Comparison of urethral sling surgery and non-ablative vaginal Erbium:YAG laser treatment in 327 patients with stress urinary incontinence: a case-matching analysis.

Stress urinary incontinence (SUI) occurs when abdominal pressure, such as from coughing or sneezing, causes urine leakage. We retrospectively compared tension-free vaginal tape (TVT) and non-ablative vaginal Erbium:YAG laser treatment (VEL) by propensity score (PS) analysis in women with SUI. No PS analysis studies have investigated urethral sling surgery using polypropylene TVT and VEL for SUI. Data from patients aged 35-50 years who were treated for SUI and registered at several institutions were selected. Patients with medical records covering 1 year for the 1-h pad test, who completed the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and the Overactive Bladder Symptom Score (OABSS), were included. We analyzed 102, 113, and 112 patients in the TVT, VEL, and control groups, respectively. Compared with the control group, the TVT and VEL groups exhibited significant improvement in the 1-h pad test and ICIQ-SF. In the PS analysis, the TVT and VEL groups similarly improved in the 1-h pad test and ICIQ-SF. As for the OABSS, the VEL group showed significantly greater improvement than the TVT group. In the odds ratio analysis for the 1-h pad test, no differences in any of the parameters were observed between TVT and VEL. VEL may be considered an alternative to TVT for SUI treatment.

Genome-wide association study identifies three novel loci for type 2 diabetes.

Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.

A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations.

To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.

Risk Classification for Metabolic Syndrome and the Incidence of Cardiovascular Disease in Japan With Low Prevalence of Obesity: A Pooled Analysis of 10 Prospective Cohort Studies.

Background It is uncertain whether risk classification under the nationwide program on screening and lifestyle modification for metabolic syndrome captures well high-risk individuals who could benefit from lifestyle interventions. We examined the validity of risk classification by linking the incidence of cardiovascular disease (CVD). Methods and Results Individual-level data of 29 288 Japanese individuals aged 40 to 74 years without a history of CVD from 10 prospective cohort studies were used. Metabolic syndrome was defined as the presence of high abdominal obesity and/or overweight plus risk factors such as high blood pressure, high triglyceride or low high-density lipoprotein cholesterol levels, and high blood glucose levels. The risk categories for lifestyle intervention were information supply only, motivation-support intervention, and intensive support intervention. Sex- and age-specific hazard ratios and population attributable fractions of CVD, which were also further adjusted to consider non-high density lipoprotein cholesterol levels, were estimated with reference to nonobese/overweight individuals, using Cox proportional hazard regression. Since the reference category included those with risk factors, we set a supernormal group (nonobese/overweight with no risk factor) as another reference. We documented 1023 incident CVD cases (565 men and 458 women). The adjusted CVD risk was 60% to 70% higher in men and women aged 40 to 64 years receiving an intensive support intervention, and 30% higher in women aged 65 to 74 years receiving a motivation-support intervention, compared with nonobese/overweight individuals. The population attributable fractions in men and women aged 40 to 64 years receiving an intensive support intervention were 17.7% and 6.6%, respectively, while that in women aged 65 to 74 years receiving a motivation-support intervention was 9.4%. Compared with the supernormal group, nonobese/overweight individuals with risk factors had similar hazard ratios and population attributable fractions as individuals with metabolic syndrome. Conclusions Similar CVD excess and attributable risks among individuals with metabolic syndrome components in the absence and presence of obesity/overweight imply the need for lifestyle modification in both high-risk groups.

Longitudinal examination of pancreatic ß-cell function in Japanese individuals.

AIMS/INTRODUCTION: We carried out a retrospective, longitudinal analysis of ß-cell function between a diabetes mellitus group, including those that progressed to diabetes mellitus during the follow-up period, and a diabetic type with glycated hemoglobin (HbA1c) <6.5 group, including those that progressed to a diabetic type during the follow-up period. ß-Cell function was assessed using homeostasis model of assessment of ß-cell function. MATERIALS AND METHODS: The relationship between the duration of diabetes mellitus or the diabetic type and pancreatic ß-cell function was compared between the diabetes mellitus group (1,817) and diabetic type with HbA1c <6.5 group (1,843) using results from an oral glucose tolerance test. Linear mixed effects models were used to analyze repeated measurements of oral glucose tolerance tests. RESULTS: The slope of the regression line of ß-cell function for the duration of the diabetes mellitus group was -2.2%/year before the diagnosis. The slope differed after the diagnosis, and the difference was 1.3. The slope of the diabetic type group was -1.2%/year, and no significant difference was observed in the slope before and after the diagnosis. ß-Cell function at the onset was 54.3% in the diabetic type group and 40.6% in the diabetes mellitus group, and the slope of the regression line was significantly higher in the diabetes mellitus group. We divided the diabetes mellitus and diabetic type with HbA1c <6.5 groups into obese and non-obese participants. ß-Cell function declined more with obesity. CONCLUSIONS: Subsequent declines in ß-cell function were faster in the diabetes mellitus group than that in the diabetic type with HbA1c <6.5 group, and increased with obesity.

Increased cancer mortality among Japanese individuals with hyperinsulinemia.

AIMS: To evaluate the effect of hyperinsulinemia on cancer death, we clarified the association between hyperinsulinemia and cancer mortality among Japanese individuals. METHODS: All the participants (5586 men and 6652 women) lived in Hiroshima City, underwent a 75 g oral glucose tolerance test between 1994 and 2012, and were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. RESULTS: During the follow-up period (median, 10.0 years), 587 participants died of cancer. Lung cancer was the most common cause of organ-specific death. We divided the participants into 3 groups according to the tertiles of fasting immunoreactive insulin (FIRI) levels (low, middle, and high groups). The high group had the highest mortality rate (5.5 per 1000 person-years). The hazard ratio (HR) for cancer mortality of the high group after adjustment for possible confounders, such as age, sex, body mass index, smoking status, alcohol intake, and radiation effects (model 1), was significantly higher than that of the low group (HR, 1.55; 95% confidence interval (CI), 1.23-1.95). In model 2 (model 1 plus fasting plasma glucose) and model 3 (model 1 plus HbA1c), the multivariate HRs for cancer mortality were 1.46 (95% CI, 1.15-1.85) and 1.48 (95% CI, 1.17-1.87), respectively.The HR for cancer death at high FIRI levels (per 1 µU/mL) was 1.04 (95% CI, 1.02-1.05) in all participants after adjusting for fasting plasma glucose level and other confounders. In the subgroup analysis, the HRs were 1.03 (95% CI, 0.98-1.09), 1.05 (95% CI, 1.02-1.08), and 1.04 (95% CI, 1.02-1.06) in the normal, prediabetes, and diabetes group, respectively. CONCLUSIONS: Hyperinsulinemia was associated with a high risk of cancer mortality and may be an important link between cancer mortality and diabetes or prediabetes.

Association between a biomarker of glucose spikes, 1,5-anhydroglucitol, and cancer mortality.

INTRODUCTION: 1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose spikes. To evaluate the effect of acute glucose excursions on cancer death, we clarified the association between 1,5-AG and cancer mortality among Japanese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: We measured 1,5-AG in 6783 (2842 men, 3941 women) individuals with normal fasting and 2-hour plasma glucose who received a 75 g oral glucose tolerance test between 1994 and 2012. They were followed for mortality until August 2013. A systematic review of death certificates was used to confirm the cause of death. We divided the participants into four groups according to the quartile of 1,5-AG level at registration. We used Cox regression to clarify the association between 1,5-AG levels and cancer mortality with multivariate adjustment for possible confounders. RESULTS: During the follow-up period (median, 10.0 years), 140 men and 109 women died of cancer. The HR for cancer mortality of the lowest quartile group was higher than that of the highest quartile group in men (HR, 2.62; 95% CI, 1.60 to 4.41) and in women (HR, 1.47; 95% CI, 0.88 to 2.47). These associations were not attenuated with further adjustment for HbA1c. CONCLUSIONS: 1,5-AG was associated with high risk of cancer mortality in Japanese men after adjustment for HbA1c.

Is there any association between subcutaneous adipose tissue area and plasma total and high molecular weight adiponectin levels?

This study was conducted for the purpose of clarifying the correlations between the subcutaneous adipose tissue area and plasma total and high-molecular weight (HMW) adiponectin levels. The subjects of this study comprised 359 men and 142 women who underwent general health examinations from October 2005 to December 2006. The abdominal subcutaneous and visceral adipose tissue areas were measured using low-dose x-ray computed tomography. Total and HMW adiponectin levels were measured using the enzyme-linked immunosorbent assay system based on a monoclonal antibody to humans. There were negative correlations between the plasma total and HMW adiponectin levels and visceral and subcutaneous adipose tissue areas using simple correlation analysis. Multiple linear regression analysis clearly indicated that the subcutaneous adipose tissue area was independently correlated with the HMW adiponectin levels in men and closely related in women. Many studies reported that only the visceral adipose tissue area showed a significant correlation with metabolic syndrome. However, these results clearly indicate that it is also important to consider the subcutaneous adipose tissue area in metabolic syndrome.

A polymorphism in the AMPKalpha2 subunit gene is associated with insulin resistance and type 2 diabetes in the Japanese population.

AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the alpha2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.

Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

Second derivative of the finger photoplethysmogram and cardiovascular mortality in middle-aged and elderly Japanese women.

The second derivative of the digital photoplethysmogram (SDPTG) is an indicator of arterial stiffness. The ratio of the height of the d wave to the a wave of the SDPTG (d/a) is associated with functional peripheral vascular tension and represents aortic-blood pressure (BP) augmented by reflection waves from the periphery. This longitudinal study aimed to investigate the relationship between SDPTG and cardiovascular mortality in middle-aged and elderly Japanese women. From 1998 to 2008, we recruited 4373 women (50-79 years old at baseline) who underwent medical check-ups and SDPTG measurement. The SDPTG index (d/a) was calculated from the wave component height, and was divided into quartiles (Q) according to the d/a value. The median follow-up period was 9.0 years. The d/a value was negatively associated with age and BP, and positively associated with heart rate and body height. Using the Cox proportional hazards model, the hazard ratios for cardiovascular mortality for Q2, Q3 and Q4 were significantly higher than that of Q1. In multivariate analysis, the hazard ratio was 2.30 for Q3 (95% confidence interval (CI): 1.06-4.99, P<0.05) and 2.60 for Q4 (95% CI: 1.21-5.60, P<0.05), after adjustment for age, height, body mass index, BP levels, heart rate and other atherosclerosis-related factors. The hazard ratios of cardiovascular mortality for Q3 and Q4 were significantly higher compared with the reference (Q1). Thus, the SDPTG d/a is an independent predictor of cardiovascular mortality in middle-aged and elderly Japanese women.

Evaluation of the new criteria of 2010 for diabetes mellitus: Japan Diabetes Society.

We investigated the characteristics of the new criteria for diabetes mellitus (DM) issued by the Japan Diabetes Society in 2010, which include HbA1C measurement, and differences between 1999 criteria, in order to indicate clinical caution points. If a person with fasting plasma glucose (FPG) ≥126 mg/dl or an oral glucose tolerance test (OGTT) 2-h value ≥200 and HbA1C ≥6.5 % is determined as having DM, the disease can be detected at a rate of ≥70 % in persons <60 years and at no more than 40-50 % in elderly persons. In longitudinal examination, we observed that individuals with DM with FPG ≥126 mg/dl and HbA1C ≥6.5 % obtained the same determination over time at a rate of nearly 90 %. The percentage of persons whose result shifted from normal type to DM was 3- to 4-fold lower than that of persons whose result shifted from normal type to diabetic type. Based on these results, measurement of FPG and HbA1C at the same time may be extremely effective in identifying DM, although we should pay attention to a higher likelihood that mild glucose metabolism disorders will be overlooked.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes.

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.

An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.

Association between the Postprandial Glucose Levels and Arterial Stiffness Measured According to the Cardio-ankle Vascular Index in Non-diabetic Subjects.

OBJECTIVE: Although a relationship between post-challenge hyperglycemia and arterial stiffness has been reported, the relationship between the postprandial glucose levels and cardio-ankle vascular index (CAVI) in non-diabetic subjects is not clear. This study thus evaluated the association between the postprandial glucose levels after a composite meal and the degree of arterial stiffness measured according to CAVI in non-diabetic subjects. METHODS: The subjects included 1,291 individuals (655 men and 636 women; mean age, 48.6 years; range, 23-85 years) who underwent medical examinations, including blood tests and CAVI assessments, between October 2005 and April 2012. The 1-hour postprandial glucose levels were determined after a 600-kcal traditional Japanese meal. RESULTS: The CAVI values were significantly higher in the subjects with higher 1-hour postprandial glucose levels (≥140 mg/dL in men; ≥158 mg/dL in women). A simple regression analysis indicated that the CAVI values were significantly correlated with the 1-hour postprandial glucose levels in men (r=0.286, p<0.0001) and women (r=0.228, p<0.0001). After adjusting for age, BMI, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, 1-hour postprandial glucose, homeostatis model assessment of insulin resistance, estimated glemerular filtration rate, and high sensitive C-reactive protein, stepwise multiple regression analysis demonstrated that the 1-hour postprandial glucose level was an independent predictor associated with the CAVI in men (p=0.003) and older women 50 years of age or older (p=0.003). CONCLUSION: This study demonstrated that the 1-hour postprandial glucose levels are associated with increased CAVI values in non-diabetic men and older women 50 years of age or older.

A prospective evaluation of the effects of salpingectomy on endometrial lymphocyte clusters in patients with hydrosalpinges.

OBJECTIVE: To investigate the effect of hydrosalpinges on embryo implantation. DESIGN: Prospective study. SETTING: Private fertility and university hospitals. PATIENT(S): Eighteen patients with unilateral or bilateral hydrosalpinges who underwent salpingectomy. INTERVENTION(S): Pre- and posttreatment endometrial biopsies for immunohistochemical evaluation. MAIN OUTCOME MEASURE(S): Pre- and posttreatment lymphocyte populations in endometrial samples, evaluated by immunohistochemical identification. RESULT(S): Endometrial samples from pretreatment exhibited small lymphocytic clusters of CD3+, CD8+, CD4+, granzyme B positive, and CD56+. After salpingectomy, the numbers of cluster lesions were significantly decreased. CONCLUSION(S): Because a characteristic distribution of lymphocytes in endometrium with hydrosalpinges was found, activation of T/NK (natural killer) lymphocytes in endometrium might be involved in the impairment of embryo implantation in cases of hydrosalpinges.

Low heart rate variability is a risk factor for sudden cardiac death in type 2 diabetes.

The purpose of this study is to examine the association between sudden cardiac death (SCD) and heart rate variability (HRV) in subjects with and without type 2 diabetes and to determine whether low HRV can predict SCD in type 2 diabetes. Subjects were 8917 consecutively examined persons (3089 diabetic, and 5828 nondiabetic subjects) aged 35-69 years who underwent a 75 g oral glucose tolerance test (OGTT) together with electrocardiography (ECG). HRV was calculated from the 12-lead ECG as the coefficient of variance for 100 R-R intervals (CV(R-R)). During a median observation period of 5.2 years, SCD occurred in 56 subjects (33 diabetic, and 23 nondiabetic). Among diabetic subjects, mortality from SCD tended to be higher in subjects with a low CV(R-R) (P=0.004). After adjustment for age, gender, systolic blood pressure, total cholesterol (TC), triglycerides (TG), BMI, ischemic ECG change, and smoking history, relative risk (RR) of SCD was 2.07 (95% CI 1.02-4.17) in diabetic subjects with a CV(R-R) <2.2% compared with those with a CV(R-R) > or =2.2%. Diabetic subjects with a CV(R-R) <2.2% had significantly higher cumulative mortality from SCD than those with a CV(R-R) > or =2.2% (P=0.007). In type 2 diabetes, a low CV(R-R) carried an increased risk of SCD.

Report of the Committee on the classification and diagnostic criteria of diabetes mellitus.

In 1995, the Japan Diabetes Society (JDS) appointed the Committee for the Classification and Diagnosis of Diabetes Mellitus. The Committee presented a final report in May 1999 in Japanese. This is the English version with minor modifications for readers outside Japan. CONCEPT OF DIABETES MELLITUS: Diabetes mellitus represents a group of diseases of heterogeneous etiology, characterized by chronic hyperglycemia and other metabolic abnormalities, which are due to deficiency of insulin effect. After a long duration of metabolic derangement, specific complications of diabetes (retinopathy, nephropathy, and neuropathy) may occur. Arteriosclerosis is also accelerated. Depending on the severity of the metabolic abnormality, diabetes may be asymptomatic, or may be associated with symptoms (thirst, polyuria, and weight loss), or may progress to ketoacidosis and coma. CLASSIFICATION: Both etiological classification and staging of pathophysiology by the degree of deficiency of insulin effect need to be considered. The etiological classification of diabetes and related disorders of glycemia includes, (1) type 1; (2) type 2; (3) those due to specific mechanisms and diseases; and (4) gestational diabetes mellitus. Type 1 is characterized by destructive lesions of pancreatic beta cells either by an autoimmune mechanism or of unknown cause. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Category (3) includes two subgroups; subgroup A is diabetes in which specific mutations have been identified as a cause of genetic susceptibility, while subgroup B is diabetes associated with other pathologic conditions or diseases. The staging of glucose metabolism includes normal, borderline and diabetic stages. The diabetic stage is further classified into three substages; non-insulin requiring, insulin-requiring for glycemic control, and insulin-dependent (ID) for survival. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. DIAGNOSIS: The confirmation of chronic hyperglycemia is a prerequisite for the diagnosis of diabetes mellitus. The state of glycemia may be classified within three categories, diabetic type; borderline type; and normal type. Diabetic type is defined when fasting plasma glucose (FPG) is 7.0 mmol/l (126 mg/dl) or higher, and/or plasma glucose 2 h after 75 g glucose load (2hPG) is 11.1 mmol/l (200 mg/dl) or higher. A casual plasma glucose (PG) > or =11.1 mmol/l (200 mg/dl) also indicates diabetic type. Normal type is defined when FPG is below 6.1 mmol/l (110 mg/dl) and 2hPG below 7.8 mmol/l (140 mg/dl). Borderline type includes those who are neither diabetic nor normal types. These cutoff values are for venous PG measurements. The persistence of 'diabetic type' in a subject indicates that he or she has diabetes. For children, a dose of 1.75 g/kg (maximum, 75 g) is used for oral glucose tolerance test (OGTT). The procedure for clinical diagnosis is as follows. Diabetes mellitus is diagnosed when hyperglycemia meeting the criteria for 'diabetic type' is shown on two or more occasions examined on separate days. Diabetes can be diagnosed by a single PG test of 'diabetic type' if one of the following three conditions co-exists, (1) typical symptoms of diabetes mellitus; (2) HbA1c > or =6.5% by a standardized method; or (3) unequivocal diabetic retinopathy. If the above conditions ((1) or (2)) have been present in the past and well documented, the subject is diagnosed either to have diabetes or to be suspected of diabetes, even if the present level of glycemia does not reach that of 'diabetic type'. If the diagnosis of diabetes cannot be established by these procedures, re-testing of PG is recommended after an appropriate interval. The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. EPIDEMIOLOGICAL ASPECTS AND SCREENING: In order to determine the prevalence of diabetes in a population, 'diabetic type' may be regarded as 'diabetes'. The use of 2hPG cutoff level of > or =11.1 mmol/l (200 mg/dl) is recommended. If this is difficult, the FPG cutoff level of > or =7.0 mmol/l (126 mg/dl) can be used, but is likely to lead to under-ascertainment. For screening, the most important point is not to overlook 'diabetes'. In addition to parameters of hyperglycemia, clinical information such as family history, obesity etc., should be regarded as indications for further testing. NORMAL TYPE AND BORDERLINE: Only FPG and 2hPG are adopted as cutoff values, but in clinical situations, it is recommended to measure PG also at 30 and 60 min during 75 g OGTT. Among people with normal type, those with 1hPG higher than 10.0 mmol/l (180 mg/dl) are at higher risk to develop diabetes than those with lower 1hPG. When OGTT is performed, the borderline type corresponds to the sum of impaired fasting glycemia (IFG) plus impaired glucose tolerance (IGT) according to the new WHO report. Subjects in this category are at higher risk of developing diabetes than those with 'normal type'. Those with low insulinogenic index (the ratio of increment of plasma insulin to that of PG at 30 min during OGTT) are at particularly high risk to develop diabetes. Microvascular complications are rare but arteriosclerotic complications are fairly frequent in this category. GESTATIONAL DIABETES MELLITUS (GDM): The current definition of GDM is ' any glucose intolerance developed or detected during pregnancy'. We adopt the proposal of the Japan Society of Gynecology and Obstetrics for the diagnosis of GDM (1984). GDM is defined when two or more values during a 75 g OGTT are higher than the following cutoff levels; FPG > or =5.5 mmol/l (100 mg/dl), 1hPG > or =10.0 mmol/l (180 mg/dl) and 2hPG > or =8.3 mmol/l (150 mg/dl). As a screening test, subjects with casual PG > or =5.5 mmol/l (100 mg/dl) are recommended for further testing. Patients who have had documented glucose intolerance before pregnancy, and who present as 'diabetic type' should be under closer supervision than those who develop GDM during pregnancy for the first time. HbA1c: There is a large overlap in the distribution of HbA1c between groups with 'normal type' and 'borderline type' and mild 'diabetic type'. Therefore, HbA1c is not a suitable parameter to detect mild glucose intolerance. HbA1c higher than 6.5% suggests diabetes, but HbA1c below 6.5% alone should not be taken as evidence against the diagnosis of diabetes. COMPARISON WITH REPORTS OF AMERICAN DIABETES ASSOCIATION (ADA) IN 1997 AND WHO IN 1999: The present report is unique in the following points when compared with those of the ADA 'Diabetes Care 20 (1997) 1183' and WHO 'Report of a WHO Consultation (1999)'. (1) Diabetes due to specific mechanisms and diseases is divided into two subgroups; diabetes in which genetic susceptibility is clarified at the DNA level and diabetes associated with other diseases or conditions. (2) Cutoff PG levels are the same as those of ADA and WHO, but a term 'type' is added to each glycemic category, because a single coding of 'diabetic type' hyperglycemia does not define diabetes. Diabetes is diagnosed when 'diabetic type' hyperglycemia is shown on two or more occasions. (3) A single 'diabetic type' hyperglycemia is considered sufficient for the diagnosis of diabetes, if the patient has typical symptoms, HbA1c > or =6.5%, or diabetic retinopathy. (4) OGTT is recommended for those with mild hyperglycemia, because FPG criteria alone would overlook many subjects with 'diabetic type' in Japan. High 1hPG without elevation of FPG and 2hPG is also considered to be a risk factor for future diabetes. (5) Borderline type in the present report corresponds to the sum of IFG and IGT by WHO when OGTT is performed. (6) New criteria for GDM by OGTT are proposed.