Accumulation of intestinal tissue 3-deoxyglucosone attenuated GLP-1 secretion and its insulinotropic effect in rats

Abstract

BackgroundOur recent findings support the idea that 3-deoxyglucosone (3DG), a dietary composition, has been suggested as an independent factor for the development of prediabetes. Secretion of glucagon-like peptide-1 (GLP-1) has been suggested to be impaired in T2DM and in conditions associated with hyperglycemia. Since low oral bioavailability of 3DG has been indicated in a single administration study, in the present study we examined if 3DG is capable of accumulating in intestinal tissue of rats after 2-week administration of 3DG, and the 3DG treatment affects GLP-1 secretion and glucose tolerance.MethodsRats were administered by gastric gavage for 2 weeks. We measured 3DG contents of intestinal tissues (by HPLC), plasma levels of total GLP-1 (by ELISA), insulin and glucagon (both by radioimmunoassay) and blood glucose concentrations. The expressions of the sweet receptor subunits (TAS1R2, TAS1R3) and its downstream molecule TRPM5 in duodenum and colon tissues of rats were quantified by WB. We examined GLP-1 secretion in enteroendocrine STC-1 cells exposured to 3DG.Results3DG treatment for 2 weeks increased 3DG content of intestinal tissues, fasting blood glucose concentration, and reduced plasma concentrations of GLP-1 and insulin at fasting and 15 and 180 min after the glucose load and oral glucose tolerance in conjunction with increased plasma glucagon concentrations. The expressions of TAS1R2, TAS1R3 and TRPM5 were shown to be reduced whereas 3DG treatment did not affect plasma dipeptidyl peptidase-4 activity, indicating an impaired GLP-1 secretion in 3DG-treated rats. This idea was further supported by the fact that exposure to 3DG directly decrease GLP-1 secretion in STC-1.ConclusionIt is the first demonstration that 3DG was capable of accumulating in intestinal tissue and thereby decreased secretion of GLP-1 and insulin in a similar manner. 3DG-treated rats developed impaired glucose regulation (IGR) with obviously pancreatic islet cell dysfunction. It is further concluded that a decrease in the biological function of GLP-1 resulting from the decreased GLP-1 secretion is the most likely mechanism for the impaired insulin secretion, which ultimately promoted the development of IGR. These results will also contribute to a better understanding of the significance for restoring physiological GLP-1 secretion.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-016-0194-9) contains supplementary material, which is available to authorized users.

Metabolic Adaptations in Pregnancy: A Review

“…During early pregnancy, the activity of the pancreatic beta cells is increased, as evidenced by the enhanced insulinotropic effect of glucose observed in both women and rats, while whole-body insulin sensitivity is unchanged or even augmented [42]. Consequently, it has been proposed that hyperinsulinemia in the first 2 trimesters of gestation is the principal factor promoting maternal lipogenesis and fat deposition.…”

The downregulation of sweet taste receptor signaling in enteroendocrine L-cells mediates 3-deoxyglucosone-induced attenuation of high glucose-stimulated GLP-1 secretion

“…Previous studies by us and others have revealed that 3DG exhibits poor absorbing characteristics (Kato et al 1990, Degen et al 2014, Zhang et al 2016), suggesting the harmful action of 3DG on the function of L-cells of the gastrointestinal tract. Indeed, we previously reported that acute administration of 3DG by gastric gavage induced the impairment in oral glucose-stimulated GLP-1 secretion in rats.…”

“…Studies in diabetic patients have suggested that 3DG is associated with diabetes (Niwa 1999, Kusunoki et al 2003. Our previous studies in clinical and animal research have indicated 3DG as an independent factor for the development of prediabetes (Jiang et al 2012, Liang et al 2016a, Zhang et al 2016, Wang et al 2017. Acute and two-week 3DG administration by gastric gavage induced acute glucose intolerance and glucose homeostatic dysregulation in rats, respectively.…”

“…The GLP-1 secretion in response to oral glucose was impaired in rats after 3DG administration by gastric gavage In mouse enteroendocrine cell line STC-1, treatment with 3DG induced a reduction in glucose-stimulated GLP-1 secretion (Zhang et al 2016, Wang et al 2017. Our previous studies revealed that 3DG-mediated inhibition of endogenous GLP-1 secretion was a mechanism linking 3DG with acute glucose intolerance and glucose homeostatic dysregulation in rats (Zhang et al 2016, Wang et al 2017. Therefore, it is conceivable that the STRs pathway is linked with the harmful effects of 3DG on glucose homeostasis by decreasing GLP-1 secretion.…”

“…Therefore, it is conceivable that the STRs pathway is linked with the harmful effects of 3DG on glucose homeostasis by decreasing GLP-1 secretion. Reduced expression of intestinal STRs subunits in fasting rats in response to two-week administration of 3DG is suggested as a possible mechanism whereby GLP-1 secretion is reduced under fasting conditions (Zhang et al 2016). 3DG reduced intracellular cyclic adenosine monophosphate (cAMP) level in STC-1 cells under high glucose condition, suggesting 3DG-mediated attenuation of GLP-1 secretion through decreasing cAMP levels involved the STRs pathway (Wang et al 2017).…”