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Biomedical subjects

C J Bailey

Publications and source records attributed to C J Bailey.

At least 37 records · Page 2Linked to original sources
PubMed2001

Sibutramine metabolites increase glucose transport by cultured rat muscle cells.

BACKGROUND: The anti-obesity agent sibutramine, a serotonin and noradrenaline reuptake inhibitor (SNRI), has been shown to reduce insulin resistance and improve glycaemic control in obese-diabetic ob/ob mice and overweight type 2 diabetic patients. OBJECTIVE: To investigate whether sibutramine or its metabolites act directly on muscle cells to improve glucose uptake and insulin action. DESIGN: Uptake of the non-metabolized glucose analogue 2-deoxyglucose was measured in cultured L6 rat muscle cells after incubation with sibutramine, its two pharmacologically active metabolites and related agents. RESULTS: Sibutramine itself (10(-8)-10(-6) M) did not significantly affect 2-deoxyglucose uptake during incubations up to 72 h. The primary amine metabolite M2 (10(-7) and 10(-6) M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 12% and 34%) after 24 h incubation. These effects of M2 were lost by 72 h incubation. However, the secondary amine metabolite M1 (10(-6) M) increased basal and insulin-stimulated 2-deoxyglucose uptake (by 50%) after 72 h incubation, although M1 was ineffective after 24 h. M2 stimulated 2-deoxyglucose uptake in the presence of LY-294,002 (an inhibitor of phosphatidylinositol 3-kinase) but the effect of M2 was inhibited by cytochalasin B, which acutely blocks glucose transporters. Incubations with serotoninergic, noradrenergic and dopaminergic agents, or agents known to stimulate release or inhibit reuptake of these substances in nervous tissues indicated that the sibutramine metabolites were not affecting 2-deoxyglucose uptake via mechanisms associated with their SNRI properties. CONCLUSIONS: Sibutramine metabolites can improve insulin-sensitive 2-deoxyglucose uptake by cultured muscle cells independently of SNRI effects.

Animals↗
PubMed2001

Delta opioid receptors mediate glucose uptake in skeletal muscles of lean and obese-diabetic (ob/ob) mice.

Specific binding sites for [125I]beta-endorphin and the delta1-opioid [3H][D-pen(2), D-pen(5)]enkephalin (DPDPE) were quantified using autoradiography in soleus and extensor digitorum longus (EDL) muscles of lean and obese-diabetic (ob/ob) mice. The density of binding was significantly higher in obese-diabetic than lean mice. The uptake of 2-deoxy-D-[1-3H]deoxyglucose, a nonmetabolized glucose analogue, into isolated soleus and EDL muscles was stimulated by beta-endorphin, beta-endorphin 1-27, and DPDPE, but not by the delta2-opioid deltorphin II. Both beta-endorphin and DPDPE stimulated deoxyglucose uptake in obese-diabetic mice. Thus, glucose transport in skeletal muscle may be partly mediated via delta1-opioid receptors. The increased receptor density in obese-diabetic mice may be an adaptive response.

Animals↗
PubMed2001

Transcranial magnetic stimulation as a tool for cognitive studies.

Transcranial Magnetic Stimulation (TMS) is a tool for the non-invasive stimulation of the human brain. It allows the activation of arbitrary sites of the superficial cortex and, combined with other brain-imaging techniques such as EEG, PET, and fMRI, it can be used to evaluate cortical excitability and connectivity. This is of major importance in, for example, the study of cognitive processes such as language, learning, memory and self-representation, which are thought to be represented in multiple brain areas. The mechanisms of action of TMS are known on a basic level, but its effect on the activation state of brain tissue is still poorly understood. Clinical applications of TMS have also been proposed and guidelines for its safe use drafted.

Brain↗
PubMed2001

Rapid assessment of adenovirus serum neutralizing antibody titer based on quantitative, morphometric evaluation of capsid binding and intracellular trafficking: population analysis of adenovirus capsid association with cells is predictive of adenovirus infectivity.

Neutralizing antiviral antibodies are typically detected on the basis of inhibition of viral function, such as propagation of a viral infection or inhibition of viral gene expression. Evidence is presented that anti-adenovirus neutralizing antibodies can be evaluated by analysis of cell-associated capsids or by analysis of intracellular trafficking of the capsids within 1 h after infection. Quantitative analyses of these morphologic parameters represent rapid, broadly applicable, functional assays for the detection of anti-adenovirus neutralizing antibodies.

Adenoviridae↗
PubMed2001

Functional enhancement of electrofusion-derived BRIN-BD11 insulin-secreting cells after implantation into diabetic mice.

Electrofusion-derived BRIN-BD11 cells are glucose-sensitive insulin-secreting cells which provide an archetypal bioengineered surrogate beta-cell for insulin replacement therapy in diabetes mellitus. 5x10(6) BRIN-BD11 cells were implanted intraperitoneally into severely hyperglycaemic (>24 mmol/l) streptozotocin-induced insulin-treated diabetic athymic nude (nu/nu) mice. The implants reduced hyperglycaemia such that insulin injections were discontinued by 5-16 days (<17 mmol/l) and normoglycaemia (<9 mmol/l) was achieved by 7-20 days. Implanted cells were removed after 28 days and re-established in culture. After re-culture for 20 days, glucose-stimulated (16.7 mmol/l) insulin release was enhanced by 121% (p<0.001) compared to non-implanted cells. Insulin responses to glucagon-like peptide-1 (10(-9) mol/l), cholecystokinin-8 (10(-8) mol/l) and L-alanine (10 mmol/l) were increased by 32%, 31% and 68% respectively (p<0.05-0.01). Insulin content of the cells was 148% greater at 20 days after re-culture than before implantation (p<0.001), but basal insulin release (at 5.6 mmol/l glucose) was not changed. After re-culture for 40 days, insulin content declined to 68% of the content before implantation (p<0.01), although basal insulin release was unchanged. However, the insulin secretory responses to glucose, glucagon-like peptide-1, cholecystokinin-8 and L-alanine were decreased after 40 days of re-culture to 65%, 72%, 73% and 42% respectively of the values before implantation (p<0.05-0.01). The functional enhancement of electrofusion-derived surrogate beta-cells that were re-cultured for 20 days after implantation and restoration of normoglycaemia indicates that the in vivo environment could greatly assist beta-cell engineering approaches to therapy for diabetes.

Animals↗
PubMed2000

Potential new treatments for type 2 diabetes.

The heterogeneous pathogenesis and progressive natural history of type 2 diabetes mellitus (T2DM) contrive a formidable therapeutic challenge. Dual endocrine deficits of impaired insulin action (insulin resistance) and inadequate insulin secretion create an environment of chronic hyperglycaemia and general metabolic disarray. This inflicts a heavy burden of morbidity and premature mortality from cardiovascular diseases, microvascular disorders (e.g. retinopathy and nephropathy) and neuropathic conditions. Improving glycaemic control delays the onset and reduces the severity of these long-term complications. However, even with intensive use of current antidiabetic agents more than 50% of T2DM patients suffer poor glycaemic control and 18% develop serious complications within six years of diagnosis. Clearly, there is a need for new antidiabetic agents.

Animals↗
PubMed2000

Insulin-like effect of pinitol.

D-pinitol (3-O-methyl-chiroinositol), an active principle of the traditional antidiabetic plant Bougainvillea spectabilis, is claimed to exert insulin-like effects. This study investigates the effect of D-pinitol on glucose homeostasis in animal models of diabetes, and on glucose transport by cultured muscle cells. Plasma glucose concentrations were measured in normal, obese-diabetic (ob/ob) and streptozotocin (STZ)-diabetic mice after oral (p.o.) and intraperitoneal (i.p.) administration of D-pinitol. Glucose transport was measured in L6 rat muscle cells by 2-deoxyglucose (2DG) uptake. In STZ-diabetic mice, 100 mg kg(-1) p.o. D-pinitol acutely decreased the hyperglycaemia (by 22% at 6 h). A similar decrease in plasma glucose (by 21%) was observed after 100 mg kg(-1) i.p. D-pinitol. Insulin concentrations and the rate of insulin-induced (1 unit kg(-1) actrapid i.p.) glucose disappearance were not altered by 100 mg kg(-1) p.o. D-pinitol. Chronic administration of D-pinitol (100 mg kg(-1) i.p. twice daily for 11 days) to STZ-diabetic mice maintained a reduction in plasma glucose concentrations from about 14 to 10 mmol l(-1). In normal non-diabetic and severely insulin resistant ob/ob mice, 100 mg kg(-1) p.o. D-pinitol did not significantly affect plasma glucose or insulin during acute studies. Incubation of L6 muscle cells with D-pinitol (10(-3) M) increased basal 2DG uptake by 41% after 10 min and by 34% after 4 h. The effect of D-pinitol was inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002. D-pinitol did not increase insulin-stimulated 2DG uptake by L6 cells. The data support the view that D-pinitol can exert an insulin-like effect to improve glycaemic control in hypoinsulinaemic STZ-diabetic mice. D-pinitol may act via a post-receptor pathway of insulin action affecting glucose uptake.

Animals↗
PubMed1999

NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice.

Quantitative autoradiography was used to characterise the binding of selective radiolabelled antagonists for the N-methyl-D-aspartate (NMDA) receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor in the dorsal, intermediate and ventral subregions of the grey matter of the upper thoracic spinal cord in male and female lean and obese-diabetic (ob/ob) mice. The density of binding sites for both receptor subtypes was greater in diabetic mice, in all three subregions of the grey matter, than the corresponding subregions in the lean mice. The affinity of the binding site for the NMDA antagonist was significantly higher in obese mice than lean mice, consistent with the presence of two subpopulations of NMDA receptors with different ligand binding affinities in obese mice. The increase in expression of the glutamate receptor subtypes, and altered ligand affinity for the NMDA receptor subtype in the obese mice may be causally involved in the peripheral neuropathies which can accompany diabetes mellitus.

Animals↗
PubMed1999

Insulin resistance and antidiabetic drugs.

Insulin resistance describes an impaired biological response to insulin, which underpins the development of type 2 (non-insulin-dependent) diabetes mellitus (T2DM). Initially, insulin resistance causes a compensatory hyperinsulinaemia, which gives way to pancreatic beta-cell failure. Insulin resistance and hyperinsulinaemia conspire together in the development of a diverse collection of risk factors for coronary heart disease, namely obesity, T2DM, dyslipidaemia, hypertension, atherosclerosis, and a pro-coagulant state. This collection of factors is commonly found in T2DM patients, and is recognised as the Insulin Resistance Syndrome or Syndrome X. By targeting insulin resistance as a treatment strategy for T2DM, it should be possible to broaden the potential benefits, so that improved glycaemic control is complemented with improvements to other components of Syndrome X. At present, metformin and thiazolidinediones are the only therapies for T2DM that directly address aspects of insulin resistance. Increasing awareness of the clinical implications of insulin resistance, and increasing knowledge of the cellular basis of insulin resistance, provide the rationale and a means for developing an anti-insulin resistance approach to the treatment of T2DM.

Arteriosclerosis↗
PubMed1999

Impact of injuries and disease on a cohort of two- and three-year-old thoroughbreds in training.

A prospective study of injuries and disease in a cohort of Australian thoroughbreds in training was conducted with the participation of 24 trainers. From the horses catalogued at a major yearling sale in 1995, 169 were enrolled in the study and followed through their two- and three-year-old racing seasons. The principal aim was to quantify the time lost in training as a result of the various categories of injuries and disease, recorded as either days of modified training, or weeks rested at pasture. Shin soreness was the most common condition in two-year-olds (affecting 42 per cent of the horses that had entered training), followed by fetlock problems (25 per cent), and coughs and nasal discharge (16 per cent). Lameness, excluding lacerations and traumatic injuries, was the most common reason for lost training days (56.2 per cent of total days modified) and for resting horses at pasture (81.2 per cent of total weeks rested for injury or disease). Of the individual categories of injury or disease, lacerations and traumatic injuries, coughs and nasal discharge, shin soreness, carpal problems and fetlock problems were the most important causes of modified training days. In terms of weeks rested at pasture, fetlock problems, shin soreness, carpal problems, and coughs and nasal discharge had the greatest impact. Major injury was uncommon in young horses in training, but there was a high incidence of relatively low-grade injuries and disease during the training of two-year-olds.

Animal Husbandry↗
PubMed1999

Prospects for insulin delivery by ex-vivo somatic cell gene therapy.

The principle of insulin delivery by ex-vivo somatic cell gene therapy involves the removal of non-B-cell somatic cells (e.g. fibroblasts) from a diabetic patient, and genetically altering them in vitro to produce and secrete insulin. The cells can be grown in culture and returned to the donor as a source of insulin replacement. Cells modified in this way could be evaluated before implantation, and reserve stocks could be cryopreserved. By using the patient's own cells, the procedure should obviate the need for immunosuppression and overcome the problem of tissue supply, while avoiding a recurrence of cell destruction. Ex-vivo somatic cell gene therapy requires an accessible and robust cell type that is amenable to multiple transfections and subject to controlled proliferation. Special problems associated with the use of non-B-cell somatic cells include the processing of proinsulin to insulin, and the conferment of sensitivity to glucose-stimulated proinsulin biosynthesis and regulated insulin release. Preliminary studies using fibroblasts, pituitary cells, kidney (COS) cells and ovarian (CHO) cells suggest that these challenges could be met, and that ex-vivo somatic cell gene therapy offers a feasible approach to insulin replacement therapy.

Animals↗
PubMed1999

New agents for Type 2 diabetes.

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.

Anti-Obesity Agents↗
PubMed1999

A risk-benefit assessment of metformin in type 2 diabetes mellitus.

Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care. Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing bodyweight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus. The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level > 130 micromol/L or > 1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected. Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced. The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.

Acidosis, Lactic↗
PubMed1999

The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms.

Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 (non-insulin-dependent) diabetes without causing overt hypoglycaemia. Its clinical efficacy requires the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent. Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates (e.g. lactate) and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake into skeletal muscle is enhanced by metformin. This has been attributed in part to increased movement of insulin-sensitive glucose transporters into the cell membrane. Metformin also appears to increase the functional properties of insulin- and glucose-sensitive transporters. The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid (Randle) cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin. Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states. Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone. These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes.

Animals↗
PubMed1999

Factors associated with time until first race and career duration for Thoroughbred racehorses.

OBJECTIVE: To determine whether sex or foaling period were associated with time to first race start and whether sex, age at time of first race start, or inter-race period were associated with career duration for Thoroughbred racehorses in Australia. ANIMALS: 553 Thoroughbred racehorses. PROCEDURE: Race records through to the end of the 6-year-old racing season were obtained for each horse. Product-limit survival analysis was used to determine whether sex or foaling period was associated with time to first race start and whether sex or age at first race was associated with career duration. A Cox proportional hazards model was used to determine whether sex, age at first possible race, age at first race, or inter-race period was associated with time to first race start or career duration. RESULTS: 472 horses (85.4%) raced. Time to first race start was not associated with sex or foaling period. However, males, who had their first race at a younger age and a greater mean number of rest days between races, had longer careers. The hazard ratio for career duration of males versus females, controlling for age at time of first race and inter-race period (0.27), confirmed that males had a higher probability of a long racing career. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that for Thoroughbred racehorses, sex and time of birth during the foaling season were not associated with time to first race. Male Thoroughbred racehorses that were raced less intensively or raced at a younger age were more likely to have long racing careers.

Age Factors↗