Sodium Butyrate Improves Liver Glycogen Metabolism in Type 2 Diabetes Mellitus.

Liver plays a central role in modulating blood glucose level. Our most recent findings suggested that supplementation with microbiota metabolite sodium butyrate (NaB) could ameliorate progression of type 2 diabetes mellitus (T2DM) and decrease blood HbA1c in db/db mice. To further investigate the role of butyrate in homeostasis of blood glucose and glycogen metabolism, we carried out the present study. In db/db mice, we found significant hypertrophy and steatosis in hepatic lobules accompanied by reduced glycogen storage, and expression of GPR43 was significantly decreased by 59.38 ± 3.33%; NaB administration significantly increased NaB receptor G-protein coupled receptor 43 (GPR43) level and increased glycogen storage in both mice and HepG2 cells. Glucose transporter 2 (GLUT2) and sodium-glucose cotransporter 1 (SGLT1) on cell membrane were upregulated by NaB. The activation of intracellular signaling Protein kinase B (PKB), also known as AKT, was inhibited while glycogen synthase kinase 3 (GSK3) was activated by NaB in both in vivo and in vitro studies. The present study demonstrated that microbiota metabolite NaB possessed beneficial effects on preserving blood glucose homeostasis by promoting glycogen metabolism in liver cells, and the GPR43-AKT-GSK3 signaling pathway should contribute to this effect.

Rosmarinic acid, major phenolic constituent of Greek sage herbal tea, modulates rat intestinal SGLT1 levels with effects on blood glucose.

SCOPE: Previous results suggested that the effects of Salvia fruticosa tea (SFT) drinking on glucose regulation might be at the intestinal level. Here we aim to characterize the effects of SFT treatment and of its main phenolic constituent--rosmarinic acid (RA)--on the levels and localization of the intestinal Na+/glucose cotransporter-1 (SGLT1), the facilitative glucose transporter 2 and glucagon-like peptide-1 (GLP-1). METHODS AND RESULTS: Two models of SGLT1 induction in rats were used: through diabetes induction with streptozotocin (STZ) and through dietary carbohydrate manipulation. Drinking water was replaced with SFT or RA and blood parameters, liver glycogen and the levels of different proteins in enterocytes quantified. Two weeks of SFT treatment stabilized fasting blood glucose levels in STZ-diabetic animals. The increase in SGLT1 localized to the enterocyte brush-border membrane (BBM) induced by STZ treatment was significantly abrogated by treatment with SFT, without significant changes in total cellular transporter protein levels. No effects were observed on glucose transporter 2, Na(+) /K(+) -ATPase or glucagon-like peptide-1 levels by SFT. Additionally, SFT and RA for 4 days significantly inhibited the carbohydrate-induced adaptive increase of SGLT1 in BBM. CONCLUSION: SFT and RA modulate the trafficking of SGLT1 to the BBM and may contribute to the control of plasma glucose.

A high-capacity membrane potential FRET-based assay for the sodium-coupled glucose co-transporter SGLT1.

Secondary active glucose transport is mediated by at least four members of the solute-linked carrier 5 gene family (sodium/glucose transporter [SGLT] 1-4). Human genetic disorders of SGLTs including glucose-galactose malabsorption and familial renal glucosuria have increased attention on members of this family of transporters as putative drug targets. Using human SGLT1 (hSGLT1) as a paradigm, we developed a functional assay that should be adaptable to ultra-high-throughput operation and to other SGLTs. Human embryonic kidney (HEK) 293 cells stably expressing hSGLT1 (hSGLT1/HEK293 cells) display a Na(+)-dependent, phlorizin-sensitive alpha-methyl-D-[(14)C]glucopyranoside flux with expected kinetic parameters. In electrophysiological studies with hSGLT1/HEK293 cells, substrate-dependent changes in membrane potential were observed, consistent with the electrogenic operation of hSGLT1. With the use of voltage-sensitive dyes, a membrane potential, fluorescence resonance energy transfer-based functional assay on a voltage/ion probe reader platform has been established for SGLT1. This high-capacity functional assay displays similar characteristics in terms of substrate specificity and phlorizin sensitivity to those determined by more traditional approaches and should provide a means to identify novel and selective SGLT inhibitors.

Effect of dietary quercetin and sphingomyelin on intestinal nutrient absorption and animal growth.

Research on cancer and other conditions has shown flavonoids and sphingolipids to be food components capable of exerting chemoprotective action. Nevertheless, little is known about their effects on healthy individuals and their potential usefulness as therapeutic agents. The present study examined the possible action of a dietary flavonoid, quercetin, and a sphingolipid, sphingomyelin, as functional foods in healthy animals. In particular, the effect on animal growth of supplementing a conventional diet with one or other of these substances (0.5 % quercetin and 0.05 % sphingomyelin) was considered. Possible action affecting intestinal physiology was also analysed by measuring the uptake of sugar and dipeptide, mediated by the Na(+)-dependent sugar transporter SGLT1 and the dipeptide Na(+)/H(+) exchanger PEPT1 respectively, and the activity of related intestinal enzymes such as sucrase, maltase and aminopeptidase N. Both substances seemed to modify small intestinal activity in healthy mice, altering intestinal enzymatic activity and nutrient uptake. These effects observed in the small intestine did not impair normal development of the animals, as no differences in serum biochemical parameters or in organ and body weights were found. The findings should help in elucidating the mechanisms of action of these food components with a view to their possible use in the prevention of certain pathological conditions.