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Background Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. Methods We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. Results A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. Conclusion Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

Summary Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative. Learning points Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative. Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness. Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia. Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK. Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

CONTEXT Studies find surgery superior to medications in the treatment of primary aldosteronism (PA). It would be ideal to compare surgical and medical therapy in patients with unilateral PA only, who have the option between these treatment modalities. However, this is challenging as most patients with unilateral PA on adrenal vein sampling (AVS) undergo surgery. OBJECTIVE To compare outcomes of surgery and medications in patients with confirmed or likely unilateral PA. DESIGN Retrospective cohort study of 274 patients with PA managed at two referral centres from 2000 to 2019. PATIENTS 154 patients identified with unilateral PA using AVS and a validated clinical prediction model were treated with surgical (n = 86) or medical (n = 68) therapy. MEASUREMENTS Primary outcome was a composite incident cardiovascular event comprising acute myocardial infarction, coronary revascularization, stroke, atrial fibrillation or congestive cardiac failure. Secondary outcomes were clinical and biochemical control. RESULTS Cardiovascular outcomes were comparable, with the surgery group having an adjusted hazard ratio of 0.93 (95% CI: 0.32-2.67), p = .89. Both treatments improved clinical and biochemical control, but surgery resulted in better systolic blood pressure, 133.0 ± 11.7 mmHg versus 137.9 ± 14.6 mmHg, p = .02, and lower defined daily dosages of antihypertensive medications, 1.0 (IQR 0.0-2.0) versus 2.6 (IQR 0.8-4.3), p

Background: Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods: In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings: Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12·2), 170 335 (44·1%) of 386 248 were women, and 111 933 (30·1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0·69, 95% CI 0·61–0·77; p

A 54-year-old woman with insulin-requiring type 2 diabetes mellitus presented with acute shortness of breath and drowsiness on a background of polydipsia, weakness and significant weight loss. One year ago, she had decided to stop her insulin and other medications and adopt lifestyle modifications instead. Initial emergency department (ED) blood samples were highly lipaemic and appeared strawberry pink. She was eventually diagnosed with diabetic ketoacidosis (DKA) with severe hypertriglyceridaemia, intubated for airway protection, and managed with fluid resuscitation and intravenous insulin to good effect. We share an uncommon DKA presentation at the ED. History was limited as the patient was drowsy and minimally communicative. Physical examination was unremarkable. Blood investigations were also delayed in view of the need for additional centrifugation. These contributed to a paucity of information in the acute setting and resulted in a diagnostic challenge.

Introduction Patients with primary aldosteronism (PA) have increased cardiovascular risk, and there are concerns about the efficacy of medical therapy. Objective We aimed to assess long-term tolerability and efficacy of medical therapy in PA patients. Methods We conducted a retrospective study on 201 PA patients treated with medical therapy (spironolactone, eplerenone, or amiloride) from 2000 to 2020 at 2 tertiary centers. Clinical and biochemical control and side effects were assessed. Results Among 155 patients on long-term medications, 57.4% achieved blood pressure (BP) 1 ng/mL/h. Concordance of biochemical control using potassium and renin levels was 49.1%. Side effects were experienced by 52.3% of patients, with 10.3% switching, 22.6% decreasing dose, and 11.0% stopping medications. Risk factors for side effects were spironolactone use, dose ≥ 50 mg, treatment duration ≥1 year, male gender, and unilateral PA. Patients with unilateral PA used higher spironolactone doses vs bilateral (57 vs 50 mg, P < 0.001) and had more side effects (63.2% vs 41.8%, P = 0.008). Forty-six unilateral PA patients who underwent surgery after initial medical therapy experienced improved BP (systolic from 141 to 135 mmHg, P = 0.045; diastolic from 85 to 79 mmHg, P = 0.002). Conclusion Dose-dependent side effects limit efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. For unilateral PA, surgery remains preferable, yielding better control with less long-term side effects.

Objective: Migrant workers, a marginalized and under-resourced population, are vulnerable to coronavirus disease 2019 (COVID-19) due to limited healthcare access. Moreover, metabolic diseases-such as diabetes mellitus (DM), hypertension, and hyperlipidemia-predispose to severe complications and mortality from COVID-19. We investigate the prevalence and consequences of undiagnosed metabolic illnesses, particularly DM and pre-diabetes, in international migrant workers with COVID-19. Methods: In this retrospective analysis, we analyzed the medical records of international migrant workers with laboratory-confirmed COVID-19 hospitalized at a tertiary hospital in Singapore from April 21 to June 1, 2020. We determined the prevalence of DM and pre-diabetes, and analyzed the risk of developing complications, such as pneumonia and electrolyte abnormalities, based on age and diagnosis of DM, and pre-diabetes. Results: Two hundred and fouty male migrant workers, with mean age of 44.2 years [standard deviation (SD), 8.5years], were included. Twenty one patients (8.8%) were diagnosed with pre-diabetes, and 19 (7.9%) with DM. DM was poorly controlled with a mean HbA1c of 9.9% (SD, 2.4%). 73.7% of the patients with DM and all the patients with pre-diabetes were previously undiagnosed. Pre-diabetes was associated with higher risk of pneumonia [odds ratio (OR), 10.8, 95% confidence interval (CI), 3.65-32.1; P < 0.0001], hyponatremia (OR, 8.83; 95% CI, 1.17-66.6; P = 0.0342), and hypokalemia (OR, 4.58; 95% CI, 1.52-13.82; P = 0.0069). Moreover, patients with DM or pre-diabetes developed COVID-19 infection with lower viral RNA levels. Conclusions: The high prevalence of undiagnosed pre-diabetes among international migrant workers increases their risk of pneumonia and electrolyte abnormalities from COVID-19.

Introduction Adrenal venous sampling (AVS) is the reference test for identifying unilateral primary aldosteronism (PA). However, in patients with corticol co-secreting adrenal nodules, elevated cortisol levels may affect the interpretation of aldosterone-cortisol (AC) ratios. ACTH-stimulation may further confound results. In such patients, the use of plasma metanephrines instead of cortisol as a correcting factor may be helpful. Case Summary A 54 year old lady presented with 8 years of hypertension and hypokalaemia (nadir 2.2mmol/L) while on amlodipine 10mg and valsartan 80mg daily. PA was confirmed by a post-saline infusion aldosterone 1075pmol/L. CT identified a 2.4cm right lipid rich adrenal adenoma. Serum cortisol post 1mg overnight dexa-suppression test was unsuppressed at 63mmol/L. First AVS was done sequentially under ACTH stimulation and suggested lateralization to the right, with lateralization ratio (LR) 3.4. However, this was She underwent right adrenalectomy and was cured of hypertension and hypokalaemia at 6 months post surgery. Aldosterone renin ratio has normalized: aldosterone Clinical Lessons While ACTH stimulation helps to improve success rates of cannulation by increasing cortisol gradients, most studies show that it lowers LR. Furthermore, this would be concerning in patients with cortisol co-secreting adenomas. In this case, repeat AVS without ACTH demonstrated improved lateralization to the right. The use of metanephrine as a correcting factor appears to be a better indicator of right sided disease. However, while plasma metanephrines have been shown to be useful to indicate correct catheter placement, it has not been adopted as a correction factor for dilution yet. Finally, in addition to affecting AVS results, cortisol-cosecreting tumors may also affect 11C-Metomidate PET-CT imaging. Conclusion In patients with suspected cortisol co-secreting adenomas, unstimulated AVS and use of plasma metanephrines may help to identify unilateral PA even when conventional AVS and metomidate scans fail to. Further studies on using metanephrines as a correcting factor for lateralisation would be helpful.

Contains fulltext : 220540.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. METHODS: Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and postoperative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in the SPARTACUS trial who underwent AVS. Previously published prediction models were also tested in our cohorts. RESULTS: Backward stepwise logistic regression analysis yielded a final tool using baseline aldosterone-to-lowest-potassium ratio (APR, ng/dl/mmol/l), with an area under receiver-operating characteristic curve of 0.80 (95% CI 0.70-0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR 15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR 15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. CONCLUSION: The novel aldosterone-to-lowest-potassium ratio is a convenient score to guide clinicians and patients of various ethnicities on the probability of primary aldosteronism subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.

Background Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high...

Background Diabetes mellitus is associated with inadequate delivery of oxygen to tissues. Cellular hypoxia is associated with mitochondrial dysfunction which increases oxidative stress and hyperglycaemia. Hyperbaric oxygenation therapy, which was shown to improve insulin sensitivity, is impractical for regular use. We evaluated the effects of water which is stably-enriched with oxygen (ELO water) to increase arterial blood oxygen levels, on mitochondrial function in the presence of normal- or high-glucose environments, and as glucose-lowering therapy in humans. Methods We compared arterial blood oxygen levels in Sprague-Dawley rats after 7 days of ad libitum ELO or tap water consumption. Mitochondrial stress testing, and flow cytometry analysis of mitochondrial mass and membrane potential, were performed on human HepG2 cells cultured in four Dulbecco’s Modified Eagle Medium media, made with ELO water or regular (control) water, at normal (5.5 mM) or high (25 mM) glucose concentrations. We also randomized 150 adults with type 2 diabetes (mean age 53 years, glycated haemoglobin HbA1c 8.9% [74 mmol/mol], average duration of diabetes 12 years) to drink 1.5 litres daily of bottled ELO water or drinking water. Results ELO water raised arterial oxygen tension pO2 significantly (335 ± 26 vs. 188 ± 18 mmHg, p = 0.006) compared with tap water. In cells cultured in control water, mitochondrial mass and membrane potential were both significantly lower at 25 mM glucose compared with 5.5 mM glucose; in contrast, mitochondrial mass and membrane potential did not differ significantly at normal or high glucose concentrations in cells cultured in ELO water. The high-glucose environment induced a greater mitochondrial proton leak in cells cultured in ELO water compared to cells cultured in control medium at similar glucose concentration. In type 2 diabetic adults, HbA1c decreased significantly (p = 0.002) by 0.3 ± 0.7% (4 ± 8 mmol/mol), with ELO water after 12 weeks of treatment but was unchanged with placebo. Conclusions ELO water raises arterial blood oxygen levels, appears to have a protective effect on hyperglycaemia-induced reduction in mitochondrial mass and mitochondrial dysfunction, and may be effective adjuvant therapy for type 2 diabetes.

Obesity is less prevalent in Asian subjects with type 2 diabetes mellitus (T2DM) in contrast to Caucasians. Whether higher axial bone mineral density (BMD) often reported in T2DM is independent of body mass index (BMI) has not been clearly shown. BMD characterization in T2DM patients with hip fractures has also not been performed. We compared the BMD of Asian diabetic and nondiabetic patients with new hip fractures and explored how BMD was influenced by BMI.We included 255 diabetic and 148 nondiabetic patients. BMD adjusted for age; BMI; race; sex; renal function; and use of statins, proton pump inhibitors, steroids, anticonvulsants, and calcium and/or vitamin D supplements were compared between the groups. We were particularly interested in the BMD comparison between underweight diabetics and nondiabetics with hip fractures.The presence of T2DM was associated with higher BMD (g/cm(2)) at the femoral neck (0.527 ± 0.103 vs. 0.491 ± 0.102, P.01) and lumbar spine [LS] (0.798 ± 0.147 vs. 0.723 ± 0.156, P.01). This association persisted after adjustment for multiple confounding variables including BMI. The age-, BMI-, and sex-adjusted LS BMD was higher in underweight (BMI18.5 kg/m(2)) diabetics compared to similar weight nondiabetics (0.733 ± 0.126 vs. 0.649 ± 0.131 g/cm(2), P = .014).T2DM is independently associated with higher axial BMD in patients with new hip fractures. The finding of higher BMD even in underweight diabetics with hip fractures compared to their nondiabetic counterparts suggests that higher BMD in subjects with T2DM is not due to higher BMI.BMD = bone mineral density BMI = body mass index CV = coefficient of variation DXA = dual-energy X-ray absorptiometry HbA1c = glycated hemoglobin IGF-1 = insulin growth factor-1 LS = lumbar spine 25(OH)D = 25-hydroxyvitamin D T2DM = type 2 diabetes mellitus.

Introduction: Whether parathyroidectomy is more beneficial to renal function when compared to medical therapy or observation in primary hyperparathyroidism (PHPT) is unclear. Neither has this premise been explored in non-Caucasian populations. The estimated glomerular filtration rate (eGFR) threshold below which parathyroid hormone (PTH) levels rise if at all in PHPT has also not been established. We determined if surgery was superior to medical therapy and observation in a multi-ethnic Asian patient population with PHPT and whether there was an eGFR threshold below which PTH levels further increased in them. Methods: Retrospective evaluation of patients with PHPT. Results: There were 68.6% Chinese, 17.4% Malays, 10.7% Indians, and 3.3% Eurasians. The median (interquartile range) follow-up was 18.0 months (4.5–46.8). At last follow-up, eGFR in the surgical (80 ± 30 ml/min) was higher than the medical (52 ± 32 ml/min) or observation groups (48 ± 33 ml/min); P < 0.01. This difference persisted after adjusting for age, gender, ethnicity, pre-intervention eGFR levels, nephrolithiasis, serum calcium, phosphate, urinary calcium, and duration of follow-up; P = 0.035. There was no definite eGFR level below which PTH values rose. Conclusion: Our study provides compelling evidence that in PHPT, surgery may be associated with a better renal outcome compared to medical management or observation. This has to be confirmed through prospective randomized controlled trials and the reasons for this finding have to be elucidated through functional and histological measures. The finding in our study of a lack of a specific eGFR threshold below which PTH levels further rose challenges the concept of a fixed renal threshold for secondary elevations of PTH in PHPT.

BACKGROUND & AIMS We compared the effects of weight loss induced with the glucagon-like peptide-1 agonist liraglutide, with that of lifestyle modification, followed by weight maintenance after discontinuing intervention, in obese adults with non-alcoholic fatty liver disease (NAFLD). METHODS Thirty obese (mean age 40.7 ± 9.1 years, BMI 33.2 ± 3.6 kg/m2 , 90% male) adults with NAFLD defined as liver fat fraction (LFF) > 5% on magnetic resonance imaging without other causes of hepatic steatosis were randomized to a supervised programme of energy restriction plus moderate-intensity exercise to induce ≥ 5% weight loss (DE group, n = 15), or liraglutide 3 mg daily (LI group, n = 15) for 26 weeks, followed by 26 weeks with only advice to prevent weight regain. RESULTS Diet and exercise and LI groups had significant (P

The short-acting glucagon-like peptide 1 receptor agonist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 μg) or saline (230 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99mTc-sulfur colloid (total volume 200 mL), was given intraduodenally (t = 0-60 min; 3 kcal/min). Duodenal motility and flow were measured using a combined manometry-impedance catheter and small intestinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was observed even in subjects with little or no nausea. The inhibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia usc Refereed/Peer-reviewed

This study aims at assessing the gap in secondary fracture prevention at a regional general hospital setting in Singapore. Male patients have significantly lower rate of being investigated and treated for osteoporosis than their female counterparts. Vitamin D deficiency is prevalent in our population. Secondary fracture prevention services are not routine in Singapore; we seek to assess the treatment gap that exists in the lack of diagnosis and treatment of osteoporosis in fragility fracture patients. We performed a retrospective analysis of all admissions for fragility fractures between December 2013 and December 2014. Demographic data, rates of BMD performance, serum vitamin D investigation and calcium and vitamin D supplementation as well as antiresorptive initiation 1 year post admission were analysed. There were 125 fragility fractures in patients below 65 and 615 fractures in older patients. There was a slightly higher proportion of males in the younger population, whereas females predominated in the older population. Median vitamin D levels were low in both younger (19.1 μg/L) and older (22.0 μg/L) groups, but supplementation was lower in younger patients (4.8 versus 16.6%, p = 0.003). Rate of BMD performance was lower in younger patients (34.4 versus 64.6%, p

Background Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of the adrenal glands and paraganglia, occurring sporadically or as a range of hereditary tumor syndromes. About 30% of PPGLs are attributed to germline mutations. Clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background. Genetic testing for PPGLs is not well studied in Southeast Asia. We reviewed clinical management of PPGLs in Singapore, highlighting current gaps in clinical practice. Methods Medical records of patients with PPGLs between 2005 and 2016 were reviewed. Diagnosis was confirmed histologically and stratified into sporadic or familial/syndromic (FS). Results Twenty-seven (21.8%) patients were referred to the Cancer Genetics Service (CGS). FS PPGLs (18.5%) and extra-adrenal PPGLs (58.1%) incidences were higher than previous studies. Referrals were lower for sporadic PPGLs compared to FS PPGLs (3.7% vs. 100%). Referrals were highest at diagnosis age

We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease (NAFLD). Obese (body mass index ≥30 kg/m2 , mean weight 96.0 ± 16.3 kg) non-diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 5.5% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate-intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks. Both DE and LI groups had significant (P < .01) and similar reductions in weight (-3.5 ± 3.3 vs -3.5 ± 2.1 kg, respectively, P = .72), LFF (-8.9 ± 13.4 vs -7.2% ± 7.1%, P = .70), serum alanine aminotransferase (-42 ± 46 vs -34 ± 27 U/L, P = .52) and aspartate aminotransferase (-23 ± 24 vs -18 ± 15 U/L, P = .53). In this first randomized study comparing the 2 weight-loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification.

Aim:To evaluate the effects of the glucagon-like peptide-1 receptor agonist, exenatide, on blood pressure and heart rate during an intraduodenal glucose infusion in type 2 diabetes.Methods:Nine subjects with type 2 diabetes were randomised to receive intravenous exenatide or saline control in a crossover design. Glucose (3 kcal min−1) was infused via an intraduodenal manometry catheter for 60 min. Blood pressure, heart rate, and the frequency and amplitude of duodenal pressure waves were measured at regular intervals. Gastrointestinal symptoms were monitored using 100 mm visual analogue scales.Results:During intraduodenal glucose infusion (0–60 min), diastolic ( p(0–60) = 0.03) and mean arterial ( p(0–60) = 0.03) blood pressures and heart rate ( p(0–60) = 0.06; p(0–120) = 0.03)) were higher with exenatide compared to placebo. The increase in the area under the curve for diastolic blood pressure and mean arterial blood pressure was related directly to the suppression of the duodenal motility index with exenatide compared to control ( p = 0.007 and 0.04, respectively).Conclusion:In type 2 diabetes, intravenous exenatide increases mean arterial blood pressure and heart rate during an intraduodenal glucose infusion, supporting the need for further research with exenatide for its potential use in postprandial hypotension.

According to World Health Organization, in 2010 there were over 1 billion overweight adults worldwide with 400 million adults who were obese. Obesity is a major risk factor for diabetes, cardiovascular disease, musculoskeletal disorders, obstructive sleep apnea, and cancers (prostate, colorectal, endometrial, and breast). Obese people may present to the gastroenterologists with gastroesophageal reflux, non-alcoholic fatty liver, and gallstones. It is important, therefore, to recognize and treat obesity. The main cause of obesity is an imbalance between calories consumed and calories expended, although in a small number of cases, genetics and diseases such as hypothyroidism, Cushing's disease, depression, and use of medications such as antidepressants and anticonvulsants are responsible for fat accumulation in the body. The main treatment for obesity is dieting, augmented by physical exercise and supported by cognitive behavioral therapy. Calorie-restriction strategies are one of the most common dietary plans. Low-calorie diet refers to a diet with a total dietary calorie intake of 800-1500, while very low-calorie diet has less than 800 calories daily. These dietary regimes need to be balanced in macronutrients, vitamins, and minerals. Fifty-five percent of the dietary calories should come from carbohydrates, 10% from proteins, and 30% from fats, of which 10% of total fat consist of saturated fats. After reaching the desired body weight, the amount of dietary calories consumed can be increased gradually to maintain a balance between calories consumed and calories expended. Regular physical exercise enhances the efficiency of diet through increase in the satiating efficiency of a fixed meal, and is useful for maintaining diet-induced weight loss. A meta-analysis by Franz found that by calorie restriction and exercise, weight loss of 5-8.5 kg was observed 6 months after intervention. After 48 months, a mean of 3-6 kg was maintained. In conclusion, there is evidence that obesity is preventable and treatable. Dieting and physical exercise can produce weight loss that can be maintained.

We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 104 and +5.8 × 104 copies, respectively) but decreased in healthy subjects during hyperglycemia (−1.4 × 104 copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 105 copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.

Secondary hypertension occurs in a significant proportion of adult patients (~10%). In young patients, renal causes (glomerulonephritis) and coarctation of the aorta should be considered. In older patients, primary aldosteronism, obstructive sleep apnoea and renal artery stenosis are more prevalent than previously thought. Primary aldosteronism can be screened by taking morning aldosterone and renin levels, and should be considered in patients with severe, resistant or hypokalaemia-associated hypertension. Symptoms of obstructive sleep apnoea should be sought. Worsening of renal function after starting an angiotensin-converting enzyme inhibitor suggests the possibility of renal artery stenosis. Recognition, diagnosis and treatment of secondary causes of hypertension lead to good clinical outcomes and the possible reversal of end-organ damage, in addition to blood pressure control. As most patients with hypertension are managed at the primary care level, it is important for primary care physicians to recognise these conditions and refer patients appropriately.

Obesity, defined as a condition of excessive body fat with adverse effects on health, is an increasing global problem which contributes to chronic disease burden and health care costs. The Singapore Ministry of Health (MOH) released Clinical Practice Guidelines (CPG) in 2004, aimed at providing best evidence-based recommendations for diagnosis, classification, evaluation and multidisciplinary management (diet, physical activity, medication and surgery) of overweight and obesity in adults and the pediatric population. This article summarizes the guidelines, discusses their utility in Singapore and strategies for increasing their use, and briefly outlines updates in management since the CPG’s publication. A revised CPG is urgently needed in view of the increasing prevalence of overweight and obesity in Singapore and the numerous advances in the management of overweight and obesity.

Introduction Abdominal obesity and type 2 diabetes mellitus are associated with sexual and endothelial dysfunction, lower urinary tract symptoms (LUTS), and chronic systemic inflammation. Aim To determine the effects of diet-induced weight loss and maintenance on sexual and endothelial function, LUTS, and inflammatory markers in obese diabetic men. Main Outcome Measures Weight, waist circumference (WC), International Index of Erectile Function (IIEF-5) score, Sexual Desire Inventory (SDI) score, International Prostate Symptom Scale (IPSS) score, plasma fasting glucose and lipids, testosterone, sex hormone binding globulin (SHBG), inflammatory markers (high-sensitivity C-reactive protein [CRP] and interleukin-6 [IL-6]) and soluble E-selectin, and brachial artery flow-mediated dilatation (FMD) were measured at baseline, 8 weeks, and 52 weeks. Methods Over 8 weeks, 31 abdominally obese (body mass index ≥ 30 kg/m2, WC ≥ 102 cm), type 2 diabetic men (mean age 59.7 years) received either a meal replacement-based low-calorie diet (LCD) ∼1,000 kcal/day (N = 19) or low-fat, high-protein, reduced-carbohydrate (HP) diet (N = 12) prescribed to decrease intake by ∼600 kcal/day. Subjects continued on, or were switched to, the HP diet for another 44 weeks. Results At 8 weeks, weight and WC decreased by ∼10% and ∼5% with the LCD and HP diet, respectively. Both diets significantly improved plasma glucose, low-density lipoprotein (LDL), SHBG, IIEF-5, SDI and IPSS scores, and endothelial function (increased FMD, reduced soluble E-selectin). Erectile function, sexual desire, and urinary symptoms improved by a similar degree with both diets. CRP and IL-6 decreased with the HP diet. At 52 weeks, reductions in weight, WC, and CRP were maintained. IIEF-5, SDI, and IPSS scores improved further. Conclusions Diet-induced weight loss induces rapid improvement of sexual, urinary, and endothelial function in obese diabetic men. A high-protein, carbohydrate-reduced, low-fat diet also reduces systemic inflammation and sustains these beneficial effects to 1 year.

Background Numerous hormones secreted by the gut,during both the fasted state and in response to a meal,influence gastrointestinal motor and/or sensory func-tion, and appear to contribute to the pathogenesis ofdelayed gastric emptying associated with gastropare-sis, functional dyspepsia (FD) and feed intolerance incritical illness. Gut hormones are, accordingly,potential targets for the management of these patients.Purpose This article will discuss the hypersensitivityto enteral fat and endogenous (nutrient-stimulated)and exogenous cholecystokinin (CCK) in patients withFD, and the elevation in both fasting and postprandialCCK levels evident in this group. It will review the useof pharmacological agonists of motilin and ghrelin,which accelerate gastric emptying, in the managementof gastroparesis and FD. The frequent finding ofmarkedly delayed gastric emptying in the critically illwill be examined; this is associated with elevatedplasma CCK and peptide YY in both the fasted andpostprandial states, which may account for theincrease in small intestinal nutrient inhibitory feed-back on gastric motility in this group. The conceptsthat the rate of gastric emptying is a major determi-nant of postprandial glycemic excursions in diabetes,and that modulation of gastric emptying may improveglycemic control, will be addressed; in type 1 andinsulin-treated type 2 diabetic patients, co-ordinationof insulin administration with nutrient delivery andabsorption should be optimized, while type 2 patientswho are not on insulin are likely to respond to dietaryand/or pharmacological interventions which slowgastric emptying.Keywords diabetes, gastroparesis, glucagon-like pep-tide-1, cholecystokinin, peptide YY, ghrelin.

Objective To determine the effect of ageing on the performance of glycosylated haemoglobin A1C (A1C) for the diagnosis of diabetes mellitus (DM) in Southeast Asians. Methods A1C was measured in 511 subjects (mean age of 52.4 years; range 14–93) undergoing the 75-g oral glucose tolerance test (OGTT). Using receiver operating curve (ROC) analysis, the performance of A1C for the diagnosis of diabetes (using different standard criteria) was compared between 4 groups: n =156), 45–54 ( n =132), 55–64 ( n =122), ≥65 years ( n =101). Results Subjects aged ≥65 years had the highest false-negative rates with fasting plasma glucose (60.8%) and A1C (35.1%), the smallest area under ROC curve (0.723, 95% CI 0.627–0.820), the lowest sensitivity (58.7%, 95% CI 50.4–65.7) and specificity (71.1%, 95% CI 57.3–82.6) of A1C 6.5%, compared to the younger age groups. Conclusion OGTT is preferable for diagnosis of DM in older Southeast Asian adults.

Aim: To investigate the relationship between outdoor work and pterygium formation in a hospital-based case-control study in Singapore. Method: Sixty-one patients with pterygium (49 males, mean age 54.2 years) and 125 controls (41 males, mean age 50.2 years), excluding patients with cataract and age-related macular degeneration presenting at outpatient clinics of the Singapore National Eye Centre were interviewed face-to-face with a standard questionnaire. Demographic data and information on outdoor work and eye protection, were collected. Results: Thirty-eight subjects (20.4%) were outdoor workers and 148 (79.6%) were indoor workers. Outdoor workers were more likely to be male smokers and alcohol drinkers with lower family income and higher sunlight exposure than indoor workers. The crude odds ratio for pterygiumin outdoor workers was 7.0 (95% confidence interval 3.2, 15.3). The adjusted odds ratio was 4.2 (95% confidence interval 1.7, 10.1). Conclusion: There is a statistically significant association between outdoor work and pterygium formation, which may be related to the higher exposure to sunlight and dust in outdoor workers. Efforts may be made to educate outdoor workers to wear proper equipment to protect their eyes against excessive sunlight.

Background Lower urinary tract symptoms (LUTS) in men are associated with obesity, particularly central obesity as measured by waist circumference (WC), and may improve with weight loss. We aimed to compare effects of a meal-replacement based diet with isocaloric reduced-fat plan on LUTS and nutrient intake in obese Asian men. Methods Obese Asian [mean (range) body mass index of 32.9 (30.5–42.3) kg m–2] men [mean (range) age 40.2 (30–61) years] were randomised to a reduced-fat (< 30% of energy) diet [conventional reduced-fat diet (CD) group; n = 23] or meal-replacement-based plan [meal replacement (MR) group; n = 23], to reduce daily intake by 2000 kJ for 12 weeks. Results CD and MR groups had statistically significant and similar reductions in weight (−2.6 ± 1.9 kg versus −4.2 ± 3.8 kg), overall LUTS severity measured with International Prostate Symptom Scale (IPSS) scores (−1.71 ± 1.93 points versus −2.42 ± 2.12 points) and insulin resistance [homeostasis model assessment (HOMA) calculated from plasma glucose and insulin]. The MR group had significantly greater decreases in WC (−4.8 ± 3.3 cm versus −2.5 ± 2.3 cm), fat mass (−2.47 ± 3.63 kg versus −1.59 ± 2.32 kg), fat intake, plasma C-reactive protein, and in storage LUTS score (−1.59 ± 1.33 points versus −1.00 ± 0.87 points), which was associated with a decreased fat intake (r = 0.48, P = 0.03). A decrease in overall IPSS score was associated with reductions in weight, WC and HOMA. Conclusions Weight loss as a result of CD or MR had similar efficacy in relieving LUTS. MR produced greater reductions in fat intake, adiposity and storage LUTS.

Introduction Obesity and inactivity are associated with erectile dysfunction and hypogonadism. Aim To compare the effects of low volume (LV) and high volume (HV) of moderate-intensity exercise on sexual function, testosterone, lower urinary tract symptoms (LUTS), endothelial function, and quality of life (QoL) in obese men. Main Outcome Measures Weight, waist circumference (WC), body composition, International Index of Erectile Function 5-item (IIEF-5), International Prostate Symptom Scale (IPSS) (for LUTS), and 36-item Short Form Survey version 2 Instrument (SF-36) (for QoL) scores, plasma testosterone, sex-hormone binding globulin, glucose, insulin and lipids, and endothelial function (by Reactive Hyperaemia Index [RHI] using finger plethysmography) were measured at baseline and 24 weeks. Methods Ninety abdominally obese (body mass index > 27.5 kg/m2, WC > 90 cm), sedentary (exercise ∼80 minutes/week) Asian men (mean age 43.6 years, range 30–60) were prescribed a diet to reduce daily intake by ∼400 kcal below calculated requirement and randomized to perform moderate-intensity exercise of LV ( Results Weekly exercise volume was significantly greater in the HV (236 ± 9 minutes) than the LV (105 ± 9 minutes) group. The HV group had significantly greater increases in IIEF-5 score (2.6 ± 0.5 points) and testosterone (2.06 ± 0.46 nmol/L) and reductions in weight (−5.9 ± 0.7 kg, −6.2%), WC (−4.9 ± 0.8 cm, −4.9%), and fat mass (−4.7 ± 1.0 kg, −14.5%) than the LV group (−2.9 ± 0.7 kg, −3.0%; −2.7 ± 0.7 cm, −2.5%; −1.1 ± 0.8 kg, −3.2%; 0.79 ± 0.46 nmol/L; and 1.8 ± 0.5 points). Improvements in IPSS and SF-36 scores, and RHI, were similar. Conclusions Moderate-intensity HV aerobic exercise > 200 minutes/week produces greater improvements in sexual function, testosterone, weight, WC, and fat mass than smaller exercise volume. Khoo J, Tian H-H, Tan B, Chew K, Ng C-S, Leong D, Teo RC-C, and Chen RY-T. Comparing effects of low- and high-volume moderate-intensity exercise on sexual function and testosterone in obese men.

Far from being a passive reservoir for digestion and absorption of food, the gastrointestinal tract is a dynamic participant in the regulation of appetite and energy homeostasis. During meals, distension of the stomach and delivery of the products of carbohydrate, lipid, and protein digestion to the small intestine act synergistically to limit food intake. Satiation is induced by the activation of vagal afferent nerves terminals in gastric and intestinal walls, and the secretion of peptide hormones such as cholecystokinin, leptin, glucagon-like peptide-1, oxyntomodulin, and peptide YY from specialized mucosal cells in the stomach and small intestine. These gut peptides exert their effects by endocrine and paracrine actions, the latter via vagal afferents. The vagus interacts with the enteric nervous system and the central nervous system to coordinate satiation signaling. In addition to inhibiting appetite centers in the hypothalamus and brainstem, gut hormones prolong the exposure of the gastrointestinal tract to nutrients by slowing gastric emptying and intestinal transit. The mechanisms by which nutrients stimulate the release of gut hormones are now known to include activation of mucosal “taste” receptors and G-protein coupled receptors in the small intestine by carbohydrates, proteins, and fatty acids. Pharmacological agonists and antagonists of gut peptides are potentially useful for the management of obesity, type 2 diabetes, gastrointestinal motility disorders, and cachexia of critical illness.

Objective American Diabetes Association (ADA) has recently recommended the use of glycated haemoglobin (HbA1c) to diagnose diabetes mellitus. We aim to determine if indeed this recommendation applies to the population in Singapore and whether it varies with age. Method This is a cross sectional study of 90 patients without previous history of diabetes who underwent screening and had both oral glucose tolerance test (OGTT) and HbA1c done at the same time. These patients were stratified into 4 age groups. Result We found that HbA1c of 6.2% is the best cut-off to diagnose diabetes using ROC curve analysis. At the specified HbA1c, the area under ROC curve (AUROC) reduces as age group increases suggesting that sensitivity and specificity of HbA1c as diagnostic marker reduces as age increases. Conclusion HbA1c has a low sensitivity to diagnose diabetes in older Asian subjects and caution is required when using HbA1c in isolation. This raises the possibility that a different cut-off value for different age groups may be more appropriate.

Abdominal obesity and type 2 diabetes mellitus are associated with erectile and urinary dysfunction in men. The extent to which sexual function and lower urinary tract symptoms (LUTSs) are improved by weight loss remains unclear.We compared the effects of 8 weeks of a low-calorie diet using meal replacements (Kicstart) on insulin sensitivity, plasma testosterone levels, erectile function (measured by the five-item version of the International Index of Erectile Function, IIEF-5), sexual desire (measured by the Sexual Desire Inventory, SDI) and LUTS (measured by the International Prostate Symptom Score, IPSS), in abdominally obese (body mass indexor=30 kg m(-2), waist circumference (WC)or=102 cm) men (mean age 49.7 years) with uncomplicated diet or oral hypoglycemic-treated type 2 diabetes mellitus (n = 19) or without type 2 diabetes mellitus (n=25), with a control group of nondiabetic men (n = 26) with similar body mass index and WC.Weight loss of ∼ 10% was significantly associated with increased insulin sensitivity, plasma testosterone levels, IIEF-5 and SDI scores, as well as reduced WC and IPSS scores, in diabetic as well as nondiabetic men. The degree of weight loss was significantly associated with improvements in plasma testosterone levels (r = -0.34), erectile function (r = -0.26) and LUTS (r=0.65). Reduction in LUTS was significantly associated with increased plasma testosterone (r = -0.35), erectile function (r = -0.42) and sexual desire (r = -0.40).Diet-induced weight loss significantly and rapidly improves sexual function, and reduces LUTS, in obese middle-aged men with or without diabetes.

Joan Khoo, Christopher K Rayner, Karen L Jones, Michael HorowitzDiscipline of Medicine, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaAbstract: The advent of ‘incretin-based therapies’ – GLP-1 agonists and dipeptidyl-peptidase-4 inhibitors – which result in improvements in glycemic control comparable to those with existing oral hypoglycemic agents, and potentially improve cardiovascular and pancreatic β-cell function, represents a major therapeutic advance in the management of type 2 diabetes. Gastrointestinal adverse effects occur commonly with GLP-1 agonists, and rarely with DPP-4 inhibitors, but are dose-dependent and usually transient. The low risk of hypoglycemia, and beneficial or neutral effects on body weight, render GLP-1 agonists and DPP-4 inhibitors suitable alternatives to insulin secretagogues and insulin in overweight and elderly patients. Incretin-based therapies also improve quality of life in patients with type 2 diabetes, and may be cost-effective in the long term.Keywords: incretin, type 2 diabetes, therapy, GLP-1, DPP-4

5,619,926.58 person years in our analysis. During a median of 3 years, ~ 10% of our cohort of first cancer patients (n: 135,725/1,391,490) developed a second primary cancer. Of them, 2,214 (1.6%) had a second esophageal cancer. Cancer patients had a 1.7 higher risk of developing any esophageal cancer (SIR: 1.7 (95% CI: 1.6-1.7)) and a 2.2 higher risk of developing ESCC (SIR: 2.2 (95% CI: 2.1-2.4)) as compared to the general population. The SIR for a second ESCC after lung cancer was 3.70 (95% CI: 3.0-4.5). There was a remarkably high risk for developing a second ESCC in patients diagnosed with head-and-neck cancer with a SIR of 22.4 (95% CI: 20.0-25.0). In male patients the SIR for head-and-neck cancer was 19.3 (95% CI: 16.9-22.0) and 36.9 (95% CI: 29.8-45.4) for female patients. Of the 9,584 female patients with a first head-and-neck cancer 92 developed a second ESCC with a Number Needed to Screen of 96. Conclusions This first nationwide, population-based study in the Western world on the incidence of ESCC in head-and-neck cancer survivors shows that these patients have a 22 times higher risk of developing ESCC. This observation is even more pronounced in female patients. These data suggest that that head-and-neck cancer survivors may benefit from periodical screening for ESCC.