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)

A number of enzymatic methods have been developed to prepare hepatocytes using collagenase and hyaluronidase. However, best cell preparations are obtained by using only low concentrations of collagenase and exposing the liver to the enzyme for a very short period of time. These isolated cells with intact cell membranes and large numbers of microvilli on the cell surface respond to hormones at physiological concentrations suggesting that these microvilli contain hormone receptors. In addition, high glycogen content is essential to maintain the in vivo metabolic characteristics of the hepatocytes suggesting that intracellular glycogen plays an important role in the hormonal regulation of metabolism in hepatocytes. Studies with glucagon and insulin on carbohydrate metabolism show that the molar ratios of these hormones control gluconeogenesis and glycogenolysis. Furthermore, in vitro addition of insulin stimulates glycogen synthesis and activates glycogen synthase. Insulin also stimulates protein synthesis in cells containing high glycogen and maintains more normal parallel strands of polyribosomes. Studies with isolated hepatocytes from diabetic, hypophysectomized and adrenalectomized animals show a reduced glucagon response to glycogenolysis. This lack of glucagon response was not due to reduction in glycogen levels. Other hormones such as somatostatin and parathyroid also give rise to alterations in carbohydrate metabolism in isolated hepatocytes.
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PMID:Studies of hormonal regulation of metabolism using isolated hepatocytes. 19 66

The effect of hyperglycemia on whole body substrate utilization and the metabolic profile of skeletal muscle has been investigated. Eight glucose-tolerant men were infused with somatostatin (S) for 190 min. During the last 120 min of S infusion, glucose was infused to achieve a steady-state plasma level of 26 mmol/l. Biopsies were obtained from the quadriceps femoris muscle immediately before and 35 and 120 min after induction of hyperglycemia. Steady-state glucose disposal during hyperglycemia averaged (+/- SE) 33.8 +/- 3.2 mumol.kg fat-free mass-1.min-1, and approximately 70% of the glucose disposal was accounted for by skeletal muscle. Intracellular glucose increased from 0.9 +/- 0.2 mmol/kg dry wt during S to 9.5 +/- 2.5 during hyperglycemia (P less than 0.01). It was estimated that approximately 35% of the glucose taken up by muscle during 120 min of hyperglycemia was not phosphorylated. Muscle contents of alpha-D-glucose 1,6-diphosphate, D-glucose 6-phosphate, ATP, ADP, and AMP (both of which are based on the phosphocreatine-to-creatine ratio), which have been shown to inhibit hexokinase in vitro, did not change significantly during hyperglycemia, nor were there any significant changes in any of the other postphosphofructokinase intermediates, D-fructose 2,6-diphosphate, and citrate. Hyperglycemia did not alter the fractional activities of glycogen synthase or phosphorylase, nor total phosphorylase activity. However, hyperglycemia resulted in a 55% increase in glycogen synthase-specific activity (P less than 0.01). It is concluded that hyperglycemia results in a marked increase in muscle glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperglycemia induces accumulation of glucose in human skeletal muscle. 167 95

Insulin receptor function, glycogen synthase activity, and activation by phosphatases were studied in biopsies of human skeletal muscle under conditions of hyperglycemia and/or hyperinsulinemia for 150 minutes. Twenty-one healthy volunteers underwent either (A) a hyperinsulinemic, euglycemic clamp (serum insulin, 160.0 +/- 7.7 mU/L; plasma glucose, 4.9 +/- 0.1 mmol/L; n = 9), (B) a hyperglycemic clamp during normoinsulinemia (serum insulin, 18.1 +/- 3.3 mU/L; plasma glucose, 12.9 +/- 0.2 mmol/L; n = 6), or (C) a combined hyperinsulinemic, hyperglycemic clamp (serum insulin, 158.3 +/- 15.0 mU/L; plasma glucose, 11.4 +/- 0.8 mmol/L; n = 6). During all studies, the endogenous insulin secretion was inhibited with somatostatin. Insulin binding and kinase activity of insulin receptors solubilized from vastus lateralis muscle biopsies were unaffected by hyperglycemia and/or hyperinsulinemia. Hyperinsulinemia activated the muscle glycogen synthase with a decrease in the half-maximal activation constant (A0.5) for glucose-6-phosphate (G6P) from 0.53 +/- 0.04 to 0.21 +/- 0.02 mmol/L (study A, P less than .02) and from 0.53 +/- 0.06 to 0.19 +/- 0.05 mmol/L (study C, P less than .03). In addition, the rate of glycogen synthase activation by phosphatases increased from 0.078 +/- 0.017 to 0.134 +/- 0.029 U/min/mg protein (study A, P less than .03) and from 0.082 +/- 0.013 to 0.145 +/- 0.033 U/min/mg protein (study C, P = .05). Hyperglycemia during normoinsulinemia did not affect A0.5 or phosphatase activity. In conclusion, (1) hyperinsulinemia for 2 1/2 hours increases glycogen synthase activity and activation by phosphatases independently on the glycemia; and (2) insulin receptor binding and basal and insulin-stimulated receptor kinase activity are not modified during short-term hyperinsulinemia and/or hyperglycemia.
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PMID:Effects of hyperinsulinemia and hyperglycemia on insulin receptor function and glycogen synthase activation in skeletal muscle of normal man. 190 47

Chronic uremia is frequently associated with an impaired carbohydrate tolerance. During the past decade considerable progress have been made in characterizing and quantifying this biochemical abnormality in end-stage renal failure (ESRF). Primarily, this has been possible by means of the glucose clamp technique which basically makes it possible to evaluate insulin sensitivity and glucose-stimulated insulin secretion. Combined with the use of tracer dilution technique, hepatic vein catheterization technique, infusion of somatostatin, forearm or leg techniques and indirect calorimetry, insight into several other major parameters of glucose kinetics has been achieved; i.e. insulin-mediated glucose uptake (IMGU), glucose-induced glucose uptake (GIGU), hepatic glucose production (HGP) splanchnic glucose uptake and oxidative and nonoxidative glucose disposal. Of course, these extra facets make the clamp procedure less feasible to accomplish for technical reasons and demand an extensive knowledge of the limitations of these methods. One major factor behind the reduced glucose tolerance in uremia is an impaired sensitivity to insulin (insulin resistance) in peripheral tissues, mainly in skeletal muscle. In non-dialysed uremic patients the insulin dose-response curve is characterized by a decreased maximal response and by a rightward shift. In general, the insulin resistance is pronounced, but a few weeks on maintenance hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) are enough to improve insulin action significantly. Occasionally, IMGU has been found normal in patients on long-term HD. In contrast to insulin-stimulated glucose uptake, basal glucose turnover is normal in patients with ESRF. The ability of glucose to enhance its own uptake is difficult to measure in human studies, because even small amounts of insulin is able to modulate GIGU profoundly. At basal insulinemia, however, GIGU is markedly impaired in uremia. Recently, it has been suggested that the uremic insulin resistance is located not only in peripheral tissues but also in the liver. At low insulin concentrations, the restraining potency of insulin on HGP seems to be decreased in uremia. Splanchnic glucose uptake is hardly affected, but is always very insensitive to insulin. The glucoregulatory function of the liver is further disturbed in uremia. Acute glucagon exposure elicits an inadequate glucose release, suggesting a coexisting resistance to glucagon. In vitro studies have shown, that the first step in the cascade of reactions initiated by insulin, namely binding to its specific receptor is normal in uremia. In addition, the activity of key enzymes such as the insulin receptor kinase and glycogen synthase have been found within normal in the uremic muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Glucose metabolism in non-diabetic and insulin-dependent diabetic subjects with end-stage renal failure. 202 51

Skeletal muscle sensitivity and responsiveness to insulin and their relationship to overall glucose disposal and insulin binding were determined in 89 premenopausal women of varying body fat topography (waist/hips girth ratio [WHR] 0.64-1.02) and obesity level (percentage of ideal body weight 92-230). As a marker of insulin action, the percentage of total glycogen synthase present in the I form (glucose-6-phosphate independent) was measured in quadriceps muscle biopsies. The increase in percentage of synthase I 1 h after oral glucose loading was not significantly different between nonobese and obese weight-matched subgroups of increasing WHR, but this response was maintained at the expense of increasing plasma insulin levels as the WHR rose. The increase in percentage of synthase I in response to submaximal steady state plasma insulin (SSPI) of approximately 100 microU/ml achieved by the infusion of somatostatin, insulin, and glucose, however, was significantly lower in obese than in nonobese subjects, and was inversely correlated with WHR. The increase in percentage of synthase I correlated inversely with the steady state plasma glucose (SSPG) concentration, which is an index of the efficiency of overall glucose disposal, and directly with insulin binding to circulating monocytes. Insulin binding also correlated inversely with WHR and with fasting plasma insulin levels. When obese subjects were separated into three weight-matched subgroups on the basis of increasing WHR, significant trends to decreased percentage of synthase I response, increased SSPG, and decreased insulin binding were found. In women with predominantly upper body obesity (WHR greater than 0.85), the increase in percentage of synthase in response to submaximal SSPI was diminished, but there was no impairment of percentage of synthase I responsiveness to supramaximal SSPI of approximately 1,000 microU/ml. At supramaximal SSPI levels, SSPG in four obese women was normal, whereas in five women, SSPG concentrations were markedly increased. Our results suggest that in premenopausal women, impaired skeletal muscle insulin sensitivity that results in decreased glucose storage capacity may contribute to the diminished efficiency of glucose disposal and insulin resistance that are associated with upper body obesity. The impairment in skeletal muscle sensitivity may be overcome in vivo at the expense of increasing plasma insulin levels, with maximal responsiveness remaining unimpaired. This defect may result from a reduction in insulin receptor number which could, in turn, be secondary to persistently elevated fasting plasma insulin levels. In some upper body segment obese women, however, an additional defect affecting other insulin-sensitive pathways may also be present.
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PMID:Relationship between skeletal muscle insulin resistance, insulin-mediated glucose disposal, and insulin binding. Effects of obesity and body fat topography. 614 58

To examine whether tissue sensitivity to insulin is dependent upon the prevailing plasma insulin concentration, the ability of acute hyperinsulinemia to stimulate glucose disposal was investigated in six normal subjects before and after prolonged reduction of the plasma insulin concentration. Glucose turnover ([6,6-2H2]glucose), whole body glucose oxidation and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthase activity in muscle were determined in the postabsorptive and in the insulin-stimulated states (euglycemic hyperinsulinemic clamp: 3 mU.kg-1.min-1) before and after a 4-day subcutaneous infusion of the somatostatin analogue octreotide (200 micrograms/24 h). Constant octreotide infusion 1) decreased postabsorptive and meal-stimulated plasma insulin levels by approximately 30-40% but did not significantly alter overall glucose tolerance, free fatty acid, growth hormone, and glucagon levels and 2) was associated with significant increases in insulin-mediated whole body glucose disposal (pre-drug: 10.29 +/- 0.49 vs. postdrug: 11.42 +/- 0.72 mg.kg-1.min-1, P < 0.04), nonoxidative glucose disposal (6.82 +/- 0.57 vs. 7.68 +/- 0.62, P < 0.03), and fractional glycogen synthase activity (0.14 +/- 0.03 vs. 0.20 +/- 0.04 mU/mg protein, P < 0.02). In contrast, infusion of saline instead of octreotide for 4 days to control subjects did not alter any of the metabolic parameters. We conclude that lowering the plasma insulin concentration over a prolonged period of time increases insulin sensitivity. The effects of insulin to stimulate whole body glucose utilization, nonoxidative glucose disposal, and glycogen synthase activity in muscle are therefore functions of the preexisting plasma insulin concentration.
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PMID:Stimulation of muscle glucose disposal by insulin in humans is a function of the preexisting plasma insulin level. 776 30

We determined the impact of variable insulinemia and glycemia on the in vivo partitioning of glucose effectiveness (GE) and insulin sensitivity (SI) and the in vitro intracellular processing of glucose metabolism. Six somatostatin- and [3-3H]glucose-infused dogs underwent euglycemic and hyperglycemic clamps at four physiological insulin (Ins) levels before a muscle biopsy. From the rates of glucose infusion (GINF), total glucose disposal (Rd), total glycolysis (GF), and glucose storage (GS), plots of delta GINF, delta Rd, delta GS vs. delta log Ins concentration were found to be linear for each dog, allowing calculation of the partitioning of GE and SI into their major in vivo sites (periphery vs. liver) and intracellular metabolic pathways (GS vs. GF). Insulinopenia induced a significant reduction in total GE. From insulinopenia to high insulinemia, the 2.3-fold increase in total GE was due to the increased peripheral glucose responsiveness of the GS pathway. Hyperglycemia induced a significant reduction in total SI, with approximately one-half of this reduction due to the decreased peripheral insulin responsiveness of the GF pathway. In skeletal muscle, both glycogen content and glycogen synthase fractional activity were positively correlated with log Ins concentration, Rd, and GS but negatively correlated with glucose 6-phosphate concentration. Moreover, both Rd and GS were negatively correlated with lactate concentration. We conclude that 1) the inhibition of GE and SI induced by insulinopenia and hyperglycemia, respectively, is due mainly to the reduced peripheral responsiveness of contrasting intracellular metabolic pathways; and 2) hyperinsulinemia and/or hyperglycemia stimulates glycogen synthesis and GF but not nonoxidative glycolysis.
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PMID:Insulinopenia and hyperglycemia influence the in vivo partitioning of GE and SI. 790 Jul 87

Phenacylimidazolium ions have the capacity to promote hepatic glycogen synthesis in vitro via activation of glycogen synthase and inactivation of phosphorylase. The purpose of the present study was to determine whether these compounds alter net hepatic substrate balance in vivo. Following a control period somatostatin was infused into 42h-fasted, conscious dogs and insulin (3X-basal) and glucagon (basal) were replaced intraportally. The glucose load to the liver was doubled with a peripheral glucose infusion and the phenacylimidazolium compound, 254236 (EX; n = 5) was infused intraportally at varying rates in four separate periods (0 (P1), 0.5 (P2), 1.0 (P3), 2.0 (P4) mumol kg-1 min-1). In a separate group of animals (C; n = 5) saline was infused intraportally during P1-P4 to match the volume rate of delivery that occurred in EX. In C net hepatic glucose uptake was 8.5 +/- 1.7 mumol kg-1 min-1 during P1 and did not change significantly throughout the study. In EX net hepatic glucose uptake increased (p < 0.05) from 9.0 +/- 2.5 during P1 to 16.2 +/- 3.1 mumol kg-1 min-1 during P4. Whereas net hepatic lactate output was evident throughout P1-P4 in C, the liver consistently switched to net lactate uptake during P3 (1.2 +/- 1.7 mumol kg-1 min-1) and P4 (2.2 +/- 1.0 mumol kg-1 min-1) in EX. Sympathoadrenal activation (increased catecholamines) was evident in EX during period 4. The increased hepatic retention of carbon (glucose and lactate) coincident with 254236 infusion in conscious dogs is less than that observed in vitro but is consistent with a role for phenacylimidazolium ions in promoting hepatic glycogen synthesis.
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PMID:Regulation of net hepatic substrate balance by phenacylimidazolium ions in the conscious dog. 791 46

To examine whether sulphonylureas influence hyperglycaemia-induced glucose disposal and suppression of hepatic glucose production (HGP) in type 2 diabetes mellitus, a 150-min hyperglycaemic (plasma glucose 14 mmol/l) clamp with concomitant somatostatin infusion was used in eight type 2 diabetic patients before and after 6 weeks of glipizide (GZ) therapy. During the clamp a small replacement dose of insulin was given (0.15 mU/kg per min). Isotopically determined glucose-induced glucose uptake was similar before and after GZ administration which led to improved glycaemic control (basal plasma glucose 12.2 +/- 1.3 vs 8.9 +/- 0.7 mmol/l; P < 0.01). Glucose-induced suppression of HGP was, however, more pronounced during GZ treatment (0.96 +/- 0.14 vs 1.44 +/- 0.20 mg/kg per min; P < 0.02). Following GZ treatment hyperglycaemia failed to stimulate glycogen synthase activity. Moreover, GZ resulted in a significant increase in the immunoreactive abundance of the insulin-regulatable glucose transport protein (GLUT 4) (P < 0.02). In conclusion, these results suggest that GZ therapy in type 2 diabetic patients enhances hepatic sensitivity to hyperglycaemia, while glucose-induced glucose uptake remains unaffected. In addition, GZ tends to normalize the activity of glycogen synthase and increases the content of GLUT 4 protein in skeletal muscle.
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PMID:Effects of glipizide on glucose metabolism and muscle content of the insulin-regulatable glucose transporter (GLUT 4) and glycogen synthase activity during hyperglycaemia in type 2 diabetic patients. 804 94

To examine the effect of the somatostatin analog, octreotide, on insulin-mediated glucose uptake, seven insulin-dependent diabetic (IDDM) subjects were studied with and without 4 days of continuous subcutaneous octreotide administration (1 mg/kg/d). Insulin dosage was adjusted after frequent measurements of plasma glucose level. On the third day a hormonal and metabolic blood profile was obtained, and on the fourth day a euglycemic (5 mmol/L), hyperinsulinemic (1 mU/kg/min) clamp was performed in combination with calorimetry and a muscle biopsy. Mean plasma glucose levels on day 3 were similar (7.9 +/- 0.9 v 9.0 +/- 0.6 mmol/L). Growth hormone (GH) (0.39 +/- 0.10 v 0.78 +/- 0.23 mg/L, P < .05), insulin-like growth factor-1 (IGF-1) (127 +/- 17 v 157 +/- 21 mg/L, P < .05), and nonesterified fatty acids (NEFA) (239 +/- 25 v 405 +/- 44 mmol/L, P < .01) were lower following octreotide administration. Insulin requirements were reduced during octreotide administration, resulting in significantly lower insulin levels (27.3 +/- 2.7 v 39.9 +/- 9.9 mU/L, P < .5). During the clamp, glucose and insulin levels wer similar. Following octreotide, glucose disposal (7.33 +/- 0.49 v 6.08 +/- 0.55 mg/kg/min, P < .05) increased and hepatic glucose production (HGP) was more suppressed (-1.56 +/- 0.07 v -0.63 +/- 0.34 mg/kg/min, P < .05, 220 to 270 minutes). Oxidative glucose disposal (indirect calorimetry) was enhanced (3.09 +/- 0.24 v 2.70 +/- 0.37 mg/kg/min, P = .08), whereas glucose storage, as well as the fractional velocity for glycogen synthase activity, were unaltered during octreotide administration. Conversely, octreotide decreased lipid oxidation (0.12 +/- 0.1 v 0.41 +/- 0.15 mg/kg/min, P < .05). In conclusion, a low-dose octrotide infusion for 4 days to IDDM subjects leads to significantly increased insulin sensitivity.
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PMID:Effects of the somatostatin analog, octreotide, on glucose metabolism and insulin sensitivity in insulin-dependent diabetes mellitus. 859 92


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