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Biomedical subjects

R Nesher

Publications and source records attributed to R Nesher.

At least 55 records · Page 3Linked to original sources
PubMed1987

Somatostatin impairs clearance of exogenous insulin in humans.

Somatostatin has been widely used to suppress endogenous pancreatic hormone secretion in research studies. Many of these studies required the simultaneous infusion of a hormone together with somatostatin. A critical assumption for its use in metabolic investigation is that somatostatin has no effect on the action or clearance of a concomitantly infused hormone. To test whether clearance of an exogenously infused hormone is affected, we infused insulin with or without somatostatin in two sets of studies. Insulin (40 mU X kg-1 X h-1) was infused for 100 min (n = 6). Plasma glucose levels fell to 55 +/- 4.1 mg/dl with insulin alone and significantly lower, to 44 +/- 1.9 mg/dl, when somatostatin (250 micrograms/h) was also infused (P less than .01). Plasma immunoreactive insulin (IRI) rose to 57 +/- 12.5 microU/ml with insulin alone, which was significantly different from 88 +/- 15 microU/ml when insulin was infused together with somatostatin (P less than .01). When a smaller dose of insulin (30 mU X kg-1 X h-1) was infused for 100 min (n = 4), similar results were observed. When somatostatin was infused together with insulin, plasma glucose fell to lower levels (41 +/- 4.2 vs. 62 +/- 9.5 mg/dl; P less than .01) and plasma IRI rose higher (39 +/- 8.5 vs. 27 +/- 5.9 microU/ml; P less than .01) than when insulin was infused alone. C-peptide was equally suppressed by hypoglycemia regardless of whether somatostatin was administered, indicating suppression of endogenous insulin during these studies. We conclude that somatostatin infusion impairs the clearance of exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1986

Induction of cell surface insulin antigenicity in fibroblasts transfected with islet genomic DNA.

Ltk- cells were transfected with total genomic DNA obtained from rat islets or from insulinoma cells mixed with DNA tagged with fluorescent dye. Fluorescence-activated cell sorter (FACS) was used for initial selection of successful transfectants, monitoring fluorescent DNA incorporated into the cell. For subsequent selections the cells were treated with anti-insulin antiserum labeled with fluorescent dye and selected by FACS. Beta-cell DNA, but not DNA from murine leukemic cells, induced the appearance of cell surface insulin antigenicity in fibroblasts. This phenotypic expression was transient. Together with our previous demonstration of the induction of insulin secretion in Ltk- cells [(1986) Biochem. Biophys. Res. Commun. 136, 638-644], these results indicate that beta-cell-specific characteristics can be transfected to non-endocrine cells by genomic DNA transfection.

Animals↗
PubMed1986

Induction of insulin release in fibroblasts transfected with genomic rat islet DNA.

L cells (tk-) were cotransfected with total genomic rat islet DNA and a plasmid containing thymidine kinase gene (ptk). Transfectants were tested for their ability to release insulin into the medium. At least 10% of the colonies contained immunoreactive insulin (IRI) during the initial two weeks. The insulin secreted competed linearly with rat insulin in RIA, the majority of the insulin antigenicity comigrating with rat insulin on G-50 Sephadex chromatography. With continuing propagation the IRI activity diminished; however 3 selected cultures demonstrated increased secretion of IRI following stimulation with glucose. These findings indicate that glucose-induced insulin secretion can be obtained in non-beta cells; however the frequency of success was below one stable transfection for every 5 X 10(8) Ltk- cells exposed to the transfection procedure.

Animals↗
PubMed1986

Delayed-onset chloroquine retinopathy.

Delayed-onset chloroquine retinopathy was diagnosed in a patient seven years after cessation of treatment by a total dose of 730 g of chloroquine for rheumatoid arthritis. Visual functions continued to deteriorate after the diagnosis. Periodic examinations by ophthalmoscopy and by functional tests such as EOG and visual fields should be continued in patients at risk of delayed-onset chloroquine retinopathy after discontinuance of the drug.

Arthritis, Rheumatoid↗
PubMed1986

Pouch ileitis--recurrence of the inflammatory bowel disease in the ileal reservoir.

"Pouchitis" is an inflammation of the ileal pouch that has been described as occurring after Kock's procedure--the continent ileal pouch. The case presented herein demonstrates clinical and histological features that resemble ulcerative colitis, implying that this disorder may be a recurrence of the patient's original inflammatory bowel disease and not merely a local and nonspecific process as previously suggested.

Adult↗
PubMed1985

Correction of diabetic pattern of insulin release from islets of the spiny mouse (Acomys cahirinus) by glucose priming in vitro.

Insulin release kinetics were studied in perifused islets of Langerhans, isolated from mildly hyperglycaemic and from normoglycaemic spiny mice (Acomys cahirinus), a rodent predisposed to develop spontaneously non-ketotic diabetes. In both groups, insulin response to glucose (16.7 mmol/l) was delayed in comparison with that of rat islets, the release kinetics being analogous to that of human Type 2 (non-insulin-dependent) diabetes. Thirty min priming of the isolated Acomys islets with glucose (16.7 mmol/l) resulted in potentiation of the insulin release to a second stimulation. The degree of potentiation decreased exponentially with the time interval between stimulations, showing a t1/2 of 18 min. Induction of potentiation by glucose was time-dependent, giving a maximal effect after 20 min of priming. In addition to overall amplification of the insulin response, priming with glucose accelerated markedly the initial release rates, correcting the dynamics of the response. We conclude that: (1) decreased and delayed insulin secretion is found in Acomys cahirinus before the development of hyperglycaemia; (2) induction of time-dependent potentiation in the islet by priming with glucose corrects the diabetic-type dynamics of insulin release; (3) therefore the deficient insulin release of Acomys is of a functional nature, the mechanism of potentiation bypassing the defect; (4) since insulin release in Acomys resembles that in prediabetic and diabetic man, similar conclusions might apply to the islet dysfunction in Type 2 diabetes.

Animals↗
PubMed1985

Dissociation of effects of insulin and contraction on glucose transport in rat epitrochlearis muscle.

The effects of insulin and contraction on glucose transport and metabolism were investigated in rat epitrochlearis muscles in vitro. Insulin dose-response curves showed a threshold (approximately 50 microunits/ml) and saturation-type (approximately 1 mU/ml) kinetics, whereas isometric contraction activated glucose transport and metabolism in a linear fashion with no evidence of a threshold. Insulin and contraction increased the apparent maximal rate of uptake of the hexose transport system with minimal effect on its apparent Km. The stimulatory effects of insulin and contraction were additive; similar results were obtained with 2-deoxy-D-glucose. Contraction stimulated glucose transport in three different preparations of muscles depleted of insulin: 1) exhaustively washed for 2 h, 2) rats infused with anti-insulin serum, and 3) chronically (streptozotocin-induced) diabetic rats. Prostaglandin E2 augmented the effect of a submaximal concentration of insulin on glucose transport without exerting any effect by itself but had no effect on contraction-augmented glucose transport. It is concluded that insulin and contraction activate glucose transport and metabolism via independent mechanisms.

Animals↗
PubMed1985

Electrophysiological correlates of visual masking.

The phenomenon of paracontrast documented by means of psychophysical techniques has not been readily demonstrable using electrophysiological responses as an index of masking. We have analyzed averaged cortical potentials during presentation of visual stimuli that produce psychophysical masking. Differences in the masking profiles obtained from the two experimental conditions are apparent. However, both electrophysiological and psychophysical data do indicate an interaction between responses to an annulus and a disc which varies with the time interval between the stimuli. Both sets of data also reflect differences in masking between right and left eyes. We conclude that the cortical potentials evoked by temporally disparate stimuli do interact, but that the masking profile is not identical to the profile obtained by psychophysical methods.

Adult↗
PubMed1985

Relative potencies of human and pork insulin during i.v. and oral glucose tolerance test in lean and obese persons.

The biological efficacy of biosynthetic human insulin (BHI) of recombinant DNA origin was compared with that of highly purified pork insulin in subjects with normal (lean persons) and decreased (obese persons) sensitivity to insulin. Sequential i.v. administration of glucose with increasing insulin doses under somatostatin coverage was used to establish the dose-response characteristics of insulin-induced glucose clearance [insulin vs. Kg (glucose disappearance rate, %/min). Insulin was also given s.c. prior to an oral glucose tolerance test (OGTT) performed under somatostatin blockade; the appearance of insulin in serum and the modification of glucose levels were followed. The insulin vs. Kg dose-response curve was flatter and shifted to the right in obese persons compared with lean persons, demonstrating insulin resistance. In both lean and obese subjects, BHI and pork insulin had comparable effects on glucose clearance. Similarly, the effect of s.c. insulin on the serum glucose values during OGTT was the same when BHI or pork insulin were used. The absorption characteristics from the injection site were similar for both insulins. Thus, in man, human and pork insulin have similar pharmacokinetic and biological characteristics.

Administration, Oral↗
PubMed1984

Time-dependent inhibition of insulin release: suppression of the arginine effect by hyperglycaemia.

Brief stimulation of the pancreas with arginine causes a refractory state which reduces the insulin response to subsequent stimulations (time-dependent inhibition). In control subjects, a pair of arginine injections (75 mg/kg) at a 30-min interval resulted in 20% reduction of peak and integrated insulin responses to the second injection. In Type 2 (non-insulin-dependent) diabetic patients and in obese subjects, the inhibitory effect of repeated arginine stimuli was abolished. Healthy subjects were made acutely hyperglycaemic (9.3 +/- 0.3 mmol/l) by the glucose clamp technique. This induced a three- to fivefold greater insulin response to arginine. Compared to the response of diabetic subjects with similar hyperglycaemia, the control subjects secreted four to nine times more insulin. When the arginine stimulation was repeated 30 min later, no inhibition was observed, the second insulin response being instead augmented 1.5- to 1.8-fold. We conclude that (1) the insulin response to arginine is markedly reduced in Type 2 diabetes; (2) arginine-induced time-dependent inhibition of insulin release is abolished in patients with minimal to moderate hyperglycaemia; (3) this is probably due to the acute synergistic action of glucose and arginine on the B cell; (4) time-dependent inhibition of insulin release may be a protective mechanism against insulin oversecretion following repetitive stimulation of the pancreas; its abolition in hyperglycaemic states may be a compensatory mechanism, allowing substantial increases in insulin output.

Adult↗
PubMed1984

Time-dependent inhibition of insulin release: glucose-arginine interactions in the perfused rat pancreas.

The isolated perfused rat pancreas was stimulated sequentially with arginine or glucose to analyze the time-dependent modulation of insulin release. A 10-min perfusion with arginine (5.0 mmol/l) induced 75% inhibition of the insulin response to repeated arginine stimulation 10 min later. When glucose (8.3 mmol/l) was given as two pulses, inhibition of the second insulin response was less pronounced. The inhibitory effect generated by arginine also suppressed the insulin response to glucose (27.7 mmol/l), and this inhibitory effect persisted for over 80 min. Stimulation for 30 min with glucose (27.7 mmol/l) strongly potentiated the insulin responses to a pair of arginine stimuli given 20 min later. However, despite augmented secretion rates, the insulin response to the second arginine pulse was still inhibited by 75%. When insulin secretion was strongly amplified by two 10 min pulses of the synergistic mixture of arginine (5.0 mmol/l) and glucose (8.3 mmol/l), there was no inhibition of the second insulin response. If glucose (8.3 mmol/l) was present during the first arginine stimulation only, the response to the second arginine pulse was inhibited as in control experiments. However, when glucose was added to the second arginine pulse only, the inhibition generated by the first arginine pulse did not express itself, insulin release remaining similar to control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Differential control of insulin secretion and somatostatin-receptor recruitment in isolated pancreatic islets.

Somatostatin receptors appear to be localized to secretory granules in pancreatic islet homogenates. Recruitment of these receptors to the islet-cell surfaces may mark the contact event between secretory granules and plasma membranes before release of insulin by fission. Isethionate, an impermeant anionic replacement for chloride, blocks the release step but does not affect receptor recruitment. By contrast, low concentrations of phenothiazine drugs, such as trifluoperazine and promethazine, inhibit both receptor recruitment and secretion. Scatchard analysis of phenothiazine effects on somatostatin receptors reveals that these drugs reduce the number of receptors but do not affect the affinity of the receptor for somatostatin. These data indicate that membrane contact and fission steps during exocytosis can be biochemically separated.

Animals↗
PubMed1982

Granule fusion and fission (discharge) are biochemically dissociable events of exocytotic hormone release.

Granule fusion and the subsequent fission leading to hormone discharge are distinct and separable events in exocytosis. As an index of fusion, we followed the recruitment of granule-bound somatostatin receptors to the islet surface, an event which accompanies secretion vesicle migration and insulin secretion. Granule fission was monitored by measuring insulin release. Substitution of the impermeant salt sodium isethionate for NaCl led to a 90% decrease in glucose-stimulated insulin release with no inhibition of somatostatin receptor recruitment. The phenothiazine drugs, trifluoperazine and promethazine, believed to inhibit calcium-sensitive proteins involved with stimulus-secretion coupling blocked insulin release and somatostatin receptor recruitment in parallel. This suggests that these agents suppress intracellular events promoting fusion of the secretion granule with the plasma membrane. IBMX appears to stimulate specifically granule fission since IBMX-induced insulin release occurs acutely without an increase in somatostatin receptor recruitment. Sodium isethionate, which inhibits granule lysis, blocked IBMX-stimulated insulin release.

1-Methyl-3-isobutylxanthine↗