Dopamine D2 receptors in the pathophysiology of insulin resistance

Leeuw van Weenen, J.E. de (2011)

Doctoral Thesis

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 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.

• DRD2 antagonist
• DRD2 agonist
• Insulin secretion
• Calorie restriction
• High fat diet
• Insulin resistance
• Diabetes Mellitus type 2
• Dopamine receptors

• All authors: Leeuw van Weenen, J.E. de
• Supervisor: Pijl, H.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2011-10-05
• ISBN (print): 9789461081933