scholarly journals Live imaging of GLUT2 glucose-dependent trafficking and its inhibition in polarized epithelial cysts

Open Biology ◽  
2014 ◽  
Vol 4 (7) ◽  
pp. 140091 ◽  
Author(s):  
Merav Cohen ◽  
Daniel Kitsberg ◽  
Sabina Tsytkin ◽  
Maria Shulman ◽  
Benjamin Aroeti ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Glucose Transporter ◽  
Critical Role ◽  
Live Imaging ◽  
Glucose Absorption ◽  
Recycling Endosome ◽  
Physiological Importance ◽  
Glucose Levels ◽  
Glucose Reabsorption ◽  
Glucose Exposure

GLUT2 is a facilitative glucose transporter, expressed in polarized epithelial cells of the liver, intestine, kidney and pancreas, where it plays a critical role in glucose homeostasis. Together with SGLT1/2, it mediates glucose absorption in metabolic epithelial tissues, where it can be translocated apically upon high glucose exposure. To track the subcellular localization and dynamics of GLUT2, we created an mCherry–hGLUT2 fusion protein and expressed it in multicellular kidney cysts, a major site of glucose reabsorption. Live imaging of GLUT2 enabled us to avoid the artefactual localization of GLUT2 in fixed cells and to confirm the apical GLUT2 model. Live cell imaging showed a rapid 15 ± 3 min PKC-dependent basal-to-apical translocation of GLUT2 in response to glucose stimulation and a fourfold slower basolateral translocation under starvation. These results mark the physiological importance of responding quickly to rising glucose levels. Importantly, we show that phloretin, an apple polyphenol, inhibits GLUT2 translocation in both directions, suggesting that it exerts its effect by PKC inhibition. Subcellular localization studies demonstrated that GLUT2 is endocytosed through a caveolae-dependent mechanism, and that it is at least partly recovered in Rab11A-positive recycling endosome. Our work illuminates GLUT2 dynamics, providing a platform for drug development for diabetes and hyperglycaemia.

scholarly journals Multifaceted interplay among mediators and regulators of intestinal glucose absorption: potential impacts on diabetes research and treatment

2015 ◽  
Vol 309 (11) ◽  
pp. E887-E899 ◽  
Author(s):  
Leo Ka Yu Chan ◽  
Po Sing Leung
Keyword(s):  
Small Intestine ◽  
Blood Glucose ◽  
Critical Role ◽  
Glucose Absorption ◽  
Therapeutic Interventions ◽  
Diabetes Research ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Patients With Diabetes ◽  
Intestinal Glucose Absorption

Glucose is the prominent molecule that characterizes diabetes and, like the vast majority of nutrients in our diet, it is absorbed and enters the bloodstream directly through the small intestine; hence, small intestine physiology impacts blood glucose levels directly. Accordingly, intestinal regulatory modulators represent a promising avenue through which diabetic blood glucose levels might be moderated clinically. Despite the critical role of small intestine in blood glucose homeostasis, most physiological diabetes research has focused on other organs, such as the pancreas, kidney, and liver. We contend that an improved understanding of intestinal regulatory mediators may be fundamental for the development of first-line preventive and therapeutic interventions in patients with diabetes and diabetes-related diseases. This review summarizes the major important intestinal regulatory mediators, discusses how they influence intestinal glucose absorption, and suggests possible candidates for future diabetes research and the development of antidiabetic therapeutic agents.

scholarly journals PHOSPHATIDYLINOSITOL -3KINASE (PI3K) DI PERBENIHAN ADIPOSIT YANG DIPAJAN GLUKOSA TINGGI DENGAN RETINOL

2018 ◽  
Vol 22 (2) ◽  
pp. 109
Author(s):  
Novi Khila Firani ◽  
Bambang Prijadi
Keyword(s):  
High Glucose ◽  
Glucose Transporter ◽  
Determination Method ◽  
Glucose Transporter 4 ◽  
Phosphatidylinositol 3 Kinase ◽  
Elisa Method ◽  
Glucose Levels ◽  
Glucose Exposure ◽  
The Mean

Retinol is one of the active forms of vitamin A. In the previous study, it was known that retinol level in serum of DM patient waslower than in healthy people, which correlated with an increase of the glucose levels in these patients. The importance of retinol in insulinsignaling mechanisms that play a role in the pathogenesis of DM is still unknown. One of the components that play a role in insulinsignaling on adipocytes is phosphatidylinositol-3 kinase (PI3K), which encourages the translocation of glucose transporter-4 (GLUT4) tothe cell surface. The aim of this study was to know the importance of retinol therapy in the levels of PI3K enzyme on visceral adipocyteculture with high glucose exposure (25 mM) as a model of DM in vitro by determination method. Retinol therapy was given at a doseof 0.1 μM, 1 μM , and 10 μM. Measurement of PI3K level was done by ELISA method. The mean (SD) levels of PI3K enzyme were 1.91(0.27), 0.94 (0.15), 1.98 (0.22), 1.69 (0.81), 2.04 (0.16) ng/mL respectively, for adipocyte cultures exposed to 5mM glucose (as aphysiological condition), 25mM glucose, and 25mM glucose concentration with doses of retinol therapy 0.1 μM, 1 μM and10 μM. Theresults of this study indicated that high glucose exposure (25 mM) decreased the level of PI3K compared with adipocyte’s culture on5 mM glucose exposure. Retinol therapy with a dose of 0.1μM, 1μM and10 μM on adipocyte culture exposed with high glucose couldincrease the levels of PI3K.

Cerebrovascular Complications of Diabetes: SGLT-2 Inhibitors as a Promising Future Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Ruju Vashi ◽  
Vishal Chavda ◽  
Snehal S. Patel
Keyword(s):  
Oxidative Stress ◽  
Glucose Transporter ◽  
Neuronal Degeneration ◽  
High Capacity ◽  
Glucose Levels ◽  
Cerebrovascular Complications ◽  
Glucose Reabsorption ◽  
Decrease Blood Glucose ◽  
Diabetic Individual ◽  
Transport Channels

Abstract: Sodium-Glucose co-transporter inhibitors are a novel class of drugs that are widely used in the treatment of type 2 diabetes mellitus medical management. This class of drugs has a simple mechanism of action by which they decrease blood glucose levels. They prevent the uptake or re-absorption of glucose in the blood by inhibiting the SGLT2 co-transport channels located in the renal proximal convoluted tubule. Since, SGLT2 is the low affinity, high capacity glucose transporter, it allows the co-transport of sodium and glucose through it. SGLT2s are accountable for around 90% of the renal glucose reuptake. Cerebrovascular complications or accidents (CVAs) are the world's leading cause of mortality, resulting in around 6 million deaths annually. Diabetics are prone to develop mitochondrian dysfunction and neurodegeneration due to hyperglycemia and oxidative stress end products. Due to hyperglycemic condition in diabetes, it’s always an elevated risk of cerebrovascular dysfunction due to hyperglycemia as it includes endothelial dysfunction, atherosclerosis, hypercoagulability, oxidative stress, renal reperfusion injury which may lead to neuronal degeneration and cognitive impairment. A diabetic individual is more prone to develop risk factors for transient ischemic attacks than non-diabetic patient. These inhibitors reduce hyperglycemia by blocking renal glucose reabsorption, therefore promoting an increase in renal glucose excretion. This review discusses the potential role of SGLT2 inhibitors in treating CVAs associated with T2DM.

Impaired intestinal and renal glucose transport in PDK-1 hypomorphic mice

2006 ◽  
Vol 291 (5) ◽  
pp. R1533-R1538 ◽  
Author(s):  
Ferruh Artunc ◽  
Rexhep Rexhepaj ◽  
Harald Völkl ◽  
Florian Grahammer ◽  
Christine Remy ◽  
...  
Keyword(s):  
Small Intestine ◽  
Glucose Transport ◽  
Glucose Transporter ◽  
Ussing Chamber ◽  
Glucose Absorption ◽  
Renal Tubules ◽  
Glucose Transporter 1 ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Proximal Tubular

The phosphoinositide-dependent kinase-1 (PDK-1) activates the serum- and glucocorticoid-inducible kinase and protein kinase B isoforms, which, in turn, are known to stimulate the renal and intestinal Na+-dependent glucose transporter 1. The present study has been performed to explore the role of PDK-1 in electrogenic glucose transport in small intestine and proximal renal tubules. To this end, mice expressing ∼20% of PDK-1 ( pdk1 hm) were compared with their wild-type littermates ( pdk1 wt). According to Ussing chamber experiments, electrogenic glucose transport was significantly smaller in the jejunum of pdk1 hm than of pdk1 wt mice. Similarly, proximal tubular electrogenic glucose transport in isolated, perfused renal tubule segments was decreased in pdk1 hm compared with pdk1 wt mice. Intraperitoneal injection of 3 g/kg body wt glucose resulted in a similar increase of plasma glucose concentration in pdk1 hm and in pdk1 wt mice but led to a higher increase of urinary glucose excretion in pdk1 hm mice. In conclusion, reduction of functional PDK-1 leads to impairment of electrogenic intestinal glucose absorption and renal glucose reabsorption. The experiments disclose a novel element of glucose transport regulation in kidney and small intestine.

scholarly journals Canagliflozin increases adenoma burden in female APCMin/+ mice

2021 ◽  
Author(s):  
Justin Korfhage ◽  
Mary E. Skinner ◽  
Jookta Basu ◽  
Joel K. Greenson ◽  
Richard A. Miller ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Immunohistochemical Analysis ◽  
Glucose Absorption ◽  
Serum Glucose ◽  
Tumor Burden ◽  
Mouse Strains ◽  
Distal Intestine ◽  
Glucose Levels ◽  
Glucose Transporter 2 ◽  
Diabetes Drug

SummaryThe diabetes drug canagliflozin acts primarily by inhibiting glucose reuptake by the sodium glucose transporter 2 (SGLT2) in the kidney proximal tubule, thereby lowering serum glucose levels. Canagliflozin also acts on SGLT1, a related transporter responsible for glucose uptake in the small intestine and more distal kidney tubules. Several cancers overexpress SGLT1 and SGLT2, where these transporters fuel tumor metabolism. A recent study by NIA’s Interventions Testing Program (ITP) showed that canagliflozin treatment extends lifespan in male mice. Since cancer is the major cause of death in most mouse strains, including the UM-HET3 strain used by the ITP, this observation suggests that canagliflozin might exert anti-cancer effects in this context. Here, we treated a commonly-used mouse neoplasia model -- the intestinal adenoma-prone APCMin/+ strain -- with canagliflozin, to test the effects of drug treatment on tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect that was most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells themselves. Instead, our results are most consistent with a model whereby canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels consistent with delayed glucose absorption. Our results suggest that canagliflozin exacerbates adenomatosis in the APCMin/+ model via complex, cell-non-autonomous mechanisms, and hint that sex differences in incretin responses may underlie differential effects of this drug on lifespan.

scholarly journals Natural Bioactive Compounds with Small-Bowel Glucose/Antiabsorption and Sugar Digestion Enzymes’ Inhibition Actions: New Strategy to Relieve Hyperglycemia and Diabetes

2019 ◽  
Vol 5 ◽  
pp. 1
Author(s):  
Kais Rtibi ◽  
Slimen Selmi ◽  
Rafik Balti ◽  
Lamjed Marzouki ◽  
Hichem Sebai ◽  
...  
Keyword(s):  
Small Bowel ◽  
Bioactive Compounds ◽  
Glucose Transporter ◽  
Scientific Evidence ◽  
Postprandial Glucose ◽  
Glucose Absorption ◽  
Glucose Levels ◽  
New Strategy

Intestinal glucose absorption/inhibition activity by natural bioactive compounds is considered a new strategy for prevention/treatment of uncontrolled hyperglycemia and diabetes as well as chronic human metabolic disorders. This mini review provides scientific evidence of the contribution of natural bioactive nutrients to inhibit glucose absorption in the small bowel. Many studies were realized on intestinal glucose transport in vitro and on postprandial glucose levels in vivo. In this context, the main designated constituents are (+)-catechin, (-)-epicatechin, (-)-epigallocatechin, epicatechingallate, tannic acid, resveratrol, and chlorogenic acid. The therapeutic approaches are to retard the absorption of glucose by inhibition of carbohydrate-hydrolyzing enzymes such as intestinal glycosidases (α-amylase and α-glycosidase) and the inhibition of intestinal Na+-dependent glucose absorption mediated by reduced expression of glucose transporter (SGLT1). These studies revealed that natural bioactive compounds, as potential candidates, can be designed as natural products for the development of novel functional foods or nutraceuticals to relieve hyperglycemia/diabetes.

scholarly journals Mechanisms of Glucose Absorption in the Small Intestine in Health and Metabolic Diseases and Their Role in Appetite Regulation

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2474
Author(s):  
Lyudmila V. Gromova ◽  
Serguei O. Fetissov ◽  
Andrey A. Gruzdkov
Keyword(s):  
Small Intestine ◽  
Blood Glucose ◽  
Metabolic Diseases ◽  
Glucose Absorption ◽  
Cellular Mechanisms ◽  
Physiological Conditions ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
New Strategy ◽  
Intestinal Glucose Absorption

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.

scholarly journals Cephalic phase insulin secretion is KATP channel independent

2013 ◽  
Vol 218 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Yusuke Seino ◽  
Takashi Miki ◽  
Wakako Fujimoto ◽  
Eun Young Lee ◽  
Yoshihisa Takahashi ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Critical Role ◽  
Pancreas Perfusion ◽  
Glucose Levels ◽  
Cephalic Phase ◽  
Plasma Insulin Levels ◽  
Atropine Methyl Nitrate ◽  
Nutrient Injection

Glucose-induced insulin secretion from pancreatic β-cells critically depends on the activity of ATP-sensitive K+channels (KATPchannel). We previously generated mice lackingKir6.2, the pore subunit of the β-cell KATPchannel (Kir6.2−/−), that show almost no insulin secretion in response to glucosein vitro. In this study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) andKir6.2−/−mice. Underad libitumfeeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar inKir6.2+/+andKir6.2−/−mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly inKir6.2−/−mice but was markedly attenuated compared with that inKir6.2+/+mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent inKir6.2−/−mice. Pretreatment with a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood–brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate inKir6.2−/−mice. Substantial glucose-induced insulin secretion was induced in the pancreas perfusion study ofKir6.2−/−mice only in the presence of carbamylcholine. These results suggest that a KATPchannel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrientsin vivo.

scholarly journals Dual roles for the Drosophila PI 4-kinase Four wheel drive in localizing Rab11 during cytokinesis

2009 ◽  
Vol 187 (6) ◽  
pp. 847-858 ◽  
Author(s):  
Gordon Polevoy ◽  
Ho-Chun Wei ◽  
Raymond Wong ◽  
Zsofia Szentpetery ◽  
Yeun Ju Kim ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Critical Role ◽  
Successful Completion ◽  
Dual Roles ◽  
Recycling Endosome ◽  
Golgi Membranes ◽  
Wheel Drive ◽  
Dividing Cells ◽  
Four Wheel Drive

Successful completion of cytokinesis relies on addition of new membrane, and requires the recycling endosome regulator Rab11, which localizes to the midzone. Despite the critical role of Rab11 in this process, little is known about the formation and composition of Rab11-containing organelles. Here, we identify the phosphatidylinositol (PI) 4-kinase III β Four wheel drive (Fwd) as a key regulator of Rab11 during cytokinesis in Drosophila melanogaster spermatocytes. We show Fwd is required for synthesis of PI 4-phosphate (PI4P) on Golgi membranes and for formation of PI4P-containing secretory organelles that localize to the midzone. Fwd binds and colocalizes with Rab11 on Golgi membranes, and is required for localization of Rab11 in dividing cells. A kinase-dead version of Fwd also binds Rab11 and partially restores cytokinesis to fwd mutant flies. Moreover, activated Rab11 partially suppresses loss of fwd. Our data suggest Fwd plays catalytic and noncatalytic roles in regulating Rab11 during cytokinesis.

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