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)

Patients with type 1 diabetes mellitus (IDDM) show augmented GH secretion, which is implicated in the pathogenesis of microvascular complications. On the other hand, it is well known that beta-adrenergic receptors have inhibitory influence on GH secretion, likely via stimulation of hypothalamic somatostatin. Since the possibility of pharmacological suppression of GH secretion would be of value in IDDM, we investigated the effect of salbutamol (SAL, 4 mg orally at -60 min) on the GH response to GHRH (1 micrograms/kg iv at 0 min) in 6 well-controlled (mean HbA1c +/- SEM: 7.3 +/- 0.5%) patients with IDDM. Salbutamol was able to inhibit basal GH levels (p < 0.05) as well as to abolish the GHRH-induced GH rise. After SAL administration, a significant (p < 0.05) reduction of glucagon levels was also found. Our data show that the enhancement of beta 2 adrenergic activity by oral therapeutical doses of SAL inhibits basal and GHRH-stimulated GH secretion in patients with IDDM.
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PMID:Inhibition by salbutamol of GHRH-induced GH release in type 1 diabetes mellitus. 133 41

A paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) has been observed in type 1 diabetic patients and was hypothetically attributed to a reduced hypothalamic somatostatin tone. We have previously reported that corticotropin-releasing hormone (CRH) inhibits GH response to growth hormone-releasing hormone (GHRH) in normal subjects, possibly by an increased release of somatostatin. To study the effect of CRH on anomalous GH response to TRH, we tested with TRH (200 micrograms intravenously [IV]) and CRH (100 micrograms IV) + TRH (200 micrograms IV) 13 patients (six males and seven women) affected by insulin-dependent diabetes mellitus. A paradoxical GH response to TRH was observed in seven of 13 patients, one man and six women. In these subjects, the simultaneous administration of CRH and TRH significantly reduced the GH response to TRH, as assessed by both the maximal GH mean peak +/- SE (2.18 +/- 0.67 v 9.2 +/- 1.26 micrograms/L, P less than 0.005) and the area under the curve (AUC) +/- SE (187 +/- 32 v 567 +/- 35 micrograms.min/L, P less than .001). CRH had no effect on TRH-induced thyroid-stimulating hormone (TSH) release. Our data demonstrate that the paradoxical GH response to TRH in patients with type 1 diabetes mellitus is blocked by CRH administration. This CRH action may be due to an enhanced somatostatin release. Our data also show that exogenous CRH has no effect on TSH response to TRH, thus suggesting the existence of separate pathways in the neuroregulation of GH and TSH secretion.
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PMID:Corticotropin-releasing hormone inhibition of paradoxical growth hormone response to thyrotropin-releasing hormone in insulin-dependent diabetics. 135 81

This article is divided into two parts. A retrospective overview summarizes some of the work that provided the framework and tools of the more recent studies. The five novel areas of research are related to the indirect effects of insulin. Regulation of plasma glucose is of central importance in health and diabetes. Understanding this precise regulation requires sensitive isotope dilution methods that can measure the rates at which glucose is produced by the liver and used by the tissues on a minute-to-minute basis. Validation studies indicated that the non-steady-state tracer method yields reasonable results when the specific activity of plasma glucose does not change abruptly. During hyperinsulinemic glucose clamps, the decrease in specific activity of glucose can be prevented by the MSTI. During exercise, the decrease of specific activity can be only in part ameliorated by step-tracer infusion. Depancreatized dogs are used extensively as a model of selective insulin deficiency, because dog stomach secretes physiological amounts of glucagon. This strategy can avoid injections of somatostatin, which can have other affects in addition to the suppression of insulin and glucagon. In human diabetes, in addition to an increase of glucose production, there is also an increase in glucose cycling in the liver. In animal models of diabetes, mild NIDDM, and in glucose intolerance, the percentage of increments of glucose cycling are much larger than those of glucose production. We hypothesize, therefore, that measurements of glucose cycling can be used as an early marker of glucose intolerance. Application of different tracer strategies and use of the depancreatized dog as a model of diabetes, we investigated the importance of the indirect effects of insulin in the pathogenesis of diabetes. 1) Because, in the treatment of IDDM, insulin is administered by the peripheral routes we compared the relative importance of hepatic and peripheral effects of insulin in regulating the rate of glucose production. Experiments were performed in depancreatized dogs that were initially maintained at moderate hyperglycemia (10 mM) with subbasal portal insulin infusion. During the experimental period, insulin was infused either peripherally or portally at 0.9 mU.kg-1.min-1. In addition, peripheral infusions were also given at 0.45 mU.kg-1.min-1. We concluded that when suprabasal insulin levels are provided to moderately hyperglycemic depancreatized dogs, the suppression of glucose production is more dependent on peripheral than portal insulin concentrations. This indirect effect of insulin may be mediated by limitation of the flow of precursors and energy substrates for gluconeogenesis and/or by suppressive effect of insulin on glucagon secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Banting Lecture: glucose turnover. A key to understanding the pathogenesis of diabetes (indirect effects of insulin). 149 70

A decline in plasma insulin and an increase in glucagon are known to occur during intense and/or prolonged exercise. However, it is not established whether changes in insulin and glucagon secretion are involved in the precise matching of hepatic glucose production to the enhanced glucose uptake by muscle during brief, low intensity exercise. We studied the effects of 30-min cycle exercise at 40% of maximal aerobic capacity in healthy subjects and C-peptide-deficient subjects with type 1 diabetes (IDDM) using [3-3H]glucose to estimate glucose turnover. Diabetic subjects were studied during continuous iv insulin infusion, which normalized glucose kinetics before experimental perturbations. In control (saline-infused) experiments, endogenous glucose appearance (Ra) increased by 80-90% above baseline to match the increase in glucose disappearance in both normal and IDDM subjects, even though the latter exercised at fixed levels of plasma free insulin, averaging 203 +/- 19 pmol/L. In other experiments, somatostatin was infused, and glucagon (1.0 ng/kg.min) and insulin (at two different rates) were maintained at constant levels. Infusion of insulin in normal subjects at doses sufficient to maintain constant peripheral plasma insulin was associated with no apparent effect on glucose turnover (plasma insulin, 80 +/- 21 pmol/L, compared to 52 +/- 5 pmol/L during saline; P = NS). However, insulin infusion at doses that normalized the portal insulin concentration (approximately 208 pmol/L) together with glucagon replacement inhibited the rise in glucose production in both normal and IDDM subjects. There were similar 45-55% reductions (P less than 0.03) of the increase in Ra seen with exercise in control experiments. When peripheral plasma free insulin (and presumably portal levels as well) were increased by about 20% in this experimental setting in IDDM (278 +/- 43 pmol/L), the suppression of Ra was even more profound, and Ra failed to increase at all with exercise. We conclude that the hormonal regulation of Ra in brief duration exercise in man does not necessitate the decrements in portal venous insulin observed under more intense exercise conditions as long as an exercise-induced glucagon secretory response can occur. Glucagon secretion alone cannot prevent hypoglycemia when portal venous insulin concentrations are increased by minimal amounts, such as in insulin-treated diabetics.
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PMID:Islet hormonal regulation of glucose turnover during exercise in type 1 diabetes. 196 78

Octreotide (Sandostatin), a potent and long-acting octapeptide analogue of somatostatin, exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end, we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose, 200 micrograms; high dose, 400 micrograms) in nine female, C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose, free insulin, glucagon, GH, and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control, despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%, glucagon by 50%, and PP by 80%. Steady-state octreotide levels varied considerably among patients (low, mean +/- SEM), 1000 +/- 101, range 638 to 1375 pg/ml; high, mean 1940 +/- 147, range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses, we observed greater interindividual variability (low, mean 2.45 +/- 0.30, range 1.31 to 3.78 ml/kg/min; high, mean 2.36 +/- 0.19, range 1.68 to 3.48 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Continuous subcutaneous octreotide infusion: dose-response relationships between metabolic effects and octreotide clearance in patients with insulin-dependent (type 1) diabetes. 206 44

Hypersecretion of growth hormone (GH) is a characteristic feature of Type 1 diabetic patients. In healthy subjects growth hormone is able to induce an increase in endothelial cell proteins such as fibrinogen and von Willebrand factor. Plasma concentrations of such proteins, which are markers of cardiovascular risk, are elevated in diabetic patients with microalbuminuria, suggesting endothelial cell dysfunction. In a randomized prospective study we therefore evaluated the possible effects of 1 year's treatment with a somatostatin analogue, octreotide, on lipoproteins and on endothelial function in Type 1 diabetes mellitus. Seven patients were allocated to treatment with a continuous subcutaneous infusion of 400 micrograms octreotide per day. Seven patients served as a control group. During treatment a decrease in plasma LDL-cholesterol (2.62 (2.17-3.11) (median (range] vs 2.00 (1.89-2.96) mmol l-1, p less than 0.05) and serum apolipoprotein A-I (1.47 (1.25-1.60) vs 1.23 (1.13-1.90) g l-1, p less than 0.05) was observed in the treated group. Furthermore a probable reduction during treatment in plasma concentrations of von Willebrand factor (1.72 (0.84-3.04) vs 1.24 (0.94-1.82) U ml-1, p = 0.08) and fibrinogen (11.3 (7.3-25.3) vs 8.1 (7.5-11.8) mumol l-1, p = 0.06) was found, and after withdrawal of treatment an increase towards the initial levels was seen. The platelet count declined (326 (301-612) vs 217 (206-400) x 10(9) l-1, p less than 0.01) during octreotide treatment and remained depressed 2 months after withdrawal.
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PMID:Effects of octreotide on lipoproteins and endothelial function of type 1 (insulin-dependent) diabetic patients. 214 88

The selective destruction of the pancreatic islet beta cells in type 1 diabetes mellitus is thought to be mediated by a cellular autoimmune process, possibly triggered by virus infection in genetically susceptible individuals. Because of the potentially important role of cell-cell adhesion in the immune response, we investigated whether cytokine products of mononuclear cells, or virus infection, induced the expression of intercellular adhesion molecule 1 (ICAM-1) on human endocrine islet cells. By flow cytofluorimetry, control islet cells did not express detectable ICAM-1. However, after a 72-hr exposure of islets to interferon gamma (IFN-gamma) and/or tumor necrosis factor alpha (TNF-alpha) (each at 250 units/ml), ICAM-1 was induced on greater than 85% of islet cells. IFN-gamma was 50% more potent than TNF-alpha; together, their effects were additive. Class I major histocompatibility complex (MHC) protein expression, detected on control islet cells, was also stimulated by IFN-gamma and/or TNF-alpha. In contrast, infection with reovirus type 3 did not induce ICAM-1 on islet cells, although it stimulated the expression of class I MHC proteins. By double-label indirect immunofluorescence microscopy, ICAM-1 expression was identified on both beta (insulin-secreting) and delta (somatostatin-secreting) islet cells. Monoclonal antibody to ICAM-1 precipitated protein of Mr 97,000 from [35S]methionine-labeled islets exposed to IFN-gamma and TNF-alpha, but not from control islets. RNA blot analysis revealed a major species of 3.3 kilobases and a minor species of 2.2 kilobases induced in islets exposed to the cytokines. These findings have implications for the molecular mechanisms of beta-cell destruction in type 1 diabetes, in that expression of ICAM-1 by beta cells may facilitate adhesion of antigen-targeted immune cells.
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PMID:Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. 249 83

A deceased 59-year-old woman with insulin dependent diabetes mellitus complicated by chronic thyroiditis and chronic hepatitis was autopsied. She had had diabetes mellitus since she was 30 years old, and insulin therapy was started at 34 years. Laboratory findings were as follows: s-GOT 85, s-GPT 31, gamma-globulin 2.45 g/dl. Immunological tests were positive for anti-smooth muscle antibody and anti-ENA antibody with high titers of antithyroglobulin and anti-microsome antibodies. HLA analysis revealed the presence of DR-4. The thyroid biopsy specimen showed microscopic features characteristic of chronic thyroiditis at 52 years of age. She had been repeatedly admitted for the control of diabetes mellitus. She was admitted for the 9th time in June, 1987 following complaints of abdominal pain. After admission, her general condition became gradually worse, and she died of peritonitis in September, 1987. Pathological examination of the liver revealed an expansion of fibrous tissue on Glisson's capsule accompanied by lymphocytic infiltration and was diagnosed to be chronic inactive hepatitis. As for the thyroid gland, fibrous tissue replaced an extensive area of the thyroid gland, and normal thyroid tissue was not observed. Lymphocytic infiltration was less in comparison with that in the previous biopsy. As for the pancreas, atrophy of exocrine pancreatic tissue and fibrous change in interstitial tissue was observed. Lymphocytic infiltration was also seen in the interstitial exocrine tissue but not in the islet. Immunohistochemical examination of the islets using anti-insulin, glucagon and somatostatin antibodies by ABC peroxidase method showed the selective disappearance of B cells in the islets. The pathological changes in the thyroid gland, liver and pancreas suggest that autoimmune mechanism may be involved in the pathogenesis of chronic thyroiditis, chronic hepatitis and IDDM with exocrine pancreatic impairment in this case.
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PMID:[An autopsied case of insulin dependent diabetes mellitus complicated by chronic thyroiditis and chronic hepatitis]. 259 7

Fig. 5 provides a summary of the natural history of diabetic nephropathy in IDDM patients. The figure also includes the possibilities of intervention in the various stages of diabetic nephropathy. GFR values in normals are shown by the hatched area in the upper part of the figure. The lower part shows development of albuminuria. The level 20-200 micrograms/min is the microalbuminuric range. At present it is not possible to predict a malignant course either from the parental history (1), or from the prediabetic course (2). Neither at clinical diagnosis of diabetes, can complications be predicted (3). The figure shows a typical course in a patient developing diabetes at the age of 14 years. The patient showed poor metabolic control as indicated by the high level of GFR (greater than 150 ml/min) (4) and the increasing albumin excretion rate (4). At the age of 22 years the patient developed microalbuminuria (5) and later clinical nephropathy at age 30 years, typically after 16 years of diabetes. Blood pressure rises, and GFR starts to decline during incipient diabetic nephropathy with increasing microalbuminuria (greater than 70 micrograms/min) (5) (6), and end-stage renal failure reached at the age of 40 years,--if intervention is not undertaken. Intervention is possible as follows: A) hyperfiltration may be reduced by non-glycemic intervention such as a moderate reduction of protein intake, treatment with aldose reductase inhibitors (work in progress) or acute administration of a somatostatin analogue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of blood pressure intervention on renal function in insulin-dependent diabetes. 261 18

Circadian rhythms of insulin needs and action are a frequently discussed issue that is both of considerable physiological interest and of clinical importance in case of insulin substitution in type 1 diabetes. Basally, insulin is released in a pulsatile fashion which seemingly is erratic but at close analysis displays 'free-running' cyclical rhythmicity of 8-30 min duration that possibly guarantees optimal insulin action. This basal mode of insulin secretion is subject to a multitude of endogenous control systems that act on the B-cell both in a stimulatory (e.g., beta-agonists, glucagon as well as glucose and amino acids) and an inhibitory fashion (e.g., alpha-agonists, somatostatin). Since impairment of target cell sensitivity to insulin action and hyperglycemia may be caused by the stress hormones, cortisol, epinephrine and growth hormone included, with in part intrinsic rhythmicity, as well as by dehydration and by prolonged insulin withdrawal, a secondary feed-back signal on insulin release may easily be induced by rising blood glucose levels. In that modulators of insulin release and action are themselves secreted in a circadian fashion they tend to secondarily imprint the mode of insulin release. Therefore, any difference between a daily maximum and minimum in plasma insulin concentration besides its free-running short-term rhythmicity has to be regarded as a composite secondary circadian rhythm. It is in particular due to variable secondary early-morning and late-afternoon insulin resistance.
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PMID:Circadian rhythms of insulin needs and actions. 266 58


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