Profiling retrospective thyroid function data in complete thyroidectomy patients to investigate the HPT axis set point (PREDICT-IT).

BACKGROUND: The homeostatic euthyroid set point of the hypothalamus-pituitary-thyroid axis of any given individual is unique and oscillates narrowly within substantially broader normal population ranges of circulating free thyroxine (FT4) and thyroid-stimulating hormone (TSH), otherwise termed 'thyroid function test (TFT)'. We developed a mathematical algorithm codenamed Thyroid-SPOT that effectively reconstructs the personalized set point in open-loop situations and evaluated its performance in a retrospective patient sample. METHODS: We computed the set points of 101 patients who underwent total thyroidectomy for non-functioning thyroid disease using Thyroid-SPOT on each patient's own serial post-thyroidectomy TFT. Every predicted set point was compared against its respective healthy pre-operative euthyroid TFT per individual and their separation (i.e. predicted-observed TFT) quantified. RESULTS: Bland-Altman analysis to measure the agreement between each pair of an individual's predicted and actual set points revealed a mean difference in FT4 and TSH of + 3.03 pmol/L (95% CI 2.64, 3.43) and - 0.03 mIU/L (95% CI - 0.25, 0.19), respectively. These differences are small compared to the width of the reference intervals. Thyroid-SPOT can predict the euthyroid set point remarkably well, especially for TSH with a 10-16-fold spread in magnitude between population normal limits. CONCLUSION: Every individual's equilibrium euthyroid set point is unique. Thyroid-SPOT serves as an accurate, precise and reliable targeting system for optimal personalized restoration of euthyroidism. This algorithm can guide clinicians in L-thyroxine dose titrations to resolve persistent dysthyroid symptoms among challenging cases harbouring "normal TFT" within the laboratory ranges but differing significantly from their actual euthyroid set points.

Associations of physical activity levels and screen time with oral glucose tolerance test profiles in Singaporean women of reproductive age actively trying to conceive: the S-PRESTO study.

AIM: To examine the associations of physical activity and screen time, a proxy for sedentary behaviour, with fasting and post-load glucose levels in Singaporean women enrolled in a multi-ethnic Asian preconception study. METHODS: Moderate and vigorous physical activity and screen time (television and other electronic devices) were self-reported by women enrolled in the S-PRESTO cohort. Fasting, 30-min and 120-min glucose levels before and during a 75-g oral glucose tolerance test were measured. Associations of physical activity and screen time with glucose levels were analysed using multivariable linear marginal regression. RESULTS: A total of 946 women aged 31.4±3.7 years were examined, of whom 72% were of Chinese, 15.5% were of Malay, 9.3% were of Indian and 3.2% were of mixed ethnicity. A total of 32% of women reported being active, 36% watched television ≥2 h/day and 26% used electronic devices ≥3 h/day. In adjusted models, vigorous, but not moderate, physical activity was associated with lower overall glucose levels, and was associated more strongly with post-challenge than fasting glucose levels. Compared to women not engaging in vigorous physical activity, those engaging in physical activity ≥75 min/week had lower mean fasting [-0.14 (95% CI -0.28, -0.01) mmol/l], 30-min [0.35 (95% CI -0.68, -0.02) mmol/l] and 120-min [-0.53 (95% CI -0.16, -0.90) mmol/l] glucose levels (overall P value=0.05). We found no associations of screen time with glucose levels. CONCLUSIONS: Independently of the time spent in non-vigorous physical activity and using screens, engaging in vigorous physical activity may be a modifiable factor to improve glucose regulation in women of Asian ethnicity who are attempting to conceive.

Associations between complications and health-related quality of life in individuals with diabetes.

OBJECTIVE: Type 2 diabetes and associated complications adversely affect health-related quality of life (HRQoL). However, it is unclear whether different complications have the same or different associations with HRQoL. We examined associations between retinopathy, nephropathy, peripheral neuropathy (microvascular), coronary heart disease, stroke and peripheral arterial disease (macrovascular) in diabetes and HRQoL. DESIGN: This study was a follow-up examination between 2004 and 2007 of participants from four previous cross-sectional population-based studies in Singapore. METHODS: Health-related quality of life was assessed through self-administered SF-36 health survey version 2. Diabetes and complications status were assessed through self-report, clinical and laboratory examinations. About 2601 individuals, 2205 healthy and 396 with diabetes, were studied. RESULTS: Lower physical component scores (PCS) were associated with microvascular (2.96 points, P < 0.001) and both macro- and microvascular complications (4.67 points, P < 0.001), but not diabetes alone. Coronary heart disease (3.86 points, P = 0.007), peripheral neuropathy (11.46 points, P < 0.001) and severe retinopathy (4.46 points, P < 0.001) were associated with lower PCS. The greatest reduction in scores was seen in peripheral neuropathy. CONCLUSIONS: Quality of life in patients with diabetes is affected mainly by presence of complications, and not diabetes per se. Peripheral neuropathy was associated with the greatest reduction in quality of life. Improved management to prevent or delay onset of complications may reduce the effect on quality of life in patients with diabetes.

Brown fat activity determined by infrared thermography and thermogenesis measurement using whole body calorimetry (BRIGHT Study).

To assess BAT activity in humans at a population level, infrared thermography (IRT) represents a safe, readily repeatable and affordable alternative to 18F-FDG-PET. Building upon a previously proposed method by our laboratory, we further refined the image computational algorithm to quantify BAT activation in the cervical-supraclavicular (C-SCV) region of healthy young men under thermo-neutral and cold exposure conditions. Additionally, we validated the whole-body calorimeter (WBC) in reliably measuring cold-induced thermogenesis. The temperature gradient between C-SCV-deltoid regions, and the corresponding difference in heat power output, increased upon cold air exposure relative to thermo-neutral conditions (by 74.88 %, p<0.0001; and by 71.34 %, p<0.0001 respectively). Resting and cumulative energy expenditure (EE) rose significantly (by 13.14 % and 9.12 % respectively, p=0.0001) while positive correlations between IRT measures and EE were found with cold air exposure (percentage change in heat power gradient between ROI and deltoid, cold air: r(2)=0.29, p=0.026, Pearson's correlation). IRT and WBC can be used to study BAT activation. The refined algorithm allows for more automation and objectivity in IRT data analysis, especially under cold air exposures.

Neuroglycopenia and adrenergic responses to hypoglycaemia: insights from a local epidemic of serendipitous massive overdose of glibenclamide.

AIMS: Recently, an unlicensed aphrodisiac formulation originating from China known as 'Power 1 Walnut' penetrated the illicit markets of South East Asia including Singapore. Subsequent toxicological analyses revealed that each 'Power 1 Walnut' pill was illegally adulterated with two prescription drugs--sildenafil 1 mg (a PDE5 inhibitor) and glibenclamide 93-98 mg (a long-acting sulphonylurea). As the drug was peddled to numerous people, a local 'hypoglycaemia epidemic' ensued, of which a small cluster presented to our hospital with severe hypoglycaemia. The aim is to characterize the demographics, clinical and labouratory aspects and postulate mechanisms for the relatively atypical presentation. METHODS: A retrospective study of all the patients admitted between 13th January to 15th June 2008 with hypoglycaemia was done with acquisition of all relevant data after ethical approval from our DSRB. RESULTS: 15 patients (25-73 years old) presented with severe hypoglycaemia. All of them presented with neuroglycopenic symptoms (5-confusion, 6-drowsiness to loss of consciousness, 4-seizures and 1-coma) 12-36 h after ingestion of 'Power 1 Walnut'. Liquid chromatography-mass spectrometry (LC/MS) confirmed the presence of glibenclamide in the urine. None experienced a full-blown hypoglycaemia-associated autonomic response defined as sweating, sensation of warmth, anxiety, tremor, nausea, palpitations, tachycardia, and hunger. Only 4/16 patients had symptoms of a partial autonomic response, and 3/16 patients had tachycardia and/or hypertension. CONCLUSIONS: The above suggests an inappropriate autonomic and catecholamine response to severe hypoglycaemia in these cases of serendipitous glibenclamide overdose. Possible reasons for the blunted autonomic responses and apparent autonomic failure are reviewed.

Oxytocin in metabolic homeostasis: implications for obesity and diabetes management.

Oxytocin was once understood solely as a neuropeptide with a central role in social bonding, reproduction, parturition, lactation and appetite regulation. Recent evidence indicates that oxytocin enhances glucose uptake and lipid utilization in adipose tissue and skeletal muscle, suggesting that dysfunction of the oxytocin system could underlie the pathogenesis of insulin resistance and dyslipidaemia. Murine studies revealed that deficiencies in oxytocin signalling and oxytocin receptor expression lead to obesity despite normal food intake, motor activity and increased leptin levels. In addition, plasma oxytocin concentration is notably lower in obese individuals with diabetes, which may suggest an involvement of the oxytocin system in the pathogenesis of cardiometabolic disease. More recently, small scale studies demonstrated that intranasal administration of oxytocin was associated with significant weight loss as well as improvements in insulin sensitivity and pancreatic ß-cell responsivity in human subjects. The multi-pronged effects of oxytocin signalling on improving peripheral insulin sensitivity, pancreatic function and lipid homeostasis strongly suggest a role for this system as a therapeutic target in obesity and diabetes management. The complexity of obesity aetiology and the pathogenesis of obesity-related metabolic complications underscore the need for a systems approach to better understand the role of oxytocin in metabolic function.

A synopsis of brown adipose tissue imaging modalities for clinical research.

Body weight gain results from a chronic excess of energy intake over energy expenditure. Accentuating endogenous energy expenditure has been accorded considerable attention ever since the presence of brown adipose tissue (BAT) in adult humans was recognized, given that BAT is known to increase energy expenditure via thermogenesis. Besides classic BAT, significant strides in our understanding of inducible brown adipocytes have been made regarding its development and function. While it is ideal to study BAT histologically, its relatively inaccessible anatomical locations and the inherent risks associated with biopsy preclude invasive techniques to evaluate BAT on a routine basis. Thus, there has been a surge in interest to employ non-invasive methods to examine BAT. The gold standard of non-invasive detection of BAT activation is 18F-fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT). However, a major limitation of PET/CT as a tool for human BAT studies is the clinically significant doses of ionizing radiation. More recently, several other imaging methods, including single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), infrared thermography (IRT)/thermal imaging and contrast ultrasonography (US) have been developed in hopes that they would allow non-invasive, quantitative measures of BAT mass and activity with lower costs. This review focuses on such methods to detect human BAT activation and white adipose tissue (WAT) browning to prompt the establishment of BAT-centric strategies for augmenting energy expenditure and combatting obesity. Clinical validation of these methods will most likely expand the scope and flexibility of future BAT studies.

Controversial endocrine interventions for the aged.

Specific endocrine changes occur with the ageing process. The last decade has witnessed significant progress in the basic and clinical science of ageing, thereby rejuvenating the interest in anti-ageing medicine, especially that of hormone replacement, by medical professionals and the lay public. However, endocrine manipulation as a therapeutic strategy for ageing is still evolving as continuing research attempts to answer the many questions of what it can achieve at the risk of incurring unknown long-term adverse effects. The current day doctor is confronted with a host of options, and will benefit from a synopsis of the latest evidence before making the most appropriate decision for aged patients seeking hormonal replacement therapy as a means to counter the effects of ageing. This review aims to give a rapid overview of the endocrine profile of geriatric population and the studies on the more controversial hormonal replacement therapies for the aged.

Ethnic differences in insulin sensitivity and beta-cell function among Asian men.

BACKGROUND AND OBJECTIVES: Lean Asian Indians are less insulin sensitive compared with Chinese and Malays, but the pancreatic beta-cell function among these ethnic groups has yet to be studied in depth. We aimed to study beta-cell function in relation to insulin sensitivity among individuals of Chinese, Malay and Asian-Indian ethnicity living in Singapore. SUBJECTS AND METHODS: This is a sub-group analysis of 59 normoglycemic lean (body mass index (BMI) <23 kg m(-)(2)) adult males (14 Chinese, 21 Malays and 24 Asian Indians) from the Singapore Adults Metabolism Study. Insulin sensitivity was determined using fasting state indices (homeostatic model assessment-insulin resistance), the euglycemic-hyperinsulinemic clamp (ISI-clamp) and a liquid mixed-meal tolerance test (LMMTT) (Matsuda insulin sensitivity index (ISI-Mat)). Beta-cell function was assessed using fasting state indices (homeostatic model assessment-beta-cell function) and from the LMMTT (insulinogenic index and insulin secretion index). The oral disposition index (DI), a measure of beta-cell function relative to insulin sensitivity during the LMMTT, was calculated as a product of ISI-Mat and insulin secretion index. RESULTS: Asian Indians had higher waist circumference and percent body fat than Chinese and Malays despite similar BMI. Overall, Asian Indians were the least insulin sensitive whereas the Chinese were most insulin sensitive. Asian Indians had higher beta-cell function compared with Chinese or Malays but these were not statistically different. Malays had the highest incremental area under the curve for glucose during LMMTT compared with Asian Indians and Chinese. However, there were no significant ethnic differences in the incremental insulin area under the curve. The oral DI was the lowest in Malays, followed by Asian Indians and Chinese. CONCLUSION: Among lean Asians, Chinese are the most insulin sensitive whereas Asian Indians are the least insulin sensitive. However, Malays demonstrate higher postprandial glucose excursion with lower beta-cell response compare with Chinese or Asian Indians. The paths leading to type 2 diabetes mellitus might differ between these Asian ethnic groups.

Current therapeutic strategies for type 2 diabetes mellitus.

Type 2 diabetes mellitus is now regarded a worldwide epidemic with diabetes-related complications exacting a heavy toll on those with poor metabolic control. Although there is no cure currently, the therapeutic armamentarium has expanded over the last few years to five classes of oral agents--sulfonylureas, biguanides, meglitinides, thiazolidinediones and alpha-glucosidase inhibitors. Sulfonylureas continue to be the mainstay oral hypoglycaemic agents for type 2 diabetics because they are potent insulin secretagogues and cost-effective. Metformin exerts its main effect by reducing hepatic glucose output and is proven to particularly benefit obese type 2 diabetics. Meglitinides are rapid-acting insulin secretagogues targeting a postprandial hyperglycaemia and this class of drug is useful for those who are at risk of hypoglycaemia with longer-acting sulfonylurea drugs. Thiazolidinediones constitute a new class of insulin sensitizers that work predominantly in improving glucose uptake by the adipose tissues and skeletal muscles. Alpha-glucosidase inhibitors delay the digestion and absorption of polysaccharides, thus attenuating postprandial hyperglycaemia. This review article briefly examines the nature of these oral agents, including the role of combination therapy and insulin where clinically indicated.

Clinical utility of selective intra-arterial calcium-stimulated hepatic venous sampling in regionalisation of insulinomas--the Singapore experience.

INTRODUCTION: To evaluate the efficacy and safety of selective intra-arterial calcium-stimulated hepatic venous sampling (ASVS) as a preoperative regionalisation modality for insulinomas. DESIGN AND METHODS: Four patients with biochemically-proven endogenous hyperinsulinism and negative spiral computed tomographic (CT) pancreas were subjected to ASVS between October 1999 to May 2001. Results obtained from ASVS were compared with localisation studies using either magnetic resonance imaging (MRI) or endoscopic ultrasonography (EUS); and these were confirmed surgically whenever possible. RESULTS: ASVS led to a definitive regionalisation in all 4 patients evaluated; the predicted location of the insulinoma matched the findings intraoperatively in all 3 patients who were operated upon. These were all proven to be insulinoma histologically. However, 1 patient showed a positive ASVS result in samples obtained from the left hepatic vein only. In the patient who was unable to undergo surgical resection due to other co-morbid factors, his ASVS findings were corroborated by localisation obtained from the MRI study. Conversely, EUS was found to give an incorrect localisation of insulinoma in 1 patient. Adverse effects were encountered in 3 patients (2 with mild hypotension and 1 with transient atrial fibrillation); however, premature termination of the procedure was not necessary in any of the patients. CONCLUSION: ASVS is accurate and reliable for regionalisation of insulinoma, especially in patients who do not have an obvious, unequivocal tumour using high quality current-generation MRI scans.

Mastication effects on the glycaemic index: impact on variability and practical implications.

Glycaemic variability challenges the accuracy and use of the glycaemic index (GI). The purpose of the current study was to determine the role of mastication on GI. Using a randomized, controlled, crossover, non-blind design, 15 healthy young subjects returned on 5 separate days for three glucose and two rice test sessions. At the rice sessions, subjects chewed each mouthful either 15 or 30 times. Rice chewed 15 times produced a total glycaemic response (GR; 155 mmol min/l), peak GR (2.4 mmol/l) and GI (68) significantly lower than when chewed for longer (30 times) (184 mmol min/l, 2.8 mmol/l and 88, respectively). The study shows that the GI of rice is affected by the degree of mastication. Chewing 15 times compared with 30 times significantly attenuates the GI, suggesting that mastication may potentially contribute to the glycaemic variability of rice. While future work must establish the extent and limits to which mastication affects glycaemia, it could also explore the potential of using mastication to reduce the glycaemic load of rice.

Latent tuberculosis in patients with diabetes mellitus: prevalence, progression and public health implications.

BACKGROUND: Diabetes mellitus (DM) confers a higher risk for tuberculosis (TB). Yet, TB screening and chemoprophylaxis for latent TB infection (LTBI) in DM remains controversial. We conducted a cross-sectional study to elucidate LTBI prevalence and longitudinal follow-up to ascertain LTBI to active TB progression rate in DM. METHODS: 220 DM patients without previous TB from the outpatient diabetes clinic of the hospital were enrolled. T-Spot TB, tuberculin-skin-test (TST) and chest radiography (CXR) were performed. LTBI was defined by negative CXR with reactive T-Spot TB. Progression to active TB was confirmed by cross-checking against the TB registry. RESULTS: The prevalence of LTBI was 28.2% (62/220) by reactive T-Spot. None progressed to active TB from 2007-2013. Multivariate analysis revealed that any co-morbidity (p=0.016) was positively associated while metformin (p=0.008) was negatively associated with LTBI. CONCLUSIONS: Over a quarter of DM patients harbor LTBI. While the lack of demonstrable progression to active TB within the follow-up time frame up to this point does not unequivocally support a routine TB screening policy or anti-TB chemoprophylaxis for LTBI in a diabetic population for now, this preliminary evidence needs re-evaluation with longer follow-up of this enrolled cohort over the next decade.

Associations between ethnicity, body composition, and bone mineral density in a Southeast Asian population.

CONTEXT AND OBJECTIVE: Chinese men in Singapore have a higher incidence of hip fractures than Malay and Indian men. We investigated whether there were corresponding ethnic differences in peak bone mineral density (BMD) in young men and whether differences in body composition influenced peak BMD. DESIGN AND SETTING: This was a cross-sectional study of healthy volunteers in a tertiary medical center. PARTICIPANTS: A total of 100 Chinese, 82 Malay, and 80 Indian men aged 21 to 40 years, with body mass index between 18 and 30 kg/m(2) underwent dual-energy x-ray absorptiometry to assess BMD, lean mass (LM) and fat mass (FM), and magnetic resonance imaging to quantify abdominal subcutaneous and visceral adipose tissue. Multiple linear regression models, with adjustment for age and height (as a proxy for skeletal size), were used. RESULTS: Malay and Indian men had significantly higher BMD than Chinese men at the lumbar spine (Malay: B, 0.06 ± 0.02, P = .001; Indian: B, 0.03 ± 0.02, P = .049), femoral neck (Malay: B 0.04 ± 0.02, P = .034; Indian: B, 0.04 ± 0.02, P = .041), hip (Malay: B, 0.05 ± 0.02, P = .016; Indian: B, 0.06 ± 0.02, P = .001), and ultradistal radius (Malay: B, 0.03 ± 0.01, P < .001; Indian: B, 0.02 ± 0.01, P = .029), and this difference was retained after adjustment for LM and FM, except in Malay men at the femoral neck and in Indian men at the ultradistal radius. LM was an important independent determinant of BMD at all sites, whereas FM, subcutaneous adipose tissue, and visceral adipose tissue were not significantly associated with BMD at any site. CONCLUSIONS: Lower peak BMD in Chinese men may partly explain the higher fracture incidence in this ethnic group. Further studies are needed to elucidate the reasons for these ethnic differences in bone accumulation.

Iodine-131 therapy for hyperthyroidism prescribed by endocrinologist - our preliminary experience.

INTRODUCTION: Radioiodine (I-131) is a useful therapeutic modality of hyperthyroidism when medical therapy fails. Traditionally, the nuclear physicians undertake the prescription of I-131 therapy. However, endocrinologists are increasingly being recognized for their competence in prescribing individualized doses of I-131 for the treatment of various thyroid disorders. METHODS: In this pilot prospective study, we collaborated with our nuclear medicine colleagues to determine the outcomes of 80 patients with hyperthyroidism who underwent I-131 ablation as prescribed by the endocrinologist. Doses administered were based primarily on thyroid volume with adjustments contingent on adverse factors, and fixed assumptions on target absorbed dose (R) and uptake (U) were used. Seventy-three had Graves' disease (GD) and seven had toxic nodular goitre (TNG) or toxic adenomas (AFTN). Therapeutic success was defined as achievement of hypothyroidism or euthyroidism. RESULTS: 95.9 percent (70 of 73) of GD patients and 85.7 percent (6 of 7) of those with TNG/AFTN achieved successful outcomes after a single dose of endocrinologist-directed I-131 therapy. More than 50 percent of patients became hypothyroid by three months and about two-thirds became hypothyroid by six months post I-131 therapy. CONCLUSION: Our results indicate that the success rate of endocrinologist-directed I-131 therapy exceeds 95 percent with a single dose and compares favourably with nuclear physician-directed therapy outcomes.

Thyrotoxicosis and acute abdomen--still as defying and misunderstood today? Brief observations over the recent decade.

BACKGROUND: Clinicians managing thyrotoxic patients with acute abdomen face challenging diagnostic and risky therapeutic dilemmas. AIM: To analyse the frequency of medical vs. surgical acute abdomen, and to characterize the poorly understood thyrotoxic medical acute abdomen phenomenon. DESIGN: Retrospective review of case notes. METHODS: All case files with a simultaneous diagnosis of thyrotoxicosis and acute abdomen admitted between 1994 and 2004 were traced and audited. RESULTS: Thirteen had a history of thyrotoxicosis while 12 were newly diagnosed. The commonest cause was Graves' disease. Twenty-three (92%) cases were thyrotoxic, of whom six (24%) had thyroid crisis, while two (8%) had subclinical thyrotoxicosis. The provisional diagnosis of acute abdomen was correct in 14 cases (56%), but discordant with the final diagnosis in 11 cases (44%). Eight cases (32%) without any demonstrable pathology were medical, vs. four (16%) with surgical acute abdomen, while 11(44%) had gastritis, hepatobiliary-pancreatic disorders or diverticulitis conservatively managed. The epigastrium and/or central abdomen (72.7%) were the commonest affected regions in medical acute abdomen. CONCLUSION: Although the majority of acute abdomen in thyrotoxicosis was medical in nature, our experience indicates that surgical conditions were not uncommon. Thus, serious causes requiring life-saving surgery should be excluded before attributing it to medical acute abdomen.