Nam H. Cho

IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040

AIM To produce current estimates of the national, regional and global impact of diabetes for 2015 and 2040. METHODS A systematic literature review was conducted to identify data sources on the prevalence of diabetes from studies conducted in the period from 1990 to 2015. An analytic hierarchy process was used to select the most appropriate studies for each country, and estimates for countries without data were modelled using extrapolation from similar countries that had available data. A logistic regression model was used to generate smoothed age-specific estimates, which were applied to UN population estimates. RESULTS 540 data sources were reviewed, of which 196 sources from 111 countries were selected. In 2015 it was estimated that there were 415 million (uncertainty interval: 340-536 million) people with diabetes aged 20-79years, 5.0 million deaths attributable to diabetes, and the total global health expenditure due to diabetes was estimated at 673 billion US dollars. Three quarters (75%) of those with diabetes were living in low- and middle-income countries. The number of people with diabetes aged 20-79years was predicted to rise to 642 million (uncertainty interval: 521-829 million) by 2040. CONCLUSION Diabetes prevalence, deaths attributable to diabetes, and health expenditure due to diabetes continue to rise across the globe with important social, financial and health system implications.

A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits

To identify genetic factors influencing quantitative traits of biomedical importance, we conducted a genome-wide association study in 8,842 samples from population-based cohorts recruited in Korea. For height and body mass index, most variants detected overlapped those reported in European samples. For the other traits examined, replication of promising GWAS signals in 7,861 independent Korean samples identified six previously unknown loci. For pulse rate, signals reaching genome-wide significance mapped to chromosomes 1q32 (rs12731740, P = 2.9 × 10−9) and 6q22 (rs12110693, P = 1.6 × 10−9), with the latter ∼400 kb from the coding sequence of GJA1. For systolic blood pressure, the most compelling association involved chromosome 12q21 and variants near the ATP2B1 gene (rs17249754, P = 1.3 × 10−7). For waist-hip ratio, variants on chromosome 12q24 (rs2074356, P = 7.8 × 10−12) showed convincing associations, although no regional transcript has strong biological candidacy. Finally, we identified two loci influencing bone mineral density at multiple sites. On chromosome 7q31, rs7776725 (within the FAM3C gene) was associated with bone density at the radius (P = 1.0 × 10−11), tibia (P = 1.6 × 10−6) and heel (P = 1.9 × 10−10). On chromosome 7p14, rs1721400 (mapping close to SFRP4, a frizzled protein gene) showed consistent associations at the same three sites (P = 2.2 × 10−3, P = 1.4 × 10−7 and P = 6.0 × 10−4, respectively). This large-scale GWA analysis of well-characterized Korean population-based samples highlights previously unknown biological pathways.

Impaired Glucose Tolerance in Adolescent Offspring of Diabetic Mothers: Relationship to fetal hyperinsulinism

OBJECTIVE To test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero. RESEARCH DESIGN AND METHODS We enrolled offspring of women with pregestational diabetes (this included insulin-dependent diabetes mellitus. [1DDM] and non-insulin-dependent diabetes mellitus [NIDDM]) and gestational diabetes in a prospective study from 1977 through 1983. Fetal /3-cell function was assessed by measurement of arrmiotic fluid insulin (AF1) at 32–38 weeks gestation. Postnatally, plasma glucose and insulin were measured yearly from 1.5 years of age after fasting and 2 h after 1.75 g/kg oral glucose. Control subjects had a single oral glucose challenge at 10-16 years. RESULTS In offspring of diabetic mothers, the prevalence of impaired glucose tolerance (IGT) (2-h glucose concentration >7.8 mmol/1) was: 1.2% at <5 years, 5.4% at 5–9 years, and 19.3% at 10–16 years. The 88 offspring of diabetic mothers (12.3 ± 1.7 years), when compared with 80 control subjects of the same age and pubertal stage, had higher 2-h glucose (6.8 ±1.4 vs. 5.7 ± 0.9 mmol/1, P < 0.001) and insulin (660 ± 720 vs. 455 ± 285 pmol/1, P < 0.03) concentrations. The 17 subjects with IGT at > 10 years of age (9 boys and 8 girls) include one girl with NIDDM. IGT was not associated with the etiology of the mothers diabetes (gestational versus pregestational) or macrosomia at birth. IGT was found in only 3.7% (1 of 27) of adolescents whose AFI was normal (≥100 pmol/l) and 33.3% (12 of 36) of those with elevated AFI (P < 0.001). Although most of the children with IGT are obese, AFI and obesity are independently associated with IGT by multiple logistic analysis. CONCLUSIONS In confirmation of our original hypothesis, IGT in the offspring is a long-term complication of maternal diabetes. Excessive insulin secretion in utero, as assessed by AFI concentration, is a strong predictor of IGT in childhood.

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians

OBJECTIVE— Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear. RESEARCH DESIGN AND METHODS— We studied 13 associated single nucleotide polymorphisms from these genes in 3,041 patients with type 2 diabetes and 3,678 control subjects of Asian ancestry from Hong Kong and Korea. RESULTS— We confirmed the associations of TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, and FTO with risk for type 2 diabetes, with odds ratios ranging from 1.13 to 1.35 (1.3 × 10−12 < Punadjusted < 0.016). In addition, the A allele of rs8050136 at FTO was associated with increased BMI in the control subjects (Punadjusted = 0.008). However, we did not observe significant association of any genetic variants with surrogate measures of insulin secretion or insulin sensitivity indexes in a subset of 2,662 control subjects. Compared with subjects carrying zero, one, or two risk alleles, each additional risk allele was associated with 17% increased risk, and there was an up to 3.3-fold increased risk for type 2 diabetes in those carrying eight or more risk alleles. Despite most of the effect sizes being similar between Asians and Europeans in the meta-analyses, the ethnic differences in risk allele frequencies in most of these genes lead to variable attributable risks in these two populations. CONCLUSIONS— Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans.

Prepregnancy Weight and Antepartum Insulin Secretion Predict Glucose Tolerance Five Years After Gestational Diabetes Mellitus

OBJECTIVE To identify phenotypic, genotypic, and metabolic parameters measured at the time of antepartum diagnosis of gestational diabetes mellitus that can indicate the risk of diabetes mellitus at early postpartum (≤6 mo after delivery) and at a 5-yr follow-up. RESEARCH DESIGN AND METHODS The recommendations from the National Diabetes Data Group and International Workshop Conferences on Gestational Diabetes Mellitus were used for screening, diagnosing, and subclassifying gestational diabetes mellitus. National Diabetes Data Group criteria were also used for classification of glucose tolerance postpartum. Plasma glucose, insulin, and free fatty acids were measured after an overnight fast. Plasma glucose and insulin were measured 15, 30, 60, 120, and 180 min after the 100-g oral glucose load. Postpartum glucose tolerance was evaluated at 3–6 mo (early), 1 yr, and annually thereafter. RESULTS The 5-yr cumulative incidence of diabetes during follow-up after gestational diabetes mellitus was nearly 50%. Among those who had diabetes within 5 yr, a history of diabetes in only the mother was nearly threefold more common than a history of diabetes in only the father (30 vs. 11%, P < 0.01). Those who displayed diabetes at early postpartum (≤6 mo) testing had significantly higher antepartum glucose levels at 60, 120, and 180 min compared with those whose early postpartum results were normal. They were also relatively insulinopenic at antepartum testing. Their fasting, acutely stimulated (15 and 30 min), and integrated 3-h response to oral glucose were all significantly lower relative to women who remained normal or had impaired glucose tolerance at early postpartum testing. Women who developed diabetes between 6 mo and 5 yr postpartum were more obese before the index pregnancy, and they had lower fasting, acutely stimulated (15 and 30 min), and integrated (1–3 h) insulin levels compared with women who remained normal or displayed impaired glucose tolerance at 5 yr postpartum. A multiple logistic regression model showed that diabetes present at early postpartum testing was independently associated with higher 2-h glucose and lower basal and total integrated insulin level. Later (≤6 mo-5 yr postpartum) development of diabetes was independently associated with prepregnancy weight and impaired insulin secretion at diagnosis of gestational diabetes mellitus. CONCLUSIONS Impaired β-cell function and obesity at diagnosis of GDM were associated with the development of diabetes during a 5-yr, follow-up period. Studies designed to prevent diabetes in this high-risk group should examine strategies to maintain both optimal β-cell function and maximum insulin sensitivity.

Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers☆

OBJECTIVE Our purpose was to assess to what extent disturbances in antepartum maternal metabolism and perinatal complications and morbidities contribute to poorer psychomotor development in offspring of diabetic mothers. STUDY DESIGN One hundred ninety-six pregnant women and their singleton offspring participated in this prospective cohort-analytic study. Ninety-five women had pregestational diabetes mellitus, and 101 women had gestational diabetes mellitus. Serial estimates of circulating maternal fuels were obtained throughout each index pregnancy along with detailed records of the perinatal course and outcome. Offspring were administered the psychomotor development index of the Bayley Scales of Infant Development at age 2 years and the Bruininks-Oseretsky Test Of Motor Proficiency at ages 6, 8, and 9 years. Tests were performed blinded to the mothers antepartum metabolic status, and perinatal history, and the childs previous test scores. Partial correlations and analyses of covariance were used to control for other influences and confounds, such as family socioeconomic status, racial or ethnic origin, patient group (i.e., pregestational or gestational diabetes mellitus), and sex of child. RESULTS Childrens average score on the Bruininks-Oseretsky test at ages 6 to 9 years correlated significantly with maternal second (p < 0.02) and third trimester (p < 0.001) beta-hydroxybutyrate. There was also a borderline association between the childrens scores on the psychomotor development index at age 2 years and maternal third-trimester beta-hydroxybutyrate levels (p = 0.06). No other correlations approached significance. CONCLUSIONS Intrauterine metabolic experiences continue to influence the neurodevelopmental course in offspring of diabetic mothers. Prevailing practices in diabetes management and obstetric and neonatal care appear to effectively mitigate the potential long-term effects of most perinatal complications and morbidities. Management and obstetric and neonatal care appear to effectively miltigate the potential long-term effects of most perinatal complications and morbidities.

A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women

Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P = 6.65 × 10−16). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P = 2.49 × 10−13). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes.

Prevalence and risk factors of osteoporosis in Korea: A community-based cohort study with lumbar spine and hip bone mineral density

PURPOSE To investigate bone mineral density (BMD) profiles, osteoporosis prevalence and risk factors in a community-based cohort in Korea. METHODS The present study is a cross-sectional study. The study population consisted of 1,547 men and 1991 women aged 40 years and older with BMD measurements using central dual energy X-ray absorptiometry from a prospective community-based cohort. The data were compared with other ethnic groups. Risk factors related to osteoporosis were analyzed. RESULTS Crude prevalence of osteoporosis in the whole subjects (40-79 years old) was 13.1% for men and 24.3% for women by WHO criteria, at any site among lumbar spine, femoral neck or total hip. Standardized prevalence of osteoporosis between age of 50 and 79 at lumbar spine, femoral neck and total hip was 12.9%, 1.3% and 0.7% in men and 24.0%, 5.7% and 5.6% in women, respectively. The mean BMD of studied female subjects after age of 50 was not significantly different from that of Chinese but significantly lower than that of Japanese, non-Hispanic whites, non-Hispanic blacks and Mexican Americans. Risk of osteoporosis was significantly associated with the presence of past fracture history (OR, 1.45; 95% CI, 1.08-1.94), smoking> or =1 pack/day (OR, 1.63; 95% CI, 1.01-2.62), menarche after age of 16 (OR, 1.46; 95% CI, 1.14-1.87), last delivery after age of 30 (OR, 1.58; 95% CI, 1.20-2.09), more than three offspring (OR, 1.42; 95% CI, 1.07-1.89), post-menopause status (OR, 7.32; 95% CI, 3.05-17.6), more than 17 years since menopause (OR, 1.53; 95% CI, 1.10-2.14), regular exercise of two to three times per week (OR, 0.40; 95% CI, 0.18-0.89), monthly income above 500,000 won per household (OR, 0.64; 95% CI, 0.45-0.92), college graduate (OR, 0.29; 95% CI, 0.13-0.63) and calcium intake> or =627.5 mg/day (OR, 0.65; 95% CI, 0.43-0.98) after adjusting for age and BMI. CONCLUSION The BMD and osteoporosis prevalence of Koreans are presented. Risk of osteoporosis was significantly associated with fracture history, smoking, reproductive history, regular exercise, income level, education background and calcium intake.

Changes in the Clinicopathological Characteristics and Outcomes of Thyroid Cancer in Korea over the Past Four Decades

BACKGROUND Thyroid cancer has increased globally, with a prominent increase in small, papillary thyroid cancers (PTC). The Korean population has a high iodine intake, high prevalence of BRAF V600E mutations, and family histories of thyroid cancer. We examined the clinicopathological characteristics and outcomes of thyroid cancers in Korean patients over four decades. METHODS The medical records of 4500 thyroid cancer patients, between 1962 and 2009 at a single center, including 3147 PTC patients, were reviewed. RESULTS The mean age of the patients was 46.8±13.2 years; women accounted for 82.9% of the patients, and the median follow-up duration was 4.8 years (mean 7.0±5.8 years, range 1-43 years). The number of patients visiting the clinic increased from 411 during 1962-1990 to 2900 during 2000-2009. Age at diagnosis increased from 39.6±12.9 to 48.6±12.4 years. The male to female ratio increased from 1:6 to 1:4.5. The proportion of small (<1 cm) tumors increased from 6.1% to 43.1%, and the proportion of cancers with lymph node (LN) involvement or extrathyroidal extension (ETE) decreased from 76.4% to 44.4% and from 65.5% to 54.8% respectively. Although there were decreases in the proportion of LN involvement and ETE, these decreasing rates were not proportional to the expected rates based on the decreased proportion of large tumors. The overall recurrence and mortality rates were 13.3% and 1.4%. The five-year recurrence rate significantly decreased (from 11% to 5.9%), and the five-year mortality also improved (from 1.5% to 0.2%). CONCLUSIONS The incidence of thyroid cancer has rapidly increased, with a decrease in tumors of large size, LN involvement, and ETE, although the decreasing rates of LN involvement and ETE were not as prominent as decreasing rates of large size tumors. The mortality and recurrence rates have also decreased. Future long-term follow-up of patients diagnosed in the most recent decade is needed to confirm the prognostic characteristics of Korean PTC patients.