To examine the association between ingested inorganic arsenic and prevalence of diabetes mellitus, in 1988, the authors studied 891 adults residing in villages in southern Taiwan where arseniasis is hyperendemic. The status of diabetes mellitus was determined by an oral glucose tolerance test and a history of diabetes regularly treated with sulfonylurea or insulin. The cumulative arsenic exposure in parts per million-years was calculated from the detailed history of residential addresses and duration of drinking artesian well water obtained through standardized interviews based on a structured questionnaire and the arsenic concentration in well water. The body mass index was derived from body height and weight measured according to a standard protocol, while the physical activity at work was also obtained by questionnaire interviews. Residents in villages where the chronic arseniasis was hyperendemic had a twofold increase in age- and sex-adjusted prevalence of diabetes mellitus compared with residents in Taipei City and the Taiwan area. There was a dose-response relation between cumulative arsenic exposure and prevalence of diabetes mellitus. The relation remained significant after adjustment for age, sex, body mass index, and activity level at work by a multiple logistic regression analysis giving a multivariate-adjusted odds ratio of 6.61 and 10.05, respectively, for those who had a cumulative arsenic exposure of 0.1-15.0 and greater than 15.0 ppm-year compared with those who were unexposed. These results suggest the chronic arsenic exposure may induce diabetes mellitus in humans.

Aim/hypothesis: Microalbuminuria represents the earliest clinical evidence of diabetic nephropathy and is a marker of increased cardiovascular morbidity and mortality. Its early detection allows the implementation of individualised and aggressive intervention programmes to reduce cardiovascular risk factors. There is limited information on the prevalence of microalbuminuria among hypertensive type 2 diabetic patients in Asia. Methods: This cross-sectional epidemiological study aimed to assess the prevalence of microalbuminuria and macroalbuminuria among consecutively screened hypertensive type 2 diabetic adult patients in 103 centres in 10 Asian countries or regions. Predictive factors for microalbuminuria and macroalbuminuria were characterised using a stepwise logistic regression model. Results: A total of 6,801 patients were enrolled and 5,549 patients constituted the per-protocol population (patients with bacteriuria and haematuria were excluded). The prevalence of microalbuminuria was 39.8% (39.2-40.5; 95% CI) and the prevalence of macroalbuminuria was 18.8% (18.2-19.3; 95% CI). Only 11.6% of the patients had systolic and diastolic blood pressure below the 130/80 mm Hg target. In the multivariate analyses, the predictive factors for the presence of microalbuminuria were age, BMI, systolic blood pressure and ethnic origin. The highlighted predictive factors for the presence of macroalbuminuria were age, sex, ethnic origin, BMI, duration of diabetes, presence of diabetic complications, intake of diuretics, intake of calcium channel blockers, diastolic and systolic blood pressure. Conclusions/interpretation: The high prevalence (58.6%) of micro or macroalbuminuria observed in these patients is alarming and indicates an impending pandemic of diabetic cardiovascular and renal diseases in Asia with its potential economic consequences.

SUMMARY (De)acetylation of histone and non-histone proteins is an important post-translational modification affecting many cellular processes. Here we report that NuA4 acetylation of Sip2, one of three regulatory β subunits of Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. We used mutations at four acetylation sites, K12, 16, 17 and 256, to study acetyl-Sip2 function. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), ultimately leads to slower growth but extends replicative lifespan. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a novel protein acetylation- phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging and extends replicative lifespan in yeast.

The cardiovascular effects of inorganic arsenic have been documented, but the dose-response relationship between ischemic heart disease (ISHD) and long-term arsenic exposure remains to be elucidated. Mortality rates from ISHD among residents in 60 villages of the area in Taiwan with endemic arseniasis from 1973 through 1986 were analyzed to examine their association with arsenic concentration in drinking water. Based on 1 355 915 person-years and 217 ISHD deaths, the cumulative ISHD mortalities from birth to age 79 years were 3.4%, 3.5%, 4.7%, and 6.6%, respectively, for residents who lived in villages in which the median arsenic concentrations in drinking water were <0.1, 0.1 to 0.34, 0.35 to 0.59, and > or = 0.6 mg/L. A cohort of 263 patients affected with blackfoot disease (BFD), a unique arsenic-related peripheral vascular disease, and 2293 non-BFD residents in the endemic area of arseniasis were recruited and followed up for an average period of 5.0 years. There was a monotonous biological gradient relationship between cumulative arsenic exposure through drinking artesian well water and ISHD mortality. The relative risks were 2.5, 4.0 and 6.5, respectively, for those who had a cumulative arsenic exposure of 0.1 to 9.9, 10.0 to 19.9, and > or = 20.0 mg/L-years compared with those without the arsenic exposure after adjustment for age, sex, cigarette smoking, body mass index, serum cholesterol and triglyceride levels, and disease status for hypertension and diabetes through proportional-hazards regression analysis. BFD patients were found to have a significantly higher ISHD mortality that non-BFD residents, showing a multivariate-adjusted relative risk of 2.5 (95% CI, 1.1 to 5.4).

To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans.