Involvement of the Niacin Receptor GPR109a in the LocalControl of Glucose Uptake in Small Intestine of Type 2Diabetic Mice

Abstract

Niacin is a popular nutritional supplement known to reduce the risk of cardiovascular diseases by enhancing high-density lipoprotein levels. Despite such health benefits, niacin impairs fasting blood glucose. In type 2 diabetes (T2DM), an increase in jejunal glucose transport has been well documented; however, this is intriguingly decreased during niacin deficient state. In this regard, the role of the niacin receptor GPR109a in T2DM jejunal glucose transport remains unknown. Therefore, the effects of diabetes and high-glucose conditions on GPR109a expression were studied using jejunal enterocytes of 10-week-old m+/db and db/db mice, as well as Caco-2 cells cultured in 5.6 or 25.2 mM glucose concentrations. Expression of the target genes and proteins were quantified using real-time polymerase chain reaction (RT-PCR) and Western blotting. Glucose uptake in Caco-2 cells and everted mouse jejunum was measured using liquid scintillation counting. 10-week T2DM increased mRNA and protein expression levels of GPR109a in jejunum by 195.0% and 75.9%, respectively, as compared with the respective m+/db control; high-glucose concentrations increased mRNA and protein expression of GPR109a in Caco-2 cells by 130.2% and 69.0%, respectively, which was also confirmed by immunohistochemistry. In conclusion, the enhanced GPR109a expression in jejunal enterocytes of T2DM mice and high-glucose treated Caco-2 cells suggests that GPR109a is involved in elevating intestinal glucose transport observed in diabetes.

Niacin fine‐tunes energy homeostasis through canonical GPR109A signaling

“…Recent studies have demonstrated that GPR109A is expressed in colonic and intestinal epithelial cells and mediates the local control of intestinal glucose absorption (34) and the tumor‐suppressive effects of the bacterial fermentation product butyrate in the colon (35). Accordingly, we further examined the role of GPR109A expression in colonic and intestinal epithelial cells in the control of intestinal fatty acid absorption.…”

“…Importantly, GPR109A has been shown to functionally express in colonic and intestinal epithelial cells (34, 35). Niacin has been found to locally control glucose uptake at the level of the small intestine through GPR109A (34). This prompts us to examine whether or not GPR109A is involved in the control of uptake of sterols and fatty acids in the level of the small intestine.…”

Na+/H+ exchanger 3 blockade ameliorates type 2 diabetes mellitus via inhibition of sodium‐glucose co‐transporter 1‐mediated glucose absorption in the small intestine

“…Caco2 cells (ATCC, Manassas, Virginia; catalogue no. : HTB‐37) were grown as reported . For intracellular pH measurements, Caco2 cells were removed from culture flasks by trypsin, and 2 × 10 5 cells were seeded onto 25‐mm‐diameter glass coverslips inserted into the 6‐well plates containing complete DMEM medium, which was changed every 2 days until 80% confluence.…”

“…: HTB-37) were grown as reported. 15 For intracellular pH measurements, Caco2 cells were removed from culture flasks by trypsin, and 2 × 10 5 cells were seeded onto 25-mm-diameter glass coverslips inserted into the 6-well plates containing complete DMEM medium, which was changed every 2 days until 80% confluence. For Western blot or PCR experiments, cells were seeded onto the 6-well plates and cultured under the same conditions as described above.…”

Pleiotropic effects of niacin: Current possibilities for its clinical use

“…It was recently found in a mouse model that long-term niacin treatment resulted in insulin resistance that may be in part explained by a niacininduced downregulation of the cAMP-degrading enzyme phosphodiesterase 3B (120) or modulated through activation of the islet beta-cell HCA2, which induce PPARg -uncoupling protein 2 pathway (121). Moreover, HCA2 seems to play a role in jejunal glucose transport (122), which is enhanced in T2DM. In a recent meta-analysis, niacin therapy was associated with a moderately increased risk of developing diabetes regardless of the background statin or combination laropiprant therapy (123).…”