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V Grill

Publications and source records attributed to V Grill.

At least 19 recordsLinked to original sources
PubMed1992

Dexamethasone treatment fails to increase arginine-induced insulin release in healthy subjects with low insulin response.

We have compared insulin responses to L-arginine before and during dexamethasone treatment in healthy subjects, previously classified as subjects with either high or low insulin response according to a standardized glucose infusion test. Arginine stimulation was administered as a 150 mg/kg bolus followed by 10 mg.kg-1.min-1 to six subjects with high insulin response and to seven subjects with low insulin response. Before dexamethasone treatment the incremental insulin level during 0-10 min of arginine was higher in subjects with high (36.5 +/- 6.8 microU/ml) than in subjects with low response (14.5 +/- 2.3 microU/ml), p less than 0.01 for difference. Dexamethasone treatment (6 mg/day for 60 h) markedly enhanced the insulin response to arginine in subjects with high response (+99% 0-30 min) but failed to affect the subjects with low response (+4% 0-30 min). The C-peptide response to arginine exhibited similar differences between groups. Decreased responsiveness to arginine in subjects with low insulin response, especially during dexamethasone treatment, suggests a Beta-cell capacity defect although a decreased potentiating-sensing effect of glucose cannot be completely ruled out.

Adult↗
PubMed1992

Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: important role of glutamine release for nitrogen balance.

We measured net uptake and release of amino acids in the brain of 7 nondiabetic and six diabetic subjects. Duration of insulin-dependent diabetes (IDDM) was 19.4 +/- 2.1 years. Arteriojugular vein measurements were performed before and after 120 minutes of insulin infusion and ensuing Biostator-regulated normoglycemia. Cerebral blood flow was measured during normoglycemia by 11-CH3-F and positron emission tomography. During hyperglycemia in the IDDM subjects, arterial concentrations of valine and leucine were higher, and those of glutamic acid and arginine lower, than in nondiabetic subjects. Insulin infusion lowered levels of most amino acids in both groups. Insulin treatment did not significantly affect the uptake or release of amino acids. Significant net uptake of branched-chain amino acids was noted in both groups, as well as uptake of lysine and phenylalanine in the IDDM subjects. The sum of measured differences was not different from zero in either group. Nitrogen balance depended on impressive release of glutamine from the brain (-963 +/- 147 and -960 +/- 303 nmol/100 g/min), which amounted to 73% and 69% of net release in nondiabetic and IDDM subjects, respectively. We conclude that balance between uptake and release of amino acids is similar in nondiabetic and in long-term IDDM subjects.

Adult↗
PubMed1992

Hypercalcemia in cancer.

Hypercalcemia may occur as a complication of haematological malignancies, in association with solid tumors with bone metastases, and with solid tumors in the absence of bone metastases. The latter syndrome, known as the humoral hypercalcemia of malignancy (HHM) shares many features with primary hyperparathyroidism. A parathyroid hormone-related protein (PTHrP) has been identified, isolated and cloned, which is most likely responsible for the calcium disturbances in HHM, PTHrP is a previously unrecognized hormone which has limited amino-terminal sequence homology with PTH and is the product of a separate gene. Tissue localization studies have identified PTHrP in squamous cell carcinomata, renal cortical carcinomata, in a proportion of breast cancers and in adult T-cell leukemia/lymphoma. In normal tissues, PTHrP has been immunohistochemically localized in keratinocytes, placenta and fetal parathyroid glands. In addition to its role in mediating hypercalcemia in cancer, PTHrP is likely to have an important endocrine role in the fetus, and perhaps a paracrine function in several organs.

Animals↗
PubMed1992

Parathyroid hormone-related protein: a possible endocrine function in lactation.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP), initially discovered as the factor responsible for the syndrome of humoral hypercalcaemia of malignancy, has also been found to be expressed in placenta, in pregnant uterus, in the fetus at many locations, and in the lactating mammary gland. This study sought to establish whether PTHrP reaches the maternal circulation when it is expressed in mammary tissue during lactation or in the maternal reproductive tract during gestation. DESIGN: Blood samples were collected from 53 subjects: 18 pregnant women in all stages of gestation, 19 lactating mothers and 16 non-lactating post-partum controls. MEASUREMENTS: PTHrP was measured using a specific and validated radioimmunoassay. Parathyroid hormone was measured by two-site immunoradiometric assay. Total calcium was measured by atomic absorption spectrophotometry. RESULTS: Circulating levels of PTHrP were readily detectable in 12 of 19 nursing mothers (range 2.7-7.8 pmol/l) but in none of the mothers who were bottle feeding. PTHrP was also detected in one of 18 pregnant subjects. Parathyroid hormone concentrations were lower in lactating mothers (2.3 +/- 1.0 pmol/l), than in non-lactating mothers (3.5 +/- 1.2 pmol/l) (P < 0.01). CONCLUSION: PTHrP reaches the maternal circulation during lactation in amounts which could produce a systemic effect.

Adult↗
PubMed1992

Impact of uncoupling glucose stimulus from secretion on B-cell release and biosynthesis.

We studied the impact of a defined degree of long-term hyperglycemia with or without blockade of attendant insulin release on subsequent B-cell secretory responsiveness and biosynthesis. Nondiabetic rats were infused for 48 h with glucose to produce marked hyperglycemia (21.3 +/- 0.5 mmol/l). Comparable levels of hyperglycemia were upheld when additions were made to this protocol. Hyperglycemia increased plasma insulin 12-fold but depressed glucose (27 mmol/l)-induced insulin secretion in vitro (isolated islets) by 67% compared with saline-infused rats. Addition of diazoxide infusion during hyperglycemia completely inhibited the hyperglycemia-induced rise in plasma insulin but enhanced glucose-induced insulin release in vitro eightfold compared with islets from rats infused with glucose alone. Addition of insulin (2 U/day) to the diazoxide plus hyperglycemia protocol inhibited the secretory response to glucose in vitro by 46% (P less than 0.05). Proinsulin biosynthesis was enhanced by 67% in islets from rats infused with glucose alone; this effect was paralleled by a similar increase in preproinsulin mRNA. Diazoxide in vivo did not affect these stimulatory effects of hyperglycemia on insulin biosynthesis; however, insulin infusion in vivo abolished the hyperglycemia-induced increase in proinsulin biosynthesis. We conclude that impairment by hyperglycemia of glucose-induced insulin secretion occurs concomitant with stimulation of biosynthesis. Uncoupling of glucose stimulus from secretion crucially affects subsequent secretory responsiveness but not biosynthesis. Insulin biosynthesis is depressed by direct or indirect effects of circulating insulin.

Animals↗
PubMed1992

Production of parathyroid hormone-related protein by the rat mammary gland in pregnancy and lactation.

Production of parathyroid hormone-related protein by the rat mammary gland in pregnancy and lactation. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E1077-E1085, 1992.--Production of parathyroid hormone-related protein (PTHrP) by the mammary gland of Sprague-Dawley rats has been examined using immunohistochemistry and in situ hybridization to detect PTHrP and PTHrP mRNA, respectively. PTHrP and PTHrP mRNA could be demonstrated in nests of epithelial cells of the developing mammary gland at day 14 of pregnancy and in the epithelial secretory cells lining the alveoli during the latter stages of pregnancy and during lactation. A specific radioimmunoassay was also used to measure the concentration of PTHrP secreted in the milk throughout lactation. The concentration of PTHrP in milk was relatively low initially but increased during the latter stages of lactation, whereas calcium concentrations remained virtually constant throughout lactation. No correlation was found between the concentrations of calcium and PTHrP in rat milk. These results show that PTHrP is present in rat milk and also in mammary tissue before parturition, and therefore it may assist in the development of the mammary gland during pregnancy.

Animals↗
PubMed1992

Circulating PTH and PTHrP levels before and after treatment of tumor induced hypercalcemia with Pamidronate Disodium (APD).

The effect of lowering ionized calcium on circulating parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) was assessed in twenty patients with hypercalcemia of malignancy following treatment with Pamidronate Disodium. Ionized calcium levels fell rapidly in all treated patients. PTH concentrations were initially suppressed below normal in 18 patients, but rose from 0.48 +/- 0.42 pmol/L to 3.63 +/- 3.13 pmol/L (p less than 0.01) after treatment, reaching higher than normal values in some patients even in the presence of persistent hypercalcemia. PTHrP concentrations did not change significantly after treatment. These findings are consistent with an increased sensitivity of parathyroid tissue to changes in ionized calcium following prolonged exposure to hypercalcemia. Regulation of tumor secretion of PTHrP by calcium was not apparent within the range of calcium concentrations in this study.

Calcium↗
PubMed1979

The metabolism of cyclic AMP and glucose in isolated islets from Acomys cahirinus.

Glucose-induced cyclic (3H) AMP accumulation, insulin secretory responses and the metabolism of glucose were studied in pancreatic islets from Acomys cahirinus. 27.7 mmol/l of glucose stimulated neither islet cyclic (3H) AMP accumulation nor insulin release during the first 5 min of incubation. Stimulation by glucose of cyclic (3H) AMP was observed after 15 min of incubation and insulin release was markedly stimulated between 15 and 30 min. The utilization of glucose, measured as the production of (3H)2O from (5--3H) glucose was stimulated by glucose after 10 min and proceeded at an apparently linear rate during a 20 min incubation period. In incubations of 5 min, glibenclamide, glucagon or chloromercuribenzene-p-sulphonic acid failed to stimulate islet cyclic (3H) AMP accumulation. 3-isobutyl-l-methylxanthine in a concentration of 1.0 mmol/l was the only agent tested that elevated rapidly (1 min) islet cyclic (3H) AMP. None of the agents tested elicited an insulin secretory response in 5 min incubations. It is concluded that 1) no gross defect is apparent in the utilization of glucose by Acomys islets, 2) the secretory derangement of the Acomys is associated with a delayed cyclic AMP response to glucose, 3) however a decreased level of cyclic AMP cannot be the sole explanation for the delayed insulin secretion in the Acomys.

Animals↗
PubMed1979

Role of cyclic AMP in glucagon-induced stimulation of hepatic glucose output in man.

The interrelationship between glucagon action on splanchnic glucose output and cyclic AMP production was studied in healthy volunteers after hepatic venous catheterization. Glucagon was infused according to four different protocols to achieve arterial levels ranging from 300 to 9000 ng/l. Infusion of glucagon which resulted in arterial levels of the hormone of 4000-9000 ng/l was associated with a marked increase in net splanchnic cyclic AMP production and in the arterial levels of the cyclic nucleotide. The rise in cyclic AMP efflux from the splanchnic area was transient but an augmented splanchnic production was still evident after 30 min of glucagon infusion. Splanchnic glucose output rose 3-5 fold. Infusion of glucagon at lower rates, resulting in arterial levels of 300-900 ng/l, did not measureably stimulate the efflux of cyclic AMP from the splanchnic area. In spite of this, splanchnic glucose output rose 2-3 fold and the blood glucose level increased 20-50% during glucagon infusion at these lower rates. It is concluded that (1) factors other than cyclic AMP are rate limiting in the stimulation of hepatic glucose production, and (2) although cyclic AMP is an established 'second messenger' of glucagon action, other factors may also be of importance in mediating the physiological response of this hormone.

Adult↗
PubMed1979

Glucose memory of pancreatic B and A2 cells: evidence for common time-dependent actions of glucose on insulin and glucagon secretion in the perfused rat pancreas.

The influence of previous exposure to glucose on the subsequent B- and A(2)-cell secretory responses to arginine was investigated in the perfused pancreas of the rat. Arginine (8 mM) was administered in two brief (9 min) pulses separated by a period of 66 min. In pancreata from 18-h-fasted animals the two pulses of arginine elicited biphasic glucagon secretory responses, while stimulation of insulin release was barely detectable. When 27.7 mM glucose was administered for 30 min during the intervening period up to 20 min before the second pulse of arginine, the glucagon response to arginine was diminished by 55% while the insulin release was markedly increased in comparison with the first pulse. 8.3 mM glucose, when administered before the second pulse of arginine, exerted effects that were smaller but otherwise similar to those of 27.7 mM glucose.The inclusion of 3.9 mM glucose during the stimulation periods with arginine decreased the glucagon and greatly increased the insulin secretory response. Under these conditions, previous exposure to 27.7 mM glucose inhibited the glucagon and enhanced the insulin response to the second stimulatory pulse of arginine to the same relative degree as when arginine was administered alone. Diazoxide (2 mM), when administered together with 27.7 mM glucose, almost completely inhibited insulin release induced by the presence of glucose, yet did not influence the modulation exerted by glucose on the subsequent insulin and glucagon secretory response to arginine. Conversely, these effects of the glucose pulse could not be reproduced by 1 mug/ml of porcine insulin. Previous exposure to glyceraldehyde (10 mM) mimicked the glucose effects.Also, in pancreata from fed rats, previous exposure to 27.7 mM glucose markedly inhibited subsequent arginine-induced glucagon secretion while the concomittant insulin response was enhanced.IT IS CONCLUDED THAT: (a) both A(2)- and B-cell responsiveness is modulated by a previous exposure to glucose which produces opposite effects in the two cell types, (b) this action of glucose does not depend on its insulin-releasing capacity, and (c) instead, a "memory" of glucose is induced as a consequence of the metabolism of the sugar in the A(2) and B cells.

Animals↗
PubMed1978

Immediate and time-dependent effects of glucose on insulin release from rat pancreatic tissue. Evidence for different mechanisms of action.

Glucose-induced insulin secretion is enhanced by a preceeding glucose stimulus. The characteristics of this action of glucose were investigated in perfused pancreas and collagenase-isolated islets of Langerhans. A 20- to 30-min pulse of 27.7 mM glucose enhanced both the first and second phase of insulin release in response to a second glucose stimulus by 76-201%. This enhancement was apparent as an augmented maximal insulin release response to glucose. The effect of priming with glucose was seen irrespective of whether the pancreatic tissue was obtained from fed or fasted rats. Separating the two pulses of hexose by a 60-min time interval of exposure to 3.3 mM glucose did not abolish the potentiation of the second pulse. Omission of Ca(++) as well as the inclusion of somatostatin or mannoheptulose during the first pulse abolished insulin secretion during this time period; however, only the inclusion of mannoheptulose deleted the potentiation of the second pulse. d-Glyceraldehyde, but not pyruvate, d-galactose, or 3-isobutyl-1-methylxanthine, could substitute for glucose in inducing potentiation. In islets labeled with [2-(3)H]adenine, the [(3)H]cyclic AMP response to glucose was increased by 35% when measured after 1 min, but was increased only marginally after 2-10 min of stimulation with a second pulse of glucose. The production of (3)H(2)O from glucose was not affected by glucose priming. It is concluded that (a) the induction of the glucose-induced, time-dependent potentiation described here is dependent on glucose metabolism but not on stimulation of cyclic AMP, calcium fluxes, or insulin release per se; (b) the mechanisms that mediate the pancreatic "memory" for glucose are unknown but do not seem to involve to a major extent an increased activity of the adenylate cyclase-cyclic AMP system of the beta-cell; (c) the evidence presented supports the hypothesis of a dual role of glucose for insulin release.

Animals↗
PubMed1978

Interacting effects of sulfonylureas and glucose on cyclic AMP metabolism and insulin release in pancreatic islets of the rat.

The effects of tolbutamide and glibenclamide on the metabolism of cyclic AMP were investigated in pancreatic islets of the rat. Changes in cyclic AMP were assessed by measuring [(3)H]cyclic AMP after labeling of the islets with [2-(3)H]adenine. In the presence of a nonstimulatory concentration of glucose (3.3 mM), both sulfonylureas caused a rapid increase in islet [(3)H]cyclic AMP, which declined within 5 (tolbutamide) or 10 min (glibenclamide). In the absence of glucose, the glibenclamide effect was shortened, but the initial (1 min) response of [(3)H]-cyclic AMP was unaffected. Glucose could be substituted with d-glyceraldehyde but not pyruvate for prolongation of the glibenclamide response. The effect of glucose withdrawal on the glibenclamide response was reproduced by the addition of d-mannoheptulose to glucose containing media. The [(3)H]cyclic AMP response to glibenclamide was influenced by prior exposure of the islets to glucose, a 30-min preincubation with 27.7 mM glucose, enhancing the response to the sulfonylurea over a subsequent 5-min stimulation period. Sulfonylureas exerted their effects at low but not at high glucose concentrations, i.e., shifted the glucose dose-response curve to the left both for [(3)H]cyclic AMP accumulation and insulin release. On the other hand, increasing concentrations of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, progressively augmented the effects of the drugs. Omission of Ca(++) from the incubation media inhibited both the glucose and the sulfonylurea [(3)H]-cyclic AMP and insulin responses. Epinephrine (1 muM) partially inhibited the [(3)H]cyclic AMP response to both glucose and sulfonylurea, whereas insulin release was completely abolished. It is concluded that the sulfonylurea effects on islet cyclic AMP are intimately related to those of glucose. It is suggested that sulfonylureas exert a major part of their action by facilitating the effect of glucose on the beta-cell adenylate cyclase; the increased cyclic AMP level, in its turn, enhances the secretion rate of insulin.

Adenylyl Cyclases↗
PubMed1977

[The role of cyclic AMP in the control of insulin secretion (author's transl)].

D-glucose stimulates the accumulation of cyclic AMP in isolated islets of Langerhans in a dose-dependent manner. This effect is present as long as the sugar remains elevated in the incubate. Under present experimental conditions the stimulation of cyclic AMP precedes insulin release. Islet or medium cyclic AMP, and insulin secretion are closely correlated at various incubation times. We conclude that the beta-cell cyclic AMP system is one of the major mediators of the glucose signal to insulin secretion. Tolbutamide and glibenclamide have similar effects in the absence or with low concentrations of glucose. These results may indicate that these sulfonylurea derivates act at sites where glucose exerts its effect.

Animals↗