Shiun Dong Hsieh

HbA1c 5·7–6·4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study

BACKGROUND The clinical relevance of the diagnostic criteria for prediabetes to prediction of progression to diabetes has been little studied. We aimed to compare the prevalence of prediabetes when assessed by the new glycated haemoglobin A(1c) (HbA(1c)) 5·7-6·4% criterion or by impaired fasting glucose, and assessed differences in progression rate to diabetes between these two criteria for prediabetes in a Japanese population. METHODS Our longitudinal cohort study included 4670 men and 1571 women aged 24-82 years without diabetes at baseline (diabetes was defined as fasting plasma glucose ≥7·0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA(1c) ≥6·5%) who attended Toranomon Hospital (Tokyo, Japan) for a routine health check between 1997 and 2003. Participants with a baseline diagnosis of prediabetes according to impaired fasting glucose (fasting plasma glucose 5·6-6·9 mmol/L) or HbA(1c) 5·7-6·4%, or both, were divided into four groups on the basis of baseline diagnosis of prediabetes. Rate of progression to diabetes was assessed annually. FINDINGS Mean follow-up was 4·7 (SD 0·7) years. 412 (7%) of 6241 participants were diagnosed with prediabetes on the basis of the HbA(1c) 5·7-6·4% criterion. Screening by HbA(1c) alone missed 1270 (61%) of the 2092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA(1c) 5·7-6·4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA(1c) or impaired fasting glucose alone (incidence was 7% for HbA(1c) alone [n=412 individuals and 30 incident cases] and 9% for impaired fasting glucose alone [n=1270, 108 cases]; log-rank test, p=0·3317). Multivariate-adjusted hazard ratios for incident diabetes were 6·16 (95% CI 4·33-8·77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6·00 (3·76-9·56) for diagnosis by HbA(1c) alone, and were substantially increased to 31·9 (22·6-45·0) for diagnosis by both impaired fasting glucose and HbA(1c) compared with normoglycaemic individuals. INTERPRETATION Diagnosis of prediabetes by both the new HbA(1c) criterion and impaired fasting glucose identified individuals with an increased risk of progression to diabetes. Although the new HbA(1c) criterion identified fewer individuals at high risk than did impaired fasting glucose, the predictive value for progression to diabetes assessed by HbA(1c) 5·7-6·4% was similar to that assessed by impaired fasting glucose alone. The two tests used together could efficiently target people who are most likely to develop diabetes and allow for early intervention. FUNDING Japan Society for the Promotion of Science; Ministry of Health Labor and Welfare, Japan.

Metabolically Healthy Obesity, Presence or Absence of Fatty Liver, and Risk of Type 2 Diabetes in Japanese Individuals: Toranomon Hospital Health Management Center Study 20 (TOPICS 20)

OBJECTIVE We investigated whether the metabolically healthy obese (MHO) phenotype was associated with an increased risk of the development of diabetes. If so, we aimed to determine what factors could explain this finding. DESIGN, SETTING, AND PARTICIPANTS Studied were 8090 Japanese individuals without diabetes. Metabolic health status was assessed by common clinical markers: blood pressure, triglycerides, high-density lipoprotein-cholesterol, and fasting glucose concentrations. The cutoff value for obesity or normal weight (NW) was a body mass index of 25.0 kg/m(2). RESULTS The 5-year incidence rate of diabetes was 1.2% (n = 58 of 4749) in metabolically healthy NW (MHNW) individuals, 2.8% (n = 20 of 719) in MHO individuals, 6.0% (n = 102 of 1709) in metabolically abnormal NW individuals, and 10.3% (n = 94 of 913) in metabolically abnormal obese individuals. Although MHO individuals had no or one metabolic factor, 47.8% had ultrasonographic fatty liver (FL). The MHO group had a significantly increased risk of diabetes compared with the MHNW group [multivariate adjusted odds ratio (OR) 2.23 (95% confidence interval [CI] 1.33, 3.75)], but this risk was attenuated after adjustment for FL. Compared with the MHNW/non-FL group, the risk of diabetes in the MHO/non-FL group was not significantly elevated [OR 1.01 (95% CI 0.35, 2.88)]. However, the MHO/FL and MHNW/FL groups had similarly elevated risks of diabetes [OR 4.09 (95% CI 2.20, 7.60) and 3.16 (1.78, 5.62), respectively]. CONCLUSIONS Almost half of the MHO participants had FL, which partially explained the increased risk of diabetes among the obese phenotypes. The presence of FL should be evaluated to assess whether an individual was actually in a metabolically benign state for the prediction of diabetes.

High serum uric acid level and low urine pH as predictors of metabolic syndrome: a retrospective cohort study in a Japanese urban population

The objective of this study was to evaluate whether hyperuricemia, acidic urine, or their combination predicts metabolic syndrome (MetS). In study 1, 69,094 subjects who received a general health checkup between 1985 and 2005 were included in a cross-sectional study of serum uric acid (SUA) and urine pH in relation to MetS. In study 2, the association of SUA and urine pH with MetS development over a 5-year period was evaluated in 5617 subjects with body mass index less than 25 kg/m(2) at the first examination. In study 1, higher SUA and lower urine pH were both positively correlated to MetS status (P < .001). The combination of high SUA and low urine pH was significantly associated with higher MetS prevalence compared with the combination of low SUA and high urine pH (odds ratio, 3.383; 95% confidence interval [CI], 3.034-3.784 in men; odds ratio, 4.000; 95% CI, 2.992-5.452 in women). In study 2, the top quartile of SUA levels was associated with higher MetS development compared with the bottom quartile during the 5-year period in men (hazard ratio [HR], 1.793; 95% CI, 1.084-2.966; P = .023). In women, the HR was 3.732 (95% CI, 0.391-35.62; P = .252) for the upper vs the lower half of SUA levels. For urine pH, the HR was 1.955 (95% CI, 1.089-3.509; P = .025) for the bottom vs the top quartile in men. A likelihood ratio test confirmed that high SUA and low urine pH act synergistically in the development of MetS. High SUA, low urine pH, and their combination are predictive risk factors for MetS development.

Effect of Postmenopausal Status and Age at Menopause on Type 2 Diabetes and Prediabetes in Japanese Individuals: Toranomon Hospital Health Management Center Study 17 (TOPICS 17)

OBJECTIVE Findings on the effect of menopause or age at menopause on the presence of hyperglycemia are controversial, and why women after menopause have a higher probability of having hyperglycemia than men in the same age range remains unknown. RESEARCH DESIGN AND METHODS We reviewed data on 29,189 men, 6,308 premenopausal women, and 4,570 postmenopausal women in Japan. Odds ratios (ORs) for diabetes or prediabetes indicated by American Diabetes Association criteria were calculated for men and for pre- and postmenopausal women. RESULTS Compared with premenopausal women, women after natural menopause had an age-adjusted OR of 1.40 (95% CI 1.03–1.89) for diabetes, and women after menopause by surgical or other causes had an age-adjusted OR of 1.59 (1.07–2.37). The age-adjusted OR in men was 4.02 (3.15–5.14). Compared with premenopausal nondiabetic women, postmenopausal nondiabetic women had a significantly elevated OR of 1.33 (1.20–1.48) for prediabetes; nondiabetic men had an OR of 1.93 (1.77–2.10) independently of age and demographic and metabolic factors. Even among women aged <50 years, postmenopausal status was significantly associated with an elevated OR (1.50 [1.18–1.91]) for dysglycemia (either diabetes or prediabetes). Postmenopausal women aged ≥50 years had a particularly elevated OR for dysglycemia, regardless of age at menopause. CONCLUSIONS The postmenopausal state was significantly associated with the presence of dysglycemia independently of normal aging, although the increased probability in postmenopausal women did not equal that in men. Among women, menopause and older age might additively influence the elevated probability of dysglycemia.

Screening for pre‐diabetes to predict future diabetes using various cut‐off points for HbA1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4)

Diabet. Med. 29, e279‐e285 (2012)

Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients

Aim:  Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non‐alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV).

Role of alcohol drinking pattern in type 2 diabetes in Japanese men: the Toranomon Hospital Health Management Center Study 11 (TOPICS 11)

BACKGROUND Findings of past studies on the effect of drinking patterns on diabetes risk have been inconsistent. OBJECTIVE We aimed to investigate the role of drinking frequency and usual quantity consumed in the development of type 2 diabetes. DESIGN Enrolled were 1650 Japanese men without diabetes (diabetes: fasting plasma glucose ≥7.0 mmol/L, glycated hemoglobin ≥6.5%, or self-reported clinician-diagnosed diabetes). Average alcohol consumption and 12 combinations of frequency and usual quantity per drinking occasion were assessed at the baseline examination. The absolute risk and HR for the development of diabetes were calculated. RESULTS During a mean follow-up period of 10.2 y, 216 individuals developed diabetes. Lifetime abstainers (n = 153) had a relatively low incidence of diabetes (9.1/1000 person-years), similar to moderate consumers (99-160 g ethanol/wk; 9.0/1000 person-years). Increasingly higher quantities of alcohol usually consumed per occasion increased the risk of diabetes regardless of drinking frequency. The lowest incidence rate of diabetes (8.5/1000 person-years) was associated with the consumption of <1 drink (<23 g ethanol) per occasion over ≥6 times/wk. Binge drinking (≥3 drinks per occasion) significantly increased the risk of future diabetes regardless of frequency (HR: 1.79; 95% CI: 1.17, 2.74) compared with <1 drink per occasion. CONCLUSIONS Among current drinkers, a drinking pattern of <1 drink per occasion regularly over 6 times within a week was associated with the lowest risk of developing diabetes. Usual quantity per drinking occasion was a more important determinant than was weekly drinking frequency in the association between alcohol consumption and risk of diabetes in Japanese men.

Longitudinal Trajectories of HbA1c and Fasting Plasma Glucose Levels During the Development of Type 2 Diabetes: The Toranomon Hospital Health Management Center Study 7 (TOPICS 7)

OBJECTIVE To describe the trajectory of HbA1c and glucose concentrations before the diagnosis of diabetes. RESEARCH DESIGN AND METHODS The study comprised 1,722 nondiabetic Japanese individuals aged 26–80 years. Fasting plasma glucose (FPG) and HbA1c were measured annually for a mean of 9.5 (SD 1.8) years. RESULTS Diabetes occurred in 193 individuals (FPG ≥7.0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA1c ≥6.5%). Mean HbA1c values were >5.6% each year before diagnosis in diabetes cases. Mean HbA1c (5.69% [95% CI 5.50–5.88]) was higher in the 21 individuals who developed diabetes 10 years after the baseline examination than in nondiabetic individuals after 10 years (5.27% [5.25–5.28]). From 3 years to 1 year prediagnosis, HbA1c increased 0.09% (SE 0.01)/year, reaching 5.90% (5.84–5.96) 1 year prediagnosis. In the entire group, marked increases in HbA1c of 0.3% (SE 0.05%)/year and FPG of 0.63 (0.07) mmol/L/year predicted diabetes. CONCLUSIONS HbA1c trajectory increased sharply after gradual long-term increases in diabetic individuals.

High normal HbA1c levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8)

Diabet. Med. 29, 1285–1290 (2012)

Urgency of reassessment of role of obesity indices for metabolic risks

The definition of metabolic syndrome places emphasis on health care for persons at risk. However, whether an obesity index should be a mandatory component of the definition and whether obesity indices can identify metabolic risks satisfactorily require further exploration. Therefore, we investigated the effectiveness of various anthropometric obesity indices in identifying the clustering of 2 or more American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI)/International Diabetes Federation (IDF)-defined metabolic risk factors (hypertension, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol) for metabolic syndrome and those of other metabolic risk factors (high low-density lipoprotein cholesterol, hyperuricemia, high gamma-glutamyltransferase, fatty liver) in 6141 men and 2137 women. The anthropometric indices were the following: (1) for both sexes--various levels of waist-to-height ratio (WHtR) including 0.5 and body mass index (BMI) of 23 and 25 kg/m(2); (2) for men and women individually--waist circumference (W) 90/80 cm (AHA/NHLBI/IDF for ethnic groups), W 85/90 cm (Japan Society for the Study of Obesity), and combined W and BMI: W 85/90 cm and/or BMI 25 kg/m(2) (Japanese government). The results showed the following: (1) The optimal value for WHtR was 0.5 for AHA/NHLBI/IDF-defined risk factors and approximately 0.5 for other risk factors in both sexes. (2) The sensitivities of various proposed obesity indices for identifying clustering of defined and other risk factors varied between 74.4% (WHtR 0.5) and 36.3% (BMI 25) and between 80.5% (WHtR 0.5) and 43.7% (BMI 25) in men, and varied between 65.6% (WHtR 0.5) and 16.8% (W 90 cm) and between 82.3% (WHtR 0.5) and 28.2% (W 90 cm) in women. Because the sensitivities of many anthropometric indices were very low, a reassessment of the effectiveness of obesity indices in evaluating metabolic risks and especially their suitability as a single mandatory component of metabolic syndrome is urgently needed. However, WHtR 0.5 provides a very useful algorithm for screening persons at risk.