Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes mellitus, exhibit chronic and slowly progressive hyperglycemia with obesity. In this study, we examined whether dietary supplementation with the α-glucosidase inhibitor miglitol from the preonset stage improves glycemic control and reduces the gene expression of inflammatory cytokines in peripheral leukocytes. The OLETF rats were fed a control diet or a diet containing 800 ppm miglitol (miglitol diet) for 40 weeks from 5 weeks of age (preonset stage). We determined nonfasting blood glucose, blood 1,5-anhydroglucitol, and messenger RNA levels of inflammatory cytokines in peripheral leukocytes in these rats. Nonfasting blood glucose concentrations gradually increased in OLETF rats fed the control diet, with significant increases at weeks 28 and 40 compared with week 0. In contrast, nonfasting blood glucose levels did not increase in miglitol-treated rats during the experimental period. Miglitol-treated rats had lower nonfasting blood glucose levels and higher 1,5-anhydroglucitol levels, a marker for glucose fluctuations, at week 40 than control rats. The gene expression of inflammatory cytokines including interleukin-6, tumor necrosis factor-α, and interferon-γ in peripheral leukocytes gradually increased during the development of diabetes in control rats, but not in miglitol-treated rats. Our results suggest that dietary supplementation with miglitol from the preonset stage in OLETF rats improves glycemic control and reduces gene expression of cytokines related to inflammation in peripheral leukocytes.

In this study, we examined the effects of switching from acarbose or voglibose to miglitol in type 2 diabetes mellitus patients for 3 months on gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes and on glucose fluctuations. We enrolled 47 Japanese patients with type 2 diabetes mellitus, aged 26 to 81 years, with hemoglobin A(₁c) levels ranging from 6.5% to 7.9% and who were treated with the highest approved dose of acarbose (100 mg per meal) or voglibose (0.3 mg per meal) in combination with insulin or sulfonylurea. Their prior α-glucosidase inhibitors were switched to a medium dose of miglitol (50 mg per meal), and the new treatments were maintained for 3 months. Forty-three patients completed the 3-month study and were analyzed. The switch to miglitol for 3 months did not affect hemoglobin A(₁c), fasting glucose, triglycerides, total cholesterol, or C-reactive protein levels, or adverse events other than hypoglycemia symptoms. Hypoglycemia symptoms and glucose fluctuations were significantly improved by the switch. The expression of interleukin-1β, tumor necrosis factor-α, and S100a4/6/9/10/11/12 genes in peripheral leukocytes, and the serum tumor necrosis factor-α protein levels were suppressed by switching to miglitol. Miglitol reduces glucose fluctuations and gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes of type 2 diabetes mellitus patients more than other α-glucosidase inhibitors and with fewer adverse effects.

β(2) integrins (CD11s/CD18) promote the attachment of leukocytes to vascular endothelial cells. We performed in this study sucrose loading to rats with moderate postprandial hyperglycemia with/without once-daily dosing of the α-glucosidase inhibitor, miglitol, for 4 days under 4-h fasting conditions. The streptozotocin (STZ)-treated rats showed moderate postprandial hyperglycemia on days 1 and 4. The gene expression was higher for CD11a with fasting and 3-h postprandial on day 1, and with fasting on day 4, for CD11b with fasting on day 1 and 3-h postprandial on day 4, and for CD18 with fasting on days 1 and 4 in peripheral leukocytes from the STZ-treated rats than in peripheral leukocytes from the saline-treated rats. Miglitol reduced postprandial hyperglycemia and the gene expression of CD11a with fasting and of CD11b 3-h postprandial on day 4. These results indicate that inhibiting postprandial hyperglycemia reduced the mRNA expression of β(2) integrins in peripheral leukocytes of moderately postprandial hyperglycemic rats.

Postprandial hyperglycemia is thought to cause inflammation in many tissues. In this study, we examined whether the gene expression of inflammatory cytokines in peripheral leukocytes are altered by chromic and/or acute postprandial hyperglycemia. Seven‐week‐old male Sprague‐Dawley rats received a high‐fat (64 energy%) diet for 77 days to induce an insulin resistance. Blood was collected from tail vein, and the total RNA extracted from peripheral leukocytes was subjected to microarrays and real‐time RT‐PCR. In another experiment, rats treated with streptozotocin (35 mg/kg BW) received an oral dose of sucrose (2 g/kg BW) in the presence or absence of α‐glucosidase inhibitor, miglitol, and the gene expressions of peripheral leukocytes were analyzed thereafter. Microarray analysis of the genes in peripheral leukocytes showed that rats with chronic postprandial hyperglycemia had greater expressions of the genes coding inflammatory cytokines (IL‐1β, S100 a8/a9) and those related to host defense. Oral sucrose loading in rats with glucose intolerance led to a 2‐fold increase in IL‐1β and TNF‐α mRNA levels in peripheral leukocytes within 3h, which was abolished by addition of miglitol to the sucrose solution. These results suggest that both chromic and acute postprandial hyperglycemia enhances the gene expression of inflammatory cytokines in peripheral leukocytes.

OBJECTIVE:Postprandial hyperglycemia is thought to cause inflammation in many tissues. In this study, we examined whether the gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes are altered by feeding streptozotocin-treated rats a diet containing an alpha-glucosidase inhibitor, miglitol. METHODS:Upregulated gene expression in peripheral leukocytes of streptozotocin-induced hyperglycemic rats was determined by microarray analysis. We examined whether gene expression was altered by supplementing the diet with miglitol. RESULTS:Microarray analysis revealed that gene expression of interleukin-1beta and putative inflammatory cytokines, S100a4/6/8/9, was induced by streptozotocin treatment. Dietary supplementation with miglitol to the streptozotocin-induced hyperglycemic rats for 20 d not only increased plasma concentrations of a marker for glucose fluctuations, 1,5-anhydroglucitol, the concentration of which is decreased by sustained or postprandial elevated blood glucose levels, but also suppressed the induction of interleukin-1beta and S100a4/6/8/9 genes by hyperglycemia. CONCLUSION:These results suggest that miglitol inhibits the gene expression of inflammatory cytokines/cytokine-like factors in peripheral leukocytes by suppressing glucose fluctuations.

Postprandial hyperglycaemia is thought to increase inflammation in leucocytes. In the present study, we examined whether sucrose loading in rats with moderate postprandial hyperglycaemia induces the expression of cytokines in peripheral leucocytes and whether these inductions are suppressed by inhibiting postprandial hyperglycaemia with the α-glucosidase inhibitor miglitol. One group of streptozotocin-treated rats and age-matched saline-treated rats were orally administered sucrose only, and another group of streptozotocin-treated rats was administered sucrose with miglitol, at a single daily dose for 4 d, under 4 h fasting conditions. Blood glucose levels at 0, 0·25, 0·5, 1, 2 and 3 h and cytokine mRNA in peripheral leucocytes at 0 and 3 h after sucrose loading on days 1 and 4 from the start of sucrose loading were determined. Streptozotocin-treated rats showed moderate postprandial hyperglycaemia (>2000 mg/l) at 0·25–1 h after sucrose loading on days 1 and 4. Postprandial hyperglycaemia was not observed in the miglitol-treated rats loaded with sucrose. Gene expression levels of IL-1β and TNF-α were higher in the streptozotocin-treated rats at fasting on day 1 than in saline-treated rats. Fasting IL-1β and TNF-α gene expression on day 1 were not only increased at 3 h on the same day of sucrose loading, but was also increased at the fasting period on day 4. These inductions on day 4 by intermittent sucrose administration were inhibited by miglitol. The present results suggest that miglitol decreases postprandial hyperglycaemia and intermittent sucrose-induced expression of the IL-1β and TNF-α genes in rat peripheral leucocytes.

The Otsuka Long–Evans Tokushima Fatty (OLETF) rat, an animal model of type 2 diabetes, exhibits obesity, hyperglycemia and hyperlipidemia, with late onset of chronic and slowly progressive hyperinsulinemia. In this study, we examined effects of long-term dietary supplementation with the α-glucosidase inhibitor miglitol on the development of diabetes and the reduction of β-cells in the pancreas of OLETF rats. The OLETF rats were fed a control diet or a diet containing 800ppm miglitol (miglitol diet) for 65weeks from pre-onset stage (5weeks old). The non-fasting blood glucose concentrations gradually increased in OLETF rats fed the control diet and, at week 64, were significantly higher than those in OLETF rats fed the miglitol diet and age-matched Long–Evans Tokushima Otsuka (LETO) rats, which are control, non-diabetic, non-obese rats of the same strain. Oral glucose tolerance tests revealed that OLETF rats fed the control diet showed pronounced impaired glucose tolerance, but those fed the miglitol diet did not. Furthermore, insulin concentrations after glucose-loading were significantly lower in OLETF rats fed the control diet than in those fed the miglitol diet. The islets of 65-week-old OLETF rats fed the control diet showed significant fibrosis and loss of β-cells, while those of age-matched control LETO rats had a normal appearance. Feeding OLETF rats a miglitol diet reduced fibrosis and the loss of β-cells. Our results suggest that dietary supplementation with miglitol from pre-onset stage in OLETF rats delays the onset and development of diabetes and preserves the insulin secretory function of pancreatic islets.