Teruhisa Ueda

Nocturnal intermittent hypoxia as an associated risk factor for microalbuminuria in Japanese patients with type 2 diabetes mellitus

OBJECTIVE We estimated the prevalence of nocturnal intermittent hypoxia, a surrogate marker of obstructive sleep apnoea, among type 2 diabetes mellitus (T2DM) patients and examined the association between nocturnal intermittent hypoxia and microvascular diseases. DESIGN AND METHODS We recruited 513 Japanese patients (292 men and 221 women) with T2DM. Nocturnal intermittent hypoxia was diagnosed using the 3% oxygen desaturation index, with less than five events per hour corresponding to normal and five events or more per hour corresponding to nocturnal intermittent hypoxia. RESULTS The prevalence of nocturnal intermittent hypoxia was 45.4% among T2DM patients. The nocturnal intermittent hypoxia group was older and had a higher BMI, greater weight change since the age of 20 years, higher smoking rate and increased prevalence of hypertension, hyperlipidaemia, microalbuminuria and macroalbuminuria. Microalbuminuria (model 1: odds ratio (OR), 3.41; 95% CI, 1.85-6.40; model 2: OR, 3.69; 95% CI, 1.85-7.59 and model 3: OR, 3.12; 95% CI, 1.45-6.95) and nephropathy (model 1: OR, 4.51; 95% CI, 1.58-15.1; model 2: OR, 7.31; 95% CI, 2.11-31.6 and model 3: OR, 5.23; 95% CI, 1.45-23.8) were derived as factors from all the three statistical models and constantly associated with nocturnal intermittent hypoxia only in women. CONCLUSIONS Nocturnal intermittent hypoxia was highly prevalent among T2DM patients and may be an independent associated risk factor for microalbuminuria in Japanese women with T2DM.

A relationship between motilin and growth hormone secretagogue receptors

The motilin receptor (MR) belongs to a family of Class I G protein-coupled receptors that also includes growth hormone secretagogue receptor (GHSR). Their potentially unique structure and the molecular basis of their binding and activation are not yet clear. We previously reported that the perimembranous residues in the predicted extracellular loops and amino-terminal tail of the MR were important for responses to the natural peptide ligand, motilin, and the transmembrane domains of the MR were important for a non-peptidyl ligand, erythromycin. We also reported that the perimembranous residues in the second extracellular loop of the GHSR were critical for natural ligand ghrelin binding and activity. The MR is 52% identical to GHSR, with 86% sequence identity in the transmembrane domains. In the current work, to gain insight into a relationship between MR and GHSR, we studied functional responses to motilin, erythromycin and ghrelin of expression cells of chimeric constructs of MR and GHSR and co-expression cells of both MR and GHSR. We also generated human MR transgenic mice, and clarified a relationship between motilin and ghrelin. MR(1-62)/GHSR(68-366) construct responded only to ghrelin, MR(1-102)/GHSR(108-366) responded to ghrelin and erythromycin, and MR(1-129)/GHSR(135-366) and MR(1-178)/GHSR(184-366) responded to erythromycin, while GHSR(1-183)/MR(179-412) responded to neither motilin, erythromycin nor ghrelin. MR and GHSR co-expression cells have no additional responses to these ligands. Motilin or erythromycin administration to human MR transgenic mice resulted in a decrease of serum acyl-ghrelin levels, while MR and GHSR mRNA expression in the gastrointestinal tracts were not changed. These data suggested that in species expressing both motilin-MR and ghrelin-GHSR, there is a compensatory relationship in vivo.

Nocturia and prevalence of erectile dysfunction in Japanese patients with type 2 diabetes mellitus: The Dogo Study

Several epidemiological studies have reported a positive association between nocturia and erectile dysfunction (ED). Yet only limited evidence exists regarding the association between nocturia and ED among patients with type 2 diabetes mellitus, although nocturia and ED are common among type 2 diabetes mellitus patients.

Mutational analysis of predicted extracellular domains of human growth hormone secretagogue receptor 1a

The Class A family of guanine nucleotide-binding protein (G protein)-coupled receptors that includes receptors for motilin, ghrelin, and growth hormone secretagogue (GHS) has substantial potential importance as drug targets. Understanding of the molecular basis of hormone binding and receptor activation should provide insights helpful in the development of such drugs. We previously reported that Cys residues and the perimembranous residues in the extracellular loops and amino-terminal tail of the motilin receptor are critical for peptide ligand, motilin, binding and biological activity. In the current work, we focused on the predicted extracellular domains of the human GHS receptor 1a, and identified functionally important residues by using sequential deletions ranging from one to twelve amino acid residues and site-directed replacement mutagenesis approach. Each construct was transiently expressed in COS cells, and characterized for ghrelin- and growth hormone releasing peptide (GHRP)-6-stimulated intracellular calcium responses and ghrelin radioligand binding. Cys residues in positions 116 and 198 in the first and second extracellular loops and the perimembranous Glu¹⁸⁷ residue in the second extracellular loop were critical for ghrelin and GHRP-6 biological activity. These results suggest that Cys residues in the extracellular domains in this family of Class A G protein-coupled receptor is likely involved in the highly conserved and functionally important disulfide bond, and that the perimembranous residues contribute peptide ligand binding and signaling.

Serum lipoprotein(a) levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus

AIMS We aimed to evaluate the association between serum lipoprotein(a) [Lp(a)] levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. METHODS This study included 581 patients with type 2 diabetes mellitus. Serum Lp(a) levels were divided into four groups; the cut-off points were at the 30th, 60th, and 90th percentile values on the basis of the distribution for all subjects. Diabetic nephropathy was defined as present when the urinary albumin-creatinine ratio was ≥33.9mg/mmol creatinine and/or the estimated glomerular filtration rate was <30ml/min/1.72m(2). Adjustment was made for age, sex, body mass index, hemoglobin A1c, duration of diabetes mellitus, current drinking, current smoking, hypertension, dyslipidemia, coronary heart disease, and stroke. RESULTS Higher serum Lp(a) levels were significantly associated with a higher prevalence of diabetic nephropathy: the adjusted odds ratios (95% confidence intervals) for diabetic nephropathy in relation to serum Lp(a) levels of ≤6, 7-15, 16-38, and ≥39mg/dl were 1.00 (reference), 2.74 (1.08-7.00), 3.31 (1.28-8.54), and 4.80 (1.57-14.60), respectively (P for trend=0.004). CONCLUSIONS The results suggest that serum Lp(a) levels may be positively associated with diabetic nephropathy among Japanese patients with type 2 diabetes mellitus.

Clinical usefulness of quantitative evaluation of visceral fat by ultrasonography.

PurposeThe aim of this work was to evaluate the usefulness of a proposed method for visceral fat volume assessment by ultrasonography (US) in identifying those at risk of metabolic syndrome, and also to establish the most suitable cutoff level of waist circumference for the diagnosis of visceral adiposity.MethodsOne hundred and fifty-two outpatients with metabolic diseases such as hypertension, diabetes, or dyslipidemia were studied. The total visceral fat volume (total-VFA) was measured by computed tomography (CT), the visceral fat area at the level of the umbilicus was measured by CT (CT-VFA), and the visceral fat area was also measured by US (US-VFA), as we recently proposed.ResultsSignificant correlation coefficients were found between total-VFA and CT-VFA, US-VFA, and waist circumference in men but not in women. The correlation co-efficient between US-VFA and waist circumference was significantly positive in men and weakly positive in women. According to receiver–operator characteristic curves, the cutoff value of waist circumference yielding the maximal sensitivity plus specificity for predicting more than 100 cm2 of US-VFA was 85 cm in men and 84 cm in women. The change in US-VFA was significantly larger than that in waist circumference after a 6-month interval.ConclusionThe US-measured visceral fat area is more useful than waist circumference in a clinical setting.

Critical residues in the transmembrane helical bundle domains of the human motilin receptor for erythromycin binding and activity.

The motilin receptor belongs to a family of Class I G protein-coupled receptors, and is an important endogenous regulator of gastrointestinal motor function. Motilin and erythromycin, two chemically distinct full agonists of the motilin receptor, are known to bind to distinct regions of this receptor, based on previous systematic mutagenesis of extracellular regions that dissociated the effects on these two agents. The action of these different chemical classes of agonists likely yields a common activation state of the cytosolic face of this receptor that is responsible for interaction with its G protein. In the current work, we studied the predicted transmembrane (TM) domains of this receptor for functional responses to motilin and erythromycin. Motilin receptor constructs were prepared in which each residue in the TM domains was mutated to alanine or valine. Each construct was expressed in COS cells and characterized for motilin and erythromycin binding and intracellular calcium responses stimulated by both agonists. Constructs with mutations of residues, Asp94, Leu95, Arg97 and Trp99 in TM2, Ser169 in TM4, and Tyr321 and Glu325 in TM6, were responsible for the negative impact on biological activity stimulated by erythromycin, but had no effect on motilin responses. On the other hand, constructs with mutations of residues, Leu113 in TM3, Pro172 in TM4, Trp250 and Tyr255 in TM5, and Gln334 in TM7, were negatively responsive to both erythromycin and motilin. These data support important roles of new regions in the TM domains of the motilin receptor for erythromycin action, suggesting differential mechanisms of actions by peptidyl and non-peptidyl ligands.

Physical activity and prevalence of erectile dysfunction in Japanese patients with type 2 diabetes mellitus: The Dogo Study

To date, there is no evidence regarding the association between physical activity (PA) and erectile dysfunction (ED) among Japanese patients with type 2 diabetes mellitus. We investigated this issue among Japanese patients with type 2 diabetes mellitus.

Self-reported sitting time and prevalence of erectile dysfunction in Japanese patients with type 2 diabetes mellitus: The Dogo Study

AIMS No evidence exists regarding the association between sitting time and erectile dysfunction (ED) among patients with type 2 diabetes mellitus. The aim of this study was to evaluate the association between self-reported sitting time and ED among patients with type 2 diabetes mellitus. METHODS Study subjects were 430 male Japanese patients with type 2 diabetes mellitus (mean age, 60.5years). A self-administered questionnaire was used to collect information on the variables under study. The study subjects were asked about time spent sitting during typical 24-hour periods over the past 12months. Subjects were divided into four groups according to self-reported sitting time: 1) <5hours, 2) 5-7hours, 3) 7-9hours, and 4) ≥9hours. ED was defined as present when a subject had a Sexual Health Inventory for Men score <8. Adjustment was made for age, body mass index, duration of type 2 diabetes, current smoking, current drinking, hypertension, coronary artery disease, stroke, glycated hemoglobin, walking habit, and diabetic neuropathy. RESULTS The prevalence values of moderate to severe ED and severe ED were 36.1% and 49.8%. At least 9hours sitting was independently positively associated with severe ED but not moderate to severe ED; the adjusted OR was 1.84 (95% CI: 1.06-3.33). In the multivariate model, there was a statistically significant inverse exposure-response relationship between the self-reported sitting time and severe ED (p for trend=0.029). CONCLUSIONS Self-reported sitting time may be positively associated with ED in Japanese patients with type 2 diabetes mellitus.

Macrovascular Complications and Prevalence of Urgency Incontinence in Japanese Patients with Type 2 Diabetes Mellitus: The Dogo Study

Objective Macrovascular diseases and urgency incontinence are common among Japanese patients with type 2 diabetes mellitus. However, little evidence exists regarding the association between stroke and urgency incontinence among patients with type 2 diabetes mellitus. We examined the associations between macrovascular complications and urgency incontinence among Japanese patients with type 2 diabetes mellitus. Methods The study subjects were 818 Japanese patients with type 2 diabetes mellitus. Urgency incontinence was defined as present when a subject answered “once a week or more” to the question: “Within one week, how often do you leak urine because you cannot defer the sudden desire to urinate?” We adjusted our analyses for sex, age, body mass index, duration of type 2 diabetes, current smoking, current drinking, hypertension, dyslipidemia, glycated hemoglobin, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy. Results The prevalence of urgency incontinence was 9.2%. Stroke was independently positively associated with urgency incontinence, with an adjusted odds ratio of 2.34 (95% confidence interval: 1.03-4.95). The associations between ischemic heart disease or peripheral artery disease and the prevalence of urgency incontinence were not significant. Conclusion In Japanese patients with type 2 diabetes mellitus, stroke, but not ischemic heart diseases or peripheral artery disease, was independently positively associated with urgency incontinence.