In this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic... Show moreIn this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic surgical procedure Roux-en-Y gastric bypass. Moreover, we found differences between NGT and T2DM subjects at baseline, which enable us to better be able to dissect the subsequent effects of the procedures. To our surprise, and in contrast to previous studies, we observed no additional effect of the RYGB as compared to calorie restriction, on our main outcome parameters: postprandial glucose, insulin and the gut peptide levels three weeks after surgery. Furthermore, both restrictive and RYGB induced weight loss resulted in comparable effects on the lipidome, circulating thyroid hormone levels and the autonomic nervous system. For these outcome parameters, it seems that calorie restriction is the common denominator of the effect of the different weight loss strategies on the short term. Clearly distinct effects of RYGB, however, were seen on bile salt, FGF21 and glucagon levels in response to food intake. Although neither the exact mechanisms, nor the eventual metabolic effect are as yet clear, the gut-liver-pancreas axis may be an important mediator of the effect of the RYGB Show less
Extensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we... Show moreExtensive literature links the dopamine receptor D2 to insulin resistance and diabetes mellitus type 2. However, many aspects of the functional relationship remain unclear. In this thesis we focused on unraveling the characteristics of the interplay between dopamine D2 receptors and glucose metabolism as well as understanding the underlying mechanism(s). We evaluated the impact of DRD2 agonistic and antagonistic drugs on glucose and insulin metabolism in healthy volunteers, mice and INS-1E cells and we assessed dopaminergic parameters under different metabolic conditions. Our results show that altered dopaminergic parameters associated with obesity are due to mechanisms other than diet composition. But, changes in dopaminergic signaling may set the stage for metabolic corollaries of high fat feeding and may be involved in the beneficial impact of calorie restriction. We also demonstrate that inhibiting DRD2 activation may affect glucose homeostasis independent of body weight alterations. The underlying mechanisms include a reduction in physical activity and a direct effect on insulin sensitivity. In addition we provide evidence that inhibition of insulin secretion may, paradoxically, underlie the beneficial impact of DRD2 activation on glucose metabolism. We believe these findings may offer new ideas for strategies to prevent of treat diabetes mellitus type 2. Show less
