Chin Meng Khoo

Ethnicity Modifies the Relationships of Insulin Resistance, Inflammation, and Adiponectin With Obesity in a Multiethnic Asian Population

OBJECTIVE The development of obesity-related metabolic disorders varies with ethnicity. We examined whether ethnicity modifies the relationship between BMI and three metabolic pathways (insulin resistance, inflammation, and adiponectin) that are involved in the pathogenesis of diabetes and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS We analyzed data from 4,804 Chinese, Malay, and Asian-Indian residents of Singapore with complete data on insulin resistance (IR), C-reactive protein (CRP), and total adiponectin levels. Linear regression models with an interaction term ethnicity*BMI were used to evaluate whether ethnicity modifies the association between BMI and IR, CRP, and adiponectin. RESULTS In both uni- and multivariate analyses, BMI was directly associated with IR and CRP and inversely with adiponectin across all ethnic groups. When compared with Chinese and Malays, Asian-Indians had higher IR and CRP and lower adiponectin levels. The associations between BMI and its metabolic pathways were significantly stronger in Chinese than in other ethnic groups. The increase in IR and CRP and the decrease in adiponectin for each unit increase in BMI were greater in Chinese than in other ethnic groups. The findings were similar when waist circumference was used in the analyses instead of BMI. CONCLUSIONS The impact of BMI on IR, CRP, and adiponectin appears greater in Chinese as compared with other major Asian ethnic groups. This may partly explain the rapid increase in the prevalence of diabetes and CVD in Chinese populations and highlights the importance of weight management in Asian ethnic groups despite the apparently low levels of obesity.

Is There a Clear Threshold for Fasting Plasma Glucose That Differentiates Between Those With and Without Neuropathy and Chronic Kidney Disease? The Singapore Prospective Study Program

Recent studies suggest that no distinct glycemic threshold consistently differentiates individuals with or without retinopathy. The authors sought to determine whether the same was true for other microvascular complications. They studied 5,094 participants with fasting plasma glucose values and concurrent microvascular complications from 4 previous cross-sectional surveys carried out in Singapore (1982-1998) who attended a follow-up examination in 2004-2007. Peripheral neuropathy was diagnosed based on abnormal responses to a 10-g monofilament or neurothesiometer test. Chronic kidney disease was defined in various ways by using albuminuria (urine albumin:creatinine ratio >30 microg/mg) and estimated glomerular filtration rate, alone and in combination. Prevalence of peripheral neuropathy was 7.5%. For chronic kidney disease, prevalence of albuminuria only was 10.5%, estimated glomerular filtration rate of <60 mL/minute per 1.73 m(2) only was 4.1%, and both was 2.1%. Prevalence of peripheral neuropathy and chronic kidney disease gradually increased in relation to fasting plasma glucose, beginning at levels below the existing diagnostic threshold for diabetes mellitus of 7.0 mmol/L (126 mg/dL). For chronic kidney disease, these associations persisted after adjustment for age, gender, ethnic group, and hypertension. Current diagnostic thresholds for diabetes mellitus have limited sensitivity for identifying individuals with these microvascular complications. Ascertaining these individuals may require development and application of novel screening strategies.

Identification of Specific Cell-Surface Markers of Adipose-Derived Stem Cells from Subcutaneous and Visceral Fat Depots

Summary Adipose-derived stem/stromal cells (ASCs) from the anatomically distinct subcutaneous and visceral depots of white adipose tissue (WAT) differ in their inherent properties. However, little is known about the molecular identity and definitive markers of ASCs from these depots. In this study, ASCs from subcutaneous fat (SC-ASCs) and visceral fat (VS-ASCs) of omental region were isolated and studied. High-content image screening of over 240 cell-surface markers identified several potential depot-specific markers of ASCs. Subsequent studies revealed consistent predominant expression of CD10 in SC-ASCs and CD200 in VS-ASCs across 12 human subjects and in mice. CD10-high-expressing cells sorted from SC-ASCs differentiated better than their CD10-low-expressing counterparts, whereas CD200-low VS-ASCs differentiated better than CD200-high VS-ASCs. The expression of CD10 and CD200 is thus depot-dependent and associates with adipogenic capacities. These markers will offer a valuable tool for tracking and screening of depot-specific stem cell populations.

Macro-Thyrotropin: A Case Report and Review of Literature

CONTEXT Isolated elevation of TSH in the absence of thyroid symptoms can be very rarely caused by a macromolecule formed between TSH and Ig (macro-TSH), confounding the interpretation of thyroid function test results. OBJECTIVE We described the use of several commonly available laboratory-based approaches to investigate an isolated TSH elevation [232 mIU/liter; free T(4), 10 pmol/liter (reference interval, 10.0-23.0 pmol/liter), Vitros platform] in a clinically euthyroid elderly gentleman, which led to the diagnosis of macro-TSH. METHODS AND RESULTS TSH concentration of the patient was significantly lower (122 mIU/liter) when measured on the Advia Centaur platform. Serial dilution of the patients sample showed a nonlinear increase in TSH recovery at increasing dilution (nonlinearity). Polyethylene glycol precipitation and mixing the patients sample with a hypothyroid patient sample showed reduced TSH recovery, suggesting the presence of a high molecular weight interfering substance and excess TSH binding capacity, respectively. Heterophile blocking tube studies and rheumatoid factors were negative. Gel filtration chromatography demonstrated a TSH peak fraction that approximated the molecular size of IgG; together with the excess TSH binding capacity, this indicated the presence of TSH-IgG macro-TSH. A review of 12 macro-TSH case reports showed that samples with macro-TSH produce over-recovery with dilution, return negative results on anti-animal and anti-heterophile blocking studies, and commonly have recovery of less than 20% when subjected to polyethylene glycol precipitation. CONCLUSION Macro-TSH is an underrecognized laboratory interference. Routine laboratory techniques described above can help diagnose this rare entity. A close dialogue between the physician and the laboratory is important in approaching such cases.

The impact of central obesity as a prerequisite for the diagnosis of metabolic syndrome.

Objective: To compare the prevalence of metabolic syndrome (MS) defined according to the American Heart Association (AHA)/National Heart Lung and Blood Institute (NHLBI) and the International Diabetes Federation (IDF) and to determine the effect of the presence of central obesity on the phenotype (insulin resistance and other cardiovascular risk factors) associated with MS.

Automated segmentation of visceral and subcutaneous (deep and superficial) adipose tissues in normal and overweight men.

To develop an automatic segmentation algorithm to classify abdominal adipose tissues into visceral fat (VAT), deep (DSAT), and superficial (SSAT) subcutaneous fat compartments and evaluate its performance against manual segmentation.

Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction.

Background:Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses and increased susceptibility to hypoglycemia. Objective:We examined whether these features are due to caloric restriction (CR) or altered nutrient handling. Methods:We performed comprehensive analysis of postprandial metabolite responses during a 2-hour mixed-meal tolerance (MMT) test in 20 morbidly obese subjects with type 2 diabetes who underwent RYGB surgery or matched CR. Acylcarnitines and amino acids (AAs) were measured using targeted mass spectrometry. A linear mixed model was used to determine the main effect of interventions and interaction term to assess the effect of interventions on postprandial kinetics. Results:Two weeks after these interventions, several gut hormones (insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide 1), glucose, and multiple AAs, including branched-chain and aromatic species, exhibited a more rapid rate of appearance and clearance in RYGB surgery subjects than in CR subjects during the MMT test. In the RYGB surgery group, changes in leucine/isoleucine, methionine, phenylalanine, and glucagon-like peptide 1 response were associated with changes in insulin response. Levels of alanine, pyruvate, and lactate decreased significantly at the later stages of meal challenge in RYGB surgery subjects but increased with CR. Conclusions:RYGB surgery results in improved metabolic flexibility (ie, greater disposal of glucose and AAs and more complete &bgr;-oxidation of fatty acids) compared with CR. The changes in the AA kinetics may augment the hormonal responses seen after RYGB surgery. The reduction in key gluconeogenic substrates in the postprandial state may contribute to increased susceptibility to hypoglycemic symptoms in RYGB surgery subjects.

Body Fat Partitioning Does Not Explain the Interethnic Variation in Insulin Sensitivity Among Asian Ethnicity: The Singapore Adults Metabolism Study

We previously showed that ethnicity modifies the association between adiposity and insulin resistance. We sought to determine whether differential body fat partitioning or abnormalities in muscle insulin signaling associated with higher levels of adiposity might underlie this observation. We measured the insulin sensitivity index (ISI), percentage of body fat (%body fat), visceral (VAT) and subcutaneous (SAT) adipose tissue, liver fat, and intramyocellular lipids (IMCL) in 101 Chinese, 82 Malays, and 81 South Asians, as well as phosphorylated (p)-Akt levels in cultured myoblasts from Chinese and South Asians. Lean Chinese and Malays had higher ISI than South Asians. Although the ISI was lower in all ethnic groups when %body fat was higher, this association was stronger in Chinese and Malays, such that no ethnic differences were observed in overweight individuals. These ethnic differences were observed even when %body fat was replaced with fat in other depots. Myoblasts obtained from lean South Asians had lower p-Akt levels than those from lean Chinese. Higher adiposity was associated with lower p-Akt levels in Chinese but not in South Asians, and no ethnic differences were observed in overweight individuals. With higher %body fat, Chinese exhibited smaller increases in deep SAT and IMCL compared with Malays and South Asians, which did not explain the ethnic differences observed. Our study suggests that body fat partitioning does not explain interethnic differences in insulin sensitivity among Asian ethnic groups. Although higher adiposity had greater effect on skeletal muscle insulin sensitivity among Chinese, obesity-independent pathways may be more relevant in South Asians.

Distribution of ankle—brachial index and the risk factors of peripheral artery disease in a multi-ethnic Asian population:

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality. We describe the prevalence and risk factors of PAD in a multi-ethnic Asian population (Chinese, Malays and Indians) in Singapore. The Singapore Prospective Study Program recruited 4132 individuals between 2004 and 2006 in which the ankle—brachial index (ABI) was measured using the Smartdop™ 20EX bi-directional blood flow detector. PAD was defined as ≤ 0.9 and a high ABI > 1.4, with ABI 1.11—1.20 as reference. The mean age (SD) of individuals in the study was 49.9 (11.8) years, with 51.8% females. PAD was present in 4.3% of the population and a high ABI (> 1.4) was rare. Malays and Indians had a higher risk (especially in females). Compared to those with an ABI between 1.11 and 1.20, those with PAD were more likely to be of Malay and Indian ethnicity, female sex, with higher systolic blood pressure and pulse pressure, with increased prevalence of diabetes mellitus, hypertension, albuminuria and renal impairment, and with a past history of stroke. In conclusion, in this large multi-ethnic Asian population, we document the distribution and risk factor associations for PAD. PAD shows an ethnic distribution similar to that of coronary artery disease in Singapore, with differences in sex distribution. Apart from traditional vascular risk factors, pulse pressure, renal impairment and a past history of stroke are important determinants of PAD.

Type 2 diabetic patients with resistant hypertension should be screened for primary aldosteronism

BP control in diabetic patients is often poor. The contribution of secondary hypertension due to undiagnosed PA in hypertensive type 2 diabetic patients is not well studied. We prospectively screened 100 consecutive Asian type 2 diabetic patients with difficult-to-control or resistant hypertension for PA. PAC (pmol/L) to PRA (ng/mL/h) ratio was measured; those with PAC-to-PRA ratio >550 (corresponding PAC >415) underwent intravenous 0.9% SLT. Patients with PAC ≥140 following SLT had CT adrenals and bilateral AVS. Thirteen patients (13%) were confirmed to have PA, and all had resistant hypertension. Eight had a surgically correctable form of PA. Patients with PA had higher mean (SD) systolic [159.0 (10.6) vs. 146.0 (10.7) mmHg, p=0.001] and diastolic BP [94.6 (6.0) vs. 87.6 (5.9) mmHg, p=0.001], lower serum potassium [3.5 (0.6) vs. 4.3 (0.5) mmol/L, p=0.001], and higher PAC [679.3 (291.0) vs. 239.5 (169.4) pmol/L, p=0.001]. Identification and institution of definitive treatment for PA resulted in better BP control and in a reduction in the use of antihypertensive medications. Our findings demonstrate a high prevalence of PA in type 2 diabetic patients with resistant hypertension. Systematic screening for PA in this select group is recommended, as targeted treatment improves BP control.