Yukitaka Ueki

Glucose tolerance, insulin secretion, and insulin sensitivity in nonobese and obese Japanese subjects.

OBJECTIVE To investigate the relative contributions of insulin secretion and insulin resistance to the development of glucose intolerance in Japanese subjects. RESEARCH DESIGN AND METHODS A cross-sectional study of 756 Japanese subjects (530 nonobese, 226 obese) was performed. A 75-g oral glucose tolerance test (OGTT) was given, and subjects were classified according to the World Health Organization (WHO) criteria (normal glucose tolerance [NGT], impaired glucose tolerance [IGT], and diabetes). Early-phase insulin secretion was assessed by the insulinogenic index (the ratio of the increment of insulin to that of plasma glucose [PG] 30 min after a glucose load [ΔIRI0-30 min/Δ PG0-30 min]). Total insulin secretion was assessed by mean immunoreactive insulin (IRI) during the OGTT, and insulin resistance was assessed by use of the homeostasis model [HOMA(R)]. RESULTS Early-phase insulin secretion was significantly decreased in IGT, compared with patients with NGT, in both the nonobese and obese subjects (0.70 ± 0.05 vs. 0.37 ± 0.03, P < 0.01 and 1.36 ± 0.19 vs. 0.73 ± 0.08, P < 0.01, respectively). However, mean IRI and HOMA(R) in both nonobese and obese subjects with IGT and NGT were not statistically different. Subjects with diabetes showed a significant decline in early-phase and total insulin secretion and a significantly higher level of insulin resistance than did subjects with IGT. When the fasting glucose (FPG) exceeded 100 mg/dl, early-phase insulin decreased progressively. The graphed relationship between FPG and mean IRI did not show an inverted U-shape, and mean IRI decreased progressively when FPG exceeded 100–130 mg/dl. The pattern of changes in insulin secretion and insulin resistance associated with the progression of glucose intolerance was similar in both the nonobese and obese subjects. CONCLUSIONS The worsening from NGT to IGT in Japanese subjects may be associated with a decrease in early-phase insulin secretion in nonobese as well as in obese subjects. Hyperinsulinemia in IGT is not common. We suggest that impaired early-phase insulin secretion may be the initial abnormality in the development of glucose intolerance in Japanese people. Insulin resistance may be a consequence of hyperglycemia and/or obesity.

Effects of voglibose on glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients

OBJECTIVE To investigate the effects of voglibose, an α-glucosidase inhibitor, on daily glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients. RESEARCH DESIGN AND METHODS An open prospective study was conducted in 27 NIDDM patients receiving diet therapy alone or treatment with a sulfonylurea drug. Of the study subjects, 14 patients were treated with voglibose; the remaining 13 patients served as the control group. The metabolic parameters were evaluated before treatment and at week 4 of treatment as follows: glycemic excursions by M-value and 1,5-anhydro-D-glucitol (1,5-AG), insulin secretion by area under the curve of daily serum insulin (AUCinsulin), and insulin sensitivity by the K index of the insulin tolerance test (KITT). RESULTS After the study treatment, HbA1c and plasma glucose in the patients who had received voglibose were comparable to those of patients in the control group. M-value was lower in the patients treated with voglibose than in the control subjects (5.7 ± 0.9 vs. 9.8 ± 1.2, P < 0.05). 1,5-AG was higher in the patients treated with voglibose than in the control subjects (12.2 ± 1.0 vs. 8.2 ± 0.7 μg/ml, P < 0.01). A statistically significant decrease in AUCinsuiin occurred after treatment with voglibose (2,223.5 ± 390.6 to 1,546.7 ± 303.4 pmol · l−1 · h, P < 0.05), but no change occurred in the control group (2,364.5 ± 315.4 to 2,464.2 ± 269.3 pmol · l−1 · h, P = 0.60). Insulin sensitivity (KITT) was improved to a statistically significant level in both the patients treated with voglibose and the patients in the control group. KITT in the patients after voglibose treatment was comparable to that of the control group (3.18 ± 0.30 vs. 3.21 ± 0.23%/min, P = 0.94). CONCLUSIONS The results suggest that voglibose lowers the daily glycemic excursions and inhibits overwork of the pancreatic β-cells but has little effect on insulin sensitivity in NIDDM patients.

Serum concentrations of soluble adhesion molecules are related to degree of hyperglycemia and insulin resistance in patients with type 2 diabetes mellitus

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.

Continuation of Methotrexate Resulted in Better Clinical and Radiographic Outcomes Than Discontinuation upon Starting Etanercept in Patients with Rheumatoid Arthritis: 52-week Results from the JESMR Study

Objective. The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA). Methods. In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6–8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score. Results. The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (–0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively). Conclusion. MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103)

Phase III Study of the Efficacy and Safety of Subcutaneous Versus Intravenous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ‐SC) monotherapy to intravenous TCZ infusion (TCZ‐IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease‐modifying antirheumatic drugs (DMARDs).

Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tocilizumab therapy

Objectives We assessed the impact of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following administration of the 23-valent pneumococcal polysaccharide vaccine (PPV23). Methods A total of 190 patients with rheumatoid arthritis (RA) received PPV23. Patients were classified into TCZ (n=50), TCZ + methotrexate (MTX) (n=54), MTX (n=62) and RA control (n=24) groups. We measured serotype-specific IgG concentrations of pneumococcal serotypes 6B and 23F using ELISA and functional antibody activity using a multiplexed opsonophagocytic killing assay, reported as the opsonisation indices (OIs), before and 4–6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in the IgG concentration or as a ≥10-fold or more increase in the OI. Results IgG concentrations and OIs were significantly increased in all treatment groups in response to vaccination. The TCZ group antibody response rates were comparable with those of the RA control group for each serotype. MTX had a negative impact on vaccine efficacy. Multivariate logistic analysis confirmed that TCZ is not associated with an inadequate antibody response to either serotype. No severe adverse effect was observed in any treatment group. Conclusions TCZ does not impair PPV23 immunogenicity in RA patients, whereas antibody responses may be reduced when TCZ is used as a combination therapy with MTX.

Inflammation and insulin resistance are independently related to all-cause of death and cardiovascular events in Japanese patients with type 2 diabetes mellitus.

Insulin resistance (IR)/hyperinsulinemia and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP]) can predict cardiovascular disease. However, because IR and inflammation (IF) have not been evaluated simultaneously, it is not known whether IR and IF are independently related to cardiovascular disease. Furthermore, the combined effect of IR and IF on the prediction of cardiovascular disease is presently unknown. Thus, we measured insulin sensitivity (K index of the insulin tolerance test; KITT) and hs-CRP in 350 Japanese patients with type 2 diabetes, and followed them for 1-7 years (mean, 4.5 years). During the follow-up, 33 patients died and 53 patients developed non-fatal coronary artery disease or stroke (endpoint). Age, systolic blood pressure, current smoking, past history of cardiovascular disease, KITT, and hs-CRP independently and significantly correlated with endpoint. One-S.D. difference was associated with a significant increase of relative risk in KITT (1.45; 95% CI 1.09-1.91) and hs-CRP (1.30; 1.04-1.67). When patients were subdivided to tertile, the relative risk in the highest tertile of KITT was 1.76 (95% CI 1.01-3.11) and hs-CRP was 2.00 (1.03-3.85) compared with the patients with lowest tertile. The relative risk in the highest tertile of both KITT and hs-CRP was 5.32 (1.18-24.0) compared with the lowest tertile of both values. In conclusion, low-grade IF and IR are independently related to all-cause of death and cardiovascular disease in Japanese patients with type 2 diabetes. Coexistence of low-grade IF and IR amplify this effect.

Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis

Objectives We assessed the influence of tocilizumab (TCZ), a humanised monoclonal anti-interleukin-6 receptor antibody, on antibody response following influenza vaccination in patients with rheumatoid arthritis (RA). Methods A total of 194 RA patients received inactive trivalent influenza vaccination (A/H1N1, A/H3N2 and B/B1 strains). All patients were classified into the TCZ (n=62), TCZ+methotrexate (MTX) (n=49), MTX (n=65) and RA control (n=18) groups. Antibody titres were measured before and 4–6 weeks after vaccination using the haemagglutination inhibitory assay. Results For the A/H1N1 and A/H3N2 strains, the TCZ and TCZ+MTX groups achieved fold increases of 9.9–14.5, postvaccination seroprotection rates greater than 70% and seroresponse rates greater than 40%. For the B/B1 strain, seroresponse rates were approximately 30%, but fold increases and seroprotection rates were 5.0–5.4 and greater than 70%, respectively, in these treatment groups. MTX had a negative impact on vaccination efficacy, but adequate responses for protection were nevertheless demonstrated in the MTX group. Neither severe adverse effects nor RA flares were observed. Conclusions TCZ does not hamper antibody response to influenza vaccine in RA patients. Influenza vaccination is considered effective in protecting RA patients receiving TCZ therapy with or without MTX.

Time‐dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis

To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long‐Term Safety (REAL) database.

Removal of LDL from plasma by adsorption reduces adhesion molecules on mononuclear cells in patients with arteriosclerotic obliterance

BACKGROUND There is increasing evidence that immune processes are important in the development of atherosclerosis. We investigated whether low density lipoprotein (LDL) adsorption therapy affected serum cytokine levels and the expression of adhesion molecules on peripheral blood mononuclear cells (lymphocytes and monocytes) in patients with arteriosclerotic obliterance (ASO). METHODS AND RESULTS LDL adsorption therapy was repeated ten times over a period of three months in ten ASO patients. The total serum cholesterol and LDL cholesterol levels were significantly reduced at the end of therapy. This was associated with a significant improvement in Fontaines classification and ankle pressure index. We also measured serum levels of inflammatory cytokines (interleukin-1 beta (IL-1 beta), IL-6 and tissue necrosis factor alpha (TNF-alpha)) and expression of adhesion molecules (lymphocyte function-associated antigen 1 alpha (LFA-1 alpha), LFA-1 beta, CD2, very late antigen (VLA)-4, VLA-5 and CD44) on mononuclear cells in the same patients and a group of healthy subjects. Serum levels of all inflammatory cytokines were markedly higher in ASO patients compared with healthy subjects, but there was no significant difference in the level before and after LDL adsorption. VLA-4 expression on CD3+ cells, but not of other adhesion molecules, was markedly higher in ASO patients compared with healthy subjects. LDL adsorption caused a significant reduction in CD2, VLA4 and VLA-5 expression on CD3+ cells. Furthermore, VLA-4 and VLA-5 expression on monocytes diminished significantly after LDL adsorption. CONCLUSIONS Our results indicate that LDL adsorption-induced immunoregulation is mediated by an indirect stimulatory effect on the immune system. The results suggests that improved peripheral circulation produced by LDL adsorption may reflect improved immune dysfunctions of atherosclerotic lesions in ASO patients.