Biomedical subjects

S G Gilbey

Publications and source records attributed to S G Gilbey.

At least 37 records · Page 2Linked to original sources

PubMed1993

Pleural involvement in the carcinoid syndrome.

Tissue fibrosis is a recognized complication of the carcinoid syndrome but pleural changes have not been described. Prompted by the finding of severe pleural thickening in two patients with the metastatic carcinoid syndrome but no thoracic metastases or previous pleural disease we reviewed the chest radiographs and CT scans in 50 patients with the carcinoid syndrome investigated from 1981 to 1990. Pleural abnormality was noted in 14 of the 50 patients (28%), five of whom had other possible causes for pleural disease. However, nine (18%) patients had 'idiopathic' pleural thickening. Pleural disease had developed within 2 years of the diagnosis in all cases, and seven of the nine patients had fibrosis elsewhere (heart valves, skin or mesentery). There were no features to suggest a more rapid disease progression in the patients with pleural disease. We suggest that the pleural abnormality is a complication of metastatic carcinoid disease.

Humans↗

PubMed1992

The physiology of calcitonin gene-related peptide in the islet compared with that of islet amyloid polypeptide (amylin).

Following the discovery of a second gene containing a CGRP-like sequence, we demonstrated that "beta-CGRP" was indeed translated as a 37-amino acid peptide in vivo and was the predominant form of CGRP produced by the enteric nervous system. The presence of CGRP in the islet has been reported by several groups. We now show that beta-CGRP is again the major form. Another 37-amino acid peptide was recently isolated from islet amyloid deposits and found to have approximately 50% amino acid sequence homology with CGRP. Islet amyloid polypeptide, or amylin, is co-localized with insulin to the beta-cell secretory granule and is synthesized and released in parallel with insulin in response to a range of physiological and pharmacological stimuli. IAPP was subsequently shown, like CGRP, to inhibit the release of insulin pharmacologically. Interestingly, it was also shown to decrease the uptake of glucose by striated muscle, though it was considerably less potent than CGRP. This led to the suggestion that IAPP might be a circulating hormone regulating peripheral insulin sensitivity. Infusion of IAPP in human volunteers to produce plasma concentrations more than 100-fold higher than those seen physiologically, however, failed to alter peripheral glucose disposal. We conclude that beta-CGRP and IAPP are likely to play a role in local paracrine control of the islet.

Amyloid↗

PubMed1992

Very high concentrations of islet amyloid polypeptide are necessary to alter the insulin response to intravenous glucose in man.

Islet amyloid polypeptide (IAPP) is a beta-cell peptide that can oppose insulin action in animal systems, but has not been shown to have any action in man; previously, we failed to show an effect of infused IAPP on iv glucose tolerance in human volunteers. We have reexamined its effects at even higher concentrations in six volunteers who received iv glucose (0.5 g/kg) during infusions of IAPP (25 and 50 pmol/kg.min) or normal saline. IAPP rose from a mean basal of 14.7 +/- 5.3 pmol/L to peak levels of 1,420 +/- 110, 2,240 +/- 140, and 27.7 +/- 9 pmol/L, respectively. IAPP at 25 pmol/kg.min had no effect on the plasma glucose disposal rate or the total incremental insulin response, but, in contrast, at 50 pmol/kg.min decreased the insulin response to glucose compared to the saline infusion (incremental area under the curve, 11,276 +/- 2,353 vs. 17,549 +/- 2,687 U; mean +/- SEM; P less than 0.02). This decrease was observed both during the first phase (0-10 min postglucose) insulin response (3,210 +/- 985 vs. 4,382 +/- 815 U; P less than 0.05) and the second phase response (11-90 min, 8,520 +/- 1,719 vs. 13,679 +/- 2,326 U; P less than 0.03). Glucose disposal rate, however, was unaffected (2.0 +/- 0.2 vs. 1.9 +/- 0.2). Thus, circulating IAPP concentrations greater than 90 times normal postprandial peaks were necessary to affect the insulin response to glucose. IAPP appears unlikely to be a circulating hormone influencing carbohydrate metabolism in man.

Adult↗

PubMed1992

Increased neuropeptide Y content in individual hypothalamic nuclei, but not neuropeptide Y mRNA, in diet-induced obesity in rats.

Neuropeptide Y (NPY) is the most powerful appetite stimulant known, and chronic administration leads to obesity. The hypothalamic content of NPY varies with nutritional status, suggesting that it is of physiological importance. We measured NPY in specific hypothalamic nuclei and NPY mRNA in the hypothalamus by Northern blotting in rats made obese by feeding a highly palatable diet compared with controls fed standard chow. In animals fed the palatable diet, NPY concentrations were increased in the paraventricular nucleus (mean +/- S.E.M.; 19.5 +/- 2.3 vs 11.1 +/- 1.1 fmol/micrograms protein, P less than 0.02), the arcuate nucleus (20.4 +/- 3.3 vs 9.3 +/- 0.6 fmol/micrograms protein, P less than 0.01), the medial preoptic area (9.1 +/- 0.9 vs 5.9 +/- 0.7 fmol/micrograms protein, P less than 0.02) and the anterior hypothalamus (2.7 +/- 0.2 vs 2.0 +/- 0.1 fmol/micrograms, P less than 0.02). Hypothalamic NPY mRNA measured by Northern blot analysis was, however, unchanged. These results suggest that the increase in NPY was due to decreased release rather than increased NPYergic activity. The findings are in accord with the neuroendocrine disturbance and increased thermogenesis observed in this model of obesity.

Animals↗

PubMed1991

Islet amyloid polypeptide: production by an osteoblast cell line and possible role as a paracrine regulator of osteoclast function in man.

1. The recently discovered peptide islet amyloid polypeptide shows considerable sequence homology with calcitonin-gene-related peptide, itself an alternative product of the calcitonin gene. The possibility that islet amyloid polypeptide might affect calcium homoeostasis and bone cell function was investigated. 2. Islet amyloid polypeptide messenger RNA was found to be expressed by human HTb 96 osteoblast-like cells in culture, and islet amyloid polypeptide immunoreactivity was present in the cell culture medium. 3. Infusion of islet amyloid polypeptide (150 pmol min-1 kg-1) caused a fall in serum calcium and phosphate concentrations in five patients with Paget's disease of the bone. This was similar to that caused by infusion of calcitonin (50 pmol min-1 kg-1). 4. These findings raise the possibility that islet amyloid polypeptide may act as a local factor within bone, produced by osteoblasts and regulating osteoclast function. The possibility of an action of islet amyloid polypeptide on the renal handling of calcium seems unlikely but is not totally excluded.

Aged↗

PubMed1991

Sural nerve morphometry in diabetic autonomic and painful sensory neuropathy. A clinicopathological study.

Observations have been made on a selected series of insulin-dependent patients with neuropathy, subdivided into three groups: (1) severe autonomic neuropathy with an accompanying painless sensory neuropathy; (2) severe autonomic neuropathy with a chronic painful sensory neuropathy; and (3) chronic or acute painful sensory neuropathy with no autonomic neuropathy. All three groups showed a loss of large and small myelinated nerve fibres in sural nerve biopsy specimens which was greater in Groups 1 and 2. Regenerative activity was prominent in all three groups, but least in Group 3. Teased fibre studies showed evidence both of axonal regeneration and remyelination. Active fibre degeneration was rare. Measurements of g ratio (axon diameter:total fibre diameter) gave no indication of axonal atrophy. The density of unmyelinated axons was reduced in all three groups, as was their median diameter. Vibration sense threshold was positively correlated with the total number of myelinated fibres and thermal sensory threshold with median unmyelinated axon diameter but not with total unmyelinated axon numbers. No correlation between the occurrence of pain and active degeneration of myelinated fibres or with regenerative activity either in myelinated or unmyelinated axons was detectable. Assessment of differential loss of large or small myelinated nerve fibres was difficult because of the presence of large numbers of small regenerating myelinated axons. The results are discussed in relation to the concept of 'diabetic small fibre neuropathy' and the causation of pain in diabetic neuropathy.

Adult↗

PubMed1990

Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man.

The presence of islet amyloid polypeptide in amyloid within pancreatic islet cells in Type 2 (non-insulin-dependent) diabetes, and its reported inhibition of glucose uptake by skeletal muscle in vitro, has prompted speculation concerning its role in the pathogenesis of diabetes. We investigated the effect of infused synthetic amidated human islet amyloid polypeptide (mol. wt. 3904, confirmed by mass spectroscopy) on intravenous glucose tolerance. Seven healthy, non-obese volunteers (age +/- SD, 27 +/- 4 years) were infused over 50 min with normal (0.9%) saline or islet amyloid polypeptide at 50 pmol.kg-1.min-1. After 20 min, a bolus of 0.5 g/kg glucose was given within 1 min and blood sampling continued for up to 60 min. Circulating concentrations of islet amyloid polypeptide reached at steady state were 1130 +/- 90 pmol/l. The calculated half-life was 11.8 +/- 0.9 min, metabolic clearance rate 5.7 +/- 0.6 ml.kg-1.min-1 and apparent distribution space therefore 94 +/- 12 ml/kg. However, islet amyloid polypeptide was found to have no effect on the peak value reached, or the total area under the curve for plasma glucose, insulin or glucagon following intravenous glucose. This study suggests circulating islet amyloid polypeptide may not be an important influence on intravenous glucose tolerance in man.

Adult↗

PubMed1989

High-dose porcine galanin infusion and effect on intravenous glucose tolerance in humans.

The neuropeptide galanin inhibits glucose-stimulated insulin release in dogs and rodents and has been proposed as having a role in the control of insulin release in humans. The effect of infused galanin on intravenous glucose tolerance in humans was investigated by giving an intravenous glucose tolerance test (0.5 g glucose/kg body wt) alone and with infusions of synthetic porcine galanin at high-dose levels (80 and 160 pmol.kg-1.min-1) to seven healthy male volunteers. The results showed no effect of galanin infusion on plasma glucose or serum insulin, although a rise in serum growth hormone even in the face of the intravenous glucose load confirmed the potent growth hormone-stimulating effect of galanin. These results suggest that caution should be exercised in extrapolating a physiological role for galanin in humans from the results of animal studies.

Animals↗

PubMed1988

Insulin as an amyloid-fibril protein at sites of repeated insulin injections in a diabetic patient.

A patient with Type 1 (insulin-dependent) diabetes mellitus developed localised amyloidosis at the sites of his injections of porcine insulin. A major amyloid fibril protein was extracted and, by means of its amino acid composition and amino acid sequence, it was shown to contain intact insulin molecules. Porcine insulin is the tenth protein and the first foreign protein to be chemically identified in human amyloid fibrils.

Adult↗

PubMed1988

Pattern of myelinated fibre loss in the sural nerve in neuropathy related to type 1 (insulin-dependent) diabetes.

Sural nerve biopsies were obtained from 17 diabetic patients with neuropathy. All patients except three had both a symmetric distal sensory and autonomic polyneuropathy related to Type 1 (insulin-dependent) diabetes mellitus; 3 patients had a purely sensory polyneuropathy. Mean age was 34.5 years (range 18-53 years). The biopsies were compared with specimens from an age-matched control series. Myelinated fibre loss in the diabetic nerves was found to be nonuniform. Although patchy fibre loss has been considered to favour a vascular basis, an identical pattern of nonuniform loss was observed in a series of sural nerve biopsies from patients with Type I hereditary motor and sensory neuropathy, a subgroup within the spectrum of peroneal muscular atrophy, mainly of autosomal dominant inheritance, and a condition in which a vascular causation can be discounted. Possible reasons for nonuniform fibre loss other than vascular disease are discussed.

Adult↗

PubMed1988

Diabetic neuropathy in the upper limb and the effect of twelve months sorbinil treatment.

Clinical and neurophysiological studies were undertaken, with particular reference to the arms, in 39 patients with diabetic neuropathy. The effects of an aldose reductase inhibitor, sorbinil, on neuropathy in these patients were studied in a 12 month double blind placebo controlled trial. Neurophysiological measurements, particularly of sensory amplitude, were considerably more sensitive than measurements of temperature and vibration sensation and remain of fundamental importance in measuring diabetic neuropathy at an early and potentially reversible stage. There was no significantly beneficial effect of sorbinil on clinical or neurophysiological measurements of nerve function in patients with established diabetic neuropathy. These results indicate that neurophysiological techniques are necessary, in conjunction with clinical measurements, for the assessment of 'early' diabetic neuropathy and that aldose reductase inhibitors are not effective in the treatment of established diabetic neuropathy.

Adult↗

PubMed1988

Cell-mediated immunity and symptomatic diabetic autonomic neuropathy.

T lymphocytes have been implicated in the nerve damage observed in allergic experimental neuritis and in idiopathic polyneuritis. Symptomatic autonomic neuropathy in long-standing Type 1 diabetes is a rare and unexplained complication, and some preliminary evidence has suggested a pathogenetic role for the immune system. We have measured levels of activated T lymphocytes in 18 Type 1 diabetic patients with symptomatic autonomic neuropathy and in 16 matched patients with uncomplicated Type 1 diabetes. Purified T lymphocytes from peripheral blood were stained with a fluorescein-labelled monoclonal antibody directed to the activation marker HLA-DR and counted under UV microscopy. Percent DR positive T lymphocytes were significantly raised in the patients with autonomic neuropathy when compared with long-standing uncomplicated diabetic patients (8.2 +/- 4.2 vs 4.9 +/- 3.3%, p less than 0.01). This finding lends support for a role of the immune system in the development of autonomic neuropathy.

Adult↗

PubMed1988

Cough threshold to citric acid in diabetic patients with and without autonomic neuropathy.

The cough reflex has been investigated in insulin dependent diabetic patients with and without autonomic neuropathy. The cough response to inhaled citric acid was determined in eight patients with diabetes who had severe autonomic neuropathy and compared with that in 10 who had no evidence of neuropathy. The patients with autonomic neuropathy had a higher median threshold for the cough response to citric acid (median 50%, range 20- greater than 100%) than non-neuropathic control patients (median 10%, range 2-20%). These results suggest that vagal innervation of the bronchial tree is damaged by diabetic autonomic neuropathy.

Adult↗

PubMed1986

Diabetes and autonomic neuropathy: an immunological association?

Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.

Adult↗

PubMedDate not supplied

Dexfenfluramine treatment and hypothalamic neuropeptides in diet-induced obesity in rats.

Neuropeptide Y (NPY) is a powerful appetite stimulant, and hypothalamic concentrations rise after food deprivation and in experimental diabetes. Serotonergic drugs such as dexfenfluramine are inhibitors of feeding. We measured hyothalamic NPY and NPY mRNA, along with galanin, neurotensin, and somatostatin in chow-fed rats and in rats with dietary obesity, and examined the effect of dexfenfluramine on these peptides in this model. Sixty-five rats were fed a palatable diet (condensed milk, sucrose and chow) for 6 weeks, which produced significant weight gain compared to twenty fed standard chow (145.1 +/- 2.3 g vs. 113.4 +/- 3.2 g, p less than 0.001). Groups of animals were treated for 7 days or 28 days with dexfenfluramine (1.8 mg/kg/day) or saline intraperitoneally via miniosmotic pumps. Hypothalami were dissected into medial and lateral blocks, and NPY, galanin, neurotensin, and somatostatin were measured by radioimmunoassay. Neuropeptide Y mRNA was measured by Northern blotting. Hypothalamic NPY was significantly higher in the palatable diet group compared to chow-fed controls (medial hypothalamus: 86.6 +/- 7.6 vs. 65.7 +/- 4.0 pmol/g tissue, p less than 0.02, lateral hypothalamus 71.2 +/- 6.6 vs. 53.1 +/- 3.6 pmol/g tissue, p less than 0.05), but NPY mRNA was unchanged. Although dexfenfluramine was effective at reducing weight gain in the animals fed the palatable diet, this did not result in any changes in the hypothalamic neuropeptides measured. Neuropeptide Y may be of importance in diet-induced obesity but the weight loss produced by dexfenfluramine in such animals is not mediated by changes in hypothalamic NPY.

Animals↗

PubMedDate not supplied

Perineurial calcification.

A study of the occurrence of extracellular deposits of calcium in the perineurium of the human sural nerve demonstrated that there is a higher incidence in abnormal nerves than in normal material and that, of the conditions examined, nerves from cases of diabetic neuropathy showed the greatest incidence of calcification. It seems likely that the process of calcification is similar to that operating in other tissues, with deposition on matrix vesicles or lipid droplets, probably derived from the perineurial cells. The increased incidence in diabetic neuropathy is presumably related to metabolic abnormality consequent upon the diabetic state.

Adolescent↗

PubMedDate not supplied

Diabetic neuropathy: abnormalities of Schwann cell and perineurial basal laminae. Implications for diabetic vasculopathy.

During Wallerian degeneration, the Schwann cell basal laminal ensheathment around myelinated nerve fibres remains after the removal of myelin and axonal debris, forming a corrugated tube within which Schwann cell proliferation takes place. In nerve biopsies from patients with diabetic neuropathy, such residual basal laminal tubes tend to be circular rather than corrugated and appear to be more persistent during regeneration; this suggests increased rigidity and durability. These changes could be the result of increased cross-linkage of type IV collagen or alterations to other components of the basal lamina. A similar mechanism may be responsible for the thickening of perineurial basal laminae and the reduplication of basal laminae around endoneurial capillaries in diabetic patients; such reduplication may lead to reduced compliance of the vessel walls and impaired vascular perfusion.

Adult↗

PubMedDate not supplied

Measurement by epigastric impedance of gastric emptying in diabetic autonomic neuropathy.

Changes in impedance across the epigastrium form the basis of a new non-invasive method of assessing gastric emptying of liquids. The apparatus is simple to use at the bedside and, in conjunction with conventional investigations, is of value in diagnosing gastroparesis in patients with diabetic autonomic neuropathy and symptoms of recurrent vomiting. We measured gastric emptying of liquids in 22 diabetics aged 33.4 +/- 9 years (mean +/- SD) with severe symptomatic autonomic neuropathy (mean heart rate variability 4.9 +/- 2.2 SD beats/min), and 15 normal controls. Median 'half emptying' time in the diabetics with autonomic neuropathy was prolonged overall but it was not always abnormal (12.25 min, range 6.5-greater than 30 compared to 8.0 min, range 3-17; p less than 0.01). Results in five diabetics with symptoms of recurrent vomiting corresponded with those using conventional radiological methods, confirming gastroparesis in three instances and excluding it in two. The effect of metoclopramide was also studied and was shown to accelerate gastric emptying in some but not all of the patients. Assessment of gastric emptying using the impedance method assists in establishing the diagnosis of gastroparesis and is of value for repeated measurements.

Adult↗