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Articles by H. Pijl
Total Records ( 2 ) for H. Pijl
  E. T Parlevliet , J. E de Leeuw van Weenen , J. A Romijn and H. Pijl
 

Glucagon-like peptide-1 (GLP-1) improves insulin sensitivity in humans and rodents. It is currently unknown to what extent the (metabolic) effects of GLP-1 treatment are mediated by central GLP-1 receptors. We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fat-fed insulin-resistant C57Bl/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icv). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57Bl/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model.

  B. Guigas , J. E. de Leeuw van Weenen , N. van Leeuwen , A. M. Simonis-Bik , T. W. van Haeften , G. Nijpels , J. J. Houwing-Duistermaat , M. Beekman , J. Deelen , L. M. Havekes , B. W. J. H. Penninx , N. Vogelzangs , E. van t Riet , A. Dehghan , A. Hofman , J. C. Witteman , A. G. Uitterlinden , N. Grarup , T. Jorgensen , D. R. Witte , T. Lauritzen , T. Hansen , O. Pedersen , J. Hottenga , J. A. Romijn , M. Diamant , M. H. H. Kramer , R. J. Heine , G. Willemsen , J. M. Dekker , E. M. Eekhoff , H. Pijl , E. J. de Geus , P. E. Slagboom and L. M. t Hart
 

Aims

Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans.

Methods

Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis.

Results

rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); = 4.1*10−4) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (= 5.5*10−4) but again not in men (= 0.34).

Conclusion

The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene.

 
 
 
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