Seiichiro Hemmi

Complement‐mediated chronic inflammation is associated with diabetic microvascular complication

Chronic inflammation is characteristic of type 2 diabetes mellitus (T2DM). Obesity‐activated adipocytes release adipocytokines, which induce the secretion of proinflammatory cytokines, resulting in vascular endothelial dysfunction and organ injury. C3a is a candidate to induce tissue inflammation.

Diminished complement-activating capacity through the classical pathway in sera from type 2 diabetes mellitus

Complement-activating capacity through the classical pathway in type 2 diabetes mellitus (T2DM) was examined in the context of free sialic acid as a potential modulator of complement activation. Complement-activating capacity was investigated in an incubation study of heat-aggregated IgG (HAG) and sera from 42 T2DM patients. The study demonstrated diminished in-vitro complement-activating capacity through the classical pathway in T2DM. Various doses of N-acetyl neuraminic acid (NANA) were incubated with normal serum and HAG. Complement activation product levels decreased in a NANA dose-dependent manner. Isoelectrofocusing analysis in a mixture of NANA and purified C3 indicated that C3 changed pI dose-dependently, resulting in the downregulation of complement activation. The serum levels of free sialic acid were determined by fluorometric assay in the 42 T2DM sera samples, and were significantly increased in patients with diminished complement activation. These data indicate that increased serum sialic acid may become a candidate for decreasing complement-activating capacity in T2DM.

Persistent Complement Activation is Associated with Insulin Resistance and Chronic Inflammation in Overweight Patients with Type 2 Diabetes with Dyslipidemia

Insulin resistance is a major player in the pathogenesis of type 2 diabetes. C3 converts to C3a and acylation stimulating protein (ASP) by complement activation. ASP activates adipose tissue macrophages and accelerates continuous inflammation. Tissuebound C3a is known to induce insulin resistance. We examined the relationship between insulin resistance and complement activation by the in vivo alteration of ASP. The levels of ASP and parameters of insulin resistance and inflammation were measured in plasma from 25 patients with type 2 diabetes. A selective peroxisome proliferator-activated receptor gamma (PPAR) agonist was administered to these 25 patients for three months, and then ASP and the parameters were measured again. The alterations of ASP and the parameters were examined in the pathophysiological state. Plasma levels of ASP and complement activation products were significantly higher in diabetes. Parameters of insulin resistance were also significantly increased. The ASP level significantly improved after PPAR agonist administration. The improvement in ASP level correlated with improvements in parameters of insulin resistance and inflammation. The levels of other relevant adipocytokines by insulin resistance correlated with the degree of inflammation. ASP and complement activation were associated with insulin resistance and chronic inflammation in diabetes.

DPP4 Inhibitor Decreases Urinary Albumin Excretion in Association with the Improvement of Glomerular Endothelial Injury in Patients with Type 2 Diabetes

Background: Glomerular endothelial injury is commonly encountered in diabetic nephropathy, as in type 2 diabetes mellitus (T2DM). Microalbuminuria is associated with endothelial cell dysfunction, and is a significant risk factor for cardiovascular mortality in diabetes. This study was undertaken to study the effect of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, on microalbuminuria as a mechanism of improving glomerular endothelial injury in patients with T2DM. Methods: Sitagliptin, a DPP4 inhibitor, was administered to twenty patients with T2DM, 50 mg/day, for 8 weeks. Plasma levels of glucose, HbA1c, stromal-cell-derived factor-1 alpha (SDF1α), thrombomodulin (TM), serum creatinine, and urinary albumin/creatinine ratio (ACR) were measured at the start and the end of the study. The alteration patterns were statistically compared and analyzed together with their pathologic states. Another nineteen control patients were enrolled in this study. Results: Sitagliptin treatment resulted in 14% decrease (P=0.0003 vs. control) in HbA1c from 7.2±1.2 to 6.2±1.4%, 74% increase (P<0.0001 vs. control) in SDF1α from 205±70 to 355±80mmol/L, 9% decrease(P=0.0029 vs. control) in TM from 3.2±1.3 to 2.9±1.1FU/mL, 41% decrease (P=0.0095 vs. control) in ACR from 5.5±5.2 to 3.3±4.5mg/mmol. Cr after 8 weeks. Regression analysis revealed a closer relationship between SDF1α and ACR. No remarkable changes were observed in controls. As microalbuminuria represents glomerular endothelial dysfunction, these data suggest the additional effect by DPP4 inhibitor on glomerular endothelial damage. Conclusion: DPP4 inhibitor decreased urinary albumin excretion in association with the improvement of glomerular endothelial injury in patients with T2DM.

A case of ANCA-associated vasculitis with glomerular eosinophilic infiltration : a possible pathogenic implication

We present a 58-year-old male patient with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis. He failed to fulfill the common American College of Rheumatology criteria for eosinophilic granulomatosis with polyangiitis and was tentatively diagnosed with microscopic polyangiitis. Kidney biopsy showed pauci-immune crescentic necrotizing glomerulonephritis with neutrophilic and eosinophilic infiltration. Previous reports implicate eosinophils in the pathogenesis of this disease. Therefore, this case suggests that infiltrated eosinophils as well as neutrophils might play roles in the development of tissue injury in systemic vasculitis.