Showing papers by "Garth J. S. Cooper published in 2004"
TL;DR: The interaction between lipid bilayers and the 37 amino acid residue polypeptide amylin, which is the primary constituent of the pancreatic amyloids associated with type 2 diabetes, is studied to provide an alternative theory to pore formation, and how amyloid peptides may cause membrane disruption and possibly cytotoxicity.
168 citations
TL;DR: Observations suggest that mature fibrils are assembled directly via longitudinal growth of full-width oligomers, making assembly by lateral association of protofibrils appear less likely.
155 citations
TL;DR: In diabetic animals with established heart failure, it is shown for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin.
Abstract: Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Although altered systemic regulation of transition metals in diabetes has been the subject of previous investigation, it is not known whether changed transition metal metabolism results in heart disease in common forms of diabetes and whether metal chelation can reverse the condition. We found that administration of the Cu-selective transition metal chelator trientine to rats with streptozotocin-induced diabetes caused increased urinary Cu excretion compared with matched controls. A Cu(II)-trientine complex was demonstrated in the urine of treated rats. In diabetic animals with established heart failure, we show here for the first time that 7 weeks of oral trientine therapy significantly alleviated heart failure without lowering blood glucose, substantially improved cardiomyocyte structure, and reversed elevations in left ventricular collagen and beta(1) integrin. Oral trientine treatment also caused elevated Cu excretion in humans with type 2 diabetes, in whom 6 months of treatment caused elevated left ventricular mass to decline significantly toward normal. These data implicate accumulation of elevated loosely bound Cu in the mechanism of cardiac damage in diabetes and support the use of selective Cu chelation in the treatment of this condition.
153 citations
TL;DR: Injection of endogenous bovine adiponectin into C57 mice potently decreased circulating glucose levels and enhanced lipid clearance after a high fat meal and Chronic administration of this protein for a period of two weeks significantly increased insulin sensitivity and glucose tolerance, and depleted hepatic lipid accumulation in high‐fat fed mice.
Abstract: Adiponectin is a plasma protein exclusively secreted from fat tissue. Many recent pharmacological studies suggest that recombinant adiponectin has multiple therapeutic potentials for obesity-related metabolic disorders, including type 2 diabetes, dyslipidemia, insulin resistance and atherosclerosis. However, the physiological relevance of these findings remains to be further established. In the present study, we have purified endogenous adiponectin from fetal bovine serum and characterized its post-translational modifications and physiological functions in animal models. Endogenous bovine serum adiponectin consists predominantly of full-length proteins that form multiple oligomeric complexes, including trimers, hexamers and higher molecular species. Two-dimensional gel electrophoresis revealed that bovine serum adiponectin exists as multiple post-translationally modified isoforms with distinct molecular weight and isoelectric point. Further analysis using mass spectrometry and Edman degradation sequencing demonstrated that five conserved lysine residues (Lys 28, 60, 63, 72 and 96) within the collagenous domain of bovine adiponectin are hydroxylated and glycosylated by a glucosyl alpha(1-2)galactosyl group. Injection of endogenous bovine adiponectin into C57 mice potently decreased circulating glucose levels and enhanced lipid clearance after a high fat meal. Chronic administration of this protein for a period of two weeks significantly increased insulin sensitivity and glucose tolerance, and depleted hepatic lipid accumulation in high-fat fed mice. These results provide direct evidence that endogenous bovine adiponectin is a physiological hormone that can regulate lipid and glucose metabolism.
79 citations
TL;DR: The results collectively suggest that GH increases adiponectin gene expression through the JAK2‐P38 MAP kinase pathway, and that elevation of adiponECTin production might represent a novel mechanism by which GH regulates systemic energy metabolism and insulin sensitivity.
35 citations
TL;DR: The results suggest that hormone treatment induces differentiation at least in part by suppression of intracellular α2 macroglobulin activity in 3T3 L1 preadipocytes.
Abstract: Adipogenesis is an important aspect of energy homeostasis. Here we have used a differential proteome mapping strategy to identify intracellular proteins that are differentially expressed during adipose conversion of 3T3 L1 preadipocytes. Two-dimensional gel electrophoresis analysis identified 8 proteins that are induced following hormone-evoked differentiation. In addition, we found that a alpha2 macroglobulin fragment was abundantly present in 3T3 L1 preadipocytes, but was virtually undetectable in fully differentiated adipocytes. Metabolic radiolabeling with (35S)methionine and Northern blot analysis indicated that the intracellular alpha2 macroglobulin fragment in preadipocytes was derived from the extracellular culture medium, not de novo synthesis. Incubation of preadipocytes with an antialpha2 macroglobulin polyclonal antibody caused depletion of the intracellular alpha2 macroglobulin fragments, and also enhanced spontaneous adipose conversion. These results suggest that intracellular alpha2 macroglobulin fragment inhibits adipocyte differentiation, and that hormone treatment induces differentiation at least in part by suppression of intracellular alpha2 macroglobulin activity in 3T3 L1 preadipocytes.
28 citations
TL;DR: In this paper, the authors investigated the effect of moderate changes in dietary fatty acid profile on post-prandial risk factors for cardiovascular disease (CVD) using double-blind, randomised, crossover, intervention trial.
Abstract: Objective: To investigate the effect of moderate changes in dietary fatty acid profile on postprandial risk factors for cardiovascular disease (CVD). Design: Double-blind, randomised, crossover, intervention trial. Setting: University of Auckland Human Nutrition Unit, New Zealand. Subjects: A total of 18 lean healthy men. Interventions: A dairy butter fat modified to reduce the saturated:unsaturated fatty acid ratio and a conventional high saturated butter fat were given on two separate occasions as a high-fat test meal (59±4 g fat; 71 en% fat) at breakfast. A fat exclusion lunch, dinner and snacks were also given. Blood samples were collected at 0 (baseline), 1, 3, 6, 10 and 24 h. Results: Maximum peak in total triacylglycerol (TAG) occurred 3 h postprandially and was highest on modified treatment (diet, P 0.05). There were no differential effects of diet on postprandial free fatty acids, apo A, apo B, glucose, insulin, amylin or haemostatic clotting factors (P>0.05). Conclusions: In a group of healthy young men, replacement of 16% of total saturated fatty acids by mono- and polyunsaturated fats within a dairy lipid did not induce postprandial changes in CVD risk that may be considered beneficial for health. Sponsorship: Fonterra, Wellington; New Zealand.
20 citations
Patent•
28 Oct 2004
TL;DR: Novel peptides and uses thereof, including polypeptides and related molecules with uses, for example, in weight loss and for the treatment of obesity and related conditions associated with increased mass of adipocytes as mentioned in this paper.
Abstract: Novel peptides and uses thereof, including polypeptides and related molecules with uses, for example, in weight loss and for the treatment of obesity and related conditions associated with, for example, increased mass of adipocytes
10 citations
TL;DR: It is found that amylin increased GSK3alpha activity, which in turn led to increased phosphorylation of glycogen synthase and decreased glycogen synthesis de novo, which resulted in reduced glycogenolytic effect in isolated skeletal muscle.
2 citations