Insulin mimetic effect of D‐allulose on apolipoprotein A‐I gene

Abstract

Several nutrients modulate the transcriptional activity of the apolipoprotein A-I (apo A-I) gene. To determine the influence of rare sugars on apo A-I expression in hepatic (HepG2) and intestinal derived (Caco-2) cell lines, apo A-I, albumin, and SP1 were quantified with enzyme immunoassay and Western blots while mRNA levels were quantified with real-time polymerase chain reaction. The promoter activity was measured using transient transfection assays with plasmids containing various segments and mutations in the promoter. D-allulose and D-tagatose, increased apo A-I concentration in culture media while D-sorbose and D-allose did not have any measurable effects. D-allulose did not increase apo A-I levels in Caco-2 cells. These changes paralleled the increased mRNA levels and promoter activity. D-allulose-response was mapped at the insulin response core element (IRCE). Mutation of the IRCE decreased the ability of D-allulose and insulin to activate the promoter. Treatment of HepG2 cells, but not Caco-2 cells, with D-alluose and insulin increased SP1 expression relative to control cells. D-allulose augmented the expression and IRCE binding of SP1, an essential transcription factor for the insulin on apo A-I promoter activity. D-allulose can modulate some insulin-responsive genes and may have anti-atherogenic properties, in part due to increasing apo A-I production. Practical applicationsCoronary artery disease (CAD) is the number one cause of mortality in industrialized countries. A risk factor associated with CAD is low high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) concentrations in plasma. Thus, novel therapeutic agents or nutrients that upregulate apo A-I production should be identified. D-allulose and D-tagatose are used as sweeteners and may have favorable effects on insulin resistance and diabetes. This study shows that D-allulose and D-tagatose increases apo A-I production through increased transcription factor SP1-binding to insulin response element of the promoter. These sweeteners modulate some insulin responsive genes, increase the production of apo-A-I, and therefore may have antiatherogenic properties.

Effects of fructose epimerson blood lipid profile: A systematic review and meta-analysis of clinical trials

“…Preclinical studies have suggested that D-allulose and D-tagatose were reported to reduce blood LDL-C or TG level (Kanasaki et al, 2019;Lee et al, 2020;Police et al, 2009b). It was reported in animal or cell experiments that fructose epimer enhanced hepatic lipid metabolism by increasing the production of scavenger receptor class B type 1, proprotein convertase subtilisin/kexin type 9 and apolipoprotein A-I, thereby improving blood lipid homeostasis (Haas et al, 2022;Kanasaki et al, 2020;Kanasaki et al, 2019). However, this antihyperlipidemia effect has not been consistently observed in clinical trials.…”

Sugar or Sweetener?

“…23 A recent revelation that highlights the complexity of this seemingly inert sugar is that it upregulates the transcription of the apolipoprotein A1 (ApoA1) gene through its interaction with the transcription factor Sp1 at the insulin response element of the promoter region of the gene. 24 The latter study in cell cultures suggests that D-allulose may have cardioprotective properties by increasing the de novo synthesis of ApoA1. 25 In addition, because glucose transporter genes harbor the insulin response element in their promoter, D-allulose may lower blood glucose levels by upregulating glucose transporters and enhancing tissue glucose uptake; however, it is not known whether ApoA1 gene overexpression can be observed in experimental animals or humans.…”

“…The revelation that d -allulose is a metabolic substrate for Klebsiella pneumoniae is disconcerting because there is the theoretical possibility that the chronic consumption of d -allulose may cause overgrowth of this intestinal pathogen 23 . A recent revelation that highlights the complexity of this seemingly inert sugar is that it upregulates the transcription of the apolipoprotein A1 (ApoA1) gene through its interaction with the transcription factor Sp1 at the insulin response element of the promoter region of the gene 24 . The latter study in cell cultures suggests that d -allulose may have cardioprotective properties by increasing the de novo synthesis of ApoA1 25 .…”

The Potential Effect of Honey-derived D-Allulose in Counteracting Hyperglycemia by Time and Dose Dependent Manner in Diabetes Mellitus

“…Overall, our result supports another evidence that D-allulose plays a beneficial role not only as a chemical sweetener but also gives pharmacological support as an anti-diabetic, probably through its chemical structure as a mimetic sugar bypassing the pancreatic and insulin functions and through its functional structure as an insulin mimetic and modulator of some insulin-responsive genes. 17 Furthermore, D-allulose possesses antiatherogenic property, 17 a metabolic regulator of glucose and lipid metabolism, 18,19 a regulator of postprandial glucose metabolism 20 and is a regulator of muscular glucose disposal. 21 In addition, administration of 25 g of D-allulose did not change blood lipids, uric acid, or hsCR, making D-allulose an excellent, effective, and safe sugar substitute.…”

“…15 Iida et al further validated the role of acute D-allulose administration in decreasing glycemic responses induced by maltodextrin in normal adults. 16 Conclusively, the potential medicinal role of Dallulose varies from its role as an insulin mimetic and modulator of some insulin-responsive genes, 17 as an anti-atherogenic property, 17 as the metabolic regulator of glucose and lipid metabolism, 18,19 as a regulator of postprandial glucose metabolism 20 and as a regulator of muscular glucose disposal. 21 Considering recent advances, D-allulose may play a beneficial role as a sweetener or sugar substitute as well as a pharmacologic treatment for diabetic conditions.…”