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Mentor Sopjani, Lulzim Millaku, Dashnor Nebija, Merita Emini, Miribane Dermaku-Sopjani, Arleta Rifati-Nixha
Glycogen synthase kinase-3 (GSK-3) is a highly evolutionarily conserved and ubiquitously expressed serine/threonine kinase, an enzyme protein profoundly specific for glycogen synthase (GS). GSK-3 is involved in various cellular functions and physiological processes, including cell proliferation, differentiation, motility, and survival as well as glycogen metabolism, protein synthesis, and apoptosis. There are two isoforms of human GSK-3 (named GSK-3α and GSK-3β) encoded by two distinct genes. Recently, GSK-3β has been reported to function as a powerful regulator of various transport processes across the cell membrane...
October 9, 2018: Current Medicinal Chemistry
L X Wang, S L Yan, J Z Li, Y L Li, X Q Ding, J Yin, X Xiong, H S Yang, Y L Yin
Understanding the regulatory mechanisms of intestinal morphology and function is essential for improving postweaning growth in pigs. The objective of this study was to identify the relationships of enterocyte proliferation with intestinal villus height, crypt depth, and nutrient digestibility in piglets. Sixty-four 21-d-old weaned piglets were used. Gastrointestinal cell proliferation was evaluated via Ki-67 immunohistochemistry. Villus height and crypt depth were measured using hematoxylin and eosin (H&E)-stained sections...
October 10, 2018: Journal of Animal Science
Katharina Schreck, Matthias F Melzig
The intestinal absorption of fatty acids, glucose and fructose is part of the basic requirements for the provision of energy in the body. High access of saturated longchain fatty acids (LCFA), glucose and fructose can facilitate the development of metabolic diseases, particularly the metabolic syndrome and type-2 diabetes mellitus (T2DM). Research has been done to find substances which decelerate or inhibit intestinal resorption of these specific food components. Promising targets are the inhibition of intestinal long-chain fatty acid (FATP2, FATP4), glucose (SGLT1, GLUT2) and fructose (GLUT2, GLUT5) transporters by plant extracts and by pure substances...
October 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Shoichi Kuroda, Yohei Kobashi, Takahiro Oi, Hideaki Amada, Lisa Okumura-Kitajima, Fusayo Io, Koji Yamamto, Hiroyuki Kakinuma
The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats...
September 29, 2018: Bioorganic & Medicinal Chemistry Letters
Kwong-Man Ng, Yee-Man Lau, Vidhu Dhandhania, Zhu-Jun Cai, Yee-Ki Lee, Wing-Hon Lai, Hung-Fat Tse, Chung-Wah Siu
Empagliflozin, a sodium-glucose co-transporter (SGLT) inhibitor, reduces heart failure and sudden cardiac death but the underlying mechanisms remain elusive. In cardiomyocytes, SGLT1 and SGLT2 expression is upregulated in diabetes mellitus, heart failure, and myocardial infarction. We hypothesise that empagliflozin exerts direct effects on cardiomyocytes that attenuate diabetic cardiomyopathy. To test this hypothesis, cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) were used to test the potential effects of empagliflozin on neutralization of cardiac dysfunction induced by diabetic-like cultures...
October 5, 2018: Scientific Reports
Ferhaan Ahmad, Zhao Li, Kamel Shibbani
No abstract text is available yet for this article.
October 9, 2018: Journal of the American College of Cardiology
Sara B Seidelmann, Elena Feofanova, Bing Yu, Nora Franceschini, Brian Claggett, Mikko Kuokkanen, Hannu Puolijoki, Tapani Ebeling, Markus Perola, Veikko Salomaa, Amil Shah, Josef Coresh, Elizabeth Selvin, Calum A MacRae, Susan Cheng, Eric Boerwinkle, Scott D Solomon
BACKGROUND: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U...
October 9, 2018: Journal of the American College of Cardiology
Pavel Balazki, Stephan Schaller, Thomas Eissing, Thorsten Lehr
The early stage of diabetes mellitus is characterized by increased glomerular filtration rate (GFR), known as hyperfiltration, which is believed to be one of the main causes leading to renal injury in diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to be able to reverse hyperfiltration in some patients. We developed a mechanistic computational model of kidney that explains the interplay of hyperglycemia and hyperfiltration and integrates the pharmacokinetics/pharmacodynamics (PK/PD) of the SGLT2i dapagliflozin...
September 30, 2018: CPT: Pharmacometrics & Systems Pharmacology
Guozhang Xu, Michael D Gaul, Gee-Hong Kuo, Fuyong Du, June Zhi Xu, Nathaniel Wallace, Simon Hinke, Thomas Kirchner, Jose Silva, Norman D Huebert, Seunghun Lee, William Murray, Yin Liang, Keith Demarest
A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5 -fluoro-lactones 3 and 4, which are key intermediates to the C5 -fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50  = 43 nM for SGLT1 and IC50  = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg...
September 19, 2018: Bioorganic & Medicinal Chemistry Letters
E B Ibitoye, I H Lokman, M N M Hezmee, Y M Goh, A B Z Zuki, A A Jimoh, A Danmaigoro, N Pilau Nicholas
Growth hormones (GH) alone does not explain the growth rate in the chicken as growth in an animal is multi-factorial. Normal morphology of the intestinal villus and crypt, with adequate regulation of intestinal nutrient transporters, is essential to a healthy gut. Nutrition plays a significant role in gut health management, but information on the effect of dietary chitin and chitosan on gut morphology, gene expression of nutrient transporter, and serum levels of GH in broiler chickens is scanty. Thus, this study aimed at evaluating the comparative effect of dietary chitin and chitosan from cricket and shrimp on the small intestinal morphology, relative gene expression of intestinal nutrient transporters and serum level of GH in the broiler...
September 27, 2018: Poultry Science
Rosa Castilla-Madrigal, Eva Gil-Iturbe, Neira Sáinz, María J Moreno-Aliaga, María Pilar Lostao
We have previously demonstrated in Caco-2 cells that tumor necrosis factor-α (TNF-α) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na+ -glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF-α from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF-α placed in the basal compartment of Caco-2 cells decreased α-methyl- d-glucose (αMG) and glutamine uptake...
September 24, 2018: Journal of Cellular Physiology
Vasilis Tsimihodimos, Sebastien Filippas-Ntekouan, Moses Elisaf
Sodium Glucose Cotransporters 1 (SGLT1) play important roles in the intestinal absorption of glucose and the renal reabsorption of glucose, especially in patients with uncontrolled diabetes and those receiving SGLT2 inhibitors. As a consequence, the inhibition of SGLT1 transporters may represent an interesting therapeutic option in patients with diabetes. However, genetic models of SGLT1 inactivation indicate that the malfunction of these transporters may have adverse effects on various tissues. In this review, we discuss the available evidence on the beneficial and detrimental effects that the inhibition of SGLT1 transporters might have...
September 18, 2018: European Journal of Pharmacology
Ayelén M Blanco, Cristina Velasco, Juan I Bertucci, José L Soengas, Suraj Unniappan
Nesfatin-1 is an 82 amino acid peptide that has been involved in a wide variety of physiological functions in both mammals and fish. This study aimed to elucidate the role of nesfatin-1 on rainbow trout food intake, and its putative effects on glucose and fatty acid sensing systems. Intracerebroventricular administration of 25 ng/g nesfatin-1 resulted in a significant inhibition of appetite, likely mediated by the activation of central POMC and CART. Nesfatin-1 stimulated the glucosensing machinery (changes in sglt1, g6pase, gsase , and gnat3 mRNA expression) in the hindbrain and hypothalamus...
2018: Frontiers in Endocrinology
Amy C Engevik, Izumi Kaji, Melinda A Engevik, Anne R Meyer, Victoria G Weis, Anna Goldstein, Michael W Hess, Thomas Müller, Hermann Koepsell, Pradeep K Dudeja, Matthew Tyska, Lukas A Huber, Mitchell D Shub, Nadia Ameen, James R Goldenring
BACKGROUND & AIMS: Inactivating mutations in myosin VB (MYO5B) cause microvillus inclusion disease (MVID), but the physiological cause of the diarrhea associated with this disease is unclear. We investigated whether loss of MYO5B results in aberrant expression of apical enterocyte transporters. METHODS: We studied alterations in apical membrane transporters in MYO5B-knockout mice, as well as mice with tamoxifen-inducible, intestine-specific disruption of Myo5b (VilCreERT2 ;Myo5bflox/flox mice) or those not given tamoxifen (controls)...
August 22, 2018: Gastroenterology
Cemal Orhan, Mehmet Tuzcu, Patrick Brice Defo Deeh, Nurhan Sahin, James R Komorowski, Kazim Sahin
In the present study, we investigated the effects of chromium-picolinate (CrPic) and chromium-histidinate (CrHis) on nutrient digestibility and nutrient transporters in laying hens exposed to heat stress (HS). Hens (n = 1800; 16 weeks old) were kept in cages in temperature-controlled rooms at either 22 ± 2 °C for 24 h/day (thermoneutral (TN)) or 34 ± 2 °C for 8 h/day, from 08:00 to 17:00, followed by 22 °C for 16 h (HS) for 12 weeks. Hens reared under both environmental conditions were fed one of three diets: a basal diet and the basal diet supplemented with either 1...
August 21, 2018: Biological Trace Element Research
Timo Rieg, Volker Vallon
Sodium-glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria...
October 2018: Diabetologia
Chiara Ghezzi, Donald D F Loo, Ernest M Wright
The concentration of glucose in plasma is held within narrow limits (4-10 mmol/l), primarily to ensure fuel supply to the brain. Kidneys play a role in glucose homeostasis in the body by ensuring that glucose is not lost in the urine. Three membrane proteins are responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule: sodium-glucose cotransporters SGLT1 and SGLT2, in the apical membrane, and GLUT2, a uniporter in the basolateral membrane. 'Knockout' of these transporters in mice and men results in the excretion of filtered glucose in the urine...
October 2018: Diabetologia
Palanikumar Manoharan, Shanmuga Sundaram, Soudamani Singh, Uma Sundaram
During chronic intestinal inflammation in rabbit intestinal villus cells brush border membrane (BBM) Na-glucose co-transport (SGLT1), but not Na/H exchange (NHE3) is inhibited. The mechanism of inhibition is secondary to a decrease in the number of BBM co-transporters. In the chronic enteritis mucosa, inducible nitric oxide (iNO) and superoxide production are known to be increased and together they produce abundant peroxynitrite (OONO), a potent oxidant. However, whether OONO mediates the SGLT1 and NHE3 changes in intestinal epithelial cells during chronic intestinal inflammation is unknown...
August 19, 2018: Cells
C Yang, J He, B Yu, J Yu, X B Mao, D W Chen, Y L Yin
This study was conducted to investigate the effects of dietary amylose/amylopectin ratio (DAR) on serum and hepatic lipid content, luminal short-chain fatty acid (SCFA) concentrations, and the expression of host genes involved in fat and glucose metabolism in liver and mucosa in growing-finishing pigs. Forty-eight Duroc × Landrace × Large White pigs (49.8 ± 2.8 kg) were randomly allocated to low amylose/amylopectin ratio (LR) and high amylose/amylopectin ratio (HR) groups, each group consisting of six replicates (pen) with four pigs per pen...
August 17, 2018: Journal of Animal Physiology and Animal Nutrition
Peijian He, Abedul Haque, Songbai Lin, Fabio Cominelli, C Chris Yun
Crohn's disease (CD) is a chronic, relapsing, inflammatory disease that is often associated with malnutrition due to inflammation in the small intestine. Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidic acid (LPA). Increasing evidence suggests that ATX is upregulated during inflammation and inhibition of ATX has been effective in attenuating chronic inflammatory conditions, such as arthritis and pulmonary fibrosis. This study is aimed to determine whether inhibition of ATX alleviates CD-associated inflammation and malnutrition by using SAMP1/Fc mice, a model of CD-like ileitis...
August 17, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
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