Re-exploring promising α-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack

Ghani, Usman

doi:10.1016/j.ejmech.2015.08.043

Cited by 218 publications

(106 citation statements)

References 166 publications

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“…Were these enzymes to function in the oral cavity, we would expect them to be inhibited by α-glucosidase inhibitors. To test this possibility and to determine whether the activity of these enzymes might contribute to taste responses to disaccharides, we recorded chorda tympani nerve responses of WT (C57BL/6) mice to a series of tastants before treatment, after incubation, and after washout of two different brush border enzyme inhibitors, miglitol and voglibose, applied to the dorsal surface of the tongue (22). Pretreatment and posttreatment washout of the inhibitors had no effect on nerve responses of WT mice to any of the taste stimuli (Fig.…”

Section: Resultsmentioning

confidence: 99%

Taste cell-expressed α-glucosidase enzymes contribute to gustatory responses to disaccharides

Sukumaran

Yee

Iwata

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The primary sweet sensor in mammalian taste cells for sugars and noncaloric sweeteners is the heteromeric combination of type 1 taste receptors 2 and 3 (T1R2+T1R3, encoded by Tas1r2 and Tas1r3 genes). However, in the absence of T1R2+T1R3 (e.g., in Tas1r3 KO mice), animals still respond to sugars, arguing for the presence of T1R-independent detection mechanism(s). Our previous findings that several glucose transporters (GLUTs), sodium glucose cotransporter 1 (SGLT1), and the ATP-gated K + (K ATP ) metabolic sensor are preferentially expressed in the same taste cells with T1R3 provides a potential explanation for the T1R-independent detection of sugars: sweet-responsive taste cells that respond to sugars and sweeteners may contain a T1R-dependent (T1R2+T1R3) sweet-sensing pathway for detecting sugars and noncaloric sweeteners, as well as a T1R-independent (GLUTs, SGLT1, K ATP ) pathway for detecting monosaccharides. However, the T1R-independent pathway would not explain responses to disaccharide and oligomeric sugars, such as sucrose, maltose, and maltotriose, which are not substrates for GLUTs or SGLT1. Using RT-PCR, quantitative PCR, in situ hybridization, and immunohistochemistry, we found that taste cells express multiple α-glycosidases (e.g., amylase and neutral α glucosidase C) and so-called intestinal "brush border" disaccharide-hydrolyzing enzymes (e.g., maltase-glucoamylase and sucrase-isomaltase). Treating the tongue with inhibitors of disaccharidases specifically decreased gustatory nerve responses to disaccharides, but not to monosaccharides or noncaloric sweeteners, indicating that lingual disaccharidases are functional. These taste cell-expressed enzymes may locally break down dietary disaccharides and starch hydrolysis products into monosaccharides that could serve as substrates for the T1R-independent sugar sensing pathways.gustation | sensory transduction | disaccharides | sucrase-isomaltase | maltase-glucoamylase

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Section: Resultsmentioning

confidence: 99%

Taste cell-expressed α-glucosidase enzymes contribute to gustatory responses to disaccharides

Sukumaran

Yee

Iwata

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The locus on chromosome 7q34 contains two independent index variants, mapping into the genes MGAM and MGAM2. MGAM encodes maltase-glucoamylase, another intestinal brush border membrane enzyme involved in carbohydrate digestion that is the target of alpha-glucosidase inhibitors such as acarbose 14, 15 . The protein is 60% homologous to sucrase-isomaltase, with the two enzymes having complementary roles in starch digestion.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of 1,5-anhydroglucitol identifies novel genetic loci linked to glucose metabolism

Maruthur

Loomis

et al. 2017

Sci Rep

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1,5-anhydroglucitol (1,5-AG) is a biomarker of hyperglycemic excursions associated with diabetic complications. Because of its structural similarity to glucose, genetic studies of 1,5-AG can deliver complementary insights into glucose metabolism. We conducted genome-wide association studies of serum 1,5-AG concentrations in 7,550 European ancestry (EA) and 2,030 African American participants (AA) free of diagnosed diabetes from the ARIC Study. Seven loci in/near EFNA1/SLC50A1, MCM6/LCT, SI, MGAM, MGAM2, SLC5A10, and SLC5A1 showed genome-wide significant associations (P < 5 × 10−8) among EA participants, five of which were novel. Six of the seven loci were successfully replicated in 8,790 independent EA individuals, and MCM6/LCT and SLC5A10 were also associated among AA. Most of 1,5-AG-associated index SNPs were not associated with the clinical glycemic markers fasting glucose or the HbA1c, and vice versa. Only the index variant in SLC5A1 showed a significant association with fasting glucose in the expected opposing direction. Products of genes in all 1,5-AG-associated loci have known roles in carbohydrate digestion and enteral or renal glucose transport, suggesting that genetic variants associated with 1,5-AG influence its concentration via effects on glucose metabolism and handling.

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“…The transglycosylation involved in this process was proposed to be catalyzed by an extracellular enzyme, acarviosyl transferase, found in the culture of the acarbose producer [105]. Acarbose has been the subject of interest and excellent reviews have been published, covering various specific aspects on the biochemistry and molecular biology of this compound [106][107][108][109][110][111][112][113][114][115][116][117].…”

Section: Natural Carbapyranosesmentioning

confidence: 99%

Biosynthesis and Biological Activity of Carbasugars

Roscales

Plumet

2016

International Journal of Carbohydrate Chemistry

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The first synthesis of carbasugars, compounds in which the ring oxygen of a monosaccharide had been replaced by a methylene moiety, was described in 1966 by Professor G. E. McCasland's group. Seven years later, the first true natural carbasugar (5a-carba-R-D-galactopyranose) was isolated from a fermentation broth of Streptomyces sp. MA-4145. In the following decades, the chemistry and biology of carbasugars have been extensively studied. Most of these compounds show interesting biological properties, especially enzymatic inhibitory activities, and, in consequence, an important number of analogues have also been prepared in the search for improved biological activities. The aim of this review is to give coverage on the progress made in two important aspects of these compounds: the elucidation of their biosynthesis and the consideration of their biological properties, including the extensively studied carbapyranoses as well as the much less studied carbafuranoses.

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Re-exploring promising α-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack

Cited by 218 publications

References 166 publications

Taste cell-expressed α-glucosidase enzymes contribute to gustatory responses to disaccharides

Taste cell-expressed α-glucosidase enzymes contribute to gustatory responses to disaccharides

Genome-wide association study of 1,5-anhydroglucitol identifies novel genetic loci linked to glucose metabolism

Biosynthesis and Biological Activity of Carbasugars

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