SSPG) concentrations at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Adiposity was estimated by body mass index (BMI) and the relationship between BMI and SSPG defined. In addition, a series of CVD risk factors were measured, including blood pressure, plasma glucose, and insulin concentrations, before and after 75 g of oral glucose, and fasting plasma lipid and lipoprotein concentrations. The results indicated that SSPG concentration and BMI were significantly correlated (r = 0.54, P >.001), and 36% of individuals in the most insulin-resistant tertile were obese (BMI >/= 30.0 kg/m(2)). However, 16% of those in the most insulin-resistant tertile were of normal weight (BMI < 25.0 kg/m(2)). Although CVD risk factors were accentuated in general with progressive increases in either BMI or SSPG concentration, important differences were noted. Thus, the higher the SSPG concentration, the more the increase in plasma glucose, insulin, and triglyceride (TG) concentrations, whereas the greater the BMI, the higher the low-density lipoprotein concentration. Furthermore, while CVD risk factors increased significantly with each tertile of insulin resistance, significant differences in CVD risk were only apparent when the lowest BMI tertile was compared with the other 2, with the values in the middle and upper BMI differing from each other. These results show that while BMI and insulin resistance are related, they are not synonymous, and that they make independent and different contributions to increasing CVD risk.
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PMID:Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. 1504 98

Angiogenesis, the development of new blood vessels is a crucial process both for tumor growth and metastatic dissemination. Additionally, dysregulation in angiogenesis has been implicated in the pathogenesis of cardiovascular disease, proliferative retinopathy, diabetic nephropathy, and rheumatoid arthritis (RA). The neuropeptide somatostatin has been shown to be a powerful inhibitor of neovascularization in several experimental models. Furthermore, somatostatin receptors (sst) are expressed on endothelial cells; particularly, sst2 has been found to be uniquely up-regulated during the angiogenic switch, from quiescent to proliferative endothelium. The present manuscript reviews the anti-angiogenic activity of somatostatin and its analogues in neoplastic and nonneoplastic disease. The role of sst subtypes particularly sst2 in mediating its angioinhibitory activity is described. Somatostatin agonists may also exert their anti-angiogenic activity indirectly by inhibition of growth factors like vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis or through its immunomodulatory effects. However, the therapeutic utility of somatostatin agonists as anti-angiogenic drugs in these diseases remains confusing because of conflicting results from different studies. More basic research, as well as patient-oriented studies, is required to firmly establish the clinical potential of somatostatin agonists in therapeutic angiogenesis. The currently available somatostatin agonists have high affinity of sst2 with lower affinities for sst3 and sst5. The emergence of novel somatostatin agonists especially bispecific analogues (agonists targeting multiple cellular receptors) and conjugates (synthesized by chemically linking somatostatin analogues with other antineoplastic agents) with improved receptor specificity signify a new generation of anti-angiogenics, which may represent novel strategies in the treatment of neovascularization-related diseases.
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PMID:Somatostatin analogues: multiple roles in cellular proliferation, neoplasia, and angiogenesis. 1505 99

Urotensin II (UII) has been found to be a potent vasoactive peptide in humans and in a number of relevant animal models of cardiovascular disease such as the mouse, rat and other non-human primates. This peptide with structural homology to somatostatin was first isolated from the urophysis of fish and was recently found to bind to an orphan receptor in mouse and human. Initially found to have potent vasoconstrictive activities in a variety of vessels from diverse species, it has also been shown to exert vasodilatation in certain vessels in the rat and human by various endothelium-dependent mechanisms. The various vasoactive properties of UII suggest that the peptide may have a physiological role in maintaining vascular tone and therefore may have a role in the pathophysiology of a number of human diseases such as heart failure. Moreover, UII has also been implicated as a mitogen of vascular smooth muscle cells suggesting a deleterious role in atherosclerosis and coronary artery disease. In addition, there is evidence to demonstrate that UII has multiple metabolic effects on cholesterol metabolism, glycemic control and hypertension and therefore may be implicated in the development of insulin resistance and the metabolic syndrome.
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PMID:Urotensin II and cardiovascular diseases. 1547 47

Acromegaly is associated with insulin resistance and an increased incidence of cardiovascular disease. However, it remains unclear to what extent the effects of growth hormone (GH) excess on cardiovascular morbidity and mortality are mediated through insulin resistance versus through other direct or indirect effects of GH. Adequate control of GH excess by surgery or pharmacologic interventions is associated with decreased insulin resistance, reflected in decreased plasma insulin levels and fasting glucose levels or improved glucose tolerance. Despite divergent effects of both somatostatin and somatostatin analogs on GH, insulin and glucagon secretion, and glucose absorption, treatment with the somatostatin analogs octreotide and lanreotide has only limited effects on glucose metabolism. However, glucose sensitivity has only been formally examined using a hyperinsulinemic euglycemic clamp in a minority of these studies. Treatment with the GH-receptor antagonist pegvisomant ameliorates insulin sensitivity, reflected in decreased fasting plasma insulin levels and fasting glucose levels. Nonetheless, the effect of pegvisomant on glucose sensitivity has not been formally tested by hyperinsulinemic clamp conditions. In acromegaly, preliminary observations on new octreotide analogs with greater specificity for somatostatin-receptor subtypes indicate that these compounds achieve better control of GH hypersecretion than octreotide, but may also negatively influence insulin release. Assessment of insulin secretion and glucose levels in acromegalic patients during administration of these compounds is thus mandatory.
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PMID:Pharmacologic therapies for acromegaly: a review of their effects on glucose metabolism and insulin resistance. 1564

Angiogenesis is characterised by activation, migration and proliferation of endothelial cells and is central to the pathology of cancer, cardiovascular disease and chronic inflammation. Somatostatin is an inhibitory polypeptide that acts through five receptors (sst 1, 2, 3, 4, 5). Sst has previously been reported in endothelium, but their role remains obscure. Here, we report the expression of sst in human umbilical vein endothelial cells (HUVECs) in vitro, during proliferation and quiescence. A protocol for culturing proliferating and quiescent HUVECs was established, and verified by analysing cell cycle distribution in propidium-iodide-stained samples using flow cytometry. Sst mRNA was then quantified in nine proliferating and quiescent HUVEC lines using quantitative reverse transcriptase-polymerase chain reaction. Sst 2 and 5 were preferentially expressed in proliferating HUVECs. All samples were negative for sst 4. Sst 1 and 3 expression and cell cycle progression were unrelated. Immunostaining for sst 2 and 5 showed positivity in proliferating but not quiescent cells, confirming sst 2 and 5 protein expression. Inhibition of proliferating cells with somatostatin analogues Octreotide and SOM230, which have sst 5 activity, was found (Octreotide 10(-10)-10(-6) M: 48.5-70.2% inhibition; SOM230 10(-9)-10(-6) M: 44.9-65.4% inhibition) in a dose-dependent manner, suggesting that sst 5 may have functional activity in proliferation. Dynamic changes in sst 2 and 5 expression during the cell cycle and the inhibition of proliferation with specific analogues suggest that these receptors may have a role in angiogenesis.
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PMID:Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium. 1581 56

Acromegaly is a chronic debilitating disorder caused by a growth hormone (GH)-producing pituitary adenoma. Active acromegaly is associated with a two- to fourfold increased mortality risk, mainly from cardiovascular disease. Transsphenoidal surgery is considered as the treatment of choice because of the rapidity of cure and normalisation of survival. Secondary treatment modalities are radiotherapy and medical treatment, and are important because surgery in the best hands cures only approximately 60% in long-term studies. Medical treatment with slow-release formulations of somatostatin are now widely used, also as primary treatment, and appear to be safe and effective in 50-60% of the patients. However, no data on mortality risk with these drugs is available. Recently, a GH-receptor blocking agent, pegvisomant, was licensed for use in acromegaly and appears to normalise IGF-1 in almost all patients. This article examines the pathophysiology of acromegaly, currently used medicines and their safety and efficacy, and the new drugs that are in development.
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PMID:Treatment strategies for acromegaly. 1626 68

Pheochromocytoma (PCC) is a rare disease, mainly sporadic, but also associated with some familial disorders, with a malignancy frequency of approximately 10%. Only the presence of distant metastases, derived from large pleomorphic chromaffin cells, is widely accepted as a criterion of malignancy. Variable symptoms may be caused by production and release of catecholamines. Since there is no curative treatment for malignant PCC and due to its unfavorable prognosis, assuring quality of life is one of the main therapeutic objectives. Besides a long-term medical treatment of symptoms using selective alpha-1 blockers and nonselective, noncompetitive alpha- and/or beta-blockers, debulking surgery is the first treatment step. In case of a sufficient uptake of (123)I-MIBG treatment with targeted radiation therapy, use of (131)I-MIBG is an option as an adjuvant therapy, following debulking surgery. Chemotherapy should be applied to patients without positive MIBG-scan, with no response to (131)I-MIBG or progression after radionuclide treatment, and especially in cases with high proliferation index. The most effective chemotherapy regimen appears to be the CVD-scheme, including cyclophosphamide, vincristine, and dacarbazine. The so-called targeted molecular therapies with treatment combinations of temozolomide and thalidomide, or sunitinib monotherapy, and novel therapeutic somatostatin analogues have shown promising results and should thus encourage clinical trials to improve the prognosis of metastatic PCC. Within this review the current treatment modalities and novel molecular strategies in the management of this disease are discussed and a treatment algorithm is suggested.
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PMID:Treatment of malignant pheochromocytoma. 1967 13


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