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Rare sugar D-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats
Abstract
A rare sugar, D-psicose has progressively been evaluated as a unique metabolic regulator of glucose and lipid metabolism, and thus represents a promising compound for the treatment of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine the underlying effector organs of D-psicose in lowering blood glucose and abdominal fat by exploiting a T2DM rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Rats were fed 5% D-psicose or 5% D-glucose supplemented in drinking water, and only water in the control for 13 weeks and the protective effects were compared. A non-diabetic Long-Evans Tokushima Otsuka (LETO), fed with water served as a counter control of OLETF. After 13 weeks feeding, D-psicose treatment significantly reduced the increase in body weight and abdominal fat mass. Oral glucose tolerance test (OGTT) showed the reduced blood glucose and insulin levels suggesting the improvement of insulin resistance in OLETF rats. Oil-red-O staining elucidated that D-psicose significantly reduced lipid accumulation in the liver. Immunohistochemical analysis showed D-psicose induced glucokinase translocation from nucleus to cytoplasm of the liver which enhances glucokinase activity and subsequent synthesis of glycogen in the liver. D-psicose also protected the pathological change of the β-cells of pancreatic islets. These data demonstrate that D-psicose controls blood glucose levels by reducing lipotoxicity in liver and by preserving pancreatic β-cell function.
... Since there is no previous study of the short-term effects of allulose consumption in patients with T2D, most available data come from in vitro and animal studies. Hossain et al. studied the effect of 13 weeks [13] and 60 weeks [14] of allulose consumption in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. OLETF rats have a deletion in the gene encoding the cholecystokinin-1 receptor, which results in hyperphagia, obesity, and eventually diabetes mellitus [15]. ...
... OLETF rats have a deletion in the gene encoding the cholecystokinin-1 receptor, which results in hyperphagia, obesity, and eventually diabetes mellitus [15]. Short-term allulose consumption in OLETF rats decreased food intake, body weight and body fat mass and prevented diabetes by preserving pancreatic beta cells, reducing inflammatory cytokines (TNF alpha, IL-6), and decreasing insulin resistance [13,14]. However, our study did not find an antihyperglycemic effect of short-term allulose consumption in patients with T2D. ...
... These divergent results may be explained by the differences between humans and rats, the glycemic status of participants and differences in antidiabetic medications. In short-term allulose OLETF rat studies [13,14], rats were fed allulose in the early stage of life when they still had normal glycemic status, but patients in our study were already diagnosed with T2D. In acute feeding of patients with T2D [9], patients were prescribed various antidiabetic medications in addition to metformin, such as dipeptidyl peptidase-4 inhibitor, sulfonylurea, thiazolidinedione, and sodium-glucose cotransporter-2 inhibitors. ...
Purpose
Allulose is a rare monosaccharide with almost zero calories. There is no study of short-term allulose consumption in patients with type 2 diabetes (T2D). Thus, we aimed to study the effect of allulose consumption for 12 weeks on glucose homeostasis, lipid profile, body composition, incretin levels, and inflammatory markers in patients with T2D.
Methods
A double-blind, randomized, controlled crossover study was conducted on sixteen patients with T2D. Patients were randomly assigned to allulose 7 g twice daily or aspartame 0.03 g twice daily for 12 weeks. After a 2-week washout, patients were crossed over to the other sweetener for an additional 12 weeks. Oral glucose tolerance tests, laboratory measurements, and dual-energy X-ray absorptiometry were conducted before and after each phase.
Results
This study revealed that short-term allulose consumption exerted no significant effect on glucose homeostasis, incretin levels, or body composition but significantly increased MCP-1 levels (259 ± 101 pg/ml at baseline vs. 297 ± 108 pg/mL after 12 weeks of allulose, p = 0.002). High-density lipoprotein cholesterol (HDL-C) significantly decreased from 51 ± 13 mg/dl at baseline to 41 ± 12 mg/dL after 12 weeks of allulose, p < 0.001.
Conclusion
Twelve weeks of allulose consumption had a neutral effect on glucose homeostasis, body composition, and incretin levels. Additionally, it decreased HDL-C levels and increased MCP-1 levels.
Trial registration
This trial was retrospectively registered on the Thai Clinical Trials Registry (TCTR20220516006) on December 5, 2022.
... Due to its chemical nature and readily absorption capacity in the small intestine, it is considered as an ultra-low energy sugar (1.6 kJ/g) (Iida et al., 2010). Moreover, this sugar possesses anti-diabetic potential due to its role as a metabolic regulator of glucose metabolism (Baek et al., 2010;Hossain et al., 2011). After several clinical trials, researchers approved the use of D-psicose as a safe ingredient in the human diet. ...
... These transporters (GLUT2 and GLUT5) are circulated in the intestine and reached other cells and tissues. D-fructose and D-glucose transportation by D-psicose are useful for health benefits, such as reducing body fat, increasing insulin resistance, and producing anti-diabetic properties (Hossain et al., 2011;Iida et al., 2013;Ochiai et al., 2013). During the oral glucose tolerance test (OGTT), D-psicose reduces the postprandial glycaemic response by decreasing glucosidase and amylase activities in the intestine, suspending the digestion of carbohydrates (Matsuo and Izumori, 2006). ...
... D-Psicose possibly helps to avoid high-fat-induced obesity and its related inflammation. Hence, D-psicose is a beneficial food that avoids and protects from obesity and obesity associated inflammation (Hossain et al., 2015b(Hossain et al., , 2011Matsuo et al., 2002a). s0135 15. ...
D-Psicose, a rare sugar is an epimer of D-fructose on the C-3 position and occurs in very minute quantity in nature. It is the substitute for sucrose having 70% of the sweetness of sucrose with zero calories. D-Psicose exhibits unique health and physiological benefits in the field of food, pharmaceutical, and agriculture. It is used against obesity, diabetes, hyperglycemia, hyperlipidemia, inflammatory actions, and glucose tolerance in the body. Due to its scary nature, the chemical synthesis of D-psicose is very difficult, expensive, and laborious. Therefore, its production is currently attained by enzymatic bioconversion, generally ketose-3-epimerase plays an important role from D-fructose to D-psicose. Recently, ketose-3-epimerases from different bacterial strains have been experimentally identified and characterized as well as their crystal structures and mechanism have been anticipated from different strains. However, the research on molecular modification is insufficient, which could improve the enzymatic activities and thermostability via directed evolution and mutagenesis of an enzyme. Herein, an outline of recent advances regarding the biological production and characterization of D-psicose, as well as their
physiological, pharmaceutical, food, and agricultural uses is mentioned in this chapter. Moreover, the comparison of biochemical characteristics of epimerases has been overviewed.
... It was reported that D-allulose intake for 48 weeks did not aggravate renal function in individuals with high levels of low-density lipoprotein cholesterol and deteriorating glucose tolerance [10]. Studies have reported that D-allulose reduces postprandial blood glucose levels by suppressing α-glucosidase [11] and enhancing hepatic glucokinase translocation [12]. Additionally, D-allulose has been reported to show beneficial antidiabetic effects in Otsuka Long-Evans Tokushima Fatty (OLETF) rats [12][13][14]. ...
... Studies have reported that D-allulose reduces postprandial blood glucose levels by suppressing α-glucosidase [11] and enhancing hepatic glucokinase translocation [12]. Additionally, D-allulose has been reported to show beneficial antidiabetic effects in Otsuka Long-Evans Tokushima Fatty (OLETF) rats [12][13][14]. However, the effect of D-allulose on the progression of diabetic complications, including those related to kidney function, has not been determined. ...
... Male LETO rats (n = 6) were used as a negative control. Based on previous studies on the anti-diabetic effect of D-allulose [12][13][14] using OLETF rats, drinking water without D-allulose was administered to the O-C and LETO groups and drinking water containing 3% (w/v) Dallulose was administered to the O-A group for 13 weeks. The dose of D-allulose was set at 3% to correspond to a quantity close to an intake amount in humans based on doses in previous clinical trials [10,17,18] and maximum non-effect level in humans [19]. ...
d -allulose is a rare sugar that has been reported to possess anti-hyperglycemic effects. In the present study, we hypothesized that d -allulose is effective in attenuating the progression of diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of type 2 diabetes mellitus. Drinking water with or without 3% d -allulose was administered to OLETF rats for 13 weeks. Long-Evans Tokushima Otsuka rats that received drinking water without d -allulose were used as non-diabetic control rats. d -allulose significantly attenuated the increase in blood glucose levels and progressive mesangial expansion in the glomerulus, which is regarded as a characteristic of diabetic nephropathy, in OLETF rats. d -allulose also attenuated the significant increases in renal IL-6 and tumor necrosis factor-α mRNA levels in OLETF rats, which is a proinflammatory parameter. Additionally, we showed that d -allulose suppresses mesangial matrix expansion, but its correlation with suppressing renal inflammation in OLETF rats should be investigated further. Collectively, our results support the hypothesis that d -allulose can prevent diabetic nephropathy in rats.
... D-Allulose has also been demonstrated to have several beneficial effects on human health. It has been reported to have anti-obesity [39], postprandial blood glucose levelreducing [40], anti-diabetes [41], and anti-atherosclerosis [42] functions. A schematic diagram of the multiple physiological functions of D-allulose is illustrated in Figure 1. ...
... Prolonged administration of D-allulose-containing syrup has suggested that it can induce the translocation of hepatic glucokinase from the nucleus to the cytoplasm, as it maintains glucose tolerance and insulin sensitivity in rats so that the blood glucose levels are maintained [41,52]. Such effects have reduced metabolic disturbances and cognitive impairments in male Wistar rats [10]. ...
... This improvement in blood glucose control was accompanied by maintenance of the plasma insulin levels and preservation of pancreatic beta cells, as well as a significant reduction in inflammation levels. Hossian et al. investigated the effects of D-allulose on insulin resistance in type 2 diabetic rats, and the results suggest that it protected B islets in the pancreas to improve insulin resistance [41]. D-allulose enhances hepatic HDL-cholesterol uptake via SR-B1 in primary rat hepatocytes [58]. ...
d-allulose has a significant application value as a sugar substitute, not only as a food ingredient and dietary supplement, but also with various physiological functions, such as improving insulin resistance, anti-obesity, and regulating glucolipid metabolism. Over the decades, the physiological functions of d-allulose and the corresponding mechanisms have been studied deeply, and this product has been applied to various foods to enhance food quality and prolong shelf life. In recent years, biotransformation technologies for the production of d-allulose using enzymatic approaches have gained more attention. However, there are few comprehensive reviews on this topic. This review focuses on the recent research advances of d-allulose, including (1) the physiological functions of d-allulose; (2) the major enzyme families used for the biotransformation of d-allulose and their microbial origins; (3) phylogenetic and structural characterization of d-allulose 3-epimerases, and the directed evolution methods for the enzymes; (4) heterologous expression of d-allulose ketose 3-epimerases and biotransformation techniques for d-allulose; and (5) production processes for biotransformation of d-allulose based on the characterized enzymes. Furthermore, the future trends on biosynthesis and applications of d-allulose in food and health industries are discussed and evaluated in this review.
... MetLRE is the first dimeric L-ribulose 3-epimerase identified to exhibit high relative activity toward D-allulose. D-Allulose (alternative name D-psicose) is a rare sugar, and its physiological functions, such as altering the blood glucose level, suppressing fat accumulation, and use as a low-calorie sweetener [1][2][3][4][5][6][7][8][9], have been focused on as a promising functional food ingredient. In Japan, a low-calorie syrup containing D-allulose, Rare Sugar Sweet Ò (Matsutani Chemical Industry Co., Ltd., Hyogo, Japan) [10], is commercially available and its labeling as a functional food was recently approved. ...
... The most structurally similar protein was ketose 3epimerase from Ar. globiformis (previously known as AgDAE, L-ribulose 3-epimerase, PDB code 5ZFS, [32]), with 54% identity, 1. 6 A r.m.s.d. and 45.6 Zscore by Dali search [36,37]. Other similar proteins were L-ribulose 3-epimerase from M. loti (MlLRE, 3VYL, 40%, 1.3 A, 42.5, [33]), D-tagatose 3-epimerase from P. cichorii (PcDTE, 2QUL, 30%, 1.7 A, 37.3, [30]), and D-allulose 3-epimerase from A. tumefaciens (AtDAE, 2HK1, 28%, 1.8 A, 36.8, [17]). ...
... In the structure of Mol-A (Fig. 5C), O4, O5, and O6 of D-fructose were slightly shifted rotating around the C3-C4 axis. O4 forms a hydrogen bond with Glu152, with a distance of 2. 6 A, and O6 interacts with His12 and Ser69, with a distance of 2.8 and 2.9 ...
D‐allulose has potential as a low calorie sweetener which can suppress fat accumulation. Several enzymes capable of D‐allulose production have been isolated, including D‐tagatose 3‐epimerases. Here, we report the isolation of a novel protein from Methylomonas sp. expected to be a putative enzyme based on sequence similarity to ketose 3‐epimerase. The synthesized gene encoding the deduced ketose 3‐epimerase was expressed as a recombinant enzyme in E. coli, and it exhibited the highest enzymatic activity toward L‐ribulose, followed by D‐ribulose and D‐allulose. The X‐ray structure analysis of L‐ribulose 3‐epimerase from Methylomonas sp. (MetLRE) revealed a homodimeric enzyme, the first reported structure of dimeric L‐ribulose 3‐epimerase. The monomeric structure of MetLRE is similar to that of homotetrameric L‐ribulose 3‐epimerases, but the short C‐terminal α‐helix of MetLRE is unique and different from those of known L‐ribulose 3 epimerases. The length of the C‐terminal α‐helix was thought to be involved in tetramerization and increasing stability; however, the addition of residues to MetLRE at the C‐terminus did not lead to tetramer formation. MetLRE is the first dimeric L‐ribulose 3‐epimerase identified to exhibit high relative activity toward D‐allulose.
... Several studies in rats have found that D-allulose harbors anti-obesity and antihyperglycemic activity (Nagata, Kanasaki, Tamaru, & Tanaka, 2015, Ochiai, Onishi, Yamada, Iida, & Matsuo, 2014. One study found that D-allulose improves insulin sensitivity and glucose tolerance in a type 2 diabetes rat model, Otsuka Long-Evans Tokushima Fatty rats (Hossain et al., 2011). Hossain et al. found that 13 weeks of 5% D-allulose supplementation reduced body weight gain and abdominal fat mass. ...
... Furthermore, an oral glucose tolerance test showed reduced blood glucose and insulin, whereas Oilred-O staining showed significantly reduced lipid accumulation in the liver. Histology demonstrated that D-allulose reduced lipotoxicity in the liver and preserved pancreatic β-cell function, contributing to better control of blood glucose levels (Hossain et al., 2011). Glucokinase translocates from the nucleus to the cytoplasm in response to glucose ingestion, and regulates the switch from glucose production to glucose uptake in response to feeding (Chu et al., 2004). ...
... In another study, a randomized, double-blind, placebo-controlled trial in adults assessed the dose-dependent effect of D-allulose supplementation. A total of 144 subjects (77 M and 67 F) with BMI >23 kg/m 2 were divided into three groups: placebo (sucralose), low-dose allulose, or high-dose allulose to compare findings to previous rodent studies (Han et al., 2016, Hossain et al., 2011, Nagata et al., 2015. Measurements of waist circumference, hip circumference, blood pressure, fasting blood glucose, glycosylated hemoglobin, and lipids were conducted at baseline and 12 weeks postsupplementation, finding that D-allulose supplementation groups reported reduced body fat mass, body fat percentage, and subcutaneous fat (Han et al., 2018). ...
The global rise in obesity, type II diabetes, and other metabolic disorders in recent years has been attributed in part to the overconsumption of added sugars. Sugar reduction strategies often rely on synthetic and naturally occurring sweetening compounds to achieve their goals, with popular synthetic sweeteners including saccharin, cyclamate, acesulfame potassium, aspartame, sucralose, neotame, alitame, and advantame. Natural sweeteners can be further partitioned into nutritive, including polyols, rare sugars, honey, maple syrup, and agave, and nonnutritive, which include steviol glycosides and rebaudiosides, luo han guo (monk fruit), and thaumatin. We choose the foods we consume largely on their sensory properties, an area in which these sugar substitutes often fall short. Here, we discuss the most popular synthetic and natural sweeteners, with the goal of providing an understanding of differences in the sensory profiles of these sweeteners versus sucrose, that they are designed to replace, essential for the effectiveness of sugar reduction strategies. In addition, we break down the influence of these sweeteners on metabolism, and present results from a large survey of consumers' opinions on these sweeteners. Consumer interest in clean label foods has driven a move toward natural sweeteners; however, neither natural nor synthetic sweeteners are metabolically inert. Identifying sugar replacements that not only closely imitate the sensory profile of sucrose but also exert advantageous effects on body weight and metabolism is critical in successfully the ultimate goals of reducing added sugar in the average consumer's diet. With so many options for sucrose replacement available, consumer opinion and cost, which vary widely with suagr replacements, will also play a vital role in which sweeteners are successful in widespread adoption.
... Hence, D-allulose has the strong potential for use as a zero-calorie sweet-ener. D-allulose has some beneficial health functions, such as suppression of postprandial blood glucose augmentation Hossain et al., 2011;Iida et al., 2008) and reduction in fat mass accumulation (Han et al., 2016(Han et al., , 2018Ochiai et al., 2014). The former mechanisms were elucidated by the inhibition of α-glucosidase activity in the small intestine (Matsuo and Izumori, 2006) and enhancement of glucokinase translocation in liver cells (Hossain et al., 2011). ...
... D-allulose has some beneficial health functions, such as suppression of postprandial blood glucose augmentation Hossain et al., 2011;Iida et al., 2008) and reduction in fat mass accumulation (Han et al., 2016(Han et al., , 2018Ochiai et al., 2014). The former mechanisms were elucidated by the inhibition of α-glucosidase activity in the small intestine (Matsuo and Izumori, 2006) and enhancement of glucokinase translocation in liver cells (Hossain et al., 2011). Additionally, D-allulose was recently found to be a glucagon-like peptide-1 (GLP-1) releaser that acts via vagal afferents and thereby restricts hyperglycemia and overfeeding (Iwasaki et al., 2018). ...
... D-allulose has been reported to suppress postprandial hyperglycemia Hossain et al., 2011;Iida et al., 2008;Matsuo and Izumori, 2006); therefore, long-term consecutive D-allulose consumption is expected to improve glucose metabolism. In this study, no significant improvements of glucose metabolism (HbA1c and glucose ∆AUC on OGTT) were found in all subjects because half of them were within normal range for glucose metabolism (Table 9(a)(c)). ...
D-allulose is one of the rare sugars with almost zero calories and several health benefits. Previous studies have reported the safety of D-allulose in normal, overweight/obese, and diabetic humans. However, one study reported significant increases in T-Cho and LDL-C after 12 weeks of D-allulose intake; this report was not a randomized controlled trial and these changes were considered to be due to seasonal variations. We, therefore, conducted a randomized, double-blind, placebo-controlled trial in 90 subjects with high LDL-C levels for 48 weeks to clarify the influence of long-term D-allulose consumption on cholesterol metabolism and efficacy. Subjects were randomly divided into 3 groups: high-dose D-allulose (15 g D-allulose/day), low-dose D-allulose (5 g D-allulose/day), and placebo group (0 g D-allulose/day); each subject consumed a daily test beverage for 48 weeks. Clinical examinations were performed every eight weeks, beginning from initial consumption until week 52. No significant increases in T-Cho and LDL-C between test groups were observed, and 48 weeks of D-allulose consumption did not change risk factors for atherosclerotic cardiovascular disease. Furthermore, no clinical problems were recognized for other parameters. Additionally, significant improvements in hepatic enzyme activities, fatty liver score, and glucose metabolism after long-term D-allulose consumption were observed. The results from our study revealed that 1) D-allulose consumption is considered safe for long-term intake up to a year, and 2) D-allulose may be effective for improving hepatic functions and glucose metabolism.
... l -Allulose has been shown to ameliorate herpesvirus-induced stromal keratitis in mice ( Muniruzzaman et al. 2016 ) . Moreover, d -allulose ameliorates hyperglycemia, abdominal obesity, and insulin resistance in Otsuka Long-Evans Tokushima Fatty ( OLETF ) rats ( Hossain et al. 2011 ;Hossain et al. 2012 ) ; increases the plasma concentrations of glucagon-like peptide 1 ( GLP-1 ) and other incretins in rats ( Hayakawa et al. 2018 ;Iwasaki et al. 2018 ) . However, the direct effects of these rare sugars, including d -allulose, on pancreatic β-cell function are unclear. ...
... In the present study, we have shown that ketohexoses are not metabolized and do not induce apoptosis in INS-1 cells, which suggests that ketohexoses do not have toxic effects as a result of by being metabolised in pancreatic β-cells. d -Allulose has been shown to induce the secretion of GLP-1 and to have antidiabetic effects, such as amelioration of the hyperglycemia and fat accumulation of OLETF rats ( Hossain et al. 2011 ;Hossain et al. 2012 ) . In the present study, we have demonstrated that d -allulose does not induce glucotoxic effects, such as suppression of insulin gene expression or apoptosis, in a pancreatic β-cell line. ...
Glucotoxicity, impaired insulin secretion, suppression of insulin gene expression and apoptosis, in pancreatic β-cells caused by chronic hyperglycemia is a key component of the pathogenesis of type 2 diabetes. Recently, it has been reported that rare sugar D-allulose has antihyperglycemic and antihyperlipidemic effects in diabetic rats. However, the direct effects of rare sugars including D-allulose on pancreatic β-cell function are unclear. In this study, we investigated whether chronic exposure to ketohexoses causes glucotoxicity, suppression of insulin gene expression and apoptosis, in INS-1 rat pancreatic insulinoma cells. D-Fructose, D-tagatose, L-allulose, and L-sorbose treatment for 1-week reduced insulin gene expression, whereas D-allulose, D-sorbose, L-fructose, and L-tagatose did not. All ketohexoses were transported into INS-1 cells, but were not metabolized. In addition, the ketohexoses did not induce apoptosis and did not affect glucose metabolism. These results suggest that long-term administration of D-allulose, D-sorbose, L-fructose and L-tagatose does not affect pancreatic β-cell function.
... D-allulose treatment promotes glucose tolerance in humans [6] and rodents including healthy mice [7], high fat diet (HFD)-induced obese (DIO) mice [7] and type-2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats [8]. Regarding the underlying mechanisms, D-allulose inhibits the gut digestive enzymes and D-glucose absorption [9], and activates the glucokinase (GK) regulatory protein in the liver [10] in rodents. ...
... Regarding the underlying mechanisms, D-allulose inhibits the gut digestive enzymes and D-glucose absorption [9], and activates the glucokinase (GK) regulatory protein in the liver [10] in rodents. D-allulose reduces weight in OLETF rats [8], DIO mice [7,11] and in overweight subjects [12]. The weight-reducing effect partly contributes to the glycemic control by D-allulose [7]. ...
D-allulose, a rare sugar, has sweetness with few calories.D-allulose regulates feeding and
glycemia, and ameliorates hyperphagia, obesity and diabetes. All these functions involve the central
nervous system. However, central mechanisms underlying these effects of D-allulose remain unknown.
We recently reported that D-allulose activates the anorexigenic neurons in the hypothalamic arcuate
nucleus (ARC), the neurons that respond to glucagon-like peptide-1 and that express proopiomelanocortin. However, its action on the orexigenic neurons remains unknown. This study investigated
the effects of D-allulose on the ARC neurons implicated in hunger, by measuring cytosolic Ca2+
concentration ([Ca2+]i
) in single neurons. D-allulose depressed the increases in [Ca2+]i
induced by
ghrelin and by low glucose in ARC neurons and inhibited spontaneous oscillatory [Ca2+]i
increases in
neuropeptide Y (NPY) neurons. D-allulose inhibited 10 of 35 (28%) ghrelin-responsive, 18 of 60 (30%)
glucose-sensitive and 3 of 8 (37.5%) NPY neurons in ARC. Intracerebroventricular injection of Dallulose inhibited food intake at 20:00 and 22:00, the early dark phase when hunger is promoted. These
results indicate that D-allulose suppresses hunger-associated feeding and inhibits hunger-promoting
neurons in ARC. These central actions of D-allulose represent the potential of D-allulose to inhibit the
hyperphagia with excessive appetite, thereby counteracting obesity and diabetes.
... D-Allulose activates the glucokinase (GK) regulatory protein that translocates GK from the nucleus to the cytosol in the hepatocytes to activate GK, thereby stimulating glycogen synthesis [4]. Administration of D-Allulose promotes glucose tolerance and insulin action in normal and high fat diet (HFD)-induced obese (DIO) mice [5] and in type 2 diabetic OLETF rats [6]. In humans, successive ingestion of D-Allulose significantly and safely reduces postprandial blood glucose [7]. ...
... D-Allulose reduces fat accumulation by decreasing enzyme activities related to fatty acid synthesis and/or enhancing energy expenditure in rats [8e11]. D-Allulose ameliorates visceral obesity in OLETF rats [6] and DIO mice [5,12]. A human study in overweight subjects showed that D-Allulose significantly reduced fat mass [13]. ...
A rare sugar D-Allulose has sweetness without calorie. Previous studies have shown that D-Allulose improves glucose and energy metabolism and ameliorates obesity. However, underlying mechanisms remain elusive. This study explored the effect of central injection of D-Allulose on feeding behavior in mice. We also examined direct effects of D-Allulose on the neurons in the hypothalamic arcuate nucleus (ARC) that regulate feeding, including the anorexigenic glucagon-like peptide-1 (GLP-1)-responsive neurons and proopiomelanocortin (POMC) neurons. Single neurons were isolated from ARC and cytosolic Ca²⁺ concentration ([Ca²⁺]i) was measured by fura-2 microfluorometry. Administration of D-Allulose at 5.6, 16.7 and 56 mM concentration-dependently increased [Ca²⁺]i in ARC neurons. The [Ca²⁺]i increases took place similarly when the osmolarity of superfusion solution was kept constant. The majority (40%) of the D-Allulose-responsive neurons also responded to GLP-1 with [Ca²⁺]i increases. D-Allulose increased [Ca²⁺]i in 33% of POMC neurons in ARC. D-Allulose potentiated the GLP-1 action to increase [Ca²⁺]i in ARC neurons including POMC neurons. Intracerebroventricular injection of D-Allulose significantly decreased food intake at 1 and 2 h after injection. These results demonstrate that D-Allulose cooperates with glucagon-like peptide-1 and activates the ARC neurons including POMC neurons. Furthermore, central injection of D-Allulose inhibits feeding. These central actions of D-Allulose may underlie the ability of D-Allulose to counteract obesity and diabetes.
... D-Allulose, also known as D-psicose, is a rare, functional sugar formed by the epimerization of D-fructose at the C-3 position [3,4]. D-Allulose has been shown to ameliorate insulin resistance [5][6][7] and glucose tolerance in rodents [8][9][10] and humans [11] and reduce abdominal fat accumulation in rodents [12][13][14] and humans [15,16]. Ten-week-old mice were divided into four groups: sedentary/chow diet group n = 6), sedentary/D-allulose group (A2, n = 6), exercise/chow diet group (E2, n = 6), exercise/D-allulose group (AE2, n = 7). ...
... In the present study, we investigated the effect of D-allulose on the exercise performance of C57BL/6J mice. We, and others, have shown that D-allulose administration improves glucose metabolism and insulin resistance in diet (high-sucrose or high-fat)-induced obese rodents, db/db mice, type 2 diabetes model rats, and humans with borderline diabetes [5][6][7][8][9][10][11]. To our knowledge, the effects of D-allulose on aerobic exercise performance have not been previously reported. ...
d-Allulose, a rare sugar, improves glucose metabolism and has been proposed as a candidate calorie restriction mimetic. This study aimed to investigate the effects of d-allulose on aerobic performance and recovery from exhaustion and compared them with the effects of exercise training. Male C57BL/6J mice were subjected to exercise and allowed to run freely on a wheel. Aerobic performance was evaluated using a treadmill. Glucose metabolism was analyzed by an intraperitoneal glucose tolerance test (ipGTT). Skeletal muscle intracellular signaling was analyzed by Western blotting. Four weeks of daily oral administration of 3% d-allulose increased running distance and shortened recovery time as assessed by an endurance test. d-Allulose administration also increased the maximal aerobic speed (MAS), which was observed following treatment for >3 or 7 days. The improved performance was associated with lower blood lactate levels and increased liver glycogen levels. Although d-allulose did not change the overall glucose levels as determined by ipGTT, it decreased plasma insulin levels, indicating enhanced insulin sensitivity. Finally, d-allulose enhanced the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase and the expression of peroxisome proliferator-activated receptor γ coactivator 1α. Our results indicate that d-allulose administration enhances endurance ability, reduces fatigue, and improves insulin sensitivity similarly to exercise training. d-Allulose administration may be a potential treatment option to alleviate obesity and enhance aerobic exercise performance.
... polymyxa) was immobilized on nanomaterials to produce the L-ribulose with 61.8% conversion rate [260] (entry 36, Table S7). A high-efficiency three-step separation-integrated route was built by combining a D-xylose isomerase, a D-tagatose epimerase, and an invertase to synthesize Dpsicose which shows the ability to enhance D-glucose tolerance and insulin sensitivity in type 2 diabetes [96], with 89% yield and 99.9% purity [240] (entry 37, Table S7). Two mutants, Var8 and IDF10-3, were obtained by the directed evolution of the D-tagatose epimerase and employed in the synthesis of the D-psicose in an enzyme membrane reactor [19] (entry 38, Table S7). ...
... It is still required to engineer function microorganisms and enzymes to enhance their stability, activity, selectivity, and productivity under the mild reaction conditions [227]. There are many routes to enhance robustness of biocatalysts and function microorganism, among them (1) immobilization may possibly be one of the most conventional methods used and studied [79]; (2) the extreme conditions have been used to screen the extremophiles for excavation of novel biochemical pathways and new enzymes [87,250,256,4,205,60,34,179,182,96,216]; (3) the use of enzyme molecular engineering techniques, substrate engineering techniques, like directed evolution [1,84,137,142,186,187,194,202,203,226,251,266,272,200], and DNA shuffling [97,98,148,220] has vastly contributed to the new function of gene cluster or biocatalysts, able to work effectively in experimental conditions greatly different from the "natural" ones, in terms of substrate spectrum, presence of organic solvents, pH, temperature, etc.; (4) the use of regulatory elements [109], such as promoter and ribosome bind site (RBS) [196], to regulate and coordinate the expression of key enzymes which are the key catalyst for the synthesis of target products, and regulation and optimization of metabolic network through gene engineering and protein engineering [247]; (5) using synthetic biology, computational systems biology, and metabolic engineering to design and optimize artificial metabolic network to synthesize high-value chemicals such as omega-3 LCPUFAs [254] and docosahexaenoic acid (DHA) [190] and chiral drug intermediates such as L-Tle [109], cis-(1S,2R)-indandiol [23], and trans-(1S,2R)-indandiol [23]. And we expect that the holistic approach of the methods described in this review will play an ideal and important enabling role in the development of chiral drug intermediates, high value-added chemicals, and chiral pharmaceuticals. ...
The chiral feature is a critical factor for the efficacy and safety of many therapeutic agents. At present, about 57% of marketed drugs are chiral drugs and about 99% of purified natural products are chiral compounds. There has been a tremendous potential of functional microorganisms and biocatalysts derived from them for the bioconversion of synthetic chemicals into drugs with high enantio-, chemo-, and regio-selectivities. Biocatalysis is becoming a key subassembly in the medicinal chemist’s toolbox. In fact, the intermediates of many important therapeutic agents such as sitagliptin, pregabalin, ragaglitazar, paclitaxel, epothilone, abacavir, atorvastatin, rosuvastatin, and omapatrilat have been successfully synthesized via biocatalysis. In this review, various biocatalytic systems that enable to synthesize these chiral drug intermediates are updated and discussed regarding their potential application in the pharmaceutical industry. Further development and increased utilization of biocatalysis for production of drugs with emphasis on green chemistry can be expected.
... D-Allulose is expected to function well as a sweetener for diabetics or individuals needing low-calorie diets, as it possesses sweetness similar to that of sucrose (70%), but has almost zero-calories. Several studies indicate that D-allulose improves glucose metabolism Izumori 2006, 2009;Hossain et al. 2011). Hossain et al. (2011) reported that D-allulose suppressed postprandial serum glucose levels by enhancing glucokinase translocation. ...
... Several studies indicate that D-allulose improves glucose metabolism Izumori 2006, 2009;Hossain et al. 2011). Hossain et al. (2011) reported that D-allulose suppressed postprandial serum glucose levels by enhancing glucokinase translocation. Matsuo and Izumori (2009) reported that D-allulose suppressed a-glucosidase and consequently reduced postprandial glucose levels. ...
d-Allulose, a C-3 epimer of d-fructose, is a rare sugar and a non-caloric sweetener. d-Allulose is reported to have several health benefits, such as suppressing a rise in postprandial glucose levels and preventing fat accumulation in rodents and humans. Additionally, low HDL-cholesterol levels post-d-allulose feeding were observed in humans but it is unclear how d-allulose decreased HDL-cholesterol levels. It is necessary to research the mechanism of HDL-cholesterol reduction by d-allulose ingestion because low HDL-cholesterol levels are known to associate with increased atherosclerosis risk. We therefore investigated the mechanism by which d-allulose lowers HDL-cholesterol using rat’s primary hepatocytes. Sprague Dawley rats were fed an AIN-93G based diet containing 3% d-allulose for 2 weeks. Thereafter, primary hepatocytes were isolated by perfusion of collagenase. We measured the ability of HDL-cholesterol uptake in hepatocytes and the protein levels of scavenger receptor class B type 1 (SR-B1) as a HDL-cholesterol receptor. d-Allulose enhanced hepatocyte uptake of HDL-cholesterol, with a concurrent increase in hepatic SR-B1 protein levels. The results suggest that d-allulose enhances HDL-cholesterol uptake into the liver by increasing SR-B1 expression. It is estimated that HDL-cholesterol levels decreased accordingly. Since SR-B1 overexpression would decrease HDL-cholesterol levels, reportedly preventing atherosclerosis development, d-allulose could be a useful sweetener for atherosclerosis prevention.
... D-allulozun, bu doku ve hücrelerde GLUT2 veya GLUT5'e bağlanarak Dglukozun alımını kısmen inhibe edebileceği düşünülmektedir. D-glukoz ve D-fruktozun alımı üzerine metabolize olmayan D-allulozun baskılayıcı etkisi, insülin direncinin ve vücut adipoz dokusunun artışının engellenmesi gibi önemli biyolojik fonksiyonlarına katkıda bulunmaktadır (12). D-allulozun karbonhidrat veya glukoz metabolizması üzerine bir diğer etkisi karaciğerde glukozun kullanımını arttıran hepatik GK'nin indüklenmesidir. ...
... Tip 2 Diyabet (T2DM), karaciğerde glukoz üretiminin ve glukozun subnormal postprandiyal klirensini içeren hepatik glukoz metabolizmasının bozulması ile ilişkilidir. Bunun nedeni, hepatik glukoz üretiminin baskılanmasının gecikmesi ve glukozun glikojene dönüşümünün bozulmasıdır (12). Glukokinaz translokasyonunun bozulması, hepatik glukoz kullanımının (glikojen depolanması ve glukoliz) baskılanmasına ve diyabetik sıçanlarda hepatik glukoz çıkışının hızlanmasına neden olarak hipergliseminin gelişmesine neden olmaktadır (43). ...
Değişen
yaşam koşulları nedeniyle obezite ve obezite ile ilişkili endokrin
hastalıkların görülme sıklığı artmıştır. Bu hastalıkların önlenmesinde yaşam
tarzı değişikliklerine ek tedavi seçenekleri aranmaya başlamıştır. D-alluloz
fruktozun 3. karbon epimeridir ve doğada nadiren bulunmaktadır. D- alluloz,
güçlü antioksidan etkileri, bağırsak sindirim enzimlerine karşı inhibe edici
aktivitesi, hepatik çekirdekten sitoplazmaya glukokinazın translokasyonu ve
intestinal mukoza yoluyla glukozla rekabetçi transport gibi çeşitli
mekanizmalar yoluyla aktivite göstermektedir. Ayrıca, yağların metabolizması
ile ilgili olarak antihiperlipidemik, antihipertrigliseridemik etkileri de
bulunmaktadır. D-alluloz ile ilgili ratlar üzerinde yapılan toksisite
çalışmalarında herhangi bir yan etkisi gösterilmemiş ve güvenli olarak kabul
edilmiştir. Oral yol ile alınan monosakkaritlerin emilimini azaltması, yağ
asidi oksidasyonunu arttırırken, glukoz oksidasyonunu baskılaması gibi
etkilerinden dolayı obezite ve ilişkili hastalıkların tedavisinde yaşam tarzı
değişikliği ile beraber alternatif bir tedavi yöntemi olarak düşünülebilir.
... Several studies reported that D-allulose decreased body weight and fat mass accumulation in both animals and humans (Han et al., 2016(Han et al., , 2018Ochiai et al., 2014). In addition, D-allulose has been reported to suppress elevation of postprandial blood glucose (Hayashi et al., lulose acts by inhibiting α-glucosidase activity (Matsuo and Izumori, 2006) and increasing glucose uptake to the liver by facilitating glucokinase translocation from the nucleus to the cytoplasm in the liver (Hossain et al., 2011). D-allulose has already been clarified not to cause mutagenesis nor toxicity (Matsuo et al., 2002;Ochiai et al., 2019). ...
... With respect to the effect of D-allulose on indicators of glucose and fat metabolism, HbA1c was significantly increased after 12 weeks of consumption and during follow-up compared to the first day of consumption. While D-allulose was reported to improve postprandial glucose metabolism Hossain et al., 2011;Iida et al., 2008;Matsuo and Izumori, 2006), HbA1c reflects the mean blood glucose over 2-3 months, which is calculated from seven blood glucose extractions (drawn before and 90 min after breakfast, lunch, and dinner, and before bedtime; McCarter et al., 2006). However, no variations were also found in other indicators of fasting glucose metabolism (i.e., glucose and insulin). ...
D-allulose is a rare sugar with an almost zero calorie and is known to suppress postprandial hyperglycemia and fat mass accumulation. Although D-allulose has been reported to be safe in healthy subjects and overweight/obese adults, its safety in borderline diabetes and diabetes patients has not been evaluated. Therefore, we conducted an open trial aimed to investigate the long-term safety of D-allulose in borderline diabetes and type 2 diabetes. Subjects took 5 g of D-allulose with meals three times daily for 12 continuous weeks. The general blood biochemical parameters, hematological parameters, urinary parameters, and anthropometric indicators were measured at 0, 2, 4, 8, and 12 weeks of the consumption periods and 4 weeks after completing consumption. Adverse events were assessed by the principal physician on each examination day. A total of 12 and 6 subjects with borderline and type 2 diabetes, respectively, were analyzed. No serious clinical problems were found in this study, although significant cholesterol variations and the improvements of some indicators of hepatic function were observed. In conclusion, the long-term ingestion of D-allulose is safe in borderline diabetes and type 2 diabetes. D-allulose can potentially suppress postprandial hyperglycemia and fat mass accumulation, and thus might be useful in diabetes.
... One possible reason for the D-allulose-induced weight increase in the liver is the increase in glycogen storage. In fact, D-allulose promotes glucokinase translocation from the nucleus to the cytoplasm, leading to increased glycogen storage in the liver (Toyoda et al., 2010;Hossain et al., 2011), as previously observed for D-tagatose and D-fructose (Lu et al., 2008). In addition to glycogen storage, D-tagatose was reported to induce an increase in the total levels of hepatic lipids, proteins and DNA, as well as a significant increment of liver weight, without any adverse effects . ...
... Relative abdominal adipose tissue weight as well as carcass and body fat percentage were not significantly altered by the D-allulose diet. Anti-obesity effects of D-allulose have been observed only when a high-fat or high-sucrose diet was supplied or when obese animal models are used (Matsuo et al., 2012;Hossain et al., 2011;Ochiai et al., 2013). Nagata et al. (2015Nagata et al. ( , 2018 also reported that a 3% D-allulose-containing starchbased normal diet favorably improved lipid metabolism but did not significantly suppress adipose fat accumulation. ...
Rare sugar D-allulose prevents obesity; however, an excessive and continuous intake of D-allulose may induce weight increases in the liver and kidney without apparent pathological and functional abnormalities. Conversely, there has not been reported about how these parameters will change after cessation of D-allulose intake. In this study, effects of a 10-week D-allulose cessation on liver and kidneys weights and biomarkers were investigated in rats previously fed a D-allulose containing diet for 4 weeks. Wistar rats were fed a control diet (C, n=16) or a 3% D-allulose diet (DA, n=16) for 4 weeks, and then the half of rats in the C and DA subgroups were dissected, while the other half of rats were fed the control diet for 10 weeks (C-C and DA-C, n=8, respectively). At the end of the first 4 weeks period, halves of rats in each diet group were euthanized, and the serum, urine, liver, and kidneys were used for pathological and biochemical analyses. The remaining rats were also similarly treated at the end of latter 10 weeks treatment. At week 4, the relative weights of the liver and kidneys were higher in the DA group than in the C group, but these differences were disappeared by cessation of D-allulose. No abnormal parameters related to liver and kidneys functions were observed in the serum and urine. These findings suggested that D-allulose-induced increases in the liver and kidneys weights could be recovered to the normal levels by D-allulose cessation without accompanying functional and pathological abnormalities.
... Despite its low natural abundance, allulose has attracted much attention because of its strong nutraceutical properties. Allulose provided as a dietary supplement exhibits anti-diabetic properties in rats by reducing plasma glucose, increasing insulin secretion, and protecting the morphology and function of pancreatic islets [2][3][4]. The mechanism underlying allulose's antidiabetic properties is due, in part, to enhanced secretion of glucagon such as peptide-1 (GLP-1) from intestinal epithelial endocrine L cells [5]. ...
Despite numerous studies on the health benefits of the rare sugar allulose, its effects on intestinal mucosal morphology and function are unclear. We therefore first determined its acute effects on the small intestinal transcriptome using DNA microarray analysis following intestinal allulose, fructose and glucose perfusion in rats. Expression levels of about 8-fold more genes were altered by allulose compared to fructose and glucose perfusion, suggesting a much greater impact on the intestinal transcriptome. Subsequent pathway analysis indicated that nutrient transport, metabolism, and digestive system development were markedly upregulated, suggesting allulose may acutely stimulate these functions. We then evaluated whether allulose can restore rat small intestinal structure and function when ingested orally following total parenteral nutrition (TPN). We also monitored allulose effects on blood levels of glucagon-like peptides (GLP) 1 and 2 in TPN rats and normal mice. Expression levels of fatty acid binding and gut barrier proteins were reduced by TPN but rescued by allulose ingestion, and paralleled GLP-2 secretion potentially acting as the mechanism mediating the rescue effect. Thus, allulose can potentially enhance disrupted gut mucosal barriers as it can more extensively modulate the intestinal transcriptome relative to glucose and fructose considered risk factors of metabolic disease.
... Hence, it has gained considerable attention as a healthy sweetener for sugar substitutes [4][5][6][7]. Additionally, D-allulose reduces abdominal fat suppressing the activity of abdominal fat-producing enzymes in the liver [8], does not increase postprandial blood sugar [9], protects islet beta cells in the pancreas [10,11], and improves insulin sensitivity [12][13][14]. D-allulose has been touted as a medicinal sweetener for obese or diabetic patients with numerous high-value functions. ...
D-allulose has received considerable attention as an alternative functional sugar for its zero caloric value with 70% relative sweetness compared to D-sucrose. Despite its strong potential as an alternative sweetener, recent industrial productions rely on a high-cost enzymatic method. Here, we advanced whole-cell conversion at high temperatures using Corynebacterium glutamicum expressing D-allulose 3-epimerase (DAE). By varying the reaction temperature from 25°C to 70°C, D-allulose conversion could reach the reaction equilibrium at high temperatures. The C. glutamicum showed superior reusability of cells at 60°C compared to Escherichia coli. We simplified the cell growth media and whole-cell conversion reaction solution. Clostridium hylemonae DAE (ChDAE) showed the highest thermostability and reusability among various DAE candidates. Finally, the ChDAE expression under the synthetic 2X-cT-T5 promoter could reduce the reaction time by 25%. Our result showed that 120 g/L of D-allulose can be produced from 400 g/L of D-fructose by reusable whole-cell conversion at 55°C in 1.5 h. This study can be highly applicable in industrial economic production.
... d-allulose is non-caloric and the sweetness of this sugar is 70% that of sucrose (Matsuo et al., 2002). Moreover, d-allulose can prevent obesity, hyperglycemia and hyperlipidemia (Iida et al., 2008;Hayashi et al., 2010;Hossain et al., 2011;Hossain et al., 2012) and is therefore a candidate substitute sweetener of regular sugar. The US Food and Drug Administration (FDA) approved d-allulose as "Generally Recognized As Safe" (GRAS) in August 2011 (GRN No 400); hence, the demand for d-allulose is expected to increase. ...
In this report, Shinella zoogloeoides NN6 was discovered to produce two rare sugar producing enzymes, D-allulose 3-epimerase (DAE) and L-rhamnose isomerase (LRhI), when cultured with L-rhamnose as the sole carbon source. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of purified DAE and LRhI revealed that the molecular masses of the monomeric subunits are 37 and 43 kDa, respectively, whereas gel filtration analysis showed that purified DAE and LRhI are 148 and 162 kDa, respectively, indicating that both enzymes form tetramers. The activity of DAE was the highest at 80°C in acetate buffer (pH 6.5) with Co2+, whereas LRhI exhibited maximum activity at 60°C in glycine-NaOH buffer (pH 9.0) with Mn2+. A co-immobilized biocatalyst was constructed using DAE (3.2 U) and LRhI (40 U). Activity profile analysis of this co-immobilized biocatalyst revealed that DAE activity was highest at 80°C in acetate buffer (pH 5.5), whereas the highest activity for LRhI was observed at 55°C in sodium phosphate buffer (pH 7.0). D-Allose was produced from 2% (w/w) D-fructose via D-allulose at 60°C and pH 9.0 in a one-pot reaction, providing a mixture of D-glucose, D-fructose, D-allulose and D-allose at a ratio of 1.3:62.7:23.6:12.4. This is the first report describing one-pot D-allose production using LRhI and DAE expressed in a single microorganism.
... Hepatic insulin resistance may crosstalk with muscle insulin resistance. Although many studies have focused on the effect of D-allulose on the liver in insulin resistance [8,[28][29][30], we did not focus on this aspect in this study. We also used only the soleus muscle for muscle insulin signaling analysis. ...
Background:
d-Allulose is a rare sugar with antiobesity and antidiabetic activities. However, its direct effect on insulin sensitivity and the underlying mechanism involved are unknown.
Objective:
This study aimed to investigate the effect of d-allulose on high-fat diet (HFD)-induced insulin resistance using the hyperinsulinemic-euglycemic (HE)-clamp method and intramuscular signaling analysis.
Methods:
Wistar rats were randomly divided into three dietary groups: chow diet, HFD with 5% cellulose (HFC), and HFD with 5% d-allulose (HFA). After four weeks of feeding, the insulin tolerance test (ITT), intraperitoneal glucose tolerance test (IPGTT), and HE-clamp study were performed. The levels of plasma leptin, adiponectin, and tumor necrosis factor (TNF)-α were measured using the enzyme-linked immunosorbent assay. We analyzed the levels of cell signaling pathway components in the skeletal muscle using Western blotting.
Results:
d-allulose alleviated the increase in HFD-induced body weight and visceral fat and reduced the area under the curve as per ITT and IPGTT. d-Allulose increased the glucose infusion rate in the two-step HE-clamp test. Consistently, the insulin-induced phosphorylation of serine 307 in the insulin receptor substrate-1 and Akt and expression of glucose transporter 4 (Glut-4) in the muscle were higher in the HFA group than HFC group. Furthermore, d-allulose decreased plasma TNF-α concentration and insulin-induced phosphorylation of stress-activated protein kinase/Jun N-terminal kinase in the muscle and inhibited adiponectin secretion in HFD-fed rats.
Conclusions:
d-allulose improved HFD-induced insulin resistance in Wistar rats. The reduction of the proinflammatory cytokine production, amelioration of adiponectin secretion, and increase in insulin signaling and Glut-4 expression in the muscle contributed to this effect.
... 208 Several mechanisms other than the reduction of body weight or abdominal fat have been reported to 209 explain the potential benefits of D-allulose in obesity and type 2 diabetes [39]. In liver cells, D-allulose 210 promotes glucokinase translocation from the nucleus to the cytoplasm, resulting in glucose utilization 211 for glycogen synthesis and suppression of D-glucose output [21,22]. In the intestine, D-allulose 212 suppresses the uptake of D-glucose by intestinal epithelial cells [40]. ...
d-Allulose, a C-3 epimer of d-fructose, is a rare sugar that has no calories. Although d-allulose has been reported to have several health benefits, such as anti-obesity and anti-diabetic effects, there have been no reports evaluating the effects of d-allulose on insulin resistance using a hyperinsulinemic-euglycemic clamp (HE-clamp). Therefore, we investigated the effects of d-allulose on a high-sucrose diet (HSD)-induced insulin resistance model. Wistar rats were randomly divided into three dietary groups: HSD containing 5% cellulose (HSC), 5% d-allulose (HSA), and a commercial diet. The insulin tolerance test (ITT) and HE-clamp were performed after administration of the diets for 4 and 7 weeks. After 7 weeks, the muscle and adipose tissues of rats were obtained to analyze Akt signaling via western blotting, and plasma adipocytokine levels were measured. ITT revealed that d-allulose ameliorated systemic insulin resistance. Furthermore, the results of the 2-step HE-clamp procedure indicated that d-allulose reversed systemic and muscular insulin resistance. d-Allulose reversed the insulin-induced suppression of Akt phosphorylation in the soleus muscle and epididymal fat tissues and reduced plasma TNF-α levels. This study is the first to show that d-allulose improves systemic and muscle insulin sensitivity in conscious rats.
... Rare sugars are defined by the International Society of Rare Sugars as "monosaccharides and their derivatives that exist in nature in limited quantities." Recent studies have shown that certain rare sugars, such as d-allulose and d-allose, have pharmacologically beneficial functions and may be used as low-calorie sweeteners (Matsuo et al. 2002;Iida et al. 2010), functional food additives (Sun et al. 2007;Shintani et al. 2017), and pharmaceuticals (Murata et al. 2003;Sui et al. 2005;Takata et al. 2005;Suna et al. 2007;Afach et al. 2008;Hossain et al. 2011Hossain et al. , 2012. They may also be used as precursors to non-natural compounds that act as antiviral agents (Mathé and Gosselin 2006). ...
We found that l-gulose, a rare sugar, was produced from d-sorbitol efficiently, using a wheat-bran culture extract of the fungus Penicillium sp. KU-1 isolated from soil. The culture extract showed enzyme activity for the oxidation of d-sorbitol to produce l-gulose; a high production yield of approximately 94% was achieved.
... D-Allulose possessed greater solubility (Fukada et al., 2010) as well as higher anti oxidative activity, which remains over a long time storage (Sun, Hayakawa, & Izumori, 2004;Sun, Hayakawa, Ogawa, & Izumori, 2005;Sun, Hayakawa, Puangmanee, & Izumori, 2006). It also demonstrated the therapeutic and hypoglycemic characteristics on type 2 diabetes (Hossain et al., 2011;Matsuo & Izumori, 2006;Toyoda et al., 2010). D-Allulose have some effects on obesity (Chung et al., 2012;Iida et al., 2013;Nagata, Kanasaki, Tamaru, & Tanaka, 2015;Yagi & Matsuo, 2009) and it can also be used as antihyperlipidemic agent (Matsuo, Suzuki, Hashiguchi, & Izumori, 2002;Ochiai, Onishi, Yamada, Iida, & Matsuo, 2014). ...
Presently, because of the extraordinary roles and potential applications, rare sugars turn into a focus point for countless researchers in the field of carbohydrates. L-ribose and L-ribulose are rare sugars and isomers of each other. This aldo and ketopentose are expensive but can be utilized as an antecedent for the manufacturing of various rare sugars and L-nucleoside analogue. The bioconversion approach turns into an excellent alternative method to L-ribulose and L-ribose production, as compared to the complex and lengthy chemical methods. The basic purpose of this research was to describe the importance of rare sugars in various fields and their easy production by using enzymatic methods. L-Ribose isomerase (L-RI) is an enzyme discovered by Tsuyoshi Shimonishi and Ken Izumori in 1996 from Acinetobacter sp. strain DL-28. L-RI structure was cupin-type-β-barrel shaped with a catalytic site between two β-sheets surrounded by metal ions. The crystal structures of the L-RI showed that it contains a homotetramer structure. Current review have concentrated on the sources, characteristics, applications, conclusions and future prospects including the potentials of L-ribose isomerase for the commercial production of L-ribose and L-ribulose. The MmL-RIse and CrL-RIse have the potential to produce the L-ribulose up to 32 % and 31%, respectively. The CrL-RIse is highly stable as compared to other L-RIs. The results explained that the L-RIs have great potential in the production of rare sugars especially, L-ribose and L-ribulose, while the immobilization technique can enhance its functionality and properties. The present study precises the applications of L-RIs acquired from various sources for L-ribose and L-ribulose production.
... D-allulose has potential to help diabetes patients and obese people by its health benefits and its feature of producing no calories with sweetness. Many previous studies have demonstrated that D-allulose inhibits blood glucose elevation after meals Iida et al., 2008) by the suppression of α-glucosidase activity in the gut (Matsuo and location in the liver (Hossain et al., 2011). Long-term D-allulose consumption improves glucose metabolism in patients with borderline diabetes (Tanaka et al., 2020). ...
D-allulose is a non-caloric natural sugar with health benefits. A few clinical trials with continuous D-allulose intake have been reported; one indicated significant increase in low-density lipoprotein cholesterol (LDL-C) levels, though the study was not a randomized controlled trial. D-allulose is predicted to be widely used in the near future by various people; therefore, the influence of D-allulose on those who have high risk for LDL-C elevation needs to be determined. Here, the effects of D-allulose on LDL-C levels in patients with hypercholesterolemia under statin therapy were investigated in a randomized controlled trial. Twenty subjects were randomly assigned to two groups: 15 g D-allulose/day or 15 g erythritol/day (placebo); each subject consumed a daily test substance for 48 weeks. Clinical examinations were performed every eight weeks, from initial consumption until week 52. No significant increase in LDL-C was observed, although significant decrease was observed in high-density lipoprotein cholesterol (HDL-C) in the D-allulose group. HDL-C values stayed within the standard ranges during the consumption period, and the mechanism was reported to be anti-atherosclerotic. In terms of risk assessment, D-allulose did not affect all risk factors that were measured for atherosclerotic cardiovascular disease. Taken together, these results suggested that long-term D-allulose consumption did not affect LDL-C values and atherosclerotic cardiovascular disease risk in patients with hypercholesterolemia under statin therapy.
... In comparison with D-fructose and D-glucose, D-allulose has a much stronger antioxidative activity that persists over a long period of storage [43][44][45][46], and is highly soluble [47]. D-allulose showed hypoglycemic properties and therapeutic effects on type 2 diabetes [48][49][50][51][52][53][54][55][56][57]. It also has antiobesity [54,55,58,59] and antihyperlipidemic effects [42,60]. ...
Rare sugars are monosaccharides with a limited availability in the nature and almost unknown biological functions. The use of industrial enzymatic and microbial processes greatly reduced their production costs, making research on these molecules more accessible. Since then, the number of studies on their medical/clinical applications grew and rare sugars emerged as potential candidates to replace conventional sugars in human nutrition thanks to their beneficial health effects. More recently, the potential use of rare sugars in agriculture was also highlighted. However, overviews and critical evaluations on this topic are missing. This review aims to provide the current knowledge about the effects of rare sugars on the organisms of the farming ecosystem, with an emphasis on their mode of action and practical use as an innovative tool for sustainable agriculture. Some rare sugars can impact the plant growth and immune responses by affecting metabolic homeostasis and the hormonal signaling pathways. These properties could be used for the development of new herbicides, plant growth regulators and resistance inducers. Other rare sugars also showed antinutritional properties on some phytopathogens and biocidal activity against some plant pests, highlighting their promising potential for the development of new sustainable pesticides. Their low risk for human health also makes them safe and ecofriendly alternatives to agrochemicals.
... D-allulose is a C-3 epimer of D-fructose having 70% sweetness and 0.3% energy relative to sucrose (Matsuo et al., 2001). Some of the notable physiological properties of D-allulose are: (1) anti-hyperglycemic effects (Hossain et al., 2011(Hossain et al., , 2015, (2) antihyperlipidemic effects (Matsuo et al., 2001;Afach et al., 2008), (3) anti-inflammatory effects (Oh, 2007), (4) neuroprotective effects (Takata et al., 2005), (5) reactive oxygen species (ROS) scavenging activity scavenging activity (Suna et al., 2007). Besides its therapeutic potential, D-allulose is also used as food flavor and processing since it reduces the oxidation process greatly (Sun et al., 2004). ...
D-allulose, which is one of the important rare sugars, has gained significant attention in the food and pharmaceutical industries as a potential alternative to sucrose and fructose. Enzymes belonging to the D-tagatose 3-epimerase (DTEase) family can reversibly catalyze the epimerization of D-fructose at the C3 position and convert it into D-allulose by a good number of naturally occurring microorganisms. However, microbial synthesis of D-allulose is still at its immature stage in the industrial arena, mostly due to the preference of slightly acidic conditions for Izumoring reactions. Discovery of novel DTEase that works at acidic conditions is highly preferred for industrial applications. In this study, a novel DTEase, DTE-CM, capable of catalyzing D-fructose into D-allulose was applications. In this study, a novel DTEase, DTE-CM, capable of catalyzing D-fructose into D-allulose was DTE-CM on D-fructose was found to be remarkably influenced and modulated by the type of metal ions (co-factors). The DTE-CM on D-fructose was found to be remarkably influenced and modulated by the type of metal ions (co-factors). The 50°C from 0.5 to 3.5 h at a concentration of 0.1 mM. The enzyme exhibited its maximum catalytic activity on D-fructose at pH 6.0 and 50°C from 0.5 to 3.5 h at a concentration of 0.1 mM. The enzyme exhibited its maximum catalytic activity on -fructose at pH 6.0 and 50°C with a K
cat
/K
m
value of 45 mM-1min-1. The 500 g/L D-fructose, which corresponded to 30% conversion rate. With these interesting catalytic properties, this enzyme could be a promising candidate for industrial biocatalytic applications.
... D-Allulose (previously called D-psicose or systematically called D-ribo-2-hexulose) (Supplementary Fig. 1) is the most wellknown rare sugar. D-Allulose is an epimer at the carbon 3 position of D-fructose ( Supplementary Fig. 1) and has antihyperlipidemic and antihyperglycemic effects that decrease adipose tissue mass in animals and humans, providing a potential use as a zerocalorie functional sweetener [4][5][6][7][8][9][10] . D-Allulose and D-allose, a C-3 epimer of D-glucose ( Supplementary Fig. 1), also have an antiaging effect as shown through lifespan studies of the nematode Caenorhabditis elegans, a model organism for longevity research 11,12 . ...
The rare sugar d-tagatose is a safe natural product used as a commercial food ingredient. Here, we show that d-tagatose controls a wide range of plant diseases and focus on downy mildews to analyze its mode of action. It likely acts directly on the pathogen, rather than as a plant defense activator. Synthesis of mannan and related products of d-mannose metabolism are essential for development of fungi and oomycetes; d-tagatose inhibits the first step of mannose metabolism, the phosphorylation of d-fructose to d-fructose 6-phosphate by fructokinase, and also produces d-tagatose 6-phosphate. d-Tagatose 6-phosphate sequentially inhibits phosphomannose isomerase, causing a reduction in d-glucose 6-phosphate and d-fructose 6-phosphate, common substrates for glycolysis, and in d-mannose 6-phosphate, needed to synthesize mannan and related products. These chain-inhibitory effects on metabolic steps are significant enough to block initial infection and structural development needed for reproduction such as conidiophore and conidiospore formation of downy mildew. Mochizuki, Fukumoto, Ohara, et al. study the protective role of the rare sugar d-tagatose against plant disease. They focus on its effects against the downy mildews and delineate the metabolic pathway that blocks the initial infection. Their work paves the way for the development of safe fungicidal agrochemicals using natural products.
... This enables the liberated and activated glucokinase to translocate from the nucleus to the cytosol, where it can increase hepatic glucose uptake, promote glycogen synthesis, suppress hepatic glucose output, and reduce plasma glucose levels [89,90]. Support for this hypothesis is provided from animal studies where rats treated with allulose or tagatose had increased hepatic glycogen content over time [40,42,92]. ...
Aims
To synthesize the evidence of the effect of small doses (<30-g/meal) of fructose and its epimers (allulose, tagatose, and sorbose) on the postprandial glucose and insulin response to carbohydrate-containing meals.
Methods
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through to April 9, 2019. We included randomized (RCTs) and non-randomized acute, single-meal, controlled feeding trials that added <30-g of fructose or its epimers either prior to or with a carbohydrate-containing meal compared with the same meal alone. Outcomes included the incremental area under the curve (iAUC) for glucose and insulin, the Matsuda Insulin Sensitivity Index, and the Early Insulin Secretion Index. Data were expressed as ratio of means (RoM) with 95% CIs and pooled using the inverse variance method. The overall certainty of the evidence was evaluated using GRADE.
Results
Forty trial comparisons (n=400) were included (none for sorbose). Allulose significantly reduced the postprandial iAUC glucose response by 10% (0.90 [0.84 to 0.96], P<0.01). Tagatose significantly reduced the postprandial iAUC insulin response by 25% (0.75 [0.62 to 0.91], P<0.01) and showed a non-significant 3% reduction in the postprandial iAUC glucose response (0.97 [0.94 to 1.00], P=0.07). There was no effect of fructose on any outcome. The certainty of the evidence was graded as low to moderate for fructose, moderate for allulose, and low for tagatose.
Conclusions
Small doses of allulose and tagatose, but not fructose, lead to modest improvements on postprandial glucose and insulin regulation. There is a need for long-term RCTs to confirm the sustainability of these improvements.
... D-Allulose exhibits almost zero calories with a low degree of energy density (Matsuo et al., 2002). D-Allulose can't raise the blood sugar levels in diabetic patients and hence has been used to be a unique metabolic regulator of fat and glucose metabolism Izumori, 2006, 2009;Hossain et al., 2011;Iida et al., 2013). Besides, D-allulose has also demonstrated a variety of activities, such as inhibitory activity toward intestinal digestive enzymes (Maeng et al., 2019), antioxidant enhancement (Sun et al., 2006), competitive transport through the intestinal mucosa with glucose (Kishida et al., 2019), enhancing glucokinase translocation of from the hepatic nucleus to cytoplasm , strong anti-hyperlipidemic and anti-hyperglycemic effects (Hossain et al., 2015b), anti-inflammatory actions on adipocytes (Hossain et al., 2015a), preventing obesity and type 2 diabetes mellitus (Hossain et al., 2015b), and inhibiting trichomonad development (Harada et al., 2012). ...
Rare sugar D-allulose as a substitute sweetener is produced through the isomerization of D-fructose by D-tagatose 3-epimerases (DTEases) or D-allulose 3-epimerases (DAEases). D-Allulose is a kind of low energy monosaccharide sugar naturally existing in some fruits in very small quantities. D-Allulose not only possesses high value as a food ingredient and dietary supplement, but also exhibits a variety of physiological functions serving as improving insulin resistance, antioxidant enhancement, and hypoglycemic controls, and so forth. Thus, D-allulose has an important development value as an alternative to high-energy sugars. This review provided a systematic analysis of D-allulose characters, application, enzymatic characteristics and molecular modification, engineered strain construction, and processing technologies. The existing problems and its proposed solutions for D-allulose production are also discussed. More importantly, a green and recycling process technology for D-allulose production is proposed for low waste formation, low energy consumption, and high sugar yield.
... D-allulose has 70% of the sweetness of sucrose, which means it is viewed as a potential alternative sweetener [6,7]. Interestingly, D-allulose does not increase blood sugar levels, has minimal calorific value in vivo [8,9], and has been shown to have beneficial physiological effects, which include improved glucose tolerance, increased insulin sensitivity, and reduced body weight gain [10][11][12][13][14]. The US Food and Drug Administration (FDA) has designated D-allulose as 'generally regarded as safe' (GRAS) for use as a food ingredient, but initially stipulated that amounts of D-allulose added be included in total and added sugar contents on product nutritional labels. ...
D-allulose, a C-3 epimer of D-fructose, is a rare monosaccharide used as a food ingredient or a sweetener. In the present study, the in vitro metabolic stability of D-allulose was examined in biorelevant media, that is, simulated gastric fluid (SGF) and fasted state simulated intestinal fluid (FaSSIF) containing digestive enzymes, and in cryopreserved human and rat hepatocytes. The hepatocyte metabolic stabilities of D-allulose were also investigated and compared with those of fructose and erythritol (a sugar-alcohol with no calorific value). D-allulose was highly stable in SGF (97.8% remained after 60 min) and in FaSSIF (101.3% remained after 240 min), indicating it is neither pH-labile nor degraded in the gastrointestinal tract. D-allulose also exhibited high levels of stability in human and rat hepatocytes (94.5–96.8% remained after 240 min), whereas fructose was rapidly metabolized (43.1–52.6% remained), which suggested these two epimers are metabolized in completely different ways in the liver. The effects of D-allulose on glucose and fructose levels were negligible in hepatocytes. Erythritol was stable in human and rat hepatocytes (102.1–102.9% remained after 240 min). Intravenous pharmacokinetic studies in rats showed D-allulose was eliminated with a mean half-life of 72.2 min and a systemic clearance of 15.8 mL/min/kg. Taken together, our results indicate that D-allulose is not metabolized in the liver, and thus, unlikely to contribute to hepatic energy production.
... Oral administration of D-allulose will induce GLP-1 release and activate vagal afferent signaling, resulting in reduce in food intake and promotion glucose tolerance in healthy and obese diabetic (Iwasaki et al., 2018). It has various specific nutritional and biological functions, such as protecting pancreas beta-islets (Hossain et al., 2012), improving insulin sensitivity and glucose tolerance (Hossain et al., 2011), reducing intra-abdominal fat accumulation (Matsuo & Izumori, 2009), scavenging reactive oxygen species activity (Murata et al., 2003), neuroprotective effects on 6hydroxydopamine-induced apoptosis (Takata et al., 2005), and lowering abdominal fat accumulation (Matsuo et al., 2001). Enzymatic transformation of D-fructose into D-allulose has been achieved by using D-allulose 3-epimerase. ...
Jujube juice has been used as ingredient in a range of foods and dietary supplements. In this study, an enzyme transformation and fermentation coupling technology was applied to increase the nutritional value of concentrated/extracted Jinsi jujube juice. Two enzymes, D‐glucose isomerase (GI) and D‐allulose 3‐epimerase (DAE), were employed to convert the glucose and fructose to a low‐calorie sweeter D‐allulose with a concentration of 110 g/L in jujube juice. Furthermore, the mixed cultures of Pediococcus pentosaceus PC‐5 and Lactobacillus plantarum M were employed to increase the content of nutrition components related to bioactivities and flavor volatiles in jujube juice. Accordingly, this fermentation accumulated 100 mg/L gamma‐aminobutyric acid (GABA), which has neurotransmission, hypotension, diuretic, and tranquilizer effects, and increased the content of branched‐chain amino acids (BCAAs) and many free amino acids (Asp, Glu, Gly, and Ala) at different level. The fermentation not only maintained the concentration of native functional components such as cyclic adenosine monophosphate (cAMP) and minerals, but also increased the content of iron (Fe2+) and zinc (Zn2+), which have blood and eyesight tonic function. The value‐added jujube juice might serve as a low‐calorie and probiotic functional beverage and show high application potential in food industry. An enzyme transformation and fermentation coupling technology was applied to increase the nutritional value of concentrated/extracted Jinsi jujube juice. The value‐added jujube juice might serve as a low‐calorie and probiotic functional beverage and show high application potential in food industry.
D-Allulose has many health-benefiting properties and therefore sustainably applied in food, pharmaceutical, and nutrition industries. The aldol reaction based route is a very promising alternative to Izumoring strategy in D-allulose production. Remarkable studies reported in the past cannot get rid of by-product formation and costly purified enzyme usage. In the present study, we explored the glycerol assimilation by modularly assembling the D-allulose synthetic cascade in Escherichia coli envelop. We achieved an efficient whole-cell catalyst that produces only D-allulose from cheap glycerol feedstock, eliminating the involvement of purified enzymes. Detailed process optimization improved the D-allulose titer by 1500.00%. Finally, the production was validated in 3-L scale using a 5-L fermenter, and 5.67 g/L D-allulose was produced with a molar yield of 31.43%. This article is protected by copyright. All rights reserved.
Scope:
D-allulose is a low-calorie rare sugar. It has been reported that D-allulose supplementation significantly inhibits diet-induced hepatic fat accumulation. However, the underlying molecular mechanisms remain unclear. This study elucidated the mechanism underlying the suppressive effect of D-allulose on hepatic fat accumulation in terms of miRNA regulation.
Methods and results:
Male C57BL/6 mice were divided into three experimental groups-normal diet and distilled water (CC group), high-fat diet (HFD) and distilled water (HC group), and HFD and 5% D-allulose water (HA group)-and fed the respective diets for eight weeks. Weight gain was significantly lower in the HA group than that in the HC group, although the caloric intake was the same in both. Histological analysis of liver tissues revealed excessive lipid accumulation in the HC group; this was greatly attenuated in the HA group. Real-time PCR and western blot analyses demonstrated that, compared to the HC group, the HA group exhibited decreased hepatic PPARγ and CD36 expression. Hepatic miR-130 expression levels were higher in the HA group than those in the CC and HC groups.
Conclusions:
These results indicate that miRNA changes associated with PPARγ may underlie the suppression of hepatic lipid accumulation induced by D-allulose intake. This article is protected by copyright. All rights reserved.
Aims:
The skeletal muscle maintains glucose disposal via insulin signaling and glucose transport. The progression of diabetes and insulin resistance is critically influenced by endoplasmic reticulum (ER) stress. D-allulose, a low-calorie sugar substitute, has shown crucial physiological activities under conditions involving hyperglycemia and insulin resistance. However, the molecular mechanisms of D-allulose in the progression of diabetes have not been fully elucidated. Here, we evaluated the effect of D-allulose on hyperglycemia-associated ER stress responses in human skeletal myoblasts and db/db diabetic and high-fat-diet (HFD)-fed mice.
Results:
D-allulose effectively controlled glycemic markers such as insulin and HbA1C, showing anti-diabetic effects by inhibiting the disruption of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and glucose transporter 4 (GLUT4) expression, in which the PI3K/Akt pathway is involved. The levels of glucose dysmetabolism-based NADPH oxidase, such as Nox4, were highly increased, and their interaction with IRE1α and the resultant sulfonation-RIDD-SIRT1 decay were also highly increased under diabetic conditions, which were controlled with D-allulose treatment. Skeletal muscle cells grown with a high glucose medium supplemented with D-allulose showed controlled IRE1α sulfonation-RIDD-SIRT1 decay, in which Nox4 was involved. Innovation and Conclusion: The study observations indicate that D-allulose contributes to the muscular glucose disposal in the diabetic state where ER-localized Nox4-induced IRE1α sulfonation results in the decay of SIRT1, a core factor for controlling glucose metabolism.
We found a putative dolichol phosphate mannose synthases (DPMS) from Bacillus sp., which exhibited the highest specific activity toward d-allulose, one of a functional rare sugars and also known as d-psicose, and identified it as d-allulose 3-epimerase (Basp_DAEase). The gene of Basp_DAEase from Bacillus sp. was cloned to the expression vector (pET-28a(+)) and then expressed as a recombinant enzyme in the Escherichia coli BL21(DE3). The recombinant enzyme was purified homogeneously on the SDS-PAGE with 34 kDa by 6XHis-tagging affinity chromatography and it was found to exist in dimer form as its activity form by Sephacryl S 200 HR 16/60 gelfiltration chromatography. The reaction conditions for a recombinant Basp_DAEase were optimized to produce d-allulose from d-fructose. The epimerization activity of Basp_DAEase toward d-fructose was maximum at pH 7.5 and 40°C with 1 mM Co2+. The half-lives of Basp_DAEase at 35°C, 40°C, 45°C, 50°C, and 55°C were 45.8, 4.18, 1.24, 0.46, and 0.17 h, respectively. At pH 7.5, 40°C, and 1mM Co2+, 215 g/L of d-allulose was produced from 700 g/L of d-fructose by 20 U/mL of Basp_DAEase after 50 min of enzyme reaction with a conversion yield of 31% and productivity of 258 g/L/h. This is the highest productivity of d-allulose from d-fructose reported to date. From this result, it is strongly suggested that Basp_DAEase has high potential application value in the industrial d-allulose production from d-fructose.
Food manufacturers are under increasing pressure to limit the amount of free sugars in their products. Many have reformulated products to replace sucrose, glucose and fructose with alternative sweeteners, but some of these have been associated with additional health concerns. Rare sugars are “monosaccharides and their derivatives that hardly exist in nature”, and there is increasing evidence that they could have health benefits. This review aimed to scope the existing literature in order to identify the most commonly researched rare sugars, to ascertain their proposed health benefits, mechanisms of action and potential uses, and to highlight knowledge gaps. A process of iterative database searching identified 55 relevant articles. The reported effects of rare sugars were noted, along with details of the research methodologies conducted. Our results indicated that the most common rare sugars investigated are D-psicose and D-tagatose, with the potential health benefits divided into three topics: glycaemic control, body composition and cardiovascular disease. All the rare sugars investigated have the potential to suppress postprandial elevation of blood glucose and improve glycaemic control in both human and animal models. Some animal studies have suggested that certain rare sugars may also improve lipid profiles, alter the gut microbiome and reduce pro-inflammatory cytokine expression. The present review demonstrates that rare sugars could play a role in reducing the development of obesity, type 2 diabetes, and/or cardiovascular disease. However, understanding of the mechanisms by which rare sugars may exert their effects is limited, and their effectiveness when used in reformulated products is unknown.
Some rare sugars can be potently medicinal, such as l-gulose. In this study, we present a novel alditol oxidase (fAldOx) from the soil fungus Penicillium sp. KU–1, and its application for the effective production of l-gulose. To the best of our knowledge, this is the first report of a successful direct conversion of d-sorbitol to l-gulose. We further purified it to homogeneity with a ∼108-fold purification and an overall yield of 3.26%, and also determined the effectors of fAldOx. The enzyme possessed broad substrate specificity for alditols such as erythritol (kcat/KM, 355 M⁻¹ s⁻¹), thus implying that the effective production of multiple rare sugars for medicinal applications may be possible.
The rare sugar d-allulose is a C-3 epimer of d-fructose and is known to have several health benefits such as anti-obesity and anti-diabetic effects through the alteration of enzymatic and genetic expressions in each organ. Most of the ingested d-allulose is absorbed in the small intestine and then rapidly excreted in the urine. As d-allulose was reported to be present in the liver before it is excreted, d-allulose may modulate some hepatic metabolites including glucose and lipid metabolism. Therefore, we investigated the hepatic metabolomics profile in rats after feeding d-allulose to study the overall alteration of hepatic metabolism. Wistar rats were fed an AIN-93G diet with/without 3% d-allulose for 4 weeks. Their liver samples were then collected and subjected to metabolomics analysis using CE-TOFMS and LC-TOFMS. The results showed that d-allulose induced significant increases in 42 metabolites and significant decreases in 21 metabolites. In particular, we found at the substance levels that d-allulose regulated metabolites involved in the metabolic pathways of fatty acid β-oxidation, cholesterol, and bile acid. In addition, this study newly showed the possibility that d-allulose alters glucuronic acid/xylulose pathways. In the future, we need more detailed research on the metabolomics profile of other organs related to these pathways for a comprehensive understanding of d-allulose functions.
In this study, D‐tagatose 3‐epimerase gene was amplified from Escherichia coli JM109 by PCR and re‐cloned into E. coli JM109 using Hinc II digested pUC18 cloning vector. Digestion of recombinant plasmid by Hinc II and PCR amplification of the gene from recombinant plasmid produced 789 bp gene band on agarose gel which indicated the gene integration. The host cell was grown in a shaking incubator at 37 °C for 24 hours and then the optical density (OD) of the cells was measured in a spectrophotometer at 600 nm wavelengths. When OD600 value reached 0.61, the protein expression was induced by the addition of 0.1 mM IPTG into the growth medium. Through His‐select gel column purification, highly purified and stable DTE protein was produced. The conversion rate of D‐fructose into D‐allulose was determined by HPLC. The native and recombinant enzymes could effectively convert D‐fructose into D‐allulose with the turnover ratio of 20.76%.
In the past few decades, the number of people dealing with obesity, diabetes, hyperlipidemia, and hypertension has grown dramatically throughout the world. The main reason leading to this case is the high-sugar and high-fat diets (Van Laar et al. 2020). With the continuous development of human’s living standards, the health awareness of the publics has gradually risen. As this result, the low-calorie rare sugars with special physiological functions have become popular, which are widely used as the sweeteners and flavor enhancers in food industries, such as healthy foods, infant formula, dairy products, baked goods, and beverage.
D-allulose is an almost zero calorie sweetener with 70% sweetness of sucrose, and has some health benefits. Here, we conducted a small-scale human trial with a single blind cross over design in 8 young healthy Japanese women to assess the utility of D-allulose as a low-calorie and functional sweetener, using chocolates as the test food. Subjects were asked to consume 50 g of chocolate containing no D-allulose (placebo), 1.8 g D-allulose, 3.6 g D-allulose, or 12.5 g D-allulose, and blood samples were collected at 0, 1, 2, 4, and 6 h after intake. The levels of postprandial free fatty acid increased and blood glucose and insulin levels decreased in the D-allulose group compared with those in the placebo group. These changes may be related to the enhanced GLP-1 secretion observed after the D-allulose intake. Our findings suggest that D-allulose can be a healthy alternative low-calorie sweetener for use in confectioneries.
Obesity and type 2 diabetes are major health problems affecting hundreds of millions of people. Caloric overfeeding with calorie-dense food ingredients like sugars may contribute to these chronic diseases. Sugar research has also identified mechanisms via which conventional sugars like sucrose and fructose can adversely influence metabolic health. To replace these sugars, numerous sugar replacers including artificial sweeteners and sugar alcohols have been developed. Rare sugars became new candidates to replace conventional sugars and their health effects are already reported in individual studies, but overviews and critical appraisals of their health effects are missing. This is the first paper to provide a detailed review of the metabolic health effects of rare sugars as a group. Especially allulose has a wide range of health effects. Tagatose and isomaltulose have several health effects as well, while other rare sugars mainly provide health benefits in mechanistic studies. Hardly any health claims have been approved for rare sugars due to a lack of evidence from human trials. Human trials with direct measures for disease risk factors are needed to allow a final appraisal of promising rare sugars. Mechanistic cell culture studies and animal models are required to enlarge our knowledge on understudied rare sugars.
Scope:
The results of recent studies on D-allulose intervention in high fat diet (HFD)-fed mice suggest that D-allulose has a substantial impact on obesity. In addition, several studies have uncovered bacterial candidates among the gut microbiota associated with obesity and inflammation in mice. To identify the D-allulose-attenuated genes related to the inflammation-associated bacterial candidates, two types of statistical analyses were performed.
Methods and results:
Using liver and epididymal fat tissues, genes with expression levels that recovered from HFD-induced dysregulation were identified through differentially expressed gene (DEG) analysis. Finally, correlation-based network analysis between the diet, microbes, and the candidates identified from DEG analysis revealed 20 genes that showed anti-obesogenic patterns and associations with Lactobacillus and Coprococcus, which are representative bacterial candidates associated with inflammation and obesity.
Conclusion:
The results of the present study suggest that D-allulose closely interacts with the candidate genes and microbes to alleviate weight gain and inflammation, partly via down regulation of Gm12250 expression in multiple tissues and increased the Lactobacillus and Coprococcus in gut microbiota composition. This article is protected by copyright. All rights reserved.
D‐psicose 3‐epimerase is an enzyme that catalyzes the synthesis of D‐Psicose from D‐fructose. We cloned the D‐psicose 3‐epimerase from Ruminococcus sp. (RDPE) and expressed it in Bacillus subtilis A311. By a two‐step pH regulation of segmented fermentation, we significantly improved the RDPE production and decreased the fermentation cost. The two‐step regulation consisted of the first step maintained the pH value at 7.0 for 24 h and the second step adjusted the pH value up to 7.5 slowly for another 24 h. Finally, the RDPE production was increased to 74 U/mL, which was about 2.5‐fold compared to the control. Our segmented fermentation strategy provides an important experimental basis for the industrial‐scale production of RDPE. This article is protected by copyright. All rights reserved
d-Allulose, a C-3 epimer of d-fructose, is a rare sugar reported to be a non-caloric sweetener having several health beneficial effects including anti-hyperglycemia and anti-obesity. However, the impact of dietary d-allulose on cholesterol metabolism remains unclear. Therefore, we studied the effects of d-allulose on the cholesterol metabolism of Golden Syrian hamsters, an animal model with a lipid metabolism similar to that of humans. Hamsters received either normal diet (ND) or high-fat diet (HFD) with or without 3% d-allulose for 4 or 8 weeks. While there were no significant differences in total serum cholesterol levels between the groups, d-allulose significantly increased HDL-cholesterol levels in ND-fed hamsters and decreased LDL-cholesterol levels in HFD-fed hamsters, causing an overall decrease in the LDL/HDL ratio. Furthermore, dietary d-allulose decreased serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in both diets. In conclusion, d-allulose may favorably modulate cholesterol metabolism by reducing PCSK9 in hamsters.
Gluconobacter oxydans sorbitol dehydrogenase (GoSLDH) exhibits a higher catalytic efficiency than other l-sorbose producing enzymes. During the reaction catalysed by GoSLDH, NADP+ is reduced to NADPH and d-sorbitol is oxidized to l-sorbose. However, GoSLDH activity is inhibited by the NADPH (Ki = 100 μM) formed during the enzymatic reaction. Therefore, Escherichia coligosldh-lrenox producing both GoSLDH for d-sorbitol oxidation and LreNOX (NAD(P)H oxidase from Lactobacillus reuteri) for NADP+ regeneration was generated and used for l-sorbose production. Whole cell biocatalysts with the LreNOX cofactor recycling system showed a high conversion rate (92%) of d-sorbitol to l-sorbose in the presence of low concentration of NADP+ (0.5 mM). By alleviating NADPH accumulation during the catalytic reactions, E. coligosldh-lrenox exhibited 23-fold higher conversion rate of d-sorbitol than E. coligosldh. l-Sorbose production by E. coligosldh-lrenox reached 4.1 g/L after 40 min, which was 20.5-fold higher than that of E. coligosldh. We also constructed G. oxydansgosldh and G. oxydansgosldh-lrenox strains, and they exhibited 1.2- and 2.9-fold higher conversion rates than the wild-type G. oxydans KCTC 1091. The results indicate that overcoming NADPH product inhibition using LreNOX improves chemical production in NADP+-dependent enzymatic reactions.
D‐allulose 3‐epimerase (DAE) has been applied to produce D‐allulose, a low‐calorie and functional sweetener. In this study, a new DAE from Paenibacillus senegalensis was characterized in Escherichia coli. Furthermore, we presented a tandem isoenzyme gene expression strategy to express multiple DAEs in one cell and construct food‐grade expression systems based on Corynebacterium glutamicum. Seventeen expression cassettes based on three DAE genes from different organisms were constructed. Among all recombinant strains, DAE16 harbouring three DAE genes in an expression vector exhibited the highest enzyme activity with 22.7 U/mg. Whole‐cell transformation of DAE16 produced 225 g/L D‐allulose with a volumetric productivity of 353 g/L/h. The catalytic efficiency of strain C‐DAE9 integrating total 11 DAE genes in chromosome was 16.4‐fold higher than strains carrying one DAE. Fed‐batch culture of C‐DAE9 gave enzyme activity of 44,700 U/L. We also expressed a thermostable invertase in C. glutamicum and obtained enzyme activity of 29 U/mg. Immobilized cells expressing DAE or invertase exhibited 80% of retained activity after 30 cycles of catalytic reactions. Those immobilized cells were coupled to produce 61.2 g/L D‐allulose from cane molasses in a two‐step reaction process. This study provided an efficient approach for enzyme preparation and allowed access to produce D‐allulose from other abundant and low‐cost feedstock enriched with sucrose.
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D-psicose is a new generation sugar substitute with low calorie value while still offering desirable sweetness. This objective of this study was to investigate the anti obesity potential of D-psicose and possible mechanism using Wistar rats as animal model. Animals were divided into five groups and supplemented with diets containing 5% of different carbohydrates including glucose, fructose, cellulose, D-psicose and control diet for 4 weeks, respectively. After sacrifice, blood lipid profile, tissue morphology and related genes participated in lipid metabolism were analyzed. Results indicated supplementation of D-psicose lead to minimum fat accumulation in rats compared with other carbohydrates. The blood lipid profile and anti-oxidative activity of the rat was also improved. D-psicose can regulate lipid metabolism by increasing lipid metabolism related enzymes such as SDH in serum and liver, and HL in the liver. D-psicose can prevent fat accumulation by suppressing the expression of lipogenesis related gene ACCα, hepatic fatty acid uptake gene including FAS and SREBP-1c gene, while stimulating the expression for fatty acid oxidation related gene including AMPK2α, HSL and PPARα. In conclusion, D-psicose can be a healthy alternative to traditional sweetener.
We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.
ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.
ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 +/- 1.9 vs. 32.5 +/- 3.2 mU/mg protein), marked hyperglycemia (23.9 +/- 1.2 vs. 7.4 +/- 0.3 mmol/l), higher endogenous glucose production (80 +/- 3 vs. 38 +/- 3 micromol x kg(-1) x min(-1)), increased glucose-6-phosphatase flux (150 +/- 11 vs. 58 +/- 8 micromol x kg(-1) x min(-1)), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 +/- 7 vs. -7 +/- 4 micromol x kg(-1) x min(-1)) and promote glucose incorporation into glycogen (15 +/- 5 vs. 43 +/- 3 micromol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.
Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.
Relationships have been observed between lipoprotein concentrations and insulin action. These relationships may be important in explaining the association of insulin resistance and abnormalities of lipoprotein metabolism found in obesity, diabetes, and hypertriglyceridemia. We have measured plasma lipoprotein concentrations and indices of insulin action in 85 men and 56 women, all of whom were normolipidemic and had normal glucose tolerance. The subjects were obese Southwestern American Indians (body mass index 34 +/- 1). Insulin action was measured via the hyperinsulinemic clamp with simultaneous indirect calorimetry. Triglyceride concentrations were inversely related to rates of total insulin-mediated glucose disposal (in men and women, respectively, r = -.37, P less than .01; r = -.24, P less than .10), glucose storage (r = -.31, P less than .01; r = -.25, P less than .10), increase in glucose oxidation (r = -.29, P less than .01; r = -.24, P less than .10), and, in men only, suppression of endogenous glucose production (r = -.32, P less than .01). High-density lipoprotein (HDL) cholesterol concentration was positively related to rates of total insulin-mediated glucose disposal (r = .35, P less than .01; r = .33, P less than .05), increase in carbohydrate oxidation (r = .40, P less than .001; r = .39, P less than .001), suppression of endogenous glucose production (r = .24, P less than .05; r = .29, P less than .05), and, in men only, glucose storage (r = .35, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Glucokinase (GK) is believed to play a key role in the control of the hepatic glucose metabolism. To address the mechanism of the regulation of glucose metabolism through GK action, we immunohistochemically studied changes in GK distribution in primary cultures of rat hepatocytes. In hepatocyte monolayers incubated in 5 mM glucose, GK staining by the immunoperoxidase method was observed predominantly in the nucleus. When cultured hepatocytes were incubated for 30 min in various concentrations (5-45 mM) of glucose, there was an appreciable decrease in nuclear GK immunoreactivity, even at 10 mM compared with that at 5 mM. After the shift of glucose concentration from 5 mM to 25 mM, the GK distribution changed time-dependently over 1 h. A time-dependent change in GK distribution was also observed when the glucose concentration was shifted from 25 mM to 5 mM. Reversal of GK distribution in response to the change in glucose concentration from 5 to 25 mM and vice versa was shown to repeatedly occur. Lower concentrations (0.05-5 mM) of fructose, which is known to stimulate glucose phosphorylation by GK, in combination with 5 mM glucose, induced the translocation of GK from the nucleus to the cytoplasm. Mannose (20 mM), a substrate of GK, and sorbitol (1 mM), a stimulator of glucose phosphorylation by GK, induced the translocation of GK from the nucleus to the cytoplasm in the presence of 5 mM glucose. L-glucose, galactose, 3-O-methylglucose, and 2-deoxyglucose at 20 mM each did not affect the GK distribution observed in the presence of 5 mM glucose. The results suggest that GK is present mainly in the nucleus under conditions where GK action is not much needed, whereas the enzyme exists mainly in the cytoplasm under conditions where it must function extensively. Our findings indicate that the shuttling of GK between the nucleus and the cytoplasm is essential for the regulation of the glucose metabolism in the liver.
The evolution of diabetes in the male leptin receptor-deficient (fa/fa) Zucker diabetic fatty (ZDF) rat is associated with disruption of normal islet architecture, beta-cell degranulation, and increased beta-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased beta-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on beta-cell mass dynamics, male fa/fa (obese) and +/fa or +/+ (lean) rats age 6 weeks were fed either chow (control group [CN]) or chow mixed with rosiglitazone (RSG group) at a dosage of 10 micromol. kg(-1) body wt.day(-1). Rats were killed after 0, 2, 4, 6, or 10 weeks of treatment (at age 6, 8, 10, 12, or 16 weeks). Plasma glucose increased from 8.9 +/- 0.4 mmol/l at 0 weeks to 34.2 +/- 1.8 mmol/l (P = 0.0001) at 6 weeks of treatment in obese CN rats and fell from 8.0 +/- 0.3 to 6.3 +/- 0.4 mmol/l in obese RSG rats (P = 0.02). beta-cell mass fell by 51% from 2 to 6 weeks of treatment (ages 8-12 weeks) in obese CN rats (6.9 +/- 0.9 to 3.4 +/- 0.5 mg; P < 0.05), whereas beta-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), beta-cell mass in obese CN rats was only 56% of that of obese RSG rats (4.4 +/- 0.4 vs. 7.8 +/- 0.3 mg, respectively; P = 0.0001). The beta-cell replication rate fell from a baseline value of 0.95 +/- 0.12% in lean rats and 0.94 +/- 0.07% in obese rats (at 0 weeks) to approximately 0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, beta-cell replication was higher in obese RSG rats than in CN rats (0.59 +/- 0.14 vs. 0.28 +/- 0.05%, respectively; P < 0.02). Application of our mass balance model of beta-cell turnover indicated that net beta-cell death was fivefold higher in obese CN rats as compared with RSG rats after 6 weeks of treatment (age 12 weeks). The increase in beta-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r2 = 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net beta-cell death. beta-cell proliferation compensates for the increased beta-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond approximately 20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of beta-cell mass in obese ZDF rats by maintaining beta-cell proliferation and preventing increased net beta-cell death.
The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to intraduodenal glucose infusion and the effect of physiological rises of plasma glucose and/or insulin on GK translocation were examined in 6-h-fasted conscious rats. Intraduodenal glucose infusion (28 mg.kg(-1).min(-1) after a priming dose at 500 mg/kg) elevated blood glucose levels (mg/dl) in the artery and portal vein from 90 +/- 3 and 87 +/- 3 to 154 +/- 4 and 185 +/- 4, respectively, at 10 min. At 120 min, the levels had decreased to 133 +/- 6 and 156 +/- 5, respectively. Plasma insulin levels (ng/ml) in the artery and the portal vein rose from 0.7 +/- 0.1 and 1.8 +/- 0.3 to 11.8 +/- 1.5 and 20.2 +/- 2.0 at 10 min, respectively, and 12.4 +/- 3.1 and 18.0 +/- 4.8 at 30 min, respectively. GK was rapidly exported from the nucleus as determined by measuring the ratio of the nuclear to the cytoplasmic immunofluorescence (N/C) of GK (2.9 +/- 0.3 at 0 min to 1.7 +/- 0.2 at 10 min, 1.5 +/- 0.1 at 20 min, 1.3 +/- 0.1 at 30 min, and 1.3 +/- 0.1 at 120 min). When plasma glucose (arterial; mg/dl) and insulin (arterial; ng/ml) levels were clamped for 30 min at 93 +/- 7 and 0.7 +/- 0.1, 81 +/- 5 and 8.9 +/- 1.3, 175 +/- 5 and 0.7 +/- 0.1, or 162 +/- 5 and 9.2 +/- 1.5, the N/C of GK was 3.0 +/- 0.5, 1.8 +/- 0.1, 1.5 +/- 0.1, and 1.2 +/- 0.1, respectively. The N/C of GK regulatory protein (GKRP) did not change in response to the intraduodenal glucose infusion or the rise in plasma glucose and/or insulin levels. The results suggest that GK but not GKRP translocates rapidly in a manner that corresponds with changes in the hepatic glucose balance in response to glucose ingestion in vivo. Additionally, the translocation of GK is induced by the postprandial rise in plasma glucose and insulin.
Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
D-Psicose is one of the rare sugars present in small quantities in commercial carbohydrates and agricultural products. We studied the effects of D-psicose and psico-rare sugar (a mixture of 75% D-fructose and 25% D-psicose) on glycemic responses after oral carbohydrate tolerance tests in rats. Male Wistar rats (6 months old) were administrated 2g/kg sucrose, maltose or soluble starch together with 0.2g/kg D-psicose or psico-rare sugar. D-Psicose or psico-rare sugar significantly inhibited the increment of plasma glucose concentration induced by sucrose or maltose. The starch-induced glycemic response tended to be suppressed by D-psicose or psico-rare sugar, although not to a significant degree. These results suggest that D-psicose and psico-rare sugar are functional monosaccharides that suppress the glycemic response after carbohydrate ingestion.
Adjunctive treatment with acarbose (possibly together with sulphonylurea or insulin treatment) can be effectively utilised to achieve blood glucose control if postprandial hyperglycaemia is a problem and cannot be sufficiently controlled by dietary modifications. The α-glucosidase inhibitor, acarbose, should be taken with meals that are rich in complex carbohydrates and low in simple sugars, as recommended by diabetes associations, to achieve the greatest possible benefit from treatment
Starch, whey or hemicellulosic waste can be used as a raw material for the industrial production of rare sugars.D-Glucose from starch, whey and hemicellulose, D-galactose from whey, and D-xylose from hemicellulose are the main starting monosaccharides for production of rare sugars. We can produce all monosaccharides; tetroses, pentoses and hexoses, from these raw materials. This is achieved by using D-tagatose 3-epimerase, aldose isomerase, aldose reductase, and oxidoreductase enzymes or whole cells as biocatalysts. Bioproduction strategies for all rare sugars are illustrated using ring form structures given the name Izumoring.
Rare sugar d-psicose has cropped up as a non-toxic and effective compound to protect and preserve pancreatic β-islets in the growing type 2 diabetes mellitus (T2DM) rats through the regulation of glucose and fat metabolism. The present study was undertaken to examine the effect of rare sugar d-psicose on the protection of pancreatic β-islets using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a T2DM model. Treated rats were fed with 5% d-psicose or 5% d-glucose supplemented drinking water, and only water in the control for 13weeks. A non-diabetic Long-Evans Tokushima Otsuka (LETO), fed with water served as a counter control of OLETF. d-Psicose significantly attenuated progressive β-islet fibrosis and preserved islets, evaluated by hematoxylin-eosin staining, Masson's trichrome staining and immunostainings of insulin and α-smooth muscle actin (SMA). d-Psicose significantly reduced increase in body weight and abdominal fat deposition. Oral glucose tolerance test (OGTT) showed reduced blood glucose levels suggesting the improvement of insulin resistance. All these data suggests that d-psicose protected and preserved pancreatic β-islets through the maintenance of hyperglycemia and by the prevention of fat accumulation in OLETF rats.
Otsuka Long-Evans Tokushima Fatty (OLETF) rats develop obesity, hyperglycemia, and non-insulin-dependent diabetes mellitus and do not express cholecystokinin A (CCK-A) receptors, the receptor subtype mediating the satiety actions of CCK. In short-term feeding tests, male OLETF rats were completely resistant to exogenous CCK, and their response to bombesin was attenuated. Comparisons of liquid meal consumption in OLETF and control Long-Evans Tokushima (LETO) rats demonstrated that 1) OLETF rats had greater intakes during 30-min scheduled daytime meals and significantly larger and fewer spontaneous night-time meals and 2) although the initial rates of licking were the same, OLETF rats maintained the initial rate longer and the rate at which their licking declined was slower. In 24-h solid food access tests, OLETF rats consumed significantly more pellets than LETO controls, and this increase was attributable to significant increases in meal size. Together, these data are consistent with the interpretation that the lack of CCK-A receptors in OLETF rats results in a satiety deficit leading to increases in meal size, overall hyperphagia, and obesity.
This clinical study was conducted to investigate the safety and effect of D-psicose on postprandial blood glucose levels in adult men and women, including borderline diabetes patients. A randomized double-blind placebo-controlled crossover experiment of single ingestion was conducted on 26 subjects who consumed zero or 5 g of D-psicose in tea with a standard meal. The blood glucose levels at fasting and 30, 60, 90, and 120 min after the meal were compared. The blood glucose level was significantly lower 30 and 60 min after the meal with D-psicose (p<0.01, p<0.05), and a significant decrease was also shown in the area under the curve (p<0.01). The results suggest that D-psicose had an effect to suppress the postprandial blood glucose elevation mainly in borderline diabetes cases. A randomized double-blind placebo-controlled parallel-group experiment of long-term ingestion was conducted on 17 normal subjects who took 5 g of D-psicose or D-glucose with meals three times a day for 12 continuous weeks. Neither any abnormal effects nor clinical problems caused by the continuous ingestion of D-psicose were found.
d-psicose is one of the rare sugars present in small quantities in commercial carbohydrates and agricultural products. In this study, we investigated the effects of d-psicose on the activities of alpha-amylases and alpha-glucosidases in vitro, and evaluated the effects of d-psicose on the in vivo postprandial glycemic response using rats. In the in vitro study, d-psicose potently inhibited the intestinal sucrase and maltase, however, slightly inhibited the intestinal and salivary alpha-amylase activities. Male Wistar rats (6 months old) were administrated 2 g/kg of sucrose, maltose or soluble starch together with 0.2 g/kg of d-psicose or d-fructose. The d-psicose significantly inhibited the increment of plasma glucose concentration induced by sucrose or maltose. The starch-induced glycemic response tended to be suppressed by d-psicose, however the suppression was not significant. These results suggest that d-psicose inhibits intestinal sucrase and maltase activities and suppresses the plasma glucose increase the normally occurs after sucrose and maltose ingestion. Thus, d-psicose may be useful in preventing postprandial hyperglycemia in diabetic patients when foods containing sucrose and maltose are ingested.
An examination was conducted to verify D-psicose suppressed the elevation of blood glucose and insulin concentration in a dose-dependent manner under the concurrent administration of maltodextrin and D-psicose to healthy humans. Twenty subjects aged 20-39 y, 11 males and 9 females were recruited. A load test of oral maltodextrin was conducted as a randomized single blind study. The subjects took one of five test beverages (7.5 g D-psicose alone, 75 g maltodextrin alone, 75 g maltodextrin +2.5, 5 or 7.5 g D-psicose). Blood was collected before an intake and at 30, 60, 90 and 120 min after an intake. Intervals of administration were at least 1 wk. The load test with 75 g maltodextrin showed significant suppressions of the elevation of blood glucose and insulin concentration under the doses of 5 g or more D-psicose with dose dependency. An independent administration of 7.5 g D-psicose had no influence on blood glucose or insulin concentration. D-Psicose is considered efficacious in the suppression of the elevation of blood glucose concentration after eating in humans.
Extracts of ginseng species show antihyperglycemic activity. We evaluated the antihyperglycemic and antiobesity effects of ginsam, a component of Panax ginseng produced by vinegar extraction, which is enriched in the ginsenoside Rg3. Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, were assigned into 1 of 3 groups (n = 8 each): controls (isotonic sodium chloride solution, 5 mL/d), rats given 300 mg/(kg d) ginsam, and rats given 500 mg/(kg d) ginsam. An intraperitoneal 2-hour glucose tolerance test was performed at the end of the 6-week treatment. After 8 weeks, body and liver weights, visceral fat measured by computed tomography, and fasting glucose and insulin concentrations and lipid profiles were recorded. Insulin-resistant rats treated with ginsam had lower fasting and postprandial glucose concentrations compared with vehicle-treated rats. Importantly, overall glucose excursion during the intraperitoneal 2-hour glucose tolerance test decreased by 21.5% (P < .01) in the treated rats, indicating improved glucose tolerance. Plasma insulin concentration was significantly lower in ginsam-treated rats. These changes may be related to increased glucose transporter 4 expression in skeletal muscle. Interestingly, when the data from both ginsam-treated groups were combined, body weight was 60% lower in the ginsam-treated rats than in the controls (P < .01). Liver weight and serum alanine aminotransferase concentrations were also lower in the ginsam-treated rats. These effects were associated with increased peroxisome proliferator-activated receptor gamma expression and adenosine monophosphate-activated protein kinase phosphorylation in liver and muscle. Our data suggest that ginsam has distinct beneficial effects on glucose metabolism and body weight control in an obese animal model of insulin resistance by changing the expression of genes involved in glucose and fatty acid metabolism.
Hypertriglyceridaemia, which is frequently seen in Type 2 (non-insulin-dependent) diabetes mellitus, is associated with insulin resistance. The connection between hypertriglyceridaemia and insulin resistance is not clear, but could be due to substrate competition between glucose and lipids. To address this question we measured glucose and lipid metabolism in 39 Type 2 diabetic patients with hypertriglyceridaemia, i.e. mean fasting serum triglyceride level equal to or above 2 mmol/l (age 59 +/- 1 years, BMI 27.4 +/- 0.5 kg/m2, HbA1c 8.0 +/- 0.2%, serum triglycerides 3.2 +/- 0.2 mmol/l) and 41 Type 2 diabetic patients with normotriglyceridaemia, i.e. mean fasting serum triglyceride level below 2 mmol/l (age 58 +/- 1 years, BMI 27.0 +/- 0.7 kg/m2, HbA1c 7.8 +/- 0.2%, serum triglycerides 1.4 +/- 0.1 mmol/l). Insulin sensitivity was assessed using a 340 pmol.(m2)-1 x min-1 euglycaemic insulin clamp. Substrate oxidation rates were measured with indirect calorimetry and hepatic glucose production was estimated using a primed (25 microCi)-constant (0.25 microCi/min) infusion of [3-3H]-glucose. Suppression of lipid oxidation by insulin was impaired in patients with hypertriglyceridaemia vs patients with normal triglyceride levels (3.5 +/- 0.2 vs 3.0 +/- 0.2 mumol.kg-1 x min-1; p < 0.05). Stimulation of glucose disposal by insulin was reduced in hypertriglyceridaemic vs normotriglyceridaemic patients (27.0 +/- 1.3 vs 31.9 +/- 1.6 mumol.kg-1 x min-1; p < 0.05) primarily due to impaired glucose storage (9.8 +/- 1.0 vs 14.6 +/- 1.4 mumol.kg-1 x min-1; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Subcellular distribution of glucokinase was studied in rat liver. With an immunohistochemical procedure, glucokinase immunoreactivity was clearly shown in the nucleus of parenchymal cells of rat liver, but faintly in the cytoplasm. Nuclei, cytosol (extranuclear fraction in the strict sense), and homogenate prepared in nonaqueous medium, i.e. glycerol, were analyzed for glucokinase by both immunoblotting and activity measurement. Such analyses demonstrated that glucokinase concentration was far higher in the nuclei than in the cytosol when compared on the basis of total protein content and that total glucokinase activity in the cytosolic fraction was about 1.8 times that in the nuclear fraction. These results indicate that hepatocyte glucokinase is present in the nucleus as well as in the cytoplasm in contradiction to the widespread belief of its exclusive localization in the cytoplasm.
Oxidation of 1,2: 4,5-di-O-isopropylidene-β-D-fructopyranose (2) with ruthenium tetroxide affords crystalline 1,2: 4,5-di-O-isopropylidene-β-D-erythro-hexopyranos-2,3-diulose (3) in high yield. The latter, on reduction with metal hydrides or on catalytic hydrogenation over platinum, yields 1,2: 4,5-di-O-isopropylidene-β-D-allulopyranose (4) as virtually the sole product. By contrast, sodium amalgam reduction of 3 yields only the D-fructose derivative (2), although in low yield. Also, metal hydride reduction of impure 3, obtained by oxidation of 2 with dimethyl sulfoxide – acetic anhydride, yields equal amounts of both isomers (2 and 4). The stereochemistry of these reductions is complicated by uncertainty as to the conformation of 4 (and possibly of 2), owing to anomalous proton magnetic resonance spectral characteristics observed.Ketone 3, which is unstable in the presence of deuteroxide ion, is smoothly deuterated at C-4 by exchange in hot deuterium oxide – pyridine.Mono-O-isopropylidene derivatives have been prepared by partial acid hydrolysis of 2 and 4.
The study was carried out using a new rat model of naturally occurring obese, nonketotic diabetes, Otsuka Long-Evans Tokushima Fatty rat (Kawano et al., Diabetes 41: 1422-1428, 1992), which closely resembles obese noninsulin-dependent diabetes in human. At the age of 3.5 wk, body weight, glucose tolerance and plasma insulin level after glucose load were normal in Otsuka Long-Evans Tokushima Fatty rats, indicating the animals are at nonobese, prediabetic phase. At this age, however, glucose-stimulated insulin release by pancreatic islets in vitro was abnormally exaggerated whereas the islet insulin content and glucose metabolism by the islet cells were normal. Administration of diazoxide (0.2% in diet), an inhibitor of insulin secretion, to Otsuka Long-Evans Tokushima Fatty rats from the age of 4 to 12 wk completely prevented the development of obesity and insulin resistance, which was accompanied by marked improvement of glucose tolerance and disappearance of exaggerated B cell response to glucose in vitro. This is the first report of successful pharmacological prevention of genetically determined obese diabetes.
To elucidate a role of glucokinase in hepatic glucose metabolism, we overexpressed hexokinase I (HKI), liver type glucokinase (LGK), or beta cell type glucokinase (beta GK) in primary rat hepatocytes using a recombinant adenovirus vector system. Overexpression of HKI and LGK induced a 34- and 25-fold increase, respectively, in glucose phosphorylation activity measured in cell homogenates. While HKI overexpression induced only a 1.3-fold increase in glucose oxidation, LGK overexpression increased glucose oxidation by 2.9-fold. Overexpression of beta GK had essentially the same effect as LGK. The results indicate that glucokinase does indeed regulate the rate of hepatic glucose oxidation and that the liver-specific sequence of this enzyme is not essential for this function.
We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.
Despite the fact that it is the prevalent view that insulin resistance is the main genetic factor predisposing to development of type 2 diabetes, review of several lines of evidence in the literature indicates a lack of overwhelming support for this concept. In fact, the literature better supports the case of impaired insulin secretion being the initial and main genetic factor predisposing to type 2 diabetes, especially 1) the studies in people at high risk to subsequently develop type 2 diabetes (discordant monozygotic twins and women with previous gestational diabetes), 2) the studies demonstrating compete alleviation of insulin resistance with weight loss, and 3) the studies finding that people with type 2 diabetes or IGT can have impaired insulin secretion and no insulin resistance compared with well matched NGT subjects. The fact that insulin resistance may be largely an acquired problem in no way lessens its importance in the pathogenesis of type 2 diabetes. Life style changes (exercise, weight reduction) and pharmacological agents (e.g., biguanides and thiazolidendiones) that reduce insulin resistance or increase insulin sensitivity clearly have major beneficial effects (122, 144-146, 153-155).
Glucokinase translocates between the cytoplasm and nucleus of hepatocytes where it is bound to a 68 kDa protein. The mechanism by which glucose induces translocation of glucokinase from the nucleus was investigated using glucose analogues that are not phosphorylated by glucokinase. There was strong synergism on glucokinase translocation between effects of glucose analogues (glucosamine, 5-thioglucose, mannoheptulose) and sorbitol, a precursor of fructose 1-phosphate. In the absence of glucose or glucose analogues, sorbitol had a smaller effect than glucose on translocation. However, sorbitol potentiated the effects of glucose analogues. In the absence of sorbitol the effect of glucose on glucokinase translocation is sigmoidal with a Hill coefficient of 1.9 suggesting involvement of two glucose-binding sites. The effects of glucosamine and 5-thioglucose were also sigmoidal but with lower Hill Coefficients. In the presence of sorbitol, the effects of glucose, glucosamine and 5-thioglucose were hyperbolic. Mannoheptulose, unlike the other glucose analogues, had a hyperbolic effect on glucokinase translocation in the absence of sorbitol suggesting interaction with one site and was synergistic rather than competitive with glucose. The results favour a two-site model for glucokinase translocation involving either two glucose-binding sites or one binding-site for glucose and one for fructose 1-phosphate. The glucose analogues differed in their effects on the kinetics of purified glucokinase. Mannoheptulose caused the greatest decrease in co-operativity of glucokinase for glucose whereas N-acetylglucosamine had the smallest effect. The anomalous effects of mannoheptulose on glucokinase translocation and on the kinetics of purified glucokinase could be explained by a second glucose-binding site on glucokinase.
We examined sugar-induced translocation of glucokinase in cultured hepatocytes from Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats, animal models of type 2 diabetes, and compared this with that in Long-Evans Tokushima Otsuka and Wistar rats, respectively, as control strains. When hepatocytes from the four strains were incubated with 5 mM glucose, glucokinase was present predominantly in the nuclei. Higher concentrations of glucose, 5 mM glucose plus 1 mM fructose, and 5 mM glucose plus 1 mM sorbitol all induced the translocation of glucokinase from the nucleus to the cytoplasm in hepatocytes from these rats. The extent of glucokinase translocation under these conditions, however, was less marked in both diabetic rat types than in the control rats. The extent of the phosphorylation of glucose as estimated by the release of 3H2O from [2- 3H] glucose is significantly lower in Goto-Kakizaki rats than in Wistar rats. The results indicate that the translocation of glucokinase is impaired in the hepatocytes of diabetic rats. They also suggest that the impaired translocation of glucokinase is associated with abnormal hepatic glucose metabolism in type 2 diabetes.
D-Psicose (D-ribo-2-hexulose), a C-3 epimer of D-fructose, is present in small quantities in commercial carbohydrate complexes and agricultural products. We have previously reported that D-psicose supplements in diets suppressed hepatic lipogenic enzyme activity The lower fat accumulation in rats fed D-psicose may be due to lower lipogenesis in the liver. The present study examined the energy available in D-psicose for rat growth. Male Wistar rats received 7 g daily of a basal diet to which fixed amounts of sucrose, D-fructose, or D-psicose (0.5-2.0 g) were added for 20 d. Body weight gain and body energy gain increased with increases in sucrose and D-fructose, but not with D-psicose. One gram of sucrose, D-fructose, and D-psicose produced a net energy gain of 2.29, 1.76, and 0.007 kcal, respectively. The efficiency of energy deposition from D-psicose was 0.3% that of sucrose. The energy value of D-psicose was effectively zero. These results suggest that D-psicose is a rare sugar providing zero energy that may be useful in sweeteners for obese people as an aid for weight reduction.
We evaluated whether ramipril, one of long-acting ACEIs, has a direct effect on pancreas islets in animal model of type 2 diabetes. OLETF rats were treated with ramipril for 24 weeks. We assessed the body weight, glucose tolerance, and the amount of islet fibrosis. RT-PCR and Western blot analysis of transforming growth factor-beta with its downstream signals were performed from the pancreas. Ramipril treatment remarkably reduced weight gain and the area under the curve of glucose. Islet fibrosis and the expression of TGF-beta with its downstream signal molecules were significantly reduced in the pancreas of ramipril-treated group than in control and paired-feeding group. These beneficial effects of ramipril might be related to the downregulation of TGF-beta and its downstream signals in OLETF rats. To our knowledge, this is the first report suggesting the potential effect of ramipril on the prevention of islet destruction by fibrosis in the animal model of type 2 diabetes mellitus.
An improved process for the mass production of D-psicose from D-fructose was developed. A D-fructose solution (60%, pH 7.0) was passed at 45 degrees C through a column filled with immobilized D-tagatose 3-epimerase (D-TE) which was produced using recombinant Escherichia coli, and 25% of the substrate was converted to D-psicose. After epimerization, the substrate, D-fructose, was removed by treatment with baker's yeast. The supernatant was concentrated to a syrup by evaporation under vacuum and D-psicose was crystallized with ethanol. Approximately 20 kg of pure crystal D-psicose was obtained in 60 d.
Starch, whey or hemicellulosic waste can be used as a raw material for the industrial production of rare sugars. D-glucose from starch, whey and hemicellulose, D-galactose from whey, and D-xylose from hemicellulose are the main starting monosaccharides for production of rare sugars. We can produce all monosaccharides; tetroses, pentoses and hexoses, from these raw materials. This is achieved by using D-tagatose 3-epimerase, aldose isomerase, aldose reductase, and oxidoreductase enzymes or whole cells as biocatalysts. Bioproduction strategies for all rare sugars are illustrated using ring form structures given the name Izumoring.
Type-2 diabetes is associated with impaired glucose clearance by the liver in the postprandial state, and with elevated glucose production in the post-absorptive state. New targets within the liver are currently being investigated for development of antihyperglycaemic drugs for type-2 diabetes. They include glucokinase, which catalyses the first step in glucose metabolism, the glucagon receptor, and enzymes of gluconeogenesis and/or glycogenolysis such as glucose 6-phosphatase, fructose 1,6-bisphosphatase and glycogen phosphorylase. Preclinical studies with candidate drugs on animal models or cell-based assays suggest that these targets have the potential for pharmacological glycaemic control. Data from clinical studies is awaited. Further work is required for better understanding of the implications of targeting these sites in terms of possible side-effects or tachyphylaxis. The advantage of combined targeting of two or more sites within the liver for minimizing side-effects and tachyphylaxis caused by single-site targeting is discussed.
Epidemiological studies in both humans and experimental animals have shown an association between visceral obesity and cardiovascular risk factors such as dyslipidemia, hyperinsulinemia, and type 2 diabetes mellitus. The objective of this study was to evaluate the effects of diazoxide, an inhibitor of glucose-stimulated insulin secretion, on the prevention of fat deposition in the liver and in the abdominal cavity of prediabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a well-established animal model of human obesity, were used. Diazoxide (25 mg/kg/day) was administered from 8 to 30 weeks of age. Various fat distribution parameters, including computerized tomography imaging, histopathological examination, lipid metabolism, and insulin resistance, were determined in prediabetic OLETF rats. Occurrences of abdominal adiposity and fatty liver were markedly reduced by diazoxide treatment. Diazoxide significantly lowered hyperinsulinemia, triglycerides, free fatty acid levels, insulin resistance, weight gain, and food intake. In addition, it inhibited the development of diabetes in these animals. Linear regression assay demonstrated a close correlation between decreasing hyperinsulinemia and the protective effects of diazoxide. The present study demonstrates that diazoxide treatment in obese OLETF rats at prediabetic stage prevents abdominal obesity and fat deposition in the liver. These metabolic changes may occur through a direct effect on beta-cells through reduction of their workload and suppression of insulin secretion.
Keishibukuryogan, one of the traditional herbal formulations, is used clinically to improve blood circulation. In this study, we examined the effects of keishibukuryogan on glucose and lipids metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. Forty-five-week-old male OLETF rats were divided into three groups: diabetic control rats given a standard chow; diabetic rats given keishibukuryogan (3%, w/w in chow); diabetic rats given pioglitazone (0.01%, w/w in chow). Oral administration of keishibukuryogan produced significant improvement against impaired glucose tolerance. On the other hand, fasting serum glucose and insulin levels, and the homeostasis index of insulin resistance did not change by keishibukuryogan treatment. Against lipid parameters, keishibukuryogan significantly lowered serum total cholesterol and triglyceride levels, and the hepatic total cholesterol level. Keishibukuryogan treatment also significantly reduced the serum leptin level, but it had no effect on the serum adiponectin level. Additionally, keishibukuryogan showed significant effects on epididymal adipose tissue by decreasing the size of fat cells and on skeletal muscle by reducing TNF-alpha protein content. From these results, it was suggested that keishibukuryogan exerts beneficial effects on the features associated with type 2 diabetes.