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Biomedical subjects

D M Findlay

Publications and source records attributed to D M Findlay.

97 records · Page 6Linked to original sources
PubMed1980

Properties of a calcitonin receptor and adenylate cyclase in BEN cells, a human cancer cell line.

A human lung cancer cell line (BEN cells) was found to have a calcitonin-responsive adenylate cyclase. Various calcitonins and synthetic analogs stimulated adenylate cyclase activity withe same relative potency as they show in lowering blood calcium in the rat. Preincubation of the cells with calcitonin, followed by washing, led to loss of subsequent adenylate cyclase response to hormone. This was a dose-dependent phenomenon. The binding of [125I]salmon calcitonin to freshly subcultured cells was studied. The ability of calcitonins and analogs to compete for binding paralleled their efficacies in stimulating adenylate cyclase. Binding was saturable, reversible, and consisted of a single class of noninteracting sites with a mean Kd of 10.75 X 10(-10) M, K of 0.93 X 10(9)/M, and mean receptor number of 2.71 X 10(4)/cell. It is not known whether the calcitonin receptor is inappropriate to the cell of origin of the tumor. The BEN cells provide a means of isolating and studying the properties of the calcitonin receptor and of evaluating the significance for the tumor of a hormone-responsive adenylate cyclase.

Adenylyl Cyclases↗
PubMed1980

Calcitonin and 1,25-dihydroxyvitamin D3 receptors in human breast cancer cell lines.

Five human breast cancer cell lines (MCF 7, T 47D, BT 20, MDA 157, and MDA 231) and a human breast epithelial cell line (HBL 100) have been found to contain specific high-affinity receptors for 1,25-dihydroxyvitamin D3, Kd values ranged from 0.6 to 2.0 X 10(-11) M and receptor concentration from 31 to 150 fmol/mg cytosol protein. Two of the breast cancer lines (MCF 7 and T 47D) contain specific high-affinity receptors for calcitonin and a calcitonin-responsive adenylate cyclase, which have been characterized with the aid of salmon, eel, and human calcitonins and in several substituted analogues of human calcitonin. The 1,25-dihydroxyvitamin D3 receptor may reflect a normal property of the breast cell. Breast cancer cell lines provide a useful source of 1,25-dihydroxyvitamin D3 receptors. Their coexistence with a calcitonin receptor and biological response in some breast cancers offers the opportunity to investigate new aspects of breast cancer endocrinology.

Adenylyl Cyclases↗
PubMed1979

Glucagon metabolism in normal subjects and in cirrhotic patients before and after portasystemic venous shunt surgery.

The effect of portasystemic shunt surgery on basal immunoreactive glucagon (IRG) levels, metabolic clearance rate (MCR) and t 1/2 for glucagon decay, and basal systemic delivery rate (BSDR) of glucagon was investigated in paired studies in ten cirrhotic subjects. The degree of hepatocellular dysfunction and extent of portasystemic venous shunting was also recorded. Basal IRG levels were highest in the post-shunt (mean +/- SEM, 382 +/- 73 pg/ml) as compared to the pre-shunt (213 +/- 27 pg/ml; P less than 0.05) cirrhotic and control (53 +/- 13 pg/ml; P less than 0.005) groups. The MCR of glucagon was similar in control (13.0 +/- 1.3 ml/kg/min) and pre-shunt cirrhotic patients (13.3 +/- 1.7 ml/kg/min) but was significantly (P less than 0.02) decreased in the post-shunt cirrhotics (7.6 +/- 1.3 ml/kg/min). The t 1/2 for glucagon decay was similar in the control and cirrhotic groups. The BSDR, an estimate of pancreatic A cell secretion, was increased four-fold (P less than 0.01) in the pre-shunt (3042 +/- 454 pg/kg/min) and post-shunt (2518 +/- 535 pg/kg/min) cirrhotic groups, as compared to controls (750 +/- 244 pg/kg/min). It is concluded that (a) in the presence of cirrhosis, the magnitude of portasystemic shunting is important in determining the degree of hyperglucagonaemia; (b) in preshunt cirrhotics raised basal IRG levels are principally due to A cell hypersecretion of glucagon whereas in post-shunt cirrhotics riased IRG levels reflect both A cell hypersecretion and delayed clearance of glucagon; and (c) acute shunting of splanchnic venous blood away from the liver reduces the clearance of glucagon, suggesting that, in man, the liver contributes to the clearance of circulating glucagon.

Adult↗
PubMed1979

Effect of portasystemic venous shunt surgery on hyperglucagonaemia in cirrhosis: paired studies of pre- and post-shunted subjects.

The effect of liver disease on glucagon metabolism was examined in nine patients with chronic liver disease who were studied both before and after the creation of a surgical portasystemic shunt. Hepatocellular function did not deteriorate after shunt surgery. However, hepatic perfusion with splanchnic venous blood, as determined by scintisplenoportography, decreased after shunt surgery in six subjects but appeared unaltered in three. Basal plasma immunoreactive glucagon (IRG) levels in the pre-shunt cirrhotic group were significantly greater (p <0.005) than in control subjects and further increased (p <0.05) after shunt surgery. Moreover, the increase in basal IRG after shunt was evident only in patients in whom portasystemic shunting was demonstrably increased by surgery. Despite the higher basal IRG levels postoperatively, shunt surgery in the cirrhotics did not alter basal glucose and insulin levels or the glucose and insulin response to a glucose or protein load. Circulating IRG was heterogeneous in the pre-shunt cirrhotic patients: the 9000 molecular weight fraction comprised 27+/-4%, the 3500 mol. wt. fraction 71+/-4%, and the > 40 000 mol. wt. fraction was minimal. After shunt surgery, the relative proportion of the 9000 mol. wt. fraction of IRG (13+/-3%) decreased significantly (p <0.05) and this fall was associated with a corresponding increase in the 3,500 mol. wt. fraction (84+/-4%). It is concluded that, in cirrhosis, hyperglucagonaemia is: (1) dependent on the degree of portasystemic shunting rather than impaired hepatocellular function; (2) predominantly due to increased circulating 3500 molecular weight glucagon; and (3) not a major factor in the pathogenesis of carbohydrate intolerance in liver disease.

Adult↗
PubMed1979

Hyperglycemia and glucagon suppression: possible importance of the vagus and enteric humoral factors.

Augmentation of insulin release after oral glucose by a gastrointestinal humoral mechanism is well accepted. The suggestion of a similar mechanism for suppression of glucagon release after oral glucose has not been previously tested. In this study, plasma glucagon levels have been estimated in five normal subjects after both oral and iv administration of glucose. A variable iv glucose infusion rate with frequent monitoring of blood glucose was used to match the hyperglycemia produced by the 50 g oral glucose and the iv glucose loads. Virtually complete suppression of plasma glucagon levels was seen in both cases (nadir of glucagon levels 16 +/- 6 pg/ml for oral glucose; 11.4 +/- 3 pg/ml for iv glucose). Thus, enteric humoral factors did not facilitate glucagon suppression after oral glucose ingestion in man. The vagus nerve is also involved in mediating the alpha-cell response to hypoglycemia and, thus, to examine whether hyperglycemia suppresses glucagon release through a vagal mechanism, iv atropine (15 microgram/kg) was given 20 min before administration of oral or iv glucose. Atropinization delayed the glucagon suppression after oral glucose, but this delay was probably related to delayed glucose absorption from the gut. With iv glucose, atropinization did not affect the degree of suppression of glucagon levels. It is concluded that alpha-cell suppression in response to hyperglycemia is not mediated via the vagus.

Adult↗
PubMed1977

Glucagon and diabetes. I. The failure of hyperglucagonaemia to influence the response of established diabetic ketoacidosis to therapy.

Clinical and biochemical variables were examined during two standardized, low-dose insulin regimens in seven subjects with diabetic ketoacidosis and one with hyperosmolar coma, in order to determine whether glucagon levels can be suppressed in ketoacidosis and whether hyperglucagonaemia influences the clinical and biochemical responses to treatment. Glucagon concentrations were significantly elevated (36.6-697.0 pmol/l) at presentation in all subjects. After institution of insulin treatment (4-8 u/h), glucose and glucagon levels decreased rapidly, and in five of the eight subjects glucagon levels reached undetectable concentrations (less than 3.0 pmol/l) during the initial treatment period. Further, neither plasma glucagon concentrations at presentation, nor the rate of glucagon decline during insulin treatment, appeared to influence the rapidity of the glucose decline or the persistence of the ketoacidosis. Thus, low-dose exogenous insulin suppresses glucagon secretion in diabetic ketoacidosis, and the changes in glucagon concentrations during treatment are unrelated to the clinical response.

Adult↗