The α-glucosidase inhibitor miglitol decreases glucose fluctuations and inflammatory cytokine gene expression in peripheral leukocytes of Japanese patients with type 2 diabetes mellitus

Abstract

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.

Introduction

Many patients with type 2 diabetes mellitus are treated with α-glucosidase inhibitors, which inhibit the activity of disaccharidases in the brush border membrane of the small intestine, often in combination with other drugs such as insulin and sulfonylureas. Compared with other oral glucose-lowering drugs, α-glucosidase inhibitors reduce glucose fluctuations by inhibiting postprandial hyperglycemia and are associated with less frequent hypoglycemia. Acarbose, a pseudotetrasaccharide, is a competitive inhibitor of sucrase, glucoamylase, and isomaltase [1], [2], [3], [4]. Voglibose, an N-substituted valiolamine derivative, has been reported to have stronger α-glucosidase inhibitory activity against maltase and sucrase [5]. Studies in animal models of type 2 diabetes mellitus have demonstrated that treatment with these α-glucosidase inhibitors decreased β-cell apoptosis and inhibited the attachment of macrophages to the vascular endothelium [6], [7], [8]. Furthermore, the epidemiologic studies Meta-analysis of Risk Improvement under Acarbose (MeRIA7) and Study TO Prevent Non-insulin-dependent diabetes mellitus (STOP-NIDDM) revealed that inhibition of postprandial hyperglycemia by acarbose in patients with type 2 diabetes mellitus or impaired glucose tolerance helped prevent the development and progression of type 2 diabetes mellitus and complications such as cardiovascular disease [9], [10], [11], [12], [13]. These findings indicate that treating type 2 diabetes mellitus patients with α-glucosidase inhibitors helps to prevent or delay the development and progression of type 2 diabetes mellitus and complications such as atherosclerosis. Miglitol, a 1-deoxynojirimycin derivative that was recently approved in Japan, is another antihyperglycemic agent [14]. Miglitol is a strong inhibitor of glucoamylase, sucrase, and isomaltase, and is absorbed from the small intestine, unlike other α-glucosidase inhibitors [15]. Using animal models of type 2 diabetes mellitus, it has been reported that miglitol decreased β-cell apoptosis and inhibited the attachment of macrophages to the vascular endothelium [16], [17]. Miglitol elicits greater reductions in the 1-hour postprandial glucose level and glucose fluctuations than other α-glucosidase inhibitors because it can be given to patients at relatively high doses with a low incidence of digestive symptoms such as diarrhea [16]. Therefore, it is expected that miglitol will reduce the development and progression of type 2 diabetes mellitus and its complications by achieving greater reductions in glucose fluctuations than other α-glucosidase inhibitors.

Several recent studies have suggested that the major molecular mechanisms involved in the development/progression of type 2 diabetes mellitus and its complications include oxidative stress, viral/bacterial infection, and activation of leukocytes such as monocytes and macrophages. Collectively, these responses are referred to as inflammation[9]. Indeed, hyperglycemia directly induces inflammation by enhancing inflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-12, and IL-18, which are mainly expressed by leukocytes, including macrophages, monocytes, and neutrophils, and by many peripheral tissues [18], [19], [20]. In addition, several studies have demonstrated that the S100 family of proteins, including S100a4, S100a6, S100a8, S100a9, and S100a12, are not only putative inflammatory cytokines that are predominantly expressed in monocytes and neutrophils, but also useful diagnostic inflammatory markers for type 1 and 2 diabetes mellitus [21], [22], [23]. The S100a8-9 heterodimer induces the expression of other cytokines such as IL-1β and IL-6 in leukocytes by activating G-protein-coupled receptor/tyrosine receptor through binding to the advanced glycation end-product receptor [24]. Thus, decreasing the expression of these cytokines/cytokine-like factors and decreasing leukocyte activation may reduce the development and progression of type 2 diabetes mellitus and its complications. A recent study in obese Japanese subjects showed that a single dose of miglitol at mealtime suppressed postprandial elevations of glucose and plasma IL-6 levels more effectively than acarbose [25]. However, the long-term effects of α-glucosidase inhibitors, including miglitol, on plasma cytokines/cytokine-like factors have not yet been studied. Using hyperglycemic rats, we recently demonstrated that dietary supplementation with miglitol for 3 weeks reduced glucose fluctuations and the gene expression of IL-1β, TNFα, and S100 proteins such as S100a4/a6/a8/a9 in peripheral leukocytes [26], [27]. However, whether the expression of these genes in peripheral leukocytes is down-regulated by reducing glucose fluctuations with miglitol in patients with type 2 diabetes mellitus has not been determined.

In this study, we enrolled patients with type 2 diabetes mellitus with hemoglobin A_1c (HbA_1c) values ranging from 6.5% to 7.9% who were being treated with a high dose of the α-glucosidase inhibitors acarbose or voglibose in combination with insulin or a sulfonylurea. Their prior α-glucosidase inhibitors were switched to a medium-strength dose of miglitol, which was administered for 3 months. We hypothesized that switching from acarbose or voglibose to miglitol in type 2 diabetes mellitus patients would reduce glucose fluctuations and the gene expression of inflammatory cytokines/cytokines-like factors in peripheral leukocytes.