Different cutoffs of hypertension, risk of incident diabetes and progression of insulin resistance: A prospective cohort study.

BACKGROUND/PURPOSE: Hypertension is a risk factor of incident diabetes. In 2017, the ACC/AHA updated the definition of hypertension to above 130/80 mmHg, while the 2018 ESC/ESH guideline and the JNC7 criteria remained the cutoff of 140/90 mmHg. This study was aimed to investigate how different cutoffs of hypertension affect the association of hypertension to incident diabetes and the progression of insulin resistance. METHODS: A total of 1177 subjects without diabetes at baseline were followed for 4.5 years. Diabetes was diagnosed by the results of oral glucose tolerance tests and hemoglobin A1c, or if anti-diabetic agents were used. RESULTS: Hypertension by both criteria was associated with incident diabetes. Change of HOMA2-IR every 5 years (ΔHOMA2-IR/5 yr) was higher in subjects with hypertension than those without (adjusted p = 0.044). Subjects with treated hypertension had the highest risk of diabetes (HR 2.98, p < 0.001) and ΔHOMA2-IR/5 yr, compared with subjects with normal blood pressure. However, the associations of hypertension, HR of incident diabetes and ΔHOMA2-IR/5 yr were attenuated by the 2017 ACC/AHA criteria, as compared with that by the JNC7 and 2018 ESC/ESH criteria. CONCLUSION: Hypertension by both criteria is associated with incident diabetes and accelerated progression of insulin resistance, and the associations are attenuated by the 2017 ACC/AHA criteria.

Serum vascular adhesion protein-1 is up-regulated in hyperglycemia and is associated with incident diabetes negatively.

BACKGROUND/OBJECTIVES: Vascular adhesion protein-1 (VAP-1) can enhance tissue glucose uptake in cell studies and normalize hyperglycemia in animal studies. However, serum VAP-1 concentration (sVAP-1) is higher in subjects with diabetes in cross-sectional studies. In this cohort study, we test our hypothesis that sVAP-1 is increased in prediabetes to counteract hyperglycemia and is associated with incident diabetes negatively. SUBJECTS/METHODS: From 2006 to 2012, 600 subjects without diabetes from Taiwan Lifestyle Study were included and followed regularly. Diabetes was diagnosed if FPG ≥ 126 mg/dL (7 mmol/L), 2-h plasma glucose (2hPG) during an oral glucose tolerance test (OGTT) ≥ 200 mg/dL (11.1 mmol/L), or hemoglobin A1c (HbA1c) ≥ 6.5%, or if the subject received anti-diabetic medications. Abdominal fat areas were measured by abdominal computed tomography and sVAP-1 was analyzed by ELISA. RESULTS: sVAP-1 was higher in subjects with prediabetes (p < 0.05) and increased during an OGTT (p < 0.001). Fasting sVAP-1 was associated with the response of sVAP-1 during an OGTT (p < 0.001). Besides, sVAP-1 was associated negatively with body mass index (BMI, r = -0.1449, p = 0.003), waist circumference (r = -0.1425, p = 0.004), abdominal visceral (r = -0.1457, p = 0.003), and subcutaneous (r = -0.1025, p = 0.035) fat areas, and serum high-sensitivity C-reactive protein (hsCRP) concentration (r = -0.2035, p < 0.0001), and positively with plasma adiponectin concentration (r = 0.2086, p < 0.0001), adjusted for age and gender. After 4.7 ± 2.6 years, 73 subjects (12.2%) developed incident diabetes. High sVAP-1 predicted a lower incidence of diabetes, adjusted for age, gender, BMI, family history of diabetes, HbA1c, HOMA2-%B and HOMA2-IR (HR = 0.66, 95% CI = 0.50-0.88, p < 0.01). CONCLUSIONS: sVAP-1 is increased in response to hyperglycemia. It is associated with obesity and serum hsCRP concentration negatively, and plasma adiponectin concentration positively. Besides, a high sVAP-1 is associated with a lower incidence of diabetes in human.

Serum vascular adhesion protein-1 level is higher in smokers than non-smokers.

BACKGROUND: Semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1) is involved in the pathogenesis of both atherosclerosis and cancer. Because chemical components and metabolites of cigarettes are deaminated by SSAO, the relationship between smoking and serum SSAO/VAP-1 was studied in humans. METHODS: A total of 451 non-diabetic and normoalbuminuric Han Chinese subjects were recruited to participate in this study. Smoking history was obtained by using a questionnaire and those who smoked more than 100 cigarettes during a 6-month period were considered smokers. Serum VAP-1 concentration was measured by time-resolved immunofluorometric assay. Age, gender, waist circumference and estimated glomerular filtration rate (GFR) were adjusted in different statistical models. RESULTS: Smokers were mainly male (85.7% versus 26.3%) and were more obese than non-smokers (p < 0.05). Subjects with higher serum VAP-1 concentrations were older (p < 0.001) and tended to have larger waist circumferences and lower estimated GFR. Serum VAP-1 concentration was higher in smokers than in non-smokers (p < 0.05) after adjusting for age, gender, waist circumference, estimated GFR, liver biochemistry and lipid profile. CONCLUSIONS: Cigarette smoking is associated with elevated serum VAP-1 concentration. Whether VAP-1 and its SSAO activity link the relationship between cigarette smoking, atherosclerosis and cancer requires further investigation.

Haemoglobin A1c is associated with carotid intima-media thickness in a Chinese population.

BACKGROUND: The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. AIM, DESIGN AND METHODS: The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross-sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9·2%) subjects were newly diagnosed with diabetes during the study. Carotid intima-media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography. RESULTS: The HbA1c level in all subjects was positively correlated with carotid IMT (ß = 0·018, P = 0·03) after being adjusted for age, gender, smoking, low-density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0·01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons, <0·05). The ability of HbA1c levels to predict thickened carotid IMT or the presence of plaques was only modest {the optimal cutoff of HbA1c level [5·7%] was determined from the receiver operating characteristic (ROC) curve (sensitivity = 67%, specificity = 61%) and the area under the ROC curve [0·666]}. CONCLUSIONS: Thus, HbA1c level is associated with subclinical atherosclerosis in carotid arteries in a Chinese population. The relationship is linear without an inflection point. However, HbA1c criterion is not a useful marker for the identification of subclinical atherosclerosis.

The performance of risk scores and hemoglobin A1c to find undiagnosed diabetes with isolated postload hyperglycemia.

The aim of this study is to develop strategies to screen diabetic subjects with isolated postload hyperglycemia (IPH) in Chinese population. We included 1175 adult subjects who did not report diabetes were included. Diabetes was diagnosed by oral glucose tolerance tests. IPH was defined as fasting plasma glucose (FPG)<7 mmol/l and 2-hour post-load plasma glucose (2hPG) greater than 11.1 mmol/l. Using FPG criteria, only 59.8% of diabetic subjects were not identified, showing a poor agreement between FPG and 2hPG criteria (kappa 0.294). Age, FPG, total cholesterol, triglycerides, blood pressure, body mass index, HbA1c and medication for hypertension were associated factors for IPH. Four scores were constructed using all these factors, age and blood test results, age and HbA1c, and data from non-invasive examinations, respectively. The area under the ROC curve were 0.9296(95%CI 0.8948-0.9643), 0.9111(95%CI 0.8713-0.9508), 0.8902(95%CI 0.8341-0.9646), 0.8924(95%CI 0.7835-0.8753), and 0.8654(95%CI 0.7963-0.9345) for score 1, 2, 3, 4, and HbA1c, respectively. The sensitivity of all four risk scores to detect IPH was better than that of impaired fasting glucose (IFG). The sensitivity and specificity of HbA1c at cutoff 6.2% for detecting IPH was also better than that of IFG. In conclusion, the risk scores and HbA1c are useful to identify subjects with undiagnosed IPH, with better performance than IFG.

Progression of insulin resistance: A link between risk factors and the incidence of diabetes.

AIMS: Insulin resistance (IR) changes over time during the development of type 2 diabetes. Some reports showed that obesity was associated with progression of IR. However, no study has explored if change of IR predicts incident diabetes, and no study has investigated other factors associated with the change. METHODS: In this study, 1184 subjects without diabetes at baseline were enrolled in 2006-2016 with a median follow-up period of 4.5 years. Diabetes was diagnosed by oral glucose tolerance test and hemoglobin A1c, or if anti-diabetic agents were used. HOMA2-IR and ISI0,120 were used to estimate IR. RESULTS: The annual changes of HOMA2-IR(ΔHOMA2-IR/year) and ISI0,120(ΔISI0,120/year) were associated with BMI, waist circumference(WC), glucose, HbA1c, triglyceride and HDL-cholesterol. Subjects with pre-diabetes or metabolic syndrome were associated with a more rapid increase of IR. ΔHOMA2-IR/year and ΔISI0,120/year were correlated with annual changes of BMI and WC. The hazard ratios for ΔHOMA2-IR/year and ΔISI0,120/year to predict incident diabetes were 1.39 (95% CI 1.22-1.59, p < 0.001) and 0.13 (95% CI 0.09-0.19, p < 0.001) in adjusted models, respectively. CONCLUSIONS: Change of IR can be used as a surrogate marker of incident diabetes. The progression of IR is an important pathophysiologic link between risk factors and the incidence of diabetes.

Illustrating the roles of C-reactive protein in the development of the metabolic syndrome in women--a cross-racial validation.

BACKGROUND AND AIMS: This study was designed to elucidate the role of C-reactive protein (CRP) as an inflammatory marker in the development of the metabolic syndrome (MS). METHODS AND RESULTS: A total of 333 women without current medication attended an obesity-screening programme held in Yun-Lin, Taiwan. Anthropometric measurements were obtained; biochemical profiles, lipid profiles and high-sensitivity CRP (hsCRP) were measured. A structural equation model (SEM) was constructed to demonstrate that obesity might initiate the sequential pathway that leads to a pro-inflammatory state and other metabolic derangements. The results of SEM in the Taiwanese women showed that obesity was positively associated with elevated CRP (B=0.69, p<0.001). The pro-inflammatory state could result in insulin resistance (B=0.57, p<0.001), which in turn could lead to dyslipidaemia (B=0.46, p<0.01). The association between obesity and hypertension was positive and direct (B=0.43, p<0.01) without the intermediation of inflammation or insulin resistance. The implications could be reproduced when the same model was applied to the metabolic profiles of the Caucasian participants in the National Health and Nutrition Examination Survey 1999-2002. CONCLUSION: Our study has demonstrated that obesity plays the central role in leading to hypertension and a pro-inflammatory state, insulin resistance and dyslipidaemia. The SEM has provided a comprehensive view to illustrate the complex interplay of the main components in the development of the MS, and this approach can be generalized to different populations.

Serum C-reactive protein levels correlates better to metabolic syndrome defined by International Diabetes Federation than by NCEP ATP III in men.

The International Diabetes Federation (IDF) proposed a new definition for metabolic syndrome (MS) in 2005. We conducted this study to compare the association of MS by IDF and ATP III definition to various metabolic variables. In 2005, we enrolled 654 Chinese people in a screening program in Taiwan. Anthropometric and biochemical profiles, including high-sensitivity C-reactive protein (hsCRP), were measured. Serum hsCRP levels were higher in those with MS by IDF definition (2.4+/-1.9mg/l versus 1.3+/-1.4mg/l, p<0.0001). Serum hsCRP levels increase with the number of components of MS they met (p for trend<0.001). Serum LDL levels were higher in those with MS by IDF definition (131+/-39 versus 125+/-32, p<0.05) but not in those with MS by ATP III definition (p=0.2). Serum hsCRP levels correlate significantly to MS by ATP III definition, after adjusting for age, sex, smoking, body mass index, serum apolipoprotein A1 and LDL levels. Adding MS status by IDF definition in this model significantly increased model fitness in men (MS by IDF definition, partial r=0.18, p<0.05, MS by ATP III definition, partial r=0.12, p=0.071). In conclusion, IDF definition of MS has a stronger relationship with serum hsCRP than ATP III definition in men.

The Impact of Gastric Atrophy on the Incidence of Diabetes.

Gastric atrophy results in lower plasma ghrelin, higher gastrin secretion, a change in gut microbiota, and altered dietary nutrient absorption, which may be associated with the incidence of diabetes. Helicobacter pylori (H. pylori) infection is a major cause of gastric atrophy and is associated with diabetes in some reports. Since there is no study which investigates the impact of gastric atrophy on diabetes, we conduct a prospective cohort study to examine the relationship between H. pylori infection, gastric atrophy, and incident diabetes. In this study, subjects with gastric atrophy had a lower risk of incident diabetes, compared to those without gastric atrophy. The extent of gastric atrophy, measured by serum pepsinogen (PG) I/II ratio, was correlated with age, H. pylori IgG titer, HOMA2-IR, and HOMA2%B. When gastric atrophy is more extensive, presented as a lower serum PG I/II ratio, the risk of incident diabetes is lower. On the other hand, there was no significant association between H. pylori infection and the incidence of diabetes. In conclusion, the presence and the extent of gastric atrophy, but not H. pylori infection, are associated with incident diabetes. Further studies are needed to investigate the detailed mechanisms and the potential applications of the findings to guide diabetes screening and treatment strategies.

Serum Glycated Albumin to Guide the Diagnosis of Diabetes Mellitus.

In the diagnosis of diabetes mellitus, hemoglobin A1c (HbA1c) is sometimes measured to determine the need of an oral glucose tolerance test (OGTT). However, HbA1c does not accurately reflect glycemic status in certain conditions. This study was performed to test the possibility that measurement of serum glycated albumin (GA) better assesses the need for OGTT. From 2006 to 2012, 1559 subjects not known to have diabetes or to use anti-diabetic medications were enrolled. Serum GA was measured, and a 75-g OGTT was then performed to diagnose diabetes. Serum GA correlated significantly to age (r = 0.27, p<0.001), serum albumin (r = -0.1179, age-adjusted p = 0.001), body mass index (r = -0.24, age-adjusted p<0.001), waist circumference (r = -0.16, age-adjusted p<0.001), and plasma GA (r = 0.999, p<0.001), but was unaffected by diet (p = 0.8). Using serum GA at 15% for diagnosis of diabetes, the sensitivity, specificity, and area under the receiver-operating characteristic curve were 74%, 85%, and 0.86, respectively. Applying a fasting plasma glucose (FPG) value of < 100 mg/dL to exclude diabetes and of ≥ 126 mg/dL to diagnose diabetes, 14.4% of the study population require an OGTT (OGTT%) with a sensitivity of 78.8% and a specificity of 100%. When serum GA value of 14% and 17% were used to exclude and diagnose diabetes, respectively, the sensitivity improved to 83.3%, with a slightly decrease in specificity (98.2%), but a significant increase in OGTT% (35%). Using combined FPG and serum GA cutoff values (FPG < 100 mg/dL plus serum GA < 15% to exclude diabetes and FPG ≥ 126 mg/dL or serum GA ≥ 17% to diagnose diabetes), the OGTT% was reduced to 22.5% and the sensitivity increased to 85.6% with no change in specificity (98.2%). In the diagnosis of diabetes, serum GA measurements can be used to determine the need of an OGTT.

Measurement of Waist Circumference: midabdominal or iliac crest?

OBJECTIVE: Waist circumference (WC) is used to define central obesity. This study aimed to compare the performance of two recommended locations of WC measurement. RESEARCH DESIGN AND METHODS: A cohort of 1,898 subjects who were without diabetes from 2006 to 2012 were followed for a median of 31 months (Taiwan Lifestyle Study). The WC-IC, recommended by the National Cholesterol Education Program Third Adult Treatment Panel, was measured at the superior border of the iliac crest, and the WC-mid, recommended by World Health Organization and International Diabetes Federation, was measured midway between the lowest ribs and the iliac crest. The abdominal subcutaneous fat area (SFA) and visceral fat area (VFA) were assessed by computed tomography. RESULTS: There was greater difference between WC-IC and WC-mid measurements in women than in men (P < 0.001). Both WC-IC and WC-mid correlated significantly with BMI, VFA, and SFA (all P < 0.001). WC-mid was better correlated to VFA than WC-IC, particularly in women, and it correlated more strongly to blood pressure, plasma glucose, hemoglobin A1c, triglyceride levels, HDL cholesterol, and C-reactive protein (all P < 0.05). The association of WC-mid with hypertension, diabetes, and metabolic syndrome was slightly better than that of WC-IC (area under the receiver operator curve 0.7 vs. 0.69, 0.71 vs. 0.68, and 0.75 vs. 0.7, respectively; all age-adjusted P < 0.05). With 90 cm (male)/80 cm (female) as criteria for central obesity, WC-mid, but not WC-IC, predicted the incidence of diabetes development (age-adjusted P = 0.003). CONCLUSIONS: WC-mid is a better measurement to define central obesity than WC-IC, particularly in women.

Low serum sex hormone-binding globulin: marker of inflammation?

BACKGROUND: Low sex hormone-binding globulin (SHBG) is associated with metabolic syndrome (MetS), but its relationship with inflammation is unclear. METHODS: This cross-sectional study included 696 subjects (255 men, 235 pre-menopausal women, and 206 postmenopausal women). Body mass index, waist circumference, blood pressure, lipid profiles, plasma glucose, insulin, FSH, LH, total testosterone (TT), estradiol, SHBG, dehydroepiandrosterone sulfate (DHEA-S), and hs-CRP concentrations were measured. MetS was defined according to the updated National Cholesterol Education Program criteria with modification of waist circumference for Asians. RESULTS: Serum hs-CRP and SHBG were negatively correlated in men (r=-0.29, p<0.001), pre-menopausal women (r=-0.38, p<0.001), and postmenopausal women (r=-0.27, p<0.001). In men, TT and hs-CRP showed a negative association (r=-0.25, p<0.001), but the association was attenuated after adjusting for SHBG (r=-0.14, p=0.039). Multivariate regression models showed that SHBG was independently associated with hs-CRP in men (r=-0.18, p=0.009), pre-menopausal women (r=-0.15, p=0.025), and postmenopausal women (r=-0.21, p=0.005), adjusted for age, MetS components, insulin resistance, low-density lipoprotein-cholesterol, and serum sex hormone levels. CONCLUSIONS: Serum SHBG and hs-CRP concentrations were inversely correlated in men, pre-menoposal, and post-menopausal women independently.

Hemoglobin A1c for the diagnosis of diabetes: To replace or to guide oral glucose tolerance tests?

UNLABELLED: Aims/Introduction: To evaluate if hemoglobin A1c (A1C) can replace the use of the oral glucose tolerance test (OGTT) to diagnose diabetes in Chinese patients. MATERIALS AND METHODS: Subjects without pre-existing diabetes were included in this community-based study. Each participant received a 75-g OGTT and A1C tests. RESULTS: A total of 1362 subjects, 512 men and 850 women, aged 18-88 years, were enrolled. The prevalence of diabetes was 7.4 and 7.3% by OGTT and by A1C ≥ 6.5% criteria, respectively. The optimal A1C cut-off for diabetes defined by OGTT was 6.1%. The performance of A1C ≥ 6.1% to find diabetes by OGTT was poor, with a kappa 0.50, sensitivity 80% and specificity 91%. Using current criteria of fasting plasma glucose (FPG) < 5.56 mmol/L to exclude and ≥7 mmol/L to diagnose diabetes (FPG criterion), the sensitivity, specificity and OGTT required were 77.2, 100 and 13.5%, respectively. Using A1C < 5.9% to exclude and ≥7.0% to diagnose diabetes (A1C criterion), the sensitivity, specificity and OGTT required were 89.1, 99.8 and 26.5%, respectively. However, using FPG < 5.56 mmol/L and A1C < 6.1% to exclude, and A1C ≥ 7.0% to diagnose diabetes (A1C plus FPG criterion), the sensitivity, specificity and OGTT required were 85.2, 100 and 18.9%, respectively. CONCLUSIONS: To screen for diabetes, the A1C criterion is more sensitive than the FPG criterion, with more OGTT needed. The A1C plus FPG criterion reduced the number of OGTT needed with acceptable sensitivity. A1C can guide, but cannot replace, OGTT to diagnose diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00181.x, 2011).

Serum vascular adhesion protein-1 predicts 10-year cardiovascular and cancer mortality in individuals with type 2 diabetes.

OBJECTIVE: Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10-year survival in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan. RESULTS: The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17-4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A(1c), diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17-28.97) for cardiovascular mortality, 6.32 (95% CI 1.25-32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57-65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly. CONCLUSIONS: Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors.