Robert P. Young

Visceral Fat and Cardiovascular Risk Factors in Chinese NIDDM Patients

OBJECTIVE The interrelations between obesity, glucose intolerance, hypertension, dyslipidemia, and insulin resistance are well recognized. These relationships are of particular interest in Hong Kongs Chinese population, in whom increasing affluence has coincided with a marked increase in the prevalence of NIDDM. We designed a pilot study to examine the relationships between visceral fat and cardiovascular risk factors in Chinese NIDDM patients. RESEARCH DESIGN AND METHODS We studied 21 Chinese NIDDM patients whose visceral fat was quantified by magnetic resonance imaging. Cardiovascular risk factors including plasma lipids and 24-h ambulatory blood pressure (BP) were measured. In addition, insulin resistance was determined by a short insulin tolerance test (SITT). RESULTS Increased visceral adiposity was significantly correlated with plasma triglycerides (r = 0.63, P = 0.004), the total cholesterol/HDL cholesterol ratio (r = 0.61, P = 0.008), the urinary albumin/creatinine ratio (r = 0.49, P = 0.04), and decreased insulin sensitivity as measured by the SITT (r = 0.47, P = 0.03). When the data were analyzed by tertiles, increasing visceral fat area was associated with higher plasma triglycerides, lower HDL cholesterol, and a smaller plasma glucose decrement during the SITT. In addition, the diurnal rhythm in BP and heart rate tended to be best preserved in those with the least visceral obesity. CONCLUSIONS This pilot study demonstrates that visceral fat accumulation is associated with dyslipidemia, hypertension, insulin resistance, and albuminuria in Chinese patients with NIDDM.

Angiotensinogen T235 and ACE Insertion/Deletion Polymorphisms Associated With Albuminuria in Chinese Type 2 Diabetic Patients

OBJECTIVE Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Ethnic differences in the frequencies of these genotypes have also been reported. To date, most of these studies have been performed in white and Japanese populations. In this study, we examined the associations between albuminuria and RAS genetic polymorphisms in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In a case-control study, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A1166C) were examined in 110 Chinese type 2 diabetic patients. Increased urinary albumin excretion (UAE) was defined as ≥ 30 mg/day on at least two occasions during a 6-week study period. RESULTS Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 diabetic patients (74/110 = 67%). The frequencies of the MM genotype were 5 and 3%, respectively, and those of the ACE DD genotype were 13 and 10%, respectively. Although 9% of subjects carried the C allele, the AT1 CC genotype was not found in either group. Chinese type 2 diabetic patients with increased albuminuria (n = 56) had higher systolic blood pressure (160 ± 26 mmHg vs 145 ± 27 mmHg, P < 0.001) than the normoalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/56] vs. 55.6% [30/54], odds ratio [OR]: 3.0 [1.3–6.8]) and the T allele (88% [99/112] vs. 77% [83/108], OR: 2.5 [1.3–5.4]) were associated with an increased risk of albuminuria. Patients with the AGT TT genotype (n = 74) had higher 24-h UAE than those with the MT or MM genotypes (n = 36) (median: 37.8 mg/day vs. 17.8 mg/day, P < 0.01). This association remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for those with the MT/MM genotype, P = 0.03). The D allele carriers (DD or DI, n = 61) had higher serum ACE activities (75.5 ± 29 U/l vs. 60.5 ± 36.3 U/l, P < 0.01) than the noncarriers (II genotype). The median 24-h UAE also tended to be higher in the D allele carriers (38.9 mg/day vs. 21.4 mg/day, P = 0.07). The lowest UAE was observed in patients with the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in patients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No association was found between the TT genotype or D allele and hypertension. CONCLUSIONS The high frequencies of the TT genotype and T allele in Chinese populations may contribute to the high prevalence of albuminuria in patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.

Lack of association between insertion/deletion polymorphism of the angiotensin-converting enzyme gene and end-stage heart failure due to ischemic or idiopathic dilated cardiomyopathy in the Chinese

Abstract In summary, we demonstrated that there is no apparent increase in the frequency of the DD ACE genotype in Chinese subjects with either idiopathic or ischemic cardiomyopathy and that the frequency of the DD genotype is considerably lower in normal Chinese subjects than in Caucasians.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM GENE POLYMORPHISMS AND HYPERTENSION IN HONG KONG CHINESE

In Chinese populations, hypertension is common and is a major risk factor for cerebrovascular and coronary heart disease. The renin-angiotensin-aldosterone system (RAAS) helps maintain blood pressure and salt homeostasis and appears important in the pathogenesis of hypertension and some forms of vascular disease. We investigated three RAAS gene polymorphisms, the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor A1166C polymorphisms in 232 hypertensive and 178 normotensive Chinese subjects. The hypertensives were generally more obese and dyslipidaemic. No significant differences in genotype or allele frequencies for any of the polymorphisms were identified between the groups, nor was there any interactive contribution to blood pressure by the ACE and AGT polymorphisms. However, there were large differences in genotype and allele frequencies between the healthy Chinese and published data for equivalent Caucasian populations. These findings suggest these polymorphisms are unlikely to be involved in the pathogenesis of hypertension in Chinese.

Influence of gene polymorphisms of the renin-angiotensin system on clinical outcome in heart failure among the Chinese

BACKGROUND An association between the DD allele of the angiotensin-converting enzyme gene and a poorer outcome in patients with heart failure has been found in whites. The DD allele frequency is lower in Chinese, but the M235T variant of the angiotensinogen gene is more common in Chinese than whites; it is not known to what extent polymorphisms of the renin-angiotensin system affect clinical status or prognosis in Chinese patients with heart failure. METHODS We assessed the relations among polymorphism of the angiotensin-converting enzyme gene, angiotensinogen M235T (AGT) gene, and angiotensin type I receptor A1166C gene with left ventricular systolic function, left and right ventricular diastolic function, serum angiotensin-converting enzyme, plasma aldosterone and atrial natriuretic peptide levels at presentation, and clinical outcome at 1 year (survival, hospital admissions) in a cohort of Chinese patients with typical systolic heart failure (n = 82). RESULTS We confirmed the low prevalence of the angiotensin-converting DD and the angiotensin type I receptor CC genotypes, and high prevalence of the AGT TT genotype in Chinese subjects compared with whites. There was no relation between the various gene polymorphisms and survival at 1 year assessed by multiple regression or Cox regression survival analysis. The AC variant of the angiotensin type I receptor gene was associated with morbidity over a 1-year period (hospital admissions) and increased baseline aldosterone levels, but none of the other polymorphisms correlated with systolic or diastolic function, aldosterone or atrial natriuretic peptide levels. By multiple regression for effects on mortality rate, only atrial natriuretic peptide and age were significant. CONCLUSIONS In Chinese patients with heart failure, polymorphisms of the renin-angiotensin system do not appear to be related to survival or severity, probably because of the different prevalence of these genotypes in the Chinese. Thus this study illustrates that large interethnic differences in the frequencies of genotype polymorphisms of the renin-angiotensin system exist and results from one ethnic group cannot be extrapolated to another.

Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics

Objective:Anticonvulsant drugs are known inducers of cytochrome P450 liver enzymes and it has been suggested that this induction increases susceptibility to paracetamol-induced hepatotoxicity.Methods:We measured the percentage urinary recovery of paracetamol and its metabolites after a dose of 20 mg kg−1, and the excretion of 6ß-hydroxycortisol as a ratio to urinary free cortisol(6ßOHF/F) in Chinese epileptic patients maintained on long term therapy with carbamazepine (n = 6) or phenytoin (n = 6).Results:Compared to the healthy controls (n = 20), patients on phenytoin had significantly lower recoveries of mercapturic acid, cysteine and sulphate metabolites, but a higher recovery of glucuronide metabolites of paracetamol. The recoveries of paracetamol metabolites in patients on carbamazepine were not different from controls. In contrast, the 6ßOHF/F was signi ficantly higher in patients on carbamazepine (3-fold) or phenytoin (2-fold) compared to controls.Healthy control Chinese subjects metabolised paracetamol in a similar way to that reported in Caucasians, indicating that the risk for hepatotoxicity would be the same. Our findings in a group of Chinese patients on phenytoin were also similar to those previously reported in Caucasians on this drug. The apparent differences in the pattern of isoenzyme induction between the groups on phenytoin and carbamazepine require verification in larger studies. The data do not suggest an increased risk of paracetamol-induced hepatotoxicity in Chinese patients on anticonvulsants.

The short insulin tolerance test : Feasibility study using venous sampling

The short insulin tolerance test (ITT) is both a simple and valid method of quantifying insulin sensitivity although arterialization of samples and the risk of hypoglycaemia remain as potential difficulties. We examined the safety and reproducibility of using venous sampling with insulin doses of 0.1U kg−1 and 0.05 U kg−1 in healthy subjects. Whole blood glucose concentrations were measured contemporaneously and the rate of plasma glucose decline (mmol l−1 min−1) for each test was estimated from unlogged venous plasma glucose concentrations measured at 1 min intervals. The mean rates of plasma glucose decline for the 0.1 U kg−1 and 0.05 U kg−1 insulin doses were 0.26 mmol l−1 min−1 (n = 11, range = 0.17–0.41, intrasubject coefficient of variation (CV) = 9.4%) and 0.25 mmol l−1 min−1 (n = 6, range 0.19–0.46, intrasubject CV = 15.9%), respectively. Reversal of significant hypoglycaemia was necessary in one subject before 15 min post‐insulin. We found that: (1) venous sampling provides a reproducible measure of glucose uptake after insulin, (2) contemporaneous bedside glucose sampling identifies those at risk of significant hypoglycaemia during the ITT, and (3) the 0.1 U kg−1 dose response is more reproducible and no less safe than the half dose response. We conclude that the current ITT protocol would be made safer and simpler with the above modifications although further studies comparing venous with arterialized sampling are needed.

Granulocyte-colony stimulating factor in the treatment of colchicine poisoning

1 Colchicine is a highly active alkaloid used in the treatment of gouty arthritis and pseudogout. In over dose colchicine inhibits cell division effecting organs with a high rate of cell turn-over, such as the gastrointestinal tract and bone marrow. Early fatality results from cardiovascular collapse and respiratory failure, however pancytopenia and overwhelming septicaemia can occur later. 2 We describe a case of suicidal ingestion of 25 - 30 mg of colchicine in a previously healthy 43-year-old woman. Initial symptoms were mainly gastrointestinal. By day 5 she had developed severe pancytopenia and early sepsis, which were successfully treated using granu locyte colony stimulating factor (G-CSF) 600 μg s.c. 3 In vitro G-CSF is produced by the haematopoietic system. However, G-CSF can now be produced by recombinant DNA cloning technology and thus is available clinically. 4 There is no recognised antidote for colchicine poison ing and treatment is symptomatic. Fab fragments may have a promising future in eliminating colchicine from the body, but are currently not clinically available. In those patients that survive the initial phase of poisoning, G-CSF offers an effective method of treating the pancytopenia and preventing overwhelming septi caemia. Daily monitoring of the patients haematolo gical status is strongly recommended.

New risk factors for coronary heart disease in Asia

The increasing prevalence of traditional atherosclerotic risk factors have been documented in Asia but the real impact on prevalence of coronary heart disease (CHD) remains unclear. Smoking, hypertension, hypercholesterolaemia, diabetes mellitus and obesity are present in only 50% of CHD. In community studies of Chinese in Hong Kong and southern mainland-China, aging, smoking and hypercholesterolaemia were found to have a less impact on endothelial function in the Chinese compared with Caucasians in London and Sydney. As endothelial dysfunction is an early event in atherogenesis, there will be a strong need to search for newer risk factors for CHD in Asia, which may become more important in many Asian countries now in the process of modernization. Recently, heterozygous hyperhomocysteinaemia (with or without folate deficiency) was found to be an independent risk factor for arterial endothelial dysfunction, and hyperhomocysteinaemia in association with smoking was a significant risk factor for premature coronary heart disease in Hong Kong Chinese. Other newer factors which have emerged include folate deficiency, low HDL-cholesterol, insulin resistance, abdominal obesity, Methylene-tetrahydrofolate Reductase and Angiotensin Converting Enzyme gene polymorphism.

A Sibling-Pair Analysis of Fasting Lipids and Anthropometric Measurements and Their Relationship to Hypertension

Fifty non-diabetic, young Chinese hypertensives were compared to their normotensive siblings with respect to body fat distribution and fasting lipid and glucose (FPG) profiles. Sitting BP in hypertensives met conventional hypertension criteria after a 4-week washout period on placebo. Hypertensives had greater body mass index (BMI), subscapular skin-fold thickness (SFT), waist circumference (W), waist-to-height (WHtR) and waist-to-hip ratio (WHR), p<0.0001 for all. Higher triglycerides (p=0.004) and lower HDL-cholesterol (p=0.015) concentrations were also observed. Weight, W, WHtR and BMI were higher in hypertensives in both male (n=9) and female gender-concordant sibling pairs (n=21). Higher WHR, hip circumference and subscapular SFT were only seen in the male hypertensives. Hypertension is associated with central adiposity and adverse lipid profiles in this group of young hypertensives, supporting the hypothesis that obesity, particularly central, is closely associated with hypertension in Chinese as in other ethnic groups.