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Abstract: Direct effects of GLP-1, kinase-mediated, on glucose and lipid metabolism in rat and human extrapancreatic tissues, are amply documented and also changes in type-2 diabetic (T2D) patients. Here, we explored the characteristics of the GLP-1 action and those of its analogs Ex-4 and Ex-9, on muscle glucose transport (GT) and metabolism in human morbid obesity (OB), as compared with normal and T2D subjects. In primary cultured myocytes from OB, GT and glycogen synthase a (GSa) activity values were lower than normal, and comparable to those reported in T2D patients; GT was increased by either GLP-1 or Ex-9 in a more efficient manner than in normal or T2D, up to normal levels; the Ex-4 increasing effect on GSa activity was two times that in normal cells, while Ex-9 failed to modify the enzyme activity. In OB, the control value of all kinases analyzed – PI3K, PKB, MAPKs, and p70s6K – although lower than that in normal or T2D subjects, the cells maintained their response capability to GLP-1, Ex-4, Ex-9 and insulin, with some exceptions. GLP-1 and exendins showed a direct normalizing action in the altered glucose uptake and metabolism in the muscle of obese subjects, which in the case of GLP-1 could account, at least in part, for the reported restoration of the metabolic conditions of these patients after restrictive surgery. [Copyright &y& Elsevier]

Abstract: Exendin-4, like GLP-1, is insulinotropic, antidiabetic and glucoregulatory among other properties, which are thought to be exerted through the pancreatic GLP-1 receptor; exendin-4 is also an agonist of the GLP-1 stimulatory action upon liver and muscle glucose metabolism, where GLP-1 receptor is distinct from that in the pancreas. We investigated the action of prolonged treatment with exendin-4 upon glucose transport parameters in skeletal muscle and liver of normal rats and streptozotocin-induced type 2 diabetic rats (T2D). Muscle of T2D showed lower than normal glucose transport; exendin-4 did not modify the value in normal but normalized that in the T2D; unlike previously detected with GLP-1, no apparent modification was observed in GLUT-4 expression in either group after exendin-4, except for an increased GLUT-4 protein in normal rats. Yet, exendin-4 significantly stimulated liver GLUT-2–mRNA and –protein in T2D and normal rats, the effect upon GLUT-2–protein in T2D being higher than that in normal animals; this was accompanied by a normalizing action of exendin-4 upon the lower than normal liver glycogen in T2D rats. These data suggest that the liver may represent at least one of the major target organs for exendin-4 to exert its plasma lowering effect in diabetic state. [Copyright &y& Elsevier]

Abstract: The aim of this study was to explore, in normal rats, the effects upon selected metabolic and hormonal variables of both the rapid intake or long-term administration of a diet containing 13% protein (wt/wt; control diet) and enriched with 40% (wt/wt) casein. The response to the intake of the control and casein diet was examined in meal-trained rats given access to these diets for 15 minutes. A glucose tolerance test involving the intragastric administration of glucose (1.2 mg/g body weight) was performed in overnight fasted rats otherwise given free access to the control or casein diet for 19 to 36 days. In meal-trained rats, the secretory response of insulin-producing cells, as judged from the increment of the paired plasma insulin/glucose ratio, was higher in the rats exposed to the casein, as compared with control diet, despite a higher integrated plasma glucose incremental area in the latter case. After intragastric administration of glucose to overnight fasted rats otherwise maintained for 19 and 36 days on either control or casein diet, the integrated values over 120 minutes for both plasma glucose and insulin concentrations were higher, however, in the casein than in the control group, without significant difference in the integrated value for the paired insulin/glucose ratio. Likewise, neither the basal plasma glucagon-like peptide 1 concentration nor the incremental area above such a basal value was significantly different in the 2 groups of rats. The gain in body weight over 50 days of observation, as well as the insulin content of the pancreas at day 50, were also comparable in the 2 groups of rats. The intestinal glucagon-like peptide 1 content was lower, however, in the casein than in the control group. These findings are consistent with the insulinotropic action of amino acids and with the role of some of them as gluconeogenic precursors. Advantage could conceivably be taken of such an approach to prevent hypoglycemia in selected situations. [Copyright &y& Elsevier]