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G Reach

Publications and source records attributed to G Reach.

At least 127 records · Page 7Linked to original sources
PubMed1985

Immunoisolation of pancreatic B cells by microencapsulation. An in vitro study.

The selective permeability of alginate microcapsules, containing isolated rat islets of Langerhans or insulin secreting RINm5F cells, was investigated in vitro. An increase in insulin release was observed when microencapsulated islets were stimulated by glucose+theophylline, and when microencapsulated RINm5F cells were stimulated by arginine+theophylline. These findings demonstrate the permeability of the microcapsule membrane to these B-cell secretagogues and to insulin. Immunoisolation of RINm5F cells by microencapsulation was assessed using a 51chromium cytotoxicity test. Significant 51Cr release was observed when nonencapsulated cells were incubated with complement and either the serum of a rabbit immunized with RIN cells or the sera of two patients with recently diagnosed Type 1 (insulin-dependent) diabetes. This effect was not observed with encapsulated cells. Both free and encapsulated cells released 80% of their initial radioactivity when incubated in the presence of HC1. These results clearly demonstrate pancreatic cell immunoisolation by microencapsulation. They also provide a method for the in vitro evaluation of the functional characteristics of microcapsules, in terms of both insulin permeability and immunoprotection.

Alginates↗
PubMed1985

Dietary and hormonal regulation of aldolase B gene expression.

Aldolase B is an enzyme of the glycolytic pathway whose activity and mRNA levels in the liver fluctuate according to dietary status. Both the enzyme activity and the mRNA concentration decline during fasting and increase four- to eightfold upon refeeding of a carbohydrate-rich diet. The mechanism, however, of the mRNA induction remains unknown. To elucidate the mechanisms that regulate this induction responsive to dietary stimuli, we have studied the roles of hormones and glycolytic substrates on aldolase B gene expression in three tissues that synthesize the enzyme. Using a cDNA probe complementary to rat aldolase B mRNA, we determined the amount of cytoplasmic RNAs in the liver, kidney, and small intestine of normal, adrenalectomized, thyroidectomized, diabetic, and glucagon- or cAMP-treated animals refed either a fructose-rich or a maltose-rich diet. The in vivo hormonal control of gene expression was found to be very different in the three organs tested. In the liver, cortisone and thyroid hormones were required for the induction of the specific mRNA by carbohydrates, while in the kidney none of the hormonal modifications tested altered the level of mRNA induction. In the liver, but not in the kidney, diabetes and glucagon administration abolished the induction of aldolase B mRNAs in animals refed the maltose-rich diets. In the small intestine, only diabetes and thyroidectomy affected the gene expression. Finally, no induction occurred when normal fasted rats were given any of the hormones. Thus, the in vivo hormonal control of liver aldolase B gene expression differs significantly from that of kidney and small intestine. In the liver, the mRNA induction requires the presence of dietary carbohydrates, of permissive hormones, and the cessation of glucagon release, while in the kidney, the induction of the mRNAs by fructose occurs regardless of the hormonal status of the animals. The hormonal control of aldolase B mRNA levels in the small intestine is intermediate.

Adrenalectomy↗
PubMed1984

Cyclic AMP as a transcriptional inhibitor of upper eukaryotic gene transcription.

Recently, glucagon and its second messenger, cyclic AMP, have been shown to stimulate the transcription rate of several upper eukaryotic genes (1-5). We show here that glucagon can also block gene transcription. Both glucagon and cyclic AMP were found to inhibit the transcription of the genes encoding three liver glycolytic enzymes, including L-type pyruvate kinase and aldolase B. Thus, cyclic AMP proves to be not only an activator but also an inhibitor of gene transcription in eukaryotes.

Animals↗
PubMed1984

In vivo hormonal control of L-type pyruvate kinase gene expression. Effects of glucagon, cyclic AMP, insulin, cortisone, and thyroid hormones on the dietary induction of mRNAs in the liver.

Using a cDNA probe complementary to rat L-type pyruvate kinase mRNAs, we studied the respective roles of glucocorticoids, thyroid hormones, glucagon, and insulin in the induction of specific mRNAs in the liver of animals refed either a maltose-rich or a fructose-rich diet. Neither adrenalectomized nor thyroidectomized nor diabetic animals could express L-type pyruvate kinase mRNAs in their liver when refed the carbohydrate-rich diets. When the animals were given the missing hormone, the level of hybridizable mRNAs returned to normal values but administration of the hormone alone failed to induce mRNA synthesis in fasted animals. Both glucagon and cyclic AMP abolished the induction of L-type pyruvate kinase mRNAs in refed animals. Exogenous insulin, whatever the dose, could not reverse the inhibitory action of glucagon. Insulin has usually been regarded as the main regulator of L-type pyruvate kinase gene expression. It appears now that glucagon, beside regulating the enzyme activity by phosphorylation mechanisms, may also modulate L-type pyruvate kinase synthesis at a pre-translational level. Consequently, our results show that three conditions are required for the synthesis of liver L-type pyruvate kinase mRNAs: (i) the presence of dietary carbohydrates, (ii) the cessation of glucagon release, and (iii) the presence of permissive hormones, including insulin.

Adrenalectomy↗
PubMed1984

A U-shaped bioartificial pancreas with rapid glucose-insulin kinetics. In vitro evaluation and kinetic modelling.

The lag in insulin release in response to glucose is an obstacle to the development of hybrid pancreatic devices, in which an artificial membrane protects transplanted islets against immune rejection. We designed a U-shaped bioartificial pancreas, in which the blood channel surrounds the islet chamber consisting of two flat membranes; blood circulates successively above the first membrane and then in the reverse direction, below the second membrane. Isolated rat islets were introduced into the chamber, which was perfused with Krebs buffer, and the kinetics of insulin release in response to glucose was determined. During a 20-min, 2.8-20-mM, square-wave glucose stimulation, insulin release in the effluent of the device rose from 0.7 +/- 0.2 to 3.2 +/- 1.0 ng/100 islets/min (P less than 0.05) within 3 min, and reached a maximal level of 12.8 +/- 3.3 ng/100 islets/min at 10 min; 5 min after the return of the glucose concentration to substimulatory level, insulin release dropped from 11.3 +/- 1.5 to 8.0 +/- 1.7 ng/100 islets/min (P less than 0.05), and reached basal value (1.0 +/- 0.2 ng/100 islets/min) 40 min after the end of the stimulation. A 0.1-mM/L/min ramp increase in glucose concentration triggered a significant rise in insulin release (P less than 0.02) when the glucose concentration reached 5.3 +/- 0.2 mM; islets concomitantly perifused within a chamber set up without membrane responded to the same glucose stimulation 5 min earlier. For up to 1000 islets, insulin release in response to glucose was linearly correlated to the number of islets (N = 12, P less than 0.01), indicating that insulin did not significantly inhibit its own secretion in this system. Finally, during glucose stimulation, the insulin concentration in the effluent from the chamber was found to be four times the concentration present at the turning point of the blood channel, suggesting that insulin was transferred into the perfusing medium in part by a countercurrent flux of ultrafiltrate crossing the membranes. We present herein the kinetic modelling of glucose and insulin transfer in this "ultrafiltration chamber," whose functional characteristics are compatible with closed-loop insulin delivery.

Animals↗
PubMed1984

Bioartificial pancreas. Present state and future prospects.

The bioartificial (hybrid) pancreas separates transplanted tissue (i.e. islets of Langerhans) from the diabetic host and thus protects it against immune rejection. The membranes employed in such devices must be impermeable for immunocytes and immunoglobulins but--due to the particular construction of the devices--more or less selectively permeable for glucose and insulin. A short survey is presented on different systems from the viewpoint of the transport functions realized, i.e. diffusion systems, ultrafiltration systems, and combined diffusion-ultrafiltration systems. All these devices are still in a developmental stage.

Animals↗
PubMed1983

Pentamidine, a new diabetogenic drug in laboratory rodents.

The antiprotozoal drug, pentamidine, has been reported to induce hypoglycaemia associated with inappropriately high plasma insulin concentrations, followed by insulin-dependent diabetes mellitus. It has been suggested that this drug can be toxic to the islet B cell, inducing early cytolytic release of insulin leading to B cell destruction. In order to test this hypothesis, mouse and rat islets were incubated with pentamidine at concentration range of 5 x 10(-11) to 5 x 10(-3) mol/l and exposure times of 3-48 h. The B cell responses to glucose + theophylline and to arginine were suppressed by pentamidine, while insulin release in non-stimulatory conditions was increased. These effects were dose-dependent, time-dependent and irreversible. They were significant for 5 x 10(-7) mol/l pentamidine, which is a concentration relevant to therapeutic uses. These effects developed more slowly than the toxic effects of streptozotocin and alloxan at the same molar concentration in vitro. 51Chromium release and Trypan blue exclusion tests support the hypothesis that pentamidine produces islet cell necrosis.

Amidines↗
PubMed1982

The brain-islet axis: the nervous control of the endocrine pancreas.

The central nervous system exerts a control on the endocrine pancreas and can modulate the basic feed-back loop linking the concentration of the main energy substrates in blood with islet cell functions. Thus, the elementary glucose-insulin system can be modulated under physiological conditions by both the long-recognized entero-insular axis and by a brain-islet axis, particularly when insulin release occurs in anticipation of meals. Experimental stimulation or section of afferent nerves to the pancreas have demonstrated the existence of this nervous control. Changes in islet cell secretion during stress illustrate this influence under clinical conditions. A variety of experimental data suggest intervention of the brain-islet axis under the physiological circumstances: 1) Manipulation of certain hypothalamic centres followed by modification of feeding behaviour and of islet secretion. 2) Input to the brain is both humoral (carried by arterial carotid blood or the cerebrospinal fluid) and nervous, of sensory and visceral origins. Changes in these afferent pathways may influence islet secretion via the efferent pathways of the vagus and splanchnic nerves. 3) Besides acetylcholine and catecholamines, peptide neurotransmitters are likely to be involved in the transmission of these nervous inputs to islet cells. 4) Furthermore, hypothalamic factor (s) may also modify the endocrine pancreatic secretions.

Adrenergic Fibers↗
PubMed1982

Diabetes mellitus following pentamidine-induced hypoglycemia in humans.

Four patients, treated with pentamidine because of Pneumocystis carinii pneumonitis, displayed severe fasting hypoglycemia during this treatment. Diabetes mellitus appeared later, requiring insulin therapy in the three of them who survived more than a few weeks. The metabolic study, performed in two cases during the hypoglycemic period, demonstrated inappropriately high insulin levels in the postabsorptive state. 28 +/- 1 microunits/ml (blood glucose 41 +/- 4 mg/dl) and 86 +/- 5 microunits/ml (blood glucose 15 +/- 5 mg/dl) vs. 15 +/- 3 microunits/ml in 10 control subjects and 55 +/- 3 microunits/ml in 6 patients with a verified B-cell tumor, respectively. Poor B-cell secretory responses followed the stimulations by oral glucose (maximal increment over basal: +5 microunits/ml vs. + 40 microunits/ml in control group and +77 microunits/ml in the insulinoma group), by i.v. arginine (maximal increment + 10 and +28 microunits/ml, respectively, vs. +55 in the controls and +90 microunits/ml in the insulinoma group) and by i.v. glucagon (+10 and +23 microunits/ml, respectively) vs. +40 microunits/ml in both the control and the insulinoma groups). Plasma cortisol and glucagon, and the A-cell response to arginine were higher than normal. These high, nonsuppressible, nonstimulable insulin levels and the sequence of hypoglycemia followed by insulin-dependent diabetes mellitus is consistent with the hypothesis of a selective toxicity turned towards the B-cells. In vitro incubation of islets with pentamidine 10(-10) M produced a passive release of insulin, followed by a significant decrease in B-cell response to glucose + theophylline. It is suggested that pentamidine can induce hypoglycemia because of an early cytolytic release of insulin, and then diabetes mellitus because of B-cell destruction and insulin deficiency.

Adult↗
PubMed1982

[New insulins].

Explore the source record for details and available documents.

Animals↗
PubMed1981

[Adrenocortical scintigraphy with 131I-19-iodocholesterol. Indications and results in 66 cases of hypercortisolism and hyperaldosteronism (author's transl)].

Scintigraphy was used in 66 patients with biochemically demonstrated hyperactivity of the adrenal cortex in order to determine the nature and site of the lesions. In cases of hypercortisolism, uptake was bilateral in 12 patients with Cushing's disease, unilateral in 7 patients with malignant or non-malignant tumours, and absent in 3 cases of large malignant tumours. In cases of hyperaldosteronism, scintigraphy performed during dexamethasone-induced ACTH suppression showed distinctly asymmetrical uptake in 13 patients with Conn's adenoma (confirmed by surgery as being on the good uptake side in 10 patients), symmetrical in 20 patients with biochemical findings indicating bilaterality, and intermediate in 9 patients. There was no false positive diagnosis of tumour. Scintigraphy appears to be of considerable value for locating adrenocortical lesions, especially small tumours.

19-Iodocholesterol↗
PubMed1981

[Substitutes for the endocrine pancreas].

Since it is generally accepted that a tight metabolic control might prevent the chronic complications of diabetes mellitus, several systems have been developed in which insulin is administered in a manner that mimicks the characteristics of insulin secretion. 1) In the so-called closed-loop systems, insulin delivery is regulated by the concomitant plasma glucose level. These systems, which involve continuous measurement of plasma glucose concentration are not to date implantable and have been used so far only for short-term studies. 2) By contrast, in the "open-loop systems", no glucose sensor is needed and insulin delivery is pre-programmed to achieve a constant basal infusion with peaks of insulin delivery during the meal periods. These systems have been used in man for several months. The present achievement and limitations of both kinds of systems are discussed in this review.

Diabetes Mellitus↗