The acute effects of different macronutrients on the secretion of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) and glucose-dependent insulinotropic polypeptide (GIP) were compared in healthy human subjects. Circulating levels of the two hormones were measured over a 24-h period during which subjects consumed a mixed diet. In the first study, eight subjects consumed three equicaloric (375 kcal) test meals of carbohydrate, fat and protein. Small increases in plasma GLP-1(7-36) amide were found after all meals. Levels reached a maximum 30 min after the carbohydrate and 150 min after the fat load. Ingestion of both carbohydrate and fat induced substantial rises in GIP secretion, but the protein meal had no effect. In a second study, eight subjects consumed 75 g glucose or the equivalent portion of complex carbohydrate as boiled brown rice or barley. Plasma GIP, insulin and glucose levels increased after all three meals, the largest increase being observed following glucose and the smallest following the barley meal. Plasma GLP-1(7-36)amide levels rose only following the glucose meal. In the 24-h study, plasma GLP-1(7-36)amide and GIP concentrations were increased following every meal and remained elevated throughout the day, only falling to fasting levels at night. The increases in circulating GLP-1(7-36)amide and GIP levels following carbohydrate or a mixed meal are consistent with their role as incretins. The more sustained rises observed in the daytime during the 24-h study are consistent with an anabolic role in lipid metabolism.

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MSC can act as a pluripotent source of reparative cells during injury and therefore have great potential in regenerative medicine and tissue engineering. However, the response of MSC to many growth factors and cytokines is unknown. Many envisioned applications of MSC, such as treating large defects in bone, involve in vivo implantation of MSC attached to a scaffold, a process that creates an acute inflammatory environment that may be hostile to MSC survival. Here, we investigated cellular responses of MSC on a biomaterial surface covalently modified with epidermal growth factor (EGF). We found that surfacetethered EGF promotes both cell spreading and survival more strongly than saturating concentrations of soluble EGF. By sustaining mitogen-activated protein kinase kinase-extracellular-regulated kinase signaling, tethered EGF increases the contact of MSC with an otherwise moderately adhesive synthetic polymer and confers resistance to cell death induced by the proinflammatory cytokine, Fas ligand. We concluded that tethered EGF may offer a protective advantage to MSC in vivo during acute inflammatory reactions to tissue engineering scaffolds. The tethered EGF-modified polymers described here could be used together with structural materials to construct MSC scaffolds for the treatment of hard-tissue lesions, such as large bony defects.

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learningdependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.

Background-Hypersecretion of insulinotropic factors such as glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-36)amide (GLP-1) have been postulated to account for the hyperinsulinaemia of obesity. Aims-To examine the role of GLP-1 and GIP in obese women and matched controls. Subjects-Six lean and six obese women subjects matched for age. Methods-The gut hormone, plasma glucose, and serum triglyceride responses were studied over 180 minutes after oral carbohydrate and fat meals. Heparin (10 000 units) was given intravenously at 120 minutes.Results-There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin. Conclusion-Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects.The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids. (Gut 1996; 38: 916-919) Keywords: GLP-1, obesity, carbohydrate meal, fat meal. strongly stimulates insulin secretion after carbohydrate, fat, and mixed meals. Molecular biology techniques have shown that posttranslational processing of proglucagon in the pancreas and ileum yields several novel glucagon-like peptides.67 Among these, the truncated fragment of GLP-1 (hitherto called GLP-1 in this paper), has been shown to be strongly insulinotropic and its secretion has been shown to increase after oral glucose and mixed meals.8 9 In addition to its insulinotropic effect, GLP-1 inhibits pancreatic glucagon secretion, decreases hepatic gluconeogenesis, and decreases insulin resistance.10 11 It has been postulated that an exaggerated 'incretin' factor may have a pathophysiological role in obesity. A role for GIP has been examined in this regard but has not been conclusively shown.5 In this context, it has been suggested that hypersecretion of GLP-1 may be the long sought 'incretin' factor in obesity. 12 Indeed, Fukase and colleagues have examined this hypothesis in a study where they showed increased secretion of glucagon-like peptide-1 in obese diabetic subjects but the responses in non-diabetic obese and matched controls were very similar.However, the methodology adopted by Fukase and workers for GLP-1 assay was indirect and less specific than that used in this study and included GLP-1(7-37), which is normally present at very low concentrations in plasma, and the two biologically inactive major proglucagon derived fragments. GLP-1 (7-36)amide, measured in this study, is the predominant circulating molecular species of glucagon-like peptides in humans. We undertook this study to clarify the conclusions of Fukase and colleagues that hypers...