ObjectivesWe sought to determine: 1) if early weight regain between one and two years after RYGB is associated with worsened hepatic and peripheral insulin sensitivity, and 2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB.Design and MethodsHepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at one month, six months, one year, and two years post operatively. Weight regain was defined as ≥ 5% increase in body weight between one and two years after RYGB.ResultsWeight regain occurred in 33% of subjects, with an average increase in body weight of 10 ± 5 % (8.5 ± 3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups.ConclusionsEarly weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB.

Aims Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). Materials and Methods We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg−1 min−1) in healthy, lean subjects (n=9) and non-diabetic, obese subjects (n=9) before and two weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinemic-euglycemic clamp. Results Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in the RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in the lean, obese, and post-RYGB in response to ghrelin infusion. Conclusions These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and after RYGB.

Background Aerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D. Methods Participants included 11 obese humans with T2D, who underwent 15 ± 2 weeks of aerobic exercise training (AEX; n = 6) or remained sedentary for 15 ± 1 weeks (SED; n = 5). After an initial screening visit, each subject underwent an oral glucose load clamp and an isoglycemic/two-step (20 and 40 mU/m 2 /min) hyperinsulinemic clamp (ISO-clamp) to assess SGU and insulin-mediated suppression of EGP, respectively. After the intervention period, both tests were repeated. Results In AEX, the ability of insulin to suppress EGP was improved during both the low (69 ± 9 and 80 ± 6% suppression; pre-post, respectively; p < 0.05) and high (67 ± 6 and 82 ± 4% suppression, respectively; p < 0.05) insulin infusion periods. Despite markedly improved muscle insulin sensitivity, SGU was reduced in AEX after training (22.9 ± 3.3 and 9.1 ± 6.0 g pre-post in AEX, respectively; p < 0.05). Conclusions In obese T2D subjects, exercise training improves whole-body glucose metabolism, in part, by improving insulin-mediated suppression of EGP and enhancing muscle glucose uptake, which occur despite reduced SGU during an oral glucose challenge.

nederlands tijdschrift voor diabetologie 71 j a a rg a n g 1 3 | n r. 3 | s e p te m b e r 2 0 1 5 CO N G R E S V E R S L AGen verzadiging. GLP-1-receptoren bevinden zich niet alleen in de perifere weefsels, maar ook in de hersenen. Behandeling met GLP-1-agonisten leidt tot gewichtsverlies en verminderde voedselinname. Deze studie in 20 mensen met type 2 diabetes onderzoekt of dit verklaard kan worden door GLP-1-effecten in de hersenen. In een crossoverstudie werden patiënten behandeld met liraglutide of glargine gedurende 12 weken. Tijdens (10 dagen na start) en na (12 weken) iedere behandeling werd een functionele MRI verricht om de respons te meten op plaatjes van voedsel versus neutrale plaatjes in nuchtere toestand en 30 minuten na een gestandaardiseerde maaltijd (450 kcal). Na 12 weken liraglutide was er een grotere daling in HbA1c en lichaamsgewicht. Na 10 dagen behandeling met liraglutide (versus glargine) vertoonden de patiënten een verminderde activatie in reactie op plaatjes van voedsel in het linker putamen en na een maaltijd vergrootte liraglutide het verlagende effect van de maaltijd op activatie van het linker putamen en de amygdala. In de beloningsgebieden in de hersenen had liraglutide ook effect na 10 dagen, want de activatie van deze gebieden in reactie op plaatjes van voedsel was verminderd na behandeling in vergelijking tot glargine. Ook de hongerscore nam af na 10 dagen liraglutide. De verschillen tussen liraglutide en glargine waren niet meer aantoonbaar na 12 weken behandeling. Deze studie laat zien dat liraglutide de respons van de hersenen op eten en het zien van eten kan beïnvloeden. Het ligt voor de hand te concluderen dat deze veranderde responsen bijdragen aan het gewichtsverlies dat we zien na behandeling met GLP-1-agonisten, maar dit is nog niet direct aangetoond. De effecten zijn van voorbijgaande aard, terwijl het verschil in lichaamsgewicht pas later optreedt. Dit maakt de rol van deze veranderde responsen in het gewichtsverlies door GLP-1-agonisten onzeker. 15.Ghrelin stimulates appetite, promotes adiposity, and worsens glucose metabolism. Ghrelin levels vary according to both chronic and acute nutritional status, but the regulation of ghrelin secretion is not well understood. The primary site of production of ghrelin is the stomach; however, evidence suggests that there is post-gastric regulation of ghrelin secretion. A reduction in fasting and postprandial ghrelin levels is implicated in the efficacy of RYGB to produce metabolic improvements in the immediate postoperative period. In this study, we determined if the enhanced postprandial ghrelin suppression observed after RYGB could be attributed to more rapid intestinal nutrient stimulation. We studied 9, Class III obese, non-diabetic but insulin resistant subjects on two occasions, where we simulated pre-and post-RYGB nutrient delivery by administering a 50 g glucose load either to the stomach or to proximal jejunum, in random order. The next day, plasma glucose excursions for each was replicated with an isoglycemic IV gluco...