Nutrient overload leads to obesity, insulin resistance, and often type 2 diabetes. Whereas increased fat intake is commonly cited as the major factor in diet-induced dysmetabolic states, increased protein consumption also contributes, through elevated circulating amino acids. Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess.

Background Ghrelin stimulates growth hormone (GH) secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and desacyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG. Objectives To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women. Methods In study 1 AG (1, 3 and 5 μg/kg/h) was infused over 65 min in 12 healthy (8F/4M) subjects in randomized order in. In study 2 AG (1 μg/kg/h), DAG (4 μg/kg/h), or both were infused over 210 min in 10 healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis. Results After the 1, 3 and 5 μg/kg/h doses of AG there was a dose-dependent increase in the maximum concentration (Cmax) and area under the curve [AUC(0-last)] of AG and total ghrelin. Among the different AG doses there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG:AG ratio approximates 2:1 during steady state infusion of AG. Infusion of AG caused an increase of DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity. Conclusions The pharmacokinetics of AG and total ghrelin appear to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation.

Glucagon‐like peptide‐1 (GLP‐1) is a product of proglucagon cleavage synthesized in L cells in the intestinal mucosa, α‐cells in the pancreatic islet, and neurons in the nucleus of the solitary tract. GLP‐1 is essential for normal glucose tolerance and acts through a specific GLP‐1 receptor that is expressed by islet β‐cells as well as other cell types. Because plasma concentrations of GLP‐1 increase following meal ingestion it has been generally presumed that GLP‐1 acts as a hormone, communicating information from the intestine to the endocrine pancreas through the circulation. However, there are a number of problems with this model including low circulating concentrations of GLP‐1 in plasma, limited changes after meal ingestion and rapid metabolism in the plasma. Moreover, antagonism of systemic GLP‐1 action impairs insulin secretion in the fasting state, suggesting that the GLP‐1r is active even when plasma GLP‐1 levels are low and unchanging. Consistent with these observations, deletion of the GLP‐1r from islet β‐cells causes intolerance after IP or IV glucose, challenges that do not induce GLP‐1 secretion. Taken together, these data support a model whereby GLP‐1 acts through neural or paracrine mechanisms to regulate physiologic insulin secretion. In contrast, bariatric surgery seems to be a condition in which circulating GLP‐1 could have an endocrine effect. Both gastric bypass and sleeve gastrectomy are associated with substantial increases in postprandial GLP‐1 release and in these conditions interference with GLP‐1r signaling has a significant impact on glucose regulation after eating. Thus, with either bariatric surgery or treatment with long‐acting GLP‐1r agonists, circulating peptide mediates insulinotropic activity. Overall, a case can be made that physiologic actions of GLP‐1 are not hormonal, but that an endocrine mechanism of GLP‐1r activation can be co‐opted for therapeutics.