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B Leighton

Publications and source records attributed to B Leighton.

At least 73 records · Page 4Linked to original sources
PubMed1989

Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus.

Amylin, the major peptide component of the islet amyloid commonly found in the pancreases of patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM), is a recently discovered islet polypeptide. This peptide has many structural and functional features suggesting that it is a novel hormone, which may control carbohydrate metabolism in partnership with insulin and other glucoregulatory factors. Amylin is synthesised in, and probably secreted from, the beta-cells of the islets of Langerhans, where it has recently been immunolocalised to secretory granules. DNA cloning studies indicate that in the human and the rat, amylin is generated from a precursor, preproamylin, which displays a typical signal peptide followed by a small prohormone-like sequence containing the amylin sequence. The presence of the signal peptide suggests that amylin is secreted and plays a physiological role. Amylin is probably generated by proteolytic processing similar to that for proinsulin and other islet prohormones. The human amylin gene encodes the complete polypeptide precursor in two exons which are separated by an intron of approx. 5 kb, and is located on chromosome 12. Amylin is a potent modulator of glycogen synthesis and glucose uptake in skeletal muscle, and is capable of inducing an insulin-resistant state in this tissue in vitro, and perhaps also in the liver in vivo. In normal metabolism, amylin could act in concert with insulin as a signal for the body to switch the site of carbohydrate disposal from glycogen to longer-term stores in adipose tissue, by making skeletal muscle relatively insulin-resistant, whilst at the same time leaving rates of insulin-stimulated carbohydrate metabolism in adipose tissue unaltered. Several lines of evidence now implicate elevated amylin levels in the pathogenic mechanisms underlying NIDDM, and suggest to us that the obesity which frequently accompanies this syndrome is a result of, rather than a risk factor for, NIDDM. Following the beta-cell destruction which occurs in type 1 (insulin-dependent) diabetes mellitus (IDDM), it is probable that amylin secretion disappears in addition to that of insulin. As patients with insulin-treated IDDM frequently experience problems with hypoglycaemia, and as amylin acts to modulate the action of insulin in various tissues, it is possible that amylin deficiency may contribute to morbidity in insulin-treated IDDM, perhaps through the loss of a natural damping mechanism which guards against hypoglycaemia under conditions of normal physiology.

Amino Acid Sequence↗
PubMed1989

Amylin hormone.

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Amyloid↗
PubMed1989

Effects of aging on the responsiveness and sensitivity of glucose metabolism to insulin in the incubated soleus muscle isolated from Sprague-Dawley and Wistar rats.

1. The effects of aging on the sensitivity and responsiveness of glucose transport, lactate formation and glycogen synthesis to insulin were studied in the incubated stripped soleus muscle isolated from aging Sprague-Dawley and Wistar rats. 2. As Sprague-Dawley rats aged from 5 to 13 weeks, there were marked increases in the concentrations of insulin that were required for half-maximal stimulation (i.e. EC50 value, which is a measure of sensitivity) of glucose transport, lactate formation and glycogen synthesis. 3. In marked contrast, there were no alterations in sensitivities of any of these processes to insulin in soleus muscle prepared from Wistar rats aged between 6 and 12 weeks. 4. However, in soleus muscles from 85-week-old Wistar rats the rates of glycogen synthesis in response to basal, sub-maximal and maximal concentrations of insulin were markedly decreased. The insulin EC50 value of glycogen synthesis was increased 4-fold, but was unchanged for lactate formation. 5. The insulin-stimulated rates of glucose transport in soleus muscles from 5- or 85-week-old Wistar rats were not significantly different.

Aging↗
PubMed1989

Calcitonin gene-related peptide-1 (CGRP-1) is a potent regulator of glycogen metabolism in rat skeletal muscle.

We investigated the effects of CGRP on glucose metabolism in intact rat skeletal muscle preparations that are largely composed of either type I (soleus) or II fibres (e.g. extensor digitorum longus (EDL) or epitrochlearis muscles). CGRP-1 inhibited insulin-stimulated glycogen synthesis in both soleus and EDL muscle preparations. Rat CGRP-1 was a potent stimulator of glycogenolysis only in muscles composed of type II fibres, which depend on high rates of glycogenolysis to produce high power outputs. These results may provide the basis for understanding how CGRP regulate glycogenolysis in type II fibres in vivo.

Animals↗
PubMed1989

Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.

1. The effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin were investigated in the isolated, incubated soleus muscle of the rat. 2. Hypothyroidism, which was induced by administration of propylthiouracil to the rats, decreased fasting plasma levels of free fatty acids and increased plasma levels of glucose but did not significantly change plasma levels of insulin. 3. The sensitivity of the rates of glycogen synthesis to insulin was increased at physiological, but decreased at supraphysiological, concentrations of insulin. 4. The rates of glycolysis in the hypothyroid muscles were decreased at all insulin concentrations studied and the EC50 for insulin was increased more than 8-fold; the latter indicates decreased sensitivity of this process to insulin. However, at physiological concentrations of insulin, the rates of glucose phosphorylation in the soleus muscles of hypothyroid rats were not different from controls. This suggests that hypothyroidism affects glucose metabolism in muscle not by affecting glucose transport but by decreasing the rate of glucose 6-phosphate conversion to lactate and increasing the rate of conversion of glucose 6-phosphate to glycogen. 5. The rates of glucose oxidation were decreased in the hypothyroid muscles at all insulin concentrations.

Animals↗
PubMed1989

Skeletal muscle glutamine metabolism during sepsis in the rat.

1. The effect of sepsis, induced by caecal ligation plus puncture (CLP) or endotoxin injection, on glutamine metabolism was studied in rat skeletal muscle. 2. The concentration of glutamine in muscle was decreased by CLP or after 24 or 48 hr after injection of endotoxin. However, the concentration was increased 3 hr after injection of endotoxin. 3. The plasma glutamine concentration was decreased by CLP, but it was unchanged after injection of endotoxin. 4. The rate of glutamine release from incubated stripped soleus muscles was increased in the muscles removed from animals subjected to CLP or from animals injected with endotoxin. 5. It is concluded that sepsis results in marked changes in skeletal muscle glutamine metabolism, which may be used as an early indicator of the septic state. During sepsis there is likely to be an increased demand for glutamine by the immune system, kidney and intestine. 6. This study provides evidence that during sepsis the rate of release of glutamine from the skeletal muscle per se is increased to a sufficient extent to satisfy this increased requirement.

Animals↗
PubMed1989

The amylin superfamily: a novel grouping of biologically active polypeptides related to the insulin A-chain.

The peptide amylin (previously termed Diabetes Associated Peptide) has recently been isolated and characterised from the amyloid of the pancreatic islets of Langerhans from human type 2 diabetics. Amylin shows about 46% identity in amino acid sequence on comparison with the calcitonin gene-related peptides (CGRPs) and also shows some similarity to insulin. Recent studies have also shown that both amylin and CGRP are potent inhibitors of insulin-stimulated glycogen synthesis in skeletal muscle in vitro. Hormones may be arranged into families, therefore a degree of order exists even though hormone-mediated effects are complex. The polypeptides insulin, insulin-like growth factors (IGFs) and relaxins have been grouped into such a family with similarities both at the protein-structural and genetic levels. We now demonstrate that this insulin-related family, along with amylin and the CGRPs, are members of a peptide superfamily defined by structural similarity in the region corresponding to the A-chain of insulin. In order to distinguish this grouping of small biologically active peptides from the previous one, we have designated it the amylin superfamily. All the members of the previously defined insulin family have a region homologous to the insulin B-chain. Insulin, the IGFs, the relaxins, the CGRPs and amylin are all involved in carbohydrate metabolism and therefore these peptides are functionally as well as structurally related. This grouping of peptides may have important implications for the study of human metabolic disease.

Amino Acid Sequence↗
PubMed1989

Effects of insulin on glucose metabolism in skeletal muscle from septic and endotoxaemic rats.

1. The effects of non-lethal bacteraemia or endotoxaemia on insulin-stimulated glucose metabolism were studied in isolated, incubated soleus muscle of rats after 24 and 48 h. 2. The insulin-stimulated rates of lactate formation and glycogen synthesis were similar in muscles isolated from control and bacteraemic rats. 3. Endotoxaemia increased the rates of lactate formation, at all levels of insulin, both at 24 h (approximately 32%) and 48 h (approximately 26%). Endotoxaemia did not alter the sensitivity of glycolysis to insulin. 4. Endotoxaemia decreased the rates of glycogen synthesis at all concentrations of insulin both at 24 h (approximately 39%) and 48 h (approximately 23%). 5. The increase in the rate of glycolysis was related in a dose-dependent manner to the amount of endotoxin given to the animals. 6. Endotoxaemia decreased plasma tri-iodothyronine levels (41%). However, the effects of endotoxaemia (48 h) on glucose metabolism in muscle are similar to those caused by hyperthyroidism. In hypothyroid rats, endotoxin administration increased the rates of glycolysis in muscle in vitro. 7. It is concluded that there are enhanced basal and insulin-stimulated rates of glycolysis in soleus muscle from endotoxaemic rats. This may be due to both increased glucose transport and decreased glycogen synthesis.

Animals↗
PubMed1989

Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus.

The 37-amino acid peptide called amylin is a major component of the islet amyloid deposited in the pancreases of persons with type 2 diabetes mellitus. We report the isolation of a partial cDNA clone and a phage lambda genomic clone of the coding region of the amylin gene. The DNA sequence encodes a protein sequence identical to that of amylin isolated from the amyloid found in the diabetic pancreas and shows that amylin is likely to be synthesized as a precursor peptide, now named proamylin. We have demonstrated that the amylin gene is present on chromosome 12 and that it is probably transcribed in the islets of Langerhans. The sequences of the genes for amylin and the calcitonin gene-related peptides (CGRPs) show strong similarity, especially over their 5' coding regions, where both peptides have a conserved intramolecular disulfide bridge, and also over their 3' coding regions, where the presence of a glycine codon strongly suggests that the carboxyl-terminal residue of amylin, like that of CGRP, is amidated. To examine the functional relevance of these posttranslational modifications, the biological activity of amylin synthesized with or without the disulfide bridge and/or amidation was measured. It was found that both features are necessary for full biological activity, thereby confirming the functional importance of those regions of the molecule whose sequences are conserved at both protein and genetic levels.

Amino Acid Sequence↗
PubMed1989

Acute and chronic effects of strenuous exercise on glucose metabolism in isolated, incubated soleus muscle of exercise-trained rats.

Male and female Wistar rats were exercise-trained for 6 or 11 weeks respectively, to examine the effects of acute exercise or exercise training per se on insulin-stimulated glucose utilization in soleus muscles isolated and incubated in vitro. The maximal activities of hexokinase and 2-oxoglutarate dehydrogenase were significantly elevated (by greater than 50%) in gastrocnemius muscle of exercise-trained male and female rats, indicating an adaptation to the training regime. No significant differences in any of the variables studied were observed between appropriately matched male and female rats. There were no significant differences in the sensitivity or responsiveness of the rates of lactate formation or glycogen synthesis in soleus muscles isolated from exercise-trained and sedentary animals at rest (exercise-trained animals were studied 40 h after the last exercise bout). On the other hand, acute exercise caused significant changes in soleus muscle glucose metabolism. Basal and insulin-stimulated rates of glycogen synthesis were significantly elevated in soleus muscles incubated from both sedentary and exercise-trained rats immediately after an exercise bout. In addition, the responsiveness of glucose utilization to insulin in soleus muscles from exercise-trained rats was significantly increased after acute exercise. The results indicate that significant changes in the control of glucose metabolism by insulin in soleus muscle occur as a result of an acute exercise bout, while no adaptive changes in insulin sensitivity occur in soleus muscle after exercise training.

Animals↗
PubMed1988

Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro.

Insulin resistance occurs in a variety of conditions, including diabetes, obesity and essential hypertension, but its underlying molecular mechanisms are unclear. In type 2 (non-insulin-dependent) diabetes mellitus, it is insulin-resistance in skeletal muscle, the chief site of insulin-mediated glucose disposal in humans, that predominantly accounts for the low rates of glucose clearance from the blood, and hence for impaired glucose tolerance. Human type 2 diabetes is characterized by a decrease in non-oxidative glucose storage (muscle glycogen synthesis), and by the deposition of amyloid in the islets of Langerhans. Amylin is a 37-amino-acid peptide which is a major component of islet amyloid and has structural similarity to human calcitonin gene-related peptide-2 (CGRP-2; ref. 8). CGRP is a neuropeptide which may be involved in motor activity in skeletal muscle. We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro. These results may provide a basis for a new understanding of the molecular mechanisms that cause insulin resistance in skeletal muscle.

Amyloid↗
PubMed1988

Effects of hyperthyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.

1. The effects of hyperthyroidism on the sensitivity and responsiveness of glycolysis and glycogen synthesis to insulin were investigated in the isolated incubated soleus muscle of the rat. 2. Hyperthyroidism, which was induced by administration of tri-iodothyronine (T3) to rats for 2, 5 or 10 days, increased fasting plasma concentrations of glucose, insulin and free fatty acids. 3. Administration of T3 for 2 or 5 days increased the rates of glycolysis at all insulin concentrations studied: this was due to increased rates of both glucose phosphorylation and glycogen breakdown, but there was no effect of T3 on the sensitivity of glycolysis to insulin. However, administration of T3 for 10 days increased the sensitivity of the rate of glycolysis to insulin. 4. The concentration of adenosine in the gastrocnemius muscles of the rats was not different from controls after 5 days, but it was markedly decreased after 10 days of T3 administration. If these changes are indicative of changes in the soleus muscle, the increased sensitivity of glycolysis to insulin found after 10 days' T3 administration could be due to the decrease in the concentration of adenosine. 5. Administration of T3 decreased the sensitivity of glycogen synthesis to insulin and the glycogen content of the soleus muscles. This may explain the decreased rates of non-oxidative glucose disposal found in spontaneous and experimental hyperthyroidism in man. 6. The rates of glucose oxidation did not change after 2 days, but they were increased after 5 and 10 days of T3 administration.

Adenosine↗
PubMed1988

An investigation of the beta-adrenoceptor that mediates metabolic responses to the novel agonist BRL28410 in rat soleus muscle.

The beta-adrenoceptor agonist BRL26830A selectively stimulates metabolic rate in the rat and this thermic effect is resistant to blockade by propranolol. These effects of BRL26830A are partly due to selective stimulation by its metabolite BRL28410, of brown adipocyte beta-adrenoceptors, these receptors being resistant to propranolol. To investigate whether the metabolic effects of BRL28410 in skeletal muscle are also mediated by atypical beta-adrenoceptors, the potencies of BRL28410 and isoprenaline were compared for beta-adrenoceptor mediated responses in rat stripped soleus muscle. In addition, pA2 values for antagonism by propranolol of these responses were determined. Isoprenaline had similar EC50 values for stimulation of lactate formation (4.3 X 10(-9) M) and inhibition of glycogen synthesis (3.4 X 10(-9) M) and these values are similar to its reported EC50 values for stimulation of atrial rate (beta 1-adrenoceptor-mediated) and relaxation of the uterus (beta 2-adrenoceptor-mediated). BRL28410 had similar EC50 values for stimulation of lactate formation (3.7 X 10(-6) M) and inhibition of glycogen synthesis (3.8 X 10(-6) M). These values are only about two-fold less than reported values for relaxation of the uterus, but ten-fold less than reported values for stimulation of atrial rate. The pA2 value of dl-propranolol for antagonism of the effect of isoprenaline on glycogen synthesis (8.38 +/- 0.13) was in the range expected for beta 1- or beta 2-adrenoceptors, but with BRL28410 as agonist the pA2 value was about one unit lower (7.39 +/- 0.11). The beta-adrenoceptors that mediate the metabolic effects of BRL28410 in soleus muscle therefore differ from those that mediate atrial rat, uterine relaxation and adipocyte lipolysis. In addition, the low pA2 value of dl-propranolol versus BRL28410 in rat soleus muscle, which contrasts with the normal pA2 value previously reported for guinea-pig trachea, suggests that beta 2-adrenoceptors in these two tissues can be differentiated with suitable pharmacological agents.

Animals↗
PubMed1988

Effects of the diuretic furosemide on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.

The diuretic furosemide (0.5 mmol/l) impaired glucose uptake in the soleus muscle of the rat by decreasing the sensitivity of glycolysis to insulin. In addition, at higher concentrations (1.0 mmol/l) the drug inhibited the basal rate of glycolysis. It did not, however, inhibit the rate of glycogen synthesis except at a concentration of 6.0 mmol/l. Since furosemide has some structural similarities to adenosine, the above effects on insulin sensitivity may be due to its ability to act as an adenosine receptor agonist in muscle. These effects of furosemide in skeletal muscle may contribute to the glucose intolerance following therapy with this and similar agents in man.

Animals↗
PubMed1988

Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat.

1. Soleus, extensor digitorum longus (EDL) or hemi-diaphragm muscles of the rat were incubated in the presence of insulin and rates of the processes of glycolysis and glycogen synthesis were measured. 2. The concentrations of insulin required to cause half-maximal stimulation of glycolysis in both soleus and EDL preparations were significantly decreased by the presence of adenosine deaminase in the medium. 3. Adenosine deaminase increased the sensitivity of the process of hexose transport to insulin (in an identical manner to the change in sensitivity of glycolysis) in the EDL preparation. 4. None of the adenosine mediated effects on insulin-stimulated rates of glycolysis were observed in the hemi-diaphragm preparation or on the rates of glycogen synthesis in any of the three muscle preparations. 5. Therefore, changes in the adenosine system in skeletal muscle influence insulin sensitivity regardless of fibre type composition of the muscle.

3-O-Methylglucose↗
PubMed1988

Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle.

Diabetes-associated peptide has recently been isolated and characterized from the amyloid of the islets of Langerhans in type 2 (non-insulin-dependent) diabetics, and immunoreactivity with antibodies to the peptide has been demonstrated in islet B cells of both normal and type 2 diabetic subjects. In view of the evidence presented in this paper that this 37-amino acid peptide may be a hormone present in normal individuals, we now propose the name "amylin" to replace "diabetes-associated peptide." Because increased amylin, deposited as amyloid within the islets of Langerhans, is characteristic of type 2 diabetes, the study below was performed to examine the possible effects of amylin on peripheral glucose metabolism. Whole amylin was synthesized by using solid-phase techniques, with formation of the disulfide linkage by oxidation in dilute aqueous solution and recovery of the peptide by lyophilization. The effects of amylin on glucose metabolism were studied in two preparations in vitro, isolated rat soleus muscle strips and isolated rat adipocytes. In skeletal muscle exposed to 120 nM amylin for 1 hr, there was a marked decrease in both basal and submaximally insulin-stimulated rates of glycogen synthesis, which resulted in significant reduction in the rates of insulin-stimulated glucose uptake. In muscles treated with amylin there was no response at the concentration of insulin required to stimulate glucose uptake half-maximally in untreated (control) muscles. In marked contrast, amylin had no effect on either basal or insulin-stimulated rates of glucose incorporation into either CO2 or triacylglycerol in isolated adipocytes. Therefore, amylin may be a factor in the etiology of the insulin resistance in type 2 diabetes mellitus, as both deposition of the peptide in islet amyloid and decreased rates of glucose uptake and glycogen synthesis in skeletal muscle are characteristic of this condition.

Amyloid↗
PubMed1988

Circadian rhythm in sensitivity of glucose metabolism to insulin in rat soleus muscle.

This study determined whether the sensitivity of glucose metabolism to insulin in skeletal muscle varies during a 24-h period. Soleus muscles were isolated from ad libitum-fed rats killed at 0900, 1600, 2100, and 0300. The animal house was illuminated between 0800 and 2000. The sensitivities of glycolysis (which is an excellent index of glucose transport) and glycogen synthesis to insulin were greatest in muscles isolated at 0900 and 2100. Marked decreases in sensitivities of both processes to insulin were observed in muscles isolated at 0300 and 1600, which are times halfway through the feeding and postabsorptive periods, respectively. Hence, this study demonstrates circadian changes in the sensitivity of glucose utilization by skeletal muscle to insulin, which may be important in control of blood glucose concentration. Glycogen levels in skeletal muscles were highest at 0300 and lowest at 2100; hepatic glycogen content reached a peak at 0900, and the lowest content was measured at 2100. The liver glycogen level was increased by only 15% midway into the feeding period (i.e., 0300). This suggests that muscle glycogen may act as a temporary store of glucose residues during the feeding period; it stores glycogen in the first half of the feeding period but during the second half some muscle glycogen is converted to lactate, which acts as a precursor for hepatic gluconeogenesis.

Animals↗