Dee Pei

A Polymorphism in the β1 Adrenergic Receptor Is Associated with Resting Heart Rate

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).

Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder

Objective  This study was designed to evaluate insulin sensitivity, proinflammatory markers and adiponectin concentration in young males with different subtypes of depressive disorder.

Genetic variation in aldosterone synthase predicts plasma glucose levels.

The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms—one in the putative promoter (T-344C) and another resulting in a lysine/arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population—were associated with fasting plasma glucose levels (P = 0.000017) and those 60 (P = 0.017) and 120 (P = 0.0019) min after an oral glucose challenge. A C/T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39–3.92; P = 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02–5.5; P = 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.

Predictive Value of Serum Uric Acid Levels for the Diagnosis of Metabolic Syndrome in Adolescents

OBJECTIVE To evaluate the cause-effect relationships between serum levels of uric acid (UA) and metabolic syndrome (MetS) in an adolescent-male cohort that was followed for 2.7 years. STUDY DESIGN We enrolled male adolescents aged between 10 and 15 years at the baseline. A total of 613 subjects were divided into quartiles according to their UA levels, from UA-1 (the lowest) to UA-4 (the highest). RESULTS After the mean follow-up period of 2.7 ± 0.97 years, 19 (3.1%) subjects developed MetS. Waist circumference (WC), systolic blood pressure, high density lipoprotein cholesterol (HDL-C), and log triglyceride levels were significantly related to baseline UA levels. Compared with the UA-1 group, subjects in the UA-4 group had significantly higher OR for abnormal WC, blood pressure, and HDL-C at the end of follow-up and had a 6.39-fold higher OR (95% CI 1.41-29.08; P < .05) for having MetS. Subjects with UA >7.6 mg/dL had a 4.32 (95% CI 1.57-11.93) higher risk of developing MetS. CONCLUSIONS In this longitudinal study, we found that serum UA is correlated with future WC, systolic blood pressure, triglyceride, and HDL-C and is a risk factor for developing MetS. UA might be valuable in predicting adolescent MetS.

Bisphosphonate pretreatment attenuates hungry bone syndrome postoperatively in subjects with primary hyperparathyroidism.

Primary hyperparathyroidism is characterized by hypercalcemia with loss of bone mass. After parathyroidectomy, hypocalcemia may develop in some patients due to unregulated bone mineralization. Preoperative administration of bisphosphonates, potent inhibitors of osteoclast activity, may prevent postoperative hypocalcemia after parathyroidectomy. We retrospectively reviewed medical records to investigate the effect of bisphosphonate pretreatment on serum calcium level changes after parathyroidectomy. Twenty-three patients with a diagnosis of primary hyperparathyroidism underwent parathyroidectomy between April 1997 and August 2002. Clinical and laboratory data were collected before and after the operation. These patients were divided into two groups; those showing hungry bone syndrome (n = 9) and those not (n = 14). None of the 9 patients with hungry bone syndrome had received bisphosphonate pretreatment. Of the 14 patients without hungry bone syndrome, 6 had received bisphosphonate pretreatment (P < 0.05). Furthermore, preoperative calcium concentration was not related to the occurrence of hypo-calcemia in those without bisphosphonate pretreatment. In conclusion, administration of bisphosphonates in primary hyperparathyroidism can prevent the occurrence of hungry bone syndrome after parathyroidectomy.

Variability in hemoglobin A1c predicts all-cause mortality in patients with type 2 diabetes

BACKGROUND To evaluate the relationship between hemoglobin A1c variability and all-cause mortality in type 2 diabetic patients. METHODS This was a retrospective cohort study in type 2 diabetic patients followed for at least 2 years between 2003 and 2009. A1C variability was determined from the standard deviation or coefficient of variation of serial A1C values (A1C(SD) or A1C(CV)). Subjects were categorized into either the high or low A1C variability group according to their A1C(CV) median. Hazard ratios (HRs) of various factors for all-cause mortality were determined from Coxs proportional hazard models. RESULTS A total of 881 subjects (422 men, 459 women) were included and 73 (8.3%) died during follow-up. The follow-up period was 4.7 ± 2.3 years. All-cause mortality was higher in subjects with high A1C(CV) (11.0% vs. 5.4%, p=0.002). In the Kaplan-Meier failure curve, subjects with higher A1C(CV) demonstrated a trend of higher mortality (p=0.1). In multivariate Coxs proportional hazards models, A1C(SD) and A1C(CV) significantly predicted all-cause mortality with an HR of 1.987 (p=0.02) and 1.062 (p=0.013), respectively, after adjusting for age, gender, body mass index, duration of diabetes, mean systolic blood pressure, use of antihypertensives and statins, mean LDL-cholesterol, smoking status, chronic kidney disease, and mean A1C values (A1C(MEAN)). The ability of A1C(SD) and A1C(CV) to predict all-cause mortality was more evident in subjects with relatively low A1C(MEAN.) CONCLUSIONS A1C variability is an important risk factor for all-cause mortality in type 2 diabetic patients.

The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent.

Diabetic neuronal damage results from hyperglycemia followed by increased formation of advanced glycosylation end products (AGEs), which leads to neurodegeneration, although the molecular mechanisms are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). AMPK is a critical evolutionarily conserved enzyme expressed in the liver, skeletal muscle and brain, and promotes cellular energy homeostasis and biogenesis by regulating several metabolic processes. While the mechanisms of AMPK as a metabolic regulator are well established, the neuronal role for AMPK is still unknown. In the present study, human neural stem cells (hNSCs) exposed to AGEs had significantly reduced cell viability, which correlated with decreased AMPK and mitochondria associated gene/protein (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3 and 9 activities. Metformin prevented AGEs induced cytochrome c release from mitochondria into cytosol in the hNSCs. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. Metformin also significantly rescued hNSCs from AGE-mediated mitochondrial deficiency (lower ATP, D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Furthermore, co-treatment of hNSCs with metformin significantly blocked AGE-mediated reductions in the expression levels of several neuroprotective genes (PPARγ, Bcl-2 and CREB). These findings extend our understanding of the molecular mechanisms of both AGE-induced neuronal toxicity, and AMPK-dependent neuroprotection by metformin. This study further suggests that AMPK may be a potential therapeutic target for treating diabetic neurodegeneration.

Uric Acid Levels Can Predict Metabolic Syndrome and Hypertension in Adolescents: A 10-Year Longitudinal Study.

The relationships between uric acid and chronic disease risk factors such as metabolic syndrome, type 2 diabetes mellitus, and hypertension have been studied in adults. However, whether these relationships exist in adolescents is unknown. We randomly selected 8,005 subjects who were between 10 to 15 years old at baseline. Measurements of uric acid were used to predict the future occurrence of metabolic syndrome, hypertension, and type 2 diabetes. In total, 5,748 adolescents were enrolled and followed for a median of 7.2 years. Using cutoff points of uric acid for males and females (7.3 and 6.2 mg/dl, respectively), a high level of uric acid was either the second or third best predictor for hypertension in both genders (hazard ratio: 2.920 for males, 5.222 for females; p<0.05). However, uric acid levels failed to predict type 2 diabetes mellitus, and only predicted metabolic syndrome in males (hazard ratio: 1.658; p<0.05). The same results were found in multivariate adjusted analysis. In conclusion, a high level of uric acid indicated a higher likelihood of developing hypertension in both genders and metabolic syndrome in males after 10 years of follow-up. However, uric acid levels did not affect the occurrence of type 2 diabetes in both genders.

Plasma apelin: A novel biomarker for predicting diabetes

BACKGROUND Apelin regulates insulin sensitivity and secretion in animals. However, whether plasma apelin predicts incident diabetes in humans remains unknown. METHODS We studied a cohort including 447 subjects (148 men, 299 women) without diabetes and followed for an average of 3y. Diabetes was diagnosed by an oral glucose tolerance test, plasma hemoglobin A1c, and if the subject was taking medications for diabetes. Plasma apelin-12 at baseline was measured with a commercial kit. RESULTS Plasma apelin concentrations were higher in women than in men at baseline (p=0.007). During follow-up, 43 subjects developed type 2 diabetes. Higher plasma apelin concentrations were associated with a higher risk of diabetes in men (p=0.049) but not in women. Plasma apelin predicted incident type 2 diabetes in men (hazard ratio, 2.13, 95% CI 1.29-3.51, p<0.05), but not in women, adjusted for age, family history of diabetes, hemoglobin A1c, body mass index, hypertension, and HOMA2-IR. Apelin could improve the prediction ability beyond traditional risk factors in men, and the sensitivity and specificity of plasma apelin at 0.9ng/ml for this prediction were 63.2% and 58.9%, respectively. In men at risk for diabetes (HbA1c 5.7-6.4%, FPG 100-125mg/dl, or OGTT-2h-PG 140-199mg/dl), the risk for developing diabetes was higher in those with higher plasma apelin concentration than in those with lower plasma apelin concentrations (10.6%/year vs. 5.1%/year, p<0.001). CONCLUSIONS Plasma apelin is a novel biomarker for predicting type 2 diabetes in men.

Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves’ hyperthyroidism

objective  The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves’ hyperthyroidism.