Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of Reprints and permissions information is available online at www.nature.com/reprints/index.html.

To explore the functional significance of cGMP-dependent protein kinase type I (cGKI) in the regulation of erythrocyte survival, gene-targeted mice lacking cGKI were compared with their control littermates. By the age of 10 weeks, cGKI-deficient mice exhibited pronounced anemia and splenomegaly. Compared with control mice, the cGKI mutants had significantly lower red blood cell count, packed cell volume, and hemoglobin concentration. Anemia was associated with a higher reticulocyte number and an increase of plasma erythropoietin concentration. The spleens of cGKI mutant mice were massively enlarged and contained a higher fraction of Ter119 ؉ erythroid cells, whereas the relative proportion of leukocyte subpopulations was not changed. The Ter119 ؉ cGKI-deficient splenocytes showed a marked increase in annexin V binding, pointing to phosphatidylserine (PS) exposure at the outer membrane leaflet, a hallmark of suicidal erythrocyte death or eryptosis. Compared with control erythrocytes, cGKI-deficient erythrocytes exhibited in vitro a higher cytosolic Ca 2؉ concentration, a known trigger of eryptosis, and showed increased PS exposure, which was paralleled by a faster clearance in vivo. Together, these results identify a role of cGKI as mediator of erythrocyte survival and extend the emerging concept that cGMP/cGKI signaling has an antiapoptotic/prosurvival function in a number of cell types in vivo.apoptosis ͉ Ca2ϩ channels ͉ phosphatidylserine ͉ spleen N itric oxide (NO) has been shown to be a powerful regulator of cell survival (1, 2). Depending on the source or concentration of NO and the influence of additional regulators, NO may stimulate or inhibit apoptosis (3). NO exerts its effects in part through S-nitrosylation of target proteins. However, the effect of NO donors on Ca 2ϩ -induced phosphatidylserine (PS) exposure, a hallmark of apoptosis, could be mimicked by cGMP analogs (4), suggesting the involvement of soluble guanylyl cyclase, cGMP, and cGMP-dependent protein kinase type I (cGKI), a well known signaling cascade downstream of NO (5, 6).Recent studies indicated that erythroid cells possess a functional NO/cGMP pathway (7-9), which may be involved in the regulation of eryptosis, the suicidal death of erythrocytes (10). Erythrocyte cGMP production might also be stimulated by NO generated in the endothelium. The cGKI can also be activated independent of cGMP in response to oxidative stress (11). Eryptosis may follow osmotic shock, energy depletion, and oxidative stress (10), which activate Ca 2ϩ -permeable cation channels (12). Subsequent Ca 2ϩ entry leads to activation of Ca 2ϩ -sensitive K ϩ channels, exit of KCl with osmotically obliged water, and thus cell shrinkage (13). In addition, Ca 2ϩ entry triggers Ca 2ϩ -sensitive scrambling of the cell membrane (14, 15) with subsequent exposure of PS at the erythrocyte surface (12). Cell membrane scrambling may further be triggered by ceramide (16) and activation of protein kinase C (17). PS-exposing erythrocytes bind to PS receptors (18) and are recognized, ...

Erythropoietin (Epo) treatment increases hematocrit (Htc) and, consequently, arterial O 2 content. This in turn improves exercise performance. However, because elevated blood viscosity associated with increasing Htc levels may limit cardiac performance, it was suggested that the highest attainable Htc may not necessarily be associated with the highest attainable exercise capacity. To test the proposed hypothesis that an optimal Htc in acute and chronic Epotreated mice exists-i.e., the Htc that facilitates the greatest O 2 flux during maximal exercise-Htc levels of wild-type mice were acutely elevated by administering novel erythropoiesis-stimulating protein (NESP; wtNESP). Furthermore, in the transgenic mouse line tg6 that reaches Htc levels of up to 0.9 because of constitutive overexpression of human Epo, the Htc was gradually reduced by application of the hemolysis-inducing compound phenylhydrazine (PHZ; tg6PHZ). Maximal cardiovascular performance was measured by using telemetry in all exercising mice. Highest maximal O 2 uptake ( _ VO 2max ) and maximal time to exhaustion at submaximal exercise intensities were reached at Htc values of 0.58 and 0.57 for wtNESP, and 0.68 and 0.66 for tg6PHZ, respectively. Rate pressure product, and thus also maximal working capacity of the heart, increased with elevated Htc values. Blood viscosity correlated with _ VO 2max . Apart from the confirmation of the Htc hypothesis, we conclude that tg6PHZ adapted better to varying Htc values than wtNESP because of the higher optimal Htc of tg6PHZ compared to wtNESP. Of note, blood viscosity plays a critical role in limiting exercise capacity.blood viscosity | doping | excessive erythrocytosis | exercise performance | hemolysis

This study tested the hypothesis that maximal oxygen uptake (VO(2max)) and performance increase upon altitude acclimatization at moderate altitude. Eight elite cyclists were studied at sea level, and after 1 (Day 1), 7 (Day 7), 14 (Day 14) and 21 (Day 21) days of exposure to 2340 m. Capillary blood samples were taken on these days before performing two consecutive maximal exercise trials. Acclimatization increased hemoglobin concentration and arterial oxygen content. On Day 1, VO(2max) and time to exhaustion (at 80% of sea-level maximal power output) decreased by 12.8% (P<0.05) and 25.8% (P<0.05), respectively, compared with the corresponding sea-level values. Subsequently, these parameters increased by 3.2% (P<0.05) and 6.0% (P<0.05) from Days 1 to 7, by 4.8% (P<0.05) and 5.7% (P<0.05) from Days 7 to 14, followed by 0.7% (P>0.05) and 1.4% (P>0.05) from Days 14 to 21, respectively. These data suggest that endurance athletes competing at altitudes around 2340 m should expose themselves to this altitude at least 14 days before competition.