Rare sugar D-psicose prevents progression and development of diabetes in T2DM model Otsuka Long-Evans Tokushima Fatty rats

Abstract

Background: The fundamental cause of overweight and obesity is consumption of calorie-dense foods. We have introduced a zero-calorie sweet sugar, d-psicose (d-allulose), a rare sugar that has been proven to have strong antihyperglycemic and antihyperlipidemic effects, and could be used as a replacement of natural sugar for the obese and diabetic subjects.

Aim: Above mentioned efficacy of d-psicose (d-allulose) has been confirmed in our previous studies on type 2 diabetes mellitus (T2DM) model Otsuka Long-Evans Tokushima Fatty (OLETF) rats with short-term treatment. In this study we investigated the long-term effect of d-psicose in preventing the commencement and progression of T2DM with the mechanism of preservation of pancreatic β-cells in OLETF rats.

Methods: Treated OLETF rats were fed 5% d-psicose dissolved in water and control rats only water. Nondiabetic control rats, Long-Evans Tokushima Otsuka (LETO), were taken as healthy control and fed water. To follow the progression of diabetes, periodic measurements of blood glucose, plasma insulin, and body weight changes were continued till sacrifice at 60 weeks. Periodic in vivo body fat mass was measured. On sacrifice, pancreas, liver, and abdominal adipose tissues were collected for various staining tests.

Results: d-Psicose prevented the commencement and progression of T2DM till 60 weeks through the maintenance of blood glucose levels, decrease in body weight gain, and the control of postprandial hyperglycemia, with decreased levels of HbA1c in comparison to nontreated control rats. This improvement in glycemic control was accompanied by the maintenance of plasma insulin levels and the preservation of pancreatic β-cells with the significant reduction in inflammatory markers. Body fat accumulation was significantly lower in the treatment group, with decreased infiltration of macrophages in the abdominal adipose tissue.

Conclusion: Our findings suggest that the rare sugar d-psicose could be beneficial for the prevention and control of obesity and hyperglycemia with the preservation of β-cells in the progression of T2DM.

Keywords: OLETF rats; adiposity; insulin resistance; rare sugar d-psicose; type 2 diabetes mellitus; β-islet preservation.

Figure 1

Periodic changes in fasting blood glucose (A) and insulin (B) concentrations with long-term treatment with or without rare sugar d-psicose in rats till age 60 weeks. Notes: The O-P group was treated with 5% d-psicose dissolved in drinking water and all the rats were supplied with a standard rat diet. (C–E) show changes in blood sugar and (F–H) show plasma insulin levels during 2-hour oral glucose (2 g/kg body weight in 50% solution) tolerance test. (I–K) show serial changes of HOMA-IR, HOMA-%β, and HOMA-%S. (L) shows changes in postprandial blood glucose levels, and (M) shows HbA_1c levels. ^aRepresents significance versus O-C group. ^bRepresents significance versus O-P group. Values are given as mean ± SD (n=9 for OLETF rats and n=6 for LETO rats). Abbreviations: HbA_1c, hemoglobin A_1c; HOMA, homeostasis model assessment; LETO, Long-Evans Tokushima Otsuka; OGTT, oral glucose tolerance test; OLETF, Otsuka Long-Evans Tokushima Fatty; O-C, OLETF control; O-P, OLETF psicose.

Figure 2

Periodic changes in individual rat body weight of O-C (A) and O-P (B) groups with long-term treatment with or without rare sugar d-psicose in rats till age 60 weeks. Notes: The O-P group was treated with 5% d-psicose dissolved in drinking water, where O-C and non-diabetic LETO were fed drinking water only. All the rats were supplied a standard rat diet. Changes in average body weight (C), quantity of average food intake (D), and average drink intake (E). ^aRepresents significance versus O-C group. ^bRepresents significance versus O-P group. Values are given as mean ± SD (n=9 for OLETF rats and n=6 for LETO rats). Abbreviations: LETO, Long-Evans Tokushima Otsuka; OLETF, Otsuka Long-Evans Tokushima Fatty; O-C, OLETF control; O-P, OLETF psicose.

Figure 3

Periodic changes of blood lipid profile in rats of all groups with long-term treatment with or without rare sugar d-psicose till age 60 weeks. Notes: The O-P group was treated with 5% d-psicose dissolved in drinking water, where O-C and non-diabetic LETO were fed drinking water only. All the rats were supplied standard rat diet. Changes in serum total cholesterol (A), triglyceride (B), FFM and FM (C), BMI (D), HDL (E), and LDL (F) were shown. Data in (G–I) represent wet weight of adipose tissue, number of large adipocytes, and number of total adipocytes, respectively. (J–L) represents HE staining of adipose tissue of O-C (J), O-P (K), and LETO (L) at age 60 weeks. ^aRepresent significance versus O-C group ^bRepresents significance versus O-P group. Values are given as mean ± SD (n=9 for OLETF rats and n=6 for LETO rats). Magnification: ×200. Scale bars: 100 μm. Abbreviations: BMI, body mass index; FM, fat mass; FFM, fat-free mass; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LETO, Long-Evans Tokushima Otsuka; OLETF, Otsuka Long-Evans Tokushima Fatty; O-C, OLETF control; O-P, OLETF psicose; HE, hematoxylin and eosin.

Figure 4

Changes in light microscopic features of pancreas of rats of all groups at week 60 with long-term treatment with or without rare sugar d-psicose. Notes: The O-P group was treated with 5% d-psicose dissolved in drinking water, where O-C and non-diabetic LETO were fed drinking water only. All the rats were supplied a standard rat diet. Changes of the pancreas of O-C (A), O-P (B), and LETO (C) rats stained with HE at age 60 weeks during sacrifice. (A) Islet disorganization with severe fibrosis, atrophy, and markedly infiltrated inflammatory cells. (B) Some islets were enlarged, but minimal fibrosis and infiltration of inflammatory cells were observed in the pancreas in d-psicose-treated rats. (C) Histological changes were absent or rarely observed in the pancreas of nondiabetic control LETO rats. The table adjacent to the HE pictures depicts the number of different-sized islets in all groups, with almost absent intact large and medium-size islets in the O-C group in comparison to O-P and LETO groups. (D–F) show immunofluorescence staining for insulin (red color) stained with anti-insulin antibody and glucagon (green color) stained with antiglucagon antibody to identify the presence and organization of both β- and α-cells in the pancreas at age 60 weeks. (G, H) Serial changes of serum levels of leptin and adiponectin, respectively. (I–K) show serum levels of TNF-α and IL-6 at age 30 weeks, and serum GSH at ages 30 and 60 weeks. ^aSignificant difference versus O-C group at corresponding age ^bSignificant difference versus O-P group at corresponding age. Values are expressed as mean ± SD (n=9 for OLETF rats and n=6 for LETO rats). Magnification: ×40; scale bars: 500 μm (Figures A–C). Magnification: ×200; scale bars: 100 μm (Figures D–F). Abbreviations: GSH, glutathione; HPF, high power field; IL-6, interleukin 6; LETO, Long-Evans Tokushima Otsuka; OLETF, Otsuka Long-Evans Tokushima Fatty; O-C, OLETF control; O-P, OLETF psicose; TNF, tumor necrotic factor; HE, hematoxylin and eosin.

Figure 5

Immunohistochemical staining of CD68-expressing neutrophils (A–C) and F4/80-expressing macrophages (D–F) in adipose tissue of rats of all groups at week 60 with long-term treatment with or without rare sugar d-psicose. Notes: The O-P group was treated with 5% d-psicose dissolved in drinking water, where O-C and non-diabetic LETO were fed drinking water only. All the rats were supplied a standard rat diet. Arrows indicate positive-stained cells for CD68 in O-C (A), O-P (B), and LETO (C), and for F4/80 in O-C (D), O-P (E), and LETO (F). Black circle in D indicates positive-stained cells in the circle. Magnification: ×400. Scale bars: 50 μm. Abbreviations: LETO, Long-Evans Tokushima Otsuka; OLETF, Otsuka Long-Evans Tokushima Fatty; O-C, OLETF control; O-P, OLETF psicose.