ObjectiveAngiopoietin-like protein-4 (ANGPTL4) is a circulating protein that is highly expressed in liver and implicated in regulation of plasma triglyceride levels. Systemic ANGPTL4 increases during prolonged fasting and is suggested to be secreted from skeletal muscle following exercise.MethodsWe investigated the origin of exercise-induced ANGPTL4 in humans by measuring the arterial-to-venous difference over the leg and the hepato-splanchnic bed during an acute bout of exercise. Furthermore, the impact of the glucagon-to-insulin ratio on plasma ANGPTL4 was studied in healthy individuals. The regulation of ANGPTL4 was investigated in both hepatic and muscle cells.ResultsThe hepato-splanchnic bed, but not the leg, contributed to exercise-induced plasma ANGPTL4. Further studies using hormone infusions revealed that the glucagon-to-insulin ratio is an important regulator of plasma ANGPTL4 as elevated glucagon in the absence of elevated insulin increased plasma ANGPTL4 in resting subjects, whereas infusion of somatostatin during exercise blunted the increase of both glucagon and ANGPTL4. Moreover, activation of the cAMP/PKA signaling cascade let to an increase in ANGPTL4 mRNA levels in hepatic cells, which was prevented by inhibition of PKA. In humans, muscle ANGPTL4 mRNA increased during fasting, with only a marginal further induction by exercise. In human muscle cells, no inhibitory effect of AMPK activation could be demonstrated on ANGPTL4 expression.ConclusionsThe data suggest that exercise-induced ANGPTL4 is secreted from the liver and driven by a glucagon-cAMP-PKA pathway in humans. These findings link the liver, insulin/glucagon, and lipid metabolism together, which could implicate a role of ANGPTL4 in metabolic diseases.

Aims: To evaluate the effects of brain insulin on endogenous glucose production in fasting humans, with a focus on hepatic glucose release by performing a randomized, placebo-controlled, blinded, crossover experiment.Materials and methods: On two separate days, 2 H 2 -glucose was infused to nine healthy lean men, and blood was sampled from the hepatic vein and a radial artery. On day 1, participants received 160 U human insulin through nasal spray, and on day 2 they received placebo spray, together with an intravenous insulin bolus to mimic spillover of nasal insulin to the circulation.Hepatic glucose fluxes and endogenous glucose production were calculated.Results: Plasma insulin concentrations were similar on the two study days, and no differences in whole-body endogenous glucose production or hepato-splanchnic glucose turnover were detected.Conclusions: Nasal administration of insulin does not influence whole-body or hepatic glucose production in fasting humans. By contrast, pharmacological delivery of insulin to the brain might modulate insulin effectiveness in glucose-producing tissue when circulating insulin levels are elevated; therefore, the metabolic consequences of brain insulin action appear to be dependent on metabolic prandial status. K E Y W O R D S basal insulin, clinical physiology, liver *Current work place: Novo Nordisk A/S. P.P. and J.S.H. contributed equally.