Disease relevance of Phloridzin

• This effect cannot be attributed to the correction of hyperglycemia because phlorizin therapy had no direct influence on the glycogenic pathway [1].
• In normal dogs made hyperglucagonemic by phloridzin pretreatment, insulin and somatostatin suppressed glucagon at rates of 47 +/- 8 and 35 +/- 8%/h (NS), respectively, despite profound hypoglycemia [2].
• Ischemia did, however, reduce the BBM sphingomyelin-to-phosphatidylcholine (SPH/PC) and cholesterol-to-phospholipid ratios and the number of specific high-affinity Na+-dependent phlorizin binding sites (390 +/- 43 vs. 146 +/- 24 pmol/mg; P less than 0.01) without altering the binding dissociation constant (Kd) [3].
• Phlorizin treatment prevented hyperglycemia (61 +/- 2 vs. 145 +/- 7 mg/dl, treated versus nontreated; P < 0.0001) and lowered islet TAG content (32.7 +/- 0.7 vs. 47.8 +/- 2.7 ng/islet, treated versus nontreated; P < 0.0001) and preserved insulin mRNA levels without preventing hypertriglyceridemia [4].
• Association of these changes with beta cell hypertrophy, increased mRNA levels of the transcription factor c-Myc, and their complete normalization by phlorizin treatment suggested a link between chronic hyperglycemia, increased c-Myc expression, and altered beta cell function [5].

Psychiatry related information on Phloridzin

• Phlorizin did not alter DMI (P = 0.39) or measures of feeding behavior, nor were there interactions with infusion type [6].

High impact information on Phloridzin

• To investigate the mechanisms of this abnormality, we measured glucose transport Vmax, the total transporter number, their average intrinsic activity, GLUT4 and GLUT1 contents in skeletal muscle plasma membrane vesicles from basal or insulin-stimulated streptozocin diabetic rats with different duration of diabetes, treated or not with phlorizin [7].
• Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity [8].
• Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9) [9].
• Levels of the HepG2/brain GT protein and mRNA are unaltered by diabetes or phlorizin treatment [10].
• These results suggest that (a) the defect in muscle glycogen synthesis is the major determinant of insulin resistance in diabetic rats; (b) both vanadate and phlorizin treatment normalize meal tolerance and insulin sensitivity in diabetic rats; (c) vanadate treatment specifically reverses the defect in muscle glycogen synthesis in diabetic rats [1].

Chemical compound and disease context of Phloridzin

• Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle [1].
• Correction of hyperglycemia with phloridzin restores the glucagon response to glucose in insulin-deficient dogs: implications for human diabetes [11].
• To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism [12].
• These results suggest that: 1) partial (90%) pancreatectomy in rats causes insulin resistance in the absence of in vitro alterations in IRTK and 2) correction of chronic hyperglycemia with vanadate, but not with phlorizin, is associated with an increased basal activation of the protein tyrosine kinase in liver insulin receptors [13].
• Studies on the depression of gamma-aminobutyric acid potentials by phloridzin in cat dorsal root ganglion cells in vitro [14].

Biological context of Phloridzin

• This postnatal increase in Vmax was paralleled by a similar increase in the number of phlorizin binding sites [15].
• To define the role of hyperglycemia in generation of the insulin resistance, we examined the effect of phlorizin treatment on tissue sensitivity to insulin in partially pancreatectomized rats [16].
• This study provides the first evidence that rat LPH has its major catalytic site at E1750, representing all of the lactase and the majority of the phlorizin hydrolase activity [17].
• Specific blockage of the phlorizin hydrolase site of LPH using 2',4'-dintrophenyl-2-fluoro-2-deoxy-beta-D-glucopyranoside did not reduce PNG hydrolysis [18].
• The expressed transport activity was 96% Na(+)-dependent, saturable (apparent Km = 15 microM) and inhibited by phloridzin (IC50 = 100 microM) [19].

Anatomical context of Phloridzin

• This is consistent with earlier studies on phlorizin binding to the brush border membrane of duodenal biopsy specimens from this patient [20].
• Accumulation of D-glucose within the enterocytes was decreased significantly by 67% and 79% when acarbose (1 mg/mL) or phloridzin (2 mmol/L), respectively, were present in the luminal perfusate [21].
• Radioautography revealed that, in chronic diabetes, specific phlorizin binding extends into the midvillus region of the ileum, whereas in age-matched controls, it is confined to villus tips [22].
• Glucose uptake into isolated vacuoles was inhibited by NH(4)(+), fructose, and phlorizin, indicating that transport is energy-dependent and that both glucose and fructose were taken up by the same carrier [23].
• In one of these, the human carcinoma cell line T84, phlorizin inhibitable uptake of beta-D-Glc-IPM was demonstrated with substrate saturation and an apparent Km of 0.4 mM [24].

Associations of Phloridzin with other chemical compounds

• 20 mM benzyl alcohol also reduced the number of Na+-dependent phlorizin binding sites (418 +/- 65 vs. 117 +/- 46; P less than 0.01) without altering Kd [3].
• BACKGROUND & AIMS: Lactase-phlorizin hydrolase (LPH) is an intestinal microvillus membrane glycoprotein that hydrolyzes lactose and phlorizin [17].
• Poly(A)+ RNA isolated from the intestinal mucosa was injected into oocytes, and the expression of the transporter in the oocyte plasma membrane was assayed by measuring the Na-dependent phlorizin-sensitive uptake of methyl alpha-D-[14C]glucopyranoside (MeGlc) [25].
• The data suggest that a part of the cyclosporin binding domain on the Na(+)-D-glucose cotransporter is identical to the phloretin binding domain of the high affinity phlorizin binding site [26].
• The phlorizin binding properties of luminal membrane vesicles isolated from the LLC-PK1 cells, a continuous epithelial cell line derived from pig kidney, are studied [27].

Gene context of Phloridzin

• In the human colon carcinoma cell line Caco-2, we investigated the effects of a defined polyphenolic apple juice extract (AJE), the major principle flavonoid/dihydrochalkone constituents quercetin and phloretin, and the corresponding prototype glycosides rutin and phlorizin on CYP1A1 expression and activity [28].
• In the phlorizin-treated diabetic rats, myocardial Hsp60 was lower than that of the normal controls [29].
• On the contrary phlorizin, the well-established inhibitor of SGLT1, decreased intrinsic fluorescence by a maximum of 50%, and induced a blue shift of maximum (5 nm) [30].
• To test the above hypotheses we employed phlorizin (as an inhibitor of SGLT1) and N-(n-butyl)-deoxygalactonojirimycin (as an inhibitor of the lactase domain of LPH) in a rat everted-jejunal sac model [31].
• A porcine 17kb genomic fragment was used as probe to map the lactase phlorizin hydrolase (LCT) gene to pig chromosome 15q13 by fluorescence in situ hybridization [32].

Analytical, diagnostic and therapeutic context of Phloridzin

• This enhancing effect of phloridzin treatment was completely abolished by giving an intravenous infusion of glucose for the 5 hr prior to surgery for isolation of the pancreas [11].
• Hybrid receptor protein content, assessed by immunoblotting, was 2.4-fold higher in diabetic rats as compared with control and phlorizin-treated diabetic rats [33].
• Stable mutants resistant to phloridzin were generated and selected within 3 weeks after treatment with 1-methyl-3-nitro-1-nitrosoguanidine [34].
• Unlike phlorizin, T-1095 is absorbed into the circulation via oral administration, is metabolized to the active form, T-1095A, and suppresses the activity of SGLTs in the kidney [35].
• These effects were blunted when hyperglycemia was corrected by phlorizin treatment of diabetic rats or not sustained during euglycemic clamp [36].

References