Glycosylated dihydrochalcones as potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitors

Dudash, Joseph; Zhang, Xiaoyan; Zeck, Roxanne E.; Johnson, Sigmond G.; Cox, Geoffrey G.; Conway, Bruce R.; Rybczynski, Philip J.; Demarest, Keith T.

doi:10.1016/j.bmcl.2004.07.082

Cited by 38 publications

(22 citation statements)

References 11 publications

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“…We think that the first option is the best explanation because SGLT2 expression in D14 does not differ from control. In accordance with us, Dudash et al [31] said that in diabetic patients, one mechanism for protection against the adverse effects of high plasma glucose levels is the compensatory increase in urinary glucose excretion. Despite the decrease in SGLT2 activity, the blood glucose is increased 3- to 5-fold showing that this compensatory mechanism is not efficient in reducing blood glucose, at least in the early phase of this model of diabetes.…”

Section: Discussionmentioning

confidence: 85%

Expression and Activity of SGLT2 in Diabetes Induced by Streptozotocin: Relationship with the Lipid Environment

Borghese

Majowicz²,

Ortiz³

et al. 2009

Nephron Physiol

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Background/Aims: Diabetes mellitus may impact on the regulation of renal Na⁺-glucose cotransporter type 2 (SGLT2), however, previous studies have yielded conflicting results on the effects of streptozotocin (STZ)-induced diabetes on SGLT-mediated glucose transport. Methods: Diabetes was induced in male Wistar rats. The studies were performed at 3 (D3), 7 (D7) and 14 (D14) days after a single i.p. injection of STZ. SGLT2 activity was measured using α-¹⁴C-methyl glucose uptake in brush-border vesicles (BBV) from renal cortex, and SGLT2 expression was assessed by immunoblotting. Phospholipids were quantified by a modification of Fiske-Subarow‘s method after being separated by thin-layer chromatography. Results: Glucose uptake was reduced in all groups of diabetic rats. SGLT2 expression decreased in D3 and D7. There was a decrease in sphingomyelin (SM) content and an increase in phosphatidylcholine (PC) content in BBV from D14 versus control, without differences in phosphatidylinositol (PI), phosphatidylserine (PS) and phosphatidylethanolamine (PE). Conclusion: The downregulation of SGLT2 activity during STZ-induced diabetes may be a protective mechanism to control the excess of circulating glucose and could be a consequence of a decrease in SGLT2 expression in D3 and D7, whereas altered activity of SGLT2 in D14 could be a consequence of changes in membrane lipid composition. However, we cannot discard the possibility that the decrease in SGLT2 activity could be due to a covalent modification of the active site of the protein.

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Section: Discussionmentioning

confidence: 85%

Expression and Activity of SGLT2 in Diabetes Induced by Streptozotocin: Relationship with the Lipid Environment

Borghese

Majowicz²,

Ortiz³

et al. 2009

Nephron Physiol

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“…Several pharmaceutical companies focus on this strategy using analogs of phlorizin that are selective for hSGLT2 in comparison to hSGLT1 (62)(63)(64). SGLT2-specific inhibitors are preferred for two reasons.…”

Section: Discussionmentioning

confidence: 99%

Tripeptides of RS1 (RSC1A1) Inhibit a Monosaccharide-dependent Exocytotic Pathway of Na+-d-Glucose Cotransporter SGLT1 with High Affinity

Vernaleken

Veyhl

Gorboulev

et al. 2007

Journal of Biological Chemistry

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؉ -peptide cotransporter PepT1 that is colocated with SGLT1 in small intestinal enterocytes. Using coexpression of SGLT1 and PepT1 in Xenopus oocytes or polarized Caco-2 cells that contain both transporters we demonstrated that the tripeptides were effective when applied to the extracellular compartment. After a 1-h perfusion of intact rat small intestine with QSP, glucose absorption was reduced by 30%. The data indicate that orally applied tripeptides can be used to down-regulate small intestinal glucose absorption, e.g. in diabetes mellitus.

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“…Naringin is a precursor for the synthesis of a food additive, an intensely sweet dihydrochalcone which sweetness equal to sucrose 100-1000 times, saccharin three to five times with no toxicity, no calories or low calories, and hence it can be good for treatment of obesity and diabetes [6]. Flavanone glucoside mixed with alkali directly hydrogenation in high pressure could be converted into dihydrochalcone [7].…”

Section: Introductionmentioning

confidence: 99%

Extraction of naringin from pomelo peels as dihydrochalcone's precursor

Dong-mei

Zhu

Zhong

et al. 2010

J of Separation Science

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A new method for the separation of naringin from pomelo peels was investigated by using ultrasonic-assisted extraction and macroporous resin purification technology. The ultrasonic extraction efficiency was dependent on agent's concentration, ratio of sample and solvent and ultrasonic time. Several parameters of macroporous resin-purified process, including resin selection, initial concentration, concentration of eluted agent and pH, were optimized. The experimental results showed that the naringin content in the mature pomelo peels was 2.20% and purification rate of naringin was 77.26% under optimum conditions of purification. The structure of synthetic naringin dihydrochalcone was determined by a series of spectroscopic methods, such as UV, NMR and MS.

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Glycosylated dihydrochalcones as potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitors

Cited by 38 publications

References 11 publications

Expression and Activity of SGLT2 in Diabetes Induced by Streptozotocin: Relationship with the Lipid Environment

Expression and Activity of SGLT2 in Diabetes Induced by Streptozotocin: Relationship with the Lipid Environment

Tripeptides of RS1 (RSC1A1) Inhibit a Monosaccharide-dependent Exocytotic Pathway of Na+-d-Glucose Cotransporter SGLT1 with High Affinity

Extraction of naringin from pomelo peels as dihydrochalcone's precursor

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