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.

Canagliflozin Increases Intestinal Adenoma Burden in Female ApcMin/+ Mice

2021 ◽  
Author(s):  
Justin Korfhage ◽  
Mary E Skinner ◽  
Jookta Basu ◽  
Joel K Greenson ◽  
Richard A Miller ◽  
...  
Keyword(s):  
Life Span ◽  
Immunohistochemical Analysis ◽  
Glucose Absorption ◽  
Tumor Burden ◽  
Mouse Strains ◽  
Malignant Neoplasms ◽  
Sexually Dimorphic ◽  
Male Mice ◽  
Distal Intestine ◽  
Diabetes Drug

Abstract The diabetes drug canagliflozin extends life span in male mice. Since malignant neoplasms are the major cause of death in most mouse strains, this observation suggests that canagliflozin might exert anti-neoplastic effects in male mice. Here, we treated a mouse neoplasia model, the adenoma-prone ApcMin/+ strain, with canagliflozin, to test the effects of this drug on intestinal tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect 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. Our results are most consistent with a model where canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels driven by delayed glucose absorption. We hypothesize that canagliflozin exacerbates adenomatosis in the ApcMin/+ model via complex, cell-non-autonomous mechanisms, and that sex differences in GLP-1 responses may in part underlie sexually dimorphic effects of this drug on life span.

scholarly journals Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

2020 ◽  
Author(s):  
Richard A. Miller ◽  
David E. Harrison ◽  
David B. Allison ◽  
Molly Bogue ◽  
Vivian Diaz ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Kidney Diseases ◽  
Rank Test ◽  
Female Mice ◽  
Glucose Levels ◽  
Glucose Transporter 2 ◽  
Log Rank Test ◽  
Wide Range ◽  
Treatment Of Diabetes ◽  
Diabetes Drug

AbstractCanagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.

IGF alters jejunal glucose transporter expression and serum glucose levels in immature rats

2002 ◽  
Vol 283 (6) ◽  
pp. R1450-R1460 ◽  
Author(s):  
Robert H. Lane ◽  
Bohuslav Dvorak ◽  
Nicole K. MacLennan ◽  
Katerina Dvorakova ◽  
Melissa D. Halpern ◽  
...  
Keyword(s):  
Growth Factors ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Serum Glucose ◽  
Mitochondrial Enzymes ◽  
Mrna Levels ◽  
Lower Serum ◽  
Glucose Levels ◽  
Glucose Transporter 2 ◽  
Igf I

Milk-borne insulin-like growth factors (IGFs) enhance nutrient absorption in the immature intestine, which is characterized by low levels of glucose oxidation. We therefore hypothesized that feeding a rat milk substitute (RMS) devoid of growth factors to rat pups would lower serum glucose levels relative to dam-fed control rats and that supplementation of RMS with physiological doses of either IGF-I or IGF-II would normalize serum glucose levels via increased jejunal glucose transporter 2 (GLUT2) and high-affinity Na+-glucose cotransporter (SGLT1) expression. We found lower serum glucose concentrations in RMS-fed pups; in contrast, serum glucose levels in the IGF-supplemented pups were similar to those of dam-fed controls. RT-PCR and laser scanning confocal microscopy similarly demonstrated that IGF supplementation increased expression of jejunal glucose transporters. Further experiments demonstrated that IGF supplementation altered mRNA levels of key mitochondrial enzymes without altering jejunal lactase activity. We conclude that IGF-I and IGF-II supplementation increases serum glucose levels in the immature rat pup fed artificial formula and alters gene expression of the jejunal glucose transporters.

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 Dapagliflozin: A Once-Daily Oral Therapy Sodium-Glucose Cotransporter-2 Inhibitor for the Treatment of Adult Patients with Type 2 Diabetes

2011 ◽  
Vol 3 ◽  
pp. CMT.S6168 ◽  
Author(s):  
Khalid Jadoon ◽  
Iskandar Idris
Keyword(s):  
Adverse Effects ◽  
Glucose Transport ◽  
Transport System ◽  
Glucose Transporter ◽  
Intestinal Transport ◽  
Selective Inhibition ◽  
Genetic Syndromes ◽  
Glucose Levels ◽  
Glucose Transporter 2 ◽  
Glucose Transport System

The induction of glycosuria using phlorizin, a nonselective inhibitor of renal and intestinal transport was well recognised to lower glucose levels and induce calorie loss in animal models of diabetes. Phlorizin and other similar molecules however were not suitable for clinical use due to adverse effects of non selective inhibition of extra-renal glucose transport system. More recent understanding of the physiology of renal glucose transport system and increased knowledge of rare genetic syndromes of renal glycosuria has resulted in the development of drugs that selectively inhibit the Sodium Glucose Transporter-2 (SGLT2). Among the various agents currently being developed within this drug class, dapagliflozin is the most advanced in clinical development. This article discusses the basic physiology of the SGLT2 transporter system, pharmacokinetics and pharmacodynamic information of dapagliflozin, its efficacy in lowering HbA1c and weight as well as its safety and adverse effects profile. This is discussed based on evidence derived from clinical trials involving a spectrum of patients with diabetes, from drug naïve to individuals already on insulin therapy.

Artocarpus lacucha Extract and Oxyresveratrol Inhibit Glucose Transporters in Human Intestinal Caco-2 Cells

Planta Medica ◽  
2021 ◽  
Author(s):  
Matusorn Wongon ◽  
Nanteetip Limpeanchob
Keyword(s):  
Glucose Transport ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Glucose Absorption ◽  
Culture Conditions ◽  
Glucose Transporter 1 ◽  
Glucose Transporter 2 ◽  
Sodium Dependent ◽  
Intestinal Glucose Absorption ◽  
Carbohydrate Digestion

AbstractReduction of intestinal glucose absorption might result from either delayed carbohydrate digestion or blockage of glucose transporters. Previously, oxyresveratrol was shown to inhibit α-glucosidase, but its effect on glucose transporters has not been explored. The present study aimed to assess oxyresveratrol-induced inhibition of the facilitative glucose transporter 2 and the active sodium-dependent glucose transporter 1. An aqueous extract of Artocarpus lacucha, Puag Haad, which is oxyresveratrol-enriched, was also investigated. Glucose transport was measured by uptake into Caco-2 cells through either glucose transporter 2 or sodium-dependent glucose transporter 1 according to the culture conditions. Oxyresveratrol (40 to 800 µM) dose-dependently reduced glucose transport, which appeared to inhibit both glucose transporter 2 and sodium-dependent glucose transporter 1. Puag Haad at similar concentrations also inhibited these transporters but with greater efficacy. Oxyresveratrol and Puag Haad could help reduce postprandial hyperglycemic peaks, which are considered to be most damaging in diabetics.

Proper mTORC1 Activity Is Required for Glucose Sensing and Early Adaptation in Human Pancreatic β Cells

2020 ◽  
Author(s):  
Qicheng Ni ◽  
Jiaxi Song ◽  
Yichen Wang ◽  
Jiajun Sun ◽  
Jing Xie ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Fasting Glucose ◽  
Dynamic Change ◽  
Human Islets ◽  
Glucose Sensing ◽  
Β Cells ◽  
Β Cell ◽  
Strong Negative Correlation ◽  
Glucose Levels ◽  
Glucose Transporter 2

Abstract Context The mechanistic target of rapamycin complex I (mTORC1) is crucial for β-cell identity and function in rodents. However, its possible relevance to the physiopathology of diabetes in humans remains unclear. Objective This work aimed to understand the participation of mTORC1 in human β cells in prediabetes and diabetes. Design We evaluated the PS6 immunofluorescence intensity in islets of pancreatic sections from 12 nondiabetic (ND), 11 impaired fasting glucose (IFG), and 11 glycemic-controlled type 2 diabetic (T2D) individuals. We also assessed the dynamic change of mTORC1 activity in β cells of db/db mice with new-onset diabetes. Results There exists intercellular heterogeneity of mTORC1 activities in human islets. Islet mTORC1 activity was independently and positively correlated with FBG in ND, but not in IFG and T2D. Moreover, we did not detect significant change in mTORC1 activities between T2D and ND. Of note, the islet mTORC1 activities were significantly higher in IFG than in ND. We further stratified IFG individuals according to their islet PS6 levels and found that IFG-PS6high exhibited remarkably higher urocortin3 and glucose transporter 2 expression in their β cells compared to IFG-PS6low. Consistently, we also detected a significant increase in mTORC1 activities in prediabetic db/db mice compared to nondiabetic littermates. Interestingly, mTORC1 activities determined β-cell adaptation or failure in db/db mice: A strong negative correlation was found between islet mTORC1 activities and fasting glucose levels in db/db mice during their diabetes progression. Conclusions Our finding highlights a dynamic islet mTORC1 response in β-cell adaption/failure in human T2D.

Glucagon-like peptide-2 protects against TPN-induced intestinal hexose malabsorption in enterally refed piglets

2006 ◽  
Vol 290 (2) ◽  
pp. G293-G300 ◽  
Author(s):  
J. J. Cottrell ◽  
B. Stoll ◽  
R. K. Buddington ◽  
J. E. Stephens ◽  
L. Cui ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Glucose Transporter ◽  
Glucose Absorption ◽  
Glucose Transporter 1 ◽  
Portal Vein Flow ◽  
Glucose Transporter 2 ◽  
Glucagon Like Peptide ◽  
Portal Veins

Premature infants receiving chronic total parenteral nutrition (TPN) due to feeding intolerance develop intestinal atrophy and reduced nutrient absorption. Although providing the intestinal trophic hormone glucagon-like peptide-2 (GLP-2) during chronic TPN improves intestinal growth and morphology, it is uncertain whether GLP-2 enhances absorptive function. We placed catheters in the carotid artery, jugular and portal veins, duodenum, and a portal vein flow probe in piglets before providing either enteral formula (ENT), TPN or a coinfusion of TPN plus GLP-2 for 6 days. On postoperative day 7, all piglets were fed enterally and digestive functions were evaluated in vivo using dual infusion of enteral (13C) and intravenous (2H) glucose, in vitro by measuring mucosal lactase activity and rates of apical glucose transport, and by assessing the abundances of sodium glucose transporter-1 (SGLT-1) and glucose transporter-2 (GLUT2). Both ENT and GLP-2 pigs had larger intestine weights, longer villi, and higher lactose digestive capacity and in vivo net glucose and galactose absorption compared with TPN alone. These endpoints were similar in ENT and GLP-2 pigs except for a lower intestinal weight and net glucose absorption in GLP-2 compared with ENT pigs. The enhanced hexose absorption in GLP-2 compared with TPN pigs corresponded with higher lactose digestive and apical glucose transport capacities, increased abundance of SGLT-1, but not GLUT-2, and lower intestinal metabolism of [13C]glucose to [13C]lactate. Our findings indicate that GLP-2 treatment during chronic TPN maintains intestinal structure and lactose digestive and hexose absorptive capacities, reduces intestinal hexose metabolism, and may facilitate the transition to enteral feeding in TPN-fed infants.

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