Administration, Oral ; Glucose Transporter Type 2 ; metabolism ; Humans ; Intestinal Absorption ; physiology ; Organic Anion Transporters ; metabolism ; Peptide Transporter 1 ; Pharmacokinetics ; Sodium-Glucose Transporter 1 ; metabolism ; Symporters ; metabolism

The management of type 2 diabetes mellitus should comprise healthy lifestyle modifications along with tailored pharmacologic treatment. Traditionally, the American Diabetes Association (ADA)'s Diabetes Management Guidelines have not prioritized specific anti-diabetic drugs over others with regard to cardiovascular disease (CVD) and mortality prevention. Recently, two novel anti-diabetic medications proved to be significantly protective against future CVD and mortality, regardless of the glycemic levels achieved in type 2 diabetic patients with pre-existing CVD. The 2018 ADA Guidelines recommend SGLT2 inhibitor and/or GLP-1 receptor agonist be used for type 2 diabetes patients with atherosclerotic CVD after metformin monotherapy failure. Considering the value of CVD protection in the management of diabetes mellitus, this minor guideline adjustment could have far-reaching implications.
Cardiovascular Diseases ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide-1 Receptor ; Humans ; Life Style ; Metformin ; Mortality ; Sodium-Glucose Transporter 2

OBJECTIVETo reveal the effects and related mechanisms of chlorogenic acid (CGA) on intestinal glucose homeostasis.

METHODSForty male Sprague-Dawley rats were randomly and equally divided into four groups: normal chow (NC), high-fat diet (HFD), HFD with low-dose CGA (20 mg/kg, HFD-LC), and HFD with high-dose CGA (90 mg/kg, HFD-HC). The oral glucose tolerance test was performed, and fast serum insulin (FSI) was detected using an enzyme-linked immunosorbent assay. The mRNA expression levels of glucose transporters (Sglt-1 and Glut-2) and proglucagon (Plg) in different intestinal segments (the duodenum, jejunum, ileum, and colon) were analyzed using quantitative real-time polymerase chain reaction. SGLT-1 protein and the morphology of epithelial cells in the duodenum and jejunum was localized by using immunofluorescence.

RESULTSAt both doses, CGA ameliorated the HFD-induced body weight gain, maintained FSI, and increased postprandial 30-min glucagon-like peptide 1 secretion. High-dose CGA inhibited the HFD-induced elevation in Sglt-1 expression. Both CGA doses normalized the HFD-induced downregulation of Glut-2 and elevated the expression of Plg in all four intestinal segments.

CONCLUSIONAn HFD can cause a glucose metabolism disorder in the rat intestine and affect body glucose homeostasis. CGA can modify intestinal glucose metabolism by regulating the expression of intestinal glucose transporters and Plg, thereby controlling the levels of blood glucose and insulin to maintain glucose homeostasis.

Animals ; Chlorogenic Acid ; pharmacology ; Diet, High-Fat ; adverse effects ; Glucagon-Like Peptide 1 ; metabolism ; Glucose ; metabolism ; Glucose Tolerance Test ; Glucose Transporter Type 2 ; metabolism ; Homeostasis ; Insulin ; blood ; Intestines ; drug effects ; metabolism ; Male ; Proglucagon ; metabolism ; Random Allocation ; Rats, Sprague-Dawley ; Sodium-Glucose Transporter 1 ; metabolism ; Weight Gain ; drug effects

The absorption of oral drug in the intestine is an important factor to determine the drug bioavailability. There are many intestinal transporters mediating drug absorption, distribution, excretion and drug-drug interaction. Understanding the transport mechanism can improve the effectiveness and safety of drug and guide clinical rational use of drugs. The in vivo and in vitro methods are used to predict the transport mechanism of drugs by intestinal transporters in the intestine. The purposes of this article are to introduce the main transporters in the intestinal tract, to explain the transport mechanism and to summarize the advantages and disadvantages of the research methods of them.
ATP-Binding Cassette Transporters ; administration & dosage ; metabolism ; Animals ; Anion Transport Proteins ; administration & dosage ; metabolism ; Biological Availability ; Humans ; Intestinal Absorption ; Membrane Transport Proteins ; administration & dosage ; metabolism ; Peptide Transporter 1 ; Symporters ; administration & dosage ; metabolism

OBJECTIVETo investigate the effect of glucagon-like peptide-1 (GLP-1) on glycolipid metabolism in 3T3-L1 adipocytes and explore the mechanism.

METHODS3T3-L1 adipocytes were treated with GLP-1, insulin, or both for 24 h, and Western blotting was used to analyze the expression levels of adipose triglyceride lipase (ATGL), glucose transporter type 4 (GLUT4), Akt1, Akt2 and phosphorylated Akt in the cells. Immunofluorescence was used to observe lipid content in 3T3-L1 adipocytes.

RESULTSAkt1 and Akt2 were not activated by insulin stimulation in 3T3-L1 adipocytes. Akt was phosphorylated by GLP-1 stimulation, which inhibited the expression of ATGL and increased the translocation of GLUT4 from the intracellular membranes to plasma membranes. These changes were more obvious under the synergistic effect of insulin in 3T3-L1 adipocytes.

CONCLUSIONGLP-1 decreases lipolysis by inhibiting the expression of ATGL and improves insulin resistance by increasing the translocation of GLUT4 in 3T3-L1 adipocytes.

3T3-L1 Cells ; Adipocytes ; cytology ; metabolism ; Animals ; Cell Membrane ; metabolism ; Down-Regulation ; Drug Synergism ; Glucagon-Like Peptide 1 ; pharmacology ; Glucose Transporter Type 4 ; metabolism ; Insulin ; pharmacology ; Insulin Resistance ; Intracellular Membranes ; metabolism ; Lipase ; metabolism ; Mice ; Phosphorylation ; Protein Transport ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism

OBJECTIVE: To evaluate the effect of Ac-hE-18A-NH2 on TNF-α secretion and mRNA expression in ox-LDL-stimulated RAW264.7 macrophages and to elucidate the possible mechanisms. METHODS: Macrophages were incubated in the medium containing various concentrations of Ac-hE18A-NH2 (1-50 μg/mL) with ox-LDL (50 μg/mL) stimulated. The TNF-α level and intracellular cholesterol content were measured by commercially available quantitation kits following the manufacturer's instructions. TNF-α and ATP-binding cassette transporter A1 (ABCA1) mRNA expression were detected by real-time PCR. ABCA1 and IκB protein -expression in the macrophages were determined by Western blot. NF-κB activity was evaluated by electrophoretic mobility shift assay (EMSA). RESULTS: Ox-LDL stimulation induced a significant increase in TNF-α secretion, mRNA expression, cholesterol accumulation and nuclear factor-κB (NF-κB) activity in RAW264.7 macrophages. Ac-hE-18A-NH2 reduced TNF-α secretion and mRNA expression, up-regulated the ABCA1 mRNA and protein expression, reduced the intracellular cholesterol content, and inhibited NF- κB activation in a dose-dependent manner. Under the same condition and the same concentration, Ac-hE-18A-NH2 was more efficient than D-4F (apoA-I mimetic peptide) in inhibiting the inflammatory response induced by ox-LDL in the macrophages. CONCLUSION Ac-hE-18A-NH2 may suppress TNF-α secretion and mRNA expression in ox-LDL stimulated RAW264.7 macrophages via IκB-NF-κB signaling pathway. The anti-inflammatory effect of Ac-hE-18A-NH2 is better than that of apoA-I mimic peptide D-4F.
ATP Binding Cassette Transporter 1 ; metabolism ; Animals ; Cell Line ; Cholesterol ; metabolism ; Gene Expression Regulation ; I-kappa B Proteins ; metabolism ; Inflammation ; metabolism ; Lipoproteins ; pharmacology ; Lipoproteins, LDL ; Macrophages ; metabolism ; Mice ; NF-kappa B ; metabolism ; Peptide Fragments ; pharmacology ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism