Masanori Emoto

Impact of Glycemic Control on Survival of Diabetic Patients on Chronic Regular Hemodialysis: A 7-Year Observational Study

OBJECTIVE—To investigate the impact of glycemic control during regular hemodialysis on the survival of diabetic patients with chronic kidney disease (CKD) in a longitudinal observational study. RESEARCH DESIGN AND METHODS—A total of 114 diabetic CKD patients on hemodialysis at Inoue Hospital (Suita, Japan) were surveyed from May 1995 to December 2002 (survey period 45.5 ± 29.3 [means ± SD] months). All subjects were categorized into three groups by mean HbA1c (A1C) level during the 3-month period on hemodialysis preceding entry, as follows: good (A1C <6.5%, 5.7 ± 0.4%, n = 34), fair (6.5 ≤ A1C < 8.0%, 7.2 ± 0.4%, n = 39), and poor (A1C ≥8.0%, 9.2 ± 0.9%, n = 41) A1C groups. RESULTS—There were no significant differences in age at entry, initiation of hemodialysis, duration of hemodialysis, blood pressure, cardiothoracic ratio, serum creatinine level, or hemoglobin level among the three groups. The cumulative survival of the poor A1C group during the survey was significantly lower than that of the fair and good A1C groups as determined by Kaplan-Meier estimation (P = 0.041, log-rank test). In a multivariate Cox proportional hazard model, both poor A1C group (hazard ratio 2.889, P = 0.010) and mean A1C (1.260 per 1.0%, P = 0.003) were significant predictors of survival. CONCLUSIONS—In diabetic CKD patients on regular hemodialysis, poor glycemic control is an independent predictor of prognosis. This finding indicates the importance of careful management of glycemic control even after initiation of hemodialysis.

Stiffness indexes beta of the common carotid and femoral arteries are associated with insulin resistance in NIDDM

OBJECTIVE To investigate the association between arterial wall stiffness indexes β of the common carotid artery (CCA) and the femoral artery (FA) and insulin resistance in NIDDM subjects in a cross-sectional study. RESEARCH DESIGN AND METHODS We evaluated the arterial stiffness indexes β of CCA and FA using an ultrasonic phase-locked echo-tracking system in 60 NIDDM subjects attending the diabetes center in Osaka City University Hospital, compared with 120 ageand sex-matched control subjects. Insulin sensitivity indexes were evaluated using a euglycemic-hyperinsulinemic clamp. RESULTS Stiffness indexes β of both CCA and FA were significantly higher in NIDDM subjects than in control subjects (CCA 18.1 ± 0.9 vs. 11.7 ± 0.3, respectively, P < 0.001; FA 35.7 ± 2.3 vs. 23.7 ± 0.8, respectively, P < 0.001). The mean insulin sensitivity index in NIDDM subjects was 4.69 ± 0.29 mg · kg−1 · min−1 · mU−1 · 1. The stiffness indexes β of both CCA and FA were inversely correlated with insulin sensitivity indexes (CCA r = −0.393, P = 0.002; FA r = −0.329, P = 0.010), as well as with age, duration of diabetes, and mean blood pressure. In stepwise multiple regression analyses, insulin sensitivity index and duration of diabetes were identified as significant independent variables for stiffness indexes 3 in both CCA and FA (CCA R2 = 0.249, P = 0.0003; FA R2 = 0.336, P < 0.0001). CONCLUSIONS Arterial stiffness indexes β of CCA and FA were associated with insulin resistance in NIDDM subjects.

Leptin is associated with vascular endothelial function in overweight patients with type 2 diabetes

BackgroundThe adipocyte-derived hormone leptin plays a key role in the regulation of appetite and body weight. Recent studies have suggested that leptin is also involved in the pathogenesis of obesity-related atherosclerosis and cardiovascular disease. In this study, we investigated the association of plasma leptin levels with vascular endothelial function in lean and overweight patients with type 2 diabetes.MethodsOne hundred seventy-one type 2 diabetic patients, of which 85 were overweight (body mass index (BMI) ≥ 25xa0kg/m2), were enrolled in this cross-sectional study. Plasma leptin concentrations were measured by enzyme-linked immunosorbent assay. Flow-mediated dilatation (FMD) of the brachial artery was measured to evaluate vascular endothelial function using ultrasound.ResultsNo significant difference in FMD was found between the lean and overweight groups (7.0 ± 3.8% and 6.5 ± 3.6%, respectively; p = 0.354). FMD was negatively correlated with age (r = −0.371, p < 0.001) and serum creatinine levels (r = −0.236, p = 0.030), but positively correlated with BMI (r = 0.330, p = 0.002) and plasma leptin levels (r = 0.290, p = 0.007) in the overweight group. FMD was not associated with any parameters in the lean group. Multiple regression analysis including possible atherosclerotic risk factors revealed that the plasma leptin level (β = 0.427, p = 0.013) was independently associated with FMD in the overweight group (R2 = 0.310, p = 0.025), but not the lean group.ConclusionPlasma leptin levels are associated with vascular endothelial function in overweight patients with type 2 diabetes.

Direct Inhibitory Effects of Pioglitazone on Hepatic Fetuin-A Expression

Fetuin-A, a circulating glycoprotein synthesized in the liver, is involved in insulin resistance and type 2 diabetes. However, regulation of fetuin-A synthesis has remained obscure. We previously reported that pioglitazone treatment significantly reduced serum fetuin-A levels in patients with type 2 diabetes. To clarify whether pioglitazone can directory inhibit hepatic fetuin-A synthesis, we investigated the effects of pioglitazone on fetuin-A expression both in vitro and in vivo. Pioglitazone treatment suppressed mRNA and protein expression of fetuin-A in Fao hepatoma cells. Interestingly, rosiglitazone but not metformin, also inhibited fetuin-A expression. In addition, GW 9662, an inhibitor of peroxisome proliferator-activated receptor (PPAR) γ, reversed pioglitazone-induced suppression of fetuin-A, suggesting that thiazolidinedione derivatives may have common characteristics with regard to fetuin-A suppression, possibly through PPARγactivation. Finally, oral administration of pioglitazone to mice for 8 weeks resulted in suppression of hepatic fetuin-A mRNA. These findings suggest that pioglitazone may partially ameliorate insulin resistance through its direct inhibitory effects on fetuin-A expression in the liver.

Improved glycemic control with teneligliptin in patients with type 2 diabetes mellitus on hemodialysis: Evaluation by continuous glucose monitoring

AIMSnRecent reports suggest that appropriate glycemic control without hypoglycemia could decrease mortality in patients with diabetes mellitus (DM) and end-stage renal disease (ESRD). However, an indication of oral anti-diabetic drugs is limited in this population. The aim of this study was to evaluate efficacy of teneligliptin, a novel DPP-4 inhibitor, by continuous glucose monitoring (CGM) in patients with type 2 DM (T2DM) on hemodialysis (HD).nnnMETHODSnThis 4-week, open label, single arm, intervention trial included 10 diabetic patients undergoing HD and with glycated albumin (GA) level of ≥18.3%. Teneligliptin treatment was administered on days with HD sessions (HD day) and on days without HD sessions (NHD day); blood glucose values were measured by CGM. The primary endpoint was improvement of glycemic control evaluated by area under the curve (AUC). As secondary endpoints, changes in GA, HbA1c and fasting plasma glucose (FPG) were evaluated.nnnRESULTSnTeneligliptin improved blood glucose AUC on both HD days (p=0.004), and NHD days (p=0.004). This was accompanied by a significant reduction in GA, HbA1c, and FPG, without severe hypoglycemia.nnnCONCLUSIONSnTeneligliptin is one of the useful options for glycemic control in T2DM patients undergoing HD.

Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells

BACKGROUNDnFetuin-A is a liver-derived circulating protein that has potent calcification-inhibitory activity. Uraemic patients exhibit decreased serum fetuin-A levels, increased vascular calcification and elevated cardiovascular mortality. Because the mechanisms for fetuin-A deficiency are unknown, we hypothesized that some uraemic toxins suppressed hepatic fetuin-A production, which resulted in accelerated vascular calcification and poor outcome. Among these potential candidates, indoxyl sulfate (IS) has highly toxic properties.nnnMETHODSnWe examined the direct effects of IS on hepatic fetuin-A expression using the human hepatoma HepG2 cell line.nnnRESULTSnIS, but not p-cresyl sulfate, suppressed the mRNA and protein expression of fetuin-A in a dose- and time-dependent manner. As reported previously, IS stimulated p38 MAPK phosphorylation and reactive oxygen species (ROS) production, although the knockdown of p38 and inhibition of ROS generation had no effect on IS-induced fetuin-A suppression. Then, because IS is a potent endogenous ligand of the aryl hydrocarbon receptor (AhR), we assessed whether IS suppresses fetuin-A production via AhR. The knockdown of AhR prevented IS-induced fetuin-A suppression. However, some attention should be paid to no effect of IS on fetuin-A expression in mouse and human primary cultured hepatocytes.nnnCONCLUSIONSnThese findings suggest that IS could suppress hepatic fetuin-A expression by activating AhR, suggesting a relationship between uraemia and fetuin-A deficiency.

Advantage of insulin glulisine over regular insulin in patients with type 2 diabetes and severe renal insufficiency.

OBJECTIVESnTo compare the efficacy and safety of insulin glulisine over regular insulin in patients with type 2 diabetes and severe renal insufficiency.nnnSUBJECTSnOur study included 18 patients with type 2 diabetes and a mean (range) estimated glomerular filtration rate of 13.2 mL/minute/1.73 m(2) (5.8-27.6), which corresponds to stage 4-5 chronic kidney disease.nnnDESIGNnAfter titration of doses, regular insulin was administered thrice daily on Day 1, along with continuous glucose monitoring for 24 h starting at 7 am. Exactly equal doses of insulin glulisine were administered on Day 2. Area under the curve (AUC) for blood glucose level variation after breakfast (AUC-B 0-4), lunch (AUC-L 0-6), and dinner (AUC-D 0-6) were evaluated.nnnRESULTSnAUC-B 0-4 and AUC-D 0-6 were significantly lower with insulin glulisine than with regular insulin (AUC-B 0-4: 3.3 ± 4.7 vs. 6.2 ± 5.4 × 10(2) mmol/L·minute, respectively, P = .028; AUC-D 0-6: 1.8 ± 7.3 vs. 6.5 ± 6.2 × 10(2) mmol/L·minute, respectively, P = .023). In contrast, AUC-L 0-6 was higher with insulin glulisine than with regular insulin (AUC-L 0-6: 7.6 ± 6.4 vs. 4.2 ± 8.7 × 10(2) mmol/L·minute, respectively, P = .099), suggesting a prolonged hypoglycemic action of regular insulin after lunch.nnnCONCLUSIONSnInsulin glulisine effectively suppressed postprandial hyperglycemia, whereas regular insulin caused a prolonged hypoglycemic action. These findings support the effectiveness and safety of insulin glulisine in patients with type 2 diabetes and severe renal insufficiency.

Linagliptin monotherapy compared with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis: a 12-week randomized trial

Objective Focusing on efficacy and tolerability, we compared linagliptin monotherapy with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis (HD). Research design and methods In this multicenter, randomized, open-label, parallel-group, active-controlled study, 78 patients were randomized (1:1) to receive a 12-week treatment with 5u2005mg linagliptin once daily or 0.2u2005mg voglibose three times a day. To assess whether linagliptin was superior to voglibose, the primary efficacy end point was the change in glycated hemoglobin (HbA1c) level between baseline and week 12. Secondary efficacy end points included changes between baseline and week 12 in glycated albumin (GA) and casual plasma glucose (PG) levels. Results At week 12, the adjusted mean HbA1c levels had decreased by −0.60% after treatment with linagliptin and by −0.20% after treatment with voglibose (treatment difference: −0.40%, 95% CI −0.74% to −0.06%, p=0.022). A significant reduction in casual PG level was also observed after treatment with linagliptin compared with treatment with voglibose. Relative to voglibose, linagliptin tended to elicit reductions in GA, although without statistical significance. No hypoglycemic symptoms or severe hypoglycemia occurred during the study. Conclusions In patients with type 2 diabetes undergoing HD, linagliptin monotherapy provided significantly better glycemic control without severe hypoglycemia than voglibose monotherapy. Linagliptin represents a promising agent for glycemic management in patients with type 2 diabetes undergoing HD. Trial registration number UMIN000007635; results.