Circadian rhythms, insulin action, and glucose homeostasis.

PURPOSE OF REVIEW: Accumulating evidence supports a role for the circadian clock in the development of metabolic disease. We discuss the influence of the circadian clock on glucose homeostasis, intermediary factors in this relationship, and potential therapies for the prevention or attenuation of metabolic disease associated with circadian misalignment. RECENT FINDINGS: Murine studies with tissue-specific deletion of core clock genes in key metabolic tissues confirm a mechanistic relationship between the circadian clock and the development of metabolic disease. Circadian misalignment increases insulin resistance and decreases pancreatic function. Clock gene polymorphisms or altered expression of clock genes induced by circadian misalignment appear to play a role in the development of obesity and diabetes in humans. Circadian disruption caused by exposure to light at night is associated with lower nocturnal melatonin, which in turn seems to affect glucose metabolism. Potential therapies for circadian misalignment include entraining the central pacemaker with timed light exposure and/or melatonin and restricting food intake to the biological day. SUMMARY: Completing the understanding of how genetic and environmental factors influence the circadian clock and the effect these have on human circadian metabolic physiology and disease will allow us to develop therapies for treating and preventing associated metabolic disease.

Pituitary apoplexy secondary to thrombocytopenia due to dengue hemorrhagic fever: a case report and review of the literature.

OBJECTIVE: To present a case of pituitary apoplexy secondary to thrombocytopenia associated with dengue hemorrhagic fever (DHF). METHODS: In this case study, we review the presentation, evaluation, diagnosis, and management of a case of pituitary apoplexy in the setting of DHF. We also searched the literature for cases of pituitary apoplexy associated with thrombocytopenia and review their clinical presentation, management, and outcome. RESULTS: A 53-year-old man presented with fever, lethargy, and worsening headache. Routine investigations revealed thrombocytopenia secondary to dengue fever. He developed symptoms of a cavernous sinus lesion the next day. Urgent magnetic resonance imaging revealed pituitary apoplexy in a pituitary macroadenoma. A transsphenoidal surgery was done and histology was consistent with apoplexy in a prolactin/follicle-stimulating hormone macroadenoma. Subsequently, the patient developed permanent deficits of anterior pituitary hormones. We review 8 other cases of pituitary apoplexy associated with thrombocytopenia reported in the literature. CONCLUSION: Thrombocytopenia due to various causes may be a predisposing factor for pituitary apoplexy in a patient with underlying pituitary disease. In view of the tendency for bleeding associated with thrombocytopenia, the risks of surgical intervention have to be carefully weighed against the potential benefits. Indications for surgery would include progressive alteration of consciousness, visual disturbances, and opthalmoplegia despite conservative management. Patients with underlying pituitary macroadenomas with optic chiasm compression have a worse prognosis, and the chances of recovery, even with early surgery, are limited.

Case Report: Hypercalcemia as a manifestation of acute adrenal crisis precipitated by fluconazole use, and a review of the literature.

Acute adrenal crisis classically presents with vomiting, altered sensorium, and hypotension. We describe a unique case manifesting with severe hypercalcemia. Addisonian crisis was unusually precipitated by fluconazole use. We reviewed other reported cases and discuss the possible mechanisms of hypercalcemia in adrenal insufficiency. This 67-year-old man presented with fever, cough, and vomiting for 1 week and with anorexia and confusion for 3 weeks. He was hypotensive and clinically dehydrated. Investigations revealed left-sided lung consolidation, acute renal failure, and severe non-parathyroid hormone (PTH)-mediated hypercalcemia (calcium, 3.55mol/L; PTH, 0.81pmol/L). Initial impression was pneumonia complicated by septic shock and hypercalcemia secondary to possible malignancy. He received mechanical ventilation; treatment with intravenous fluids, inotropes, and hydrocortisone for septic shock; and continuous renal replacement therapy with low-calcium dialysate. Although hypercalcemia resolved and he was weaned off inotropes, dialysis, and hydrocortisone, his confusion persisted. When hypercalcemia recurred on day 19 of admission, early morning cortisol was <8 nmol/L, with low ACTH level (3.2 ng/L). Other pituitary hormones were normal. Hypercalcemia resolved 3 days after reinstating stress doses of hydrocortisone, and his mentation normalized. On further questioning, he recently received fluconazole for a forearm abscess. He previously consumed traditional medications but stopped several years ago, which may have contained glucocorticoids. He was discharged on oral hydrocortisone. Cortisol levels improved gradually, and glucocorticoid replacement was ceased after 8 years, without any recurrence of hypercalcemia or Addisonian crisis. Both hypercalcemia and adrenal insufficiency may present with similar non-specific symptoms. It is important to consider adrenal insufficiency in hypercalcemia of unclear etiology.

Proton-pump inhibitor use amongst patients with severe hypomagnesemia.

Introduction: Long-term proton pump inhibitor (PPI) use has been associated with hypomagnesemia. It is unknown how frequently PPI use is implicated in patients with severe hypomagnesemia, and its clinical course or risk factors. Methods: All patients with severe hypomagnesemia from 2013 to 2016 in a tertiary center were assessed for likelihood of PPI-related hypomagnesemia using Naranjo algorithm, and we described the clinical course. The clinical characteristics of each case of PPI-related severe hypomagnesemia was compared with three controls on long-term PPI without hypomagnesemia, to assess for risk factors of developing severe hypomagnesemia. Results: Amongst 53,149 patients with serum magnesium measurements, 360 patients had severe hypomagnesemia (<0.4 mmol/L). 189 of 360 (52.5%) patients had at least possible PPI-related hypomagnesemia (128 possible, 59 probable, two definite). 49 of 189 (24.7%) patients had no other etiology for hypomagnesemia. PPI was stopped in 43 (22.8%) patients. Seventy (37.0%) patients had no indication for long-term PPI use. Hypomagnesemia resolved in most patients after supplementation, but recurrence was higher in patients who continued PPI, 69.7% versus 35.7%, p = 0.009. On multivariate analysis, risk factors for hypomagnesemia were female gender (OR 1.73; 95% CI: 1.17-2.57), diabetes mellitus (OR, 4.62; 95% CI: 3.05-7.00), low BMI (OR, 0.90; 95% CI: 0.86-0.94), high-dose PPI (OR, 1.96; 95% CI: 1.29-2.98), renal impairment (OR, 3.85; 95% CI: 2.58-5.75), and diuretic use (OR, 1.68; 95% CI: 1.09-2.61). Conclusion: In patients with severe hypomagnesemia, clinicians should consider the possibility of PPI-related hypomagnesemia and re-examine the indication for continued PPI use, or consider a lower dose.

Insulin Allergy to Detemir Followed by Rapid Onset of Diabetic Ketoacidosis: A Case Report and Literature Review.

The management of diabetes mellitus in an insulin-dependent patient is challenging in the setting of concomitant antibody-mediated-insulin hypersensitivity. We report a case of a 62-year-old woman with pre-existing type 2 diabetes mellitus of 10 years duration who developed type 3 hypersensitivity reaction to insulin analogue detemir, and subsequently, severe diabetic ketoacidosis (DKA). She was C-peptide negative and was diagnosed with insulin-dependent diabetes. Despite increasing dose adjustments, insulin-meal matching, and compliance with insulin, she experienced episodes of unexpected hyperglycaemia and hypoglycaemia. The development of rash after detemir initiation and rapid progression to DKA suggests an aberrant immune response leading to the insulin allergy and antibody-induced interference with insulin analogues. Glycaemic control in the patient initially improved after being started on subcutaneous insulin infusion pump with reduced insulin requirements. However, after a year on pump therapy, localised insulin hypersensitivity reactions started, and glycaemic control gradually deteriorated.

Treatment of Primary Aldosteronism and Reversal of Renin Suppression Improves Left Ventricular Systolic Function.

Introduction: Primary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA. Methods: We prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment. Results: At baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP (P = 0.038) and glomerular filtration rate (P = 0.026). GLS improved post-surgery by -2.3, 95% CI: -3.9 to -0.6, P = 0.010, and post-medications by -1.3, 95% CI: -2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS (P < 0.001) and increase in plasma renin activity (P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS (P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index (P = 0.012), left atrial volume index (P = 0.002), and mitral E/e' (P = 0.006), whereas it was not statistically significant in patients treated with medications. Conclusion: Treatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03174847.

Effects of water stably-enriched with oxygen as a novel method of tissue oxygenation on mitochondrial function, and as adjuvant therapy for type 2 diabetes in a randomized placebo-controlled trial.

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.

Tolerability and Efficacy of Long-Term Medical Therapy in Primary Aldosteronism.

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) <140/90 mmHg, 90.1% achieved normokalemia (48.0% potassium ≥4.3 mmol/L), and 63.2% achieved renin >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.

Improvement in quality of life and psychological symptoms after treatment for primary aldosteronism: Asian Cohort Study.

BACKGROUND: In addition to increased cardiovascular risk, patients with primary aldosteronism (PA) also suffer from impaired health-related quality of life (HRQoL) and psychological symptoms. We assessed for changes in HRQoL and depressive symptoms in a cohort of Asian patients with PA, after surgical and medical therapy. METHODS: Thirty-four patients with PA were prospectively recruited and completed questionnaires from 2017 to 2020. HRQoL was assessed using RAND-36 and EQ-5D-3L, and depressive symptoms were assessed using Beck Depression Inventory (BDI-II) at baseline, 6 months, and 1 year post-treatment. RESULTS: At 1 year post-treatment, significant improvement was observed in both physical and mental summative scores of RAND-36, +3.65, P = 0.023, and +3.41, P = 0.033, respectively, as well as four subscale domains (physical functioning, bodily pain, role emotional, and mental health). Significant improvement was also seen in EQ-5D dimension of anxiety/depression at 1 year post-treatment. Patients treated with surgery (n = 21) had significant improvement in EQ-5D index score post-treatment and better EQ-5D outcomes compared to the medical group (n = 13) at 1 year post-treatment. 37.9, 41.6 and 58.6% of patients had symptoms in the cognitive, affective and somatic domains of BDI-II, respectively. There was a significant improvement in the affective domain of BDI-II at 1 year post-treatment. CONCLUSION: Both surgical and medical therapy improve HRQoL and psychological symptoms in patients with PA, with surgery providing better outcomes. This highlights the importance of early diagnosis, accurate subtyping and appropriate treatment of PA.

Correction: A Smartphone App to Improve Medication Adherence in Patients With Type 2 Diabetes in Asia: Feasibility Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/14914.].

A Smartphone App to Improve Medication Adherence in Patients With Type 2 Diabetes in Asia: Feasibility Randomized Controlled Trial.

BACKGROUND: The efficacy of smartphone apps for improving medication adherence in type 2 diabetes is not well studied in Asian populations. OBJECTIVE: This study aimed to determine the feasibility, acceptability, and clinical outcomes of using a smartphone app to improve medication adherence in a multiethnic Asian population with type 2 diabetes. METHODS: We block randomized 51 nonadherent and digitally literate patients with type 2 diabetes between the ages of 21 and 75 years into two treatment arms (control: usual care; intervention: usual care+Medisafe app) and followed them up for 12 weeks. Recruitment occurred at a public tertiary diabetes specialist outpatient center in Singapore. The intervention group received email reminders to complete online surveys monthly, while the control group only received an email reminder(s) at the end of the study. Barriers to medication adherence and self-appraisal of diabetes were assessed using the Adherence Starts with Knowledge-12 (ASK-12) and Appraisal of Diabetes Scale (ADS) questionnaires at baseline and poststudy in both groups. Perception toward medication adherence and app usage, attitude, and satisfaction were assessed in the intervention group during and after the follow-up period. Sociodemographic data were collected at baseline. Clinical data (ie, hemoglobin A1c, body mass index, low-density lipoprotein, high-density lipoprotein, and total cholesterol levels) were extracted from patients' electronic medical records. RESULTS: A total of 51 (intervention group: 25 [49%]; control group: 26 [51%]) participants were randomized, of which 41 (intervention group: 22 [88.0%]; control group: 19 [73.1%]) completed the poststudy survey. The baseline-adjusted poststudy ASK-12 score was significantly lower in the intervention group than in the control group (mean difference: 4.7, P=.01). No changes were observed in the clinical outcomes. The average 12-week medication adherence rate of participants tracked by the app was between 38.3% and 100% in the intervention group. The majority (>80%) of the participants agreed that the app was easy to use and made them more adherent to their medication. CONCLUSIONS: Our feasibility study showed that among medication-nonadherent patients with type 2 diabetes, a smartphone app intervention was acceptable, improved awareness of medication adherence, and reduced self-reported barriers to medication adherence, but did not improve clinical outcomes in a developed Asian setting.

Effect of multidisciplinary intensive targeted care in improving diabetes mellitus outcomes: a randomized controlled pilot study - the Integrated Diabetes Education, Awareness and Lifestyle modification in Singapore (IDEALS) Program.

BACKGROUND: There is a global pandemic of type 2 diabetes mellitus (T2DM), especially in Asia. Singapore has a prevalence of T2DM at 10.5%, which is higher than the world average of 8.8%. Multiple studies have shown that multidisciplinary, team-based, coordinated care has been associated with improved measures of quality care and reduced healthcare utilization. Patients with poor glycemic control and nephropathy are at the highest risk of developing cardiovascular complications and renal failure. In this study, we aimed to investigate the impact of intensive multidisciplinary diabetes mellitus care with patient empowerment versus routine clinical care on the rate of progression of micro and macrovascular complications and peripheral atherosclerotic burden, as measured by changes in femoral intima-media thickness (IMT) in patients with persistently elevated HbA1c and nephropathy. METHODS: The study is a single-center randomized controlled trial (RCT) with two study arms - intensive diabetes mellitus care versus routine clinical care. Patients in the intensive arm will receive care from a multidisciplinary team consisting of an endocrinologist, diabetes nurse educator, dietitian, renal pharmacist and medical social worker for counselling. In addition, patients will be provided with tools for self-care empowerment such as glucometers, blood pressure monitors and android tablets to facilitate care, monitoring and education. Patients in the routine clinical care arm will receive standard clinical care. Follow up (FU) will be for 3 years. Primary outcomes include cardiovascular events, rate of progression of nephropathy and development of end-stage renal disease. Secondary endpoints include the proportions of patients with documented improved control of cardiovascular risk factors (HbA1c, blood pressure, low density lipoprotein-C (LDL-C), reduction in body weight), frequency of hypoglycemia, hospitalization days and changes in femoral IMT. We will also examine the prevalence of peripheral atherosclerosis and the predictive value and usability of lower extremity arterial ultrasound to predict cardio-cerebrovascular events, amputation and peripheral intervention. DISCUSSION: Diabetes mellitus carries significant healthcare costs. Patients with poor glycemic control and nephropathy are at highest risk of developing cardiovascular complications and renal failure. Intensive diabetes mellitus care with patient empowerment may lead to sustained glycemic control, reduction of clinical complications and progression of nephropathy, and incidence of cardiovascular complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413215 . Registered on 29 January 2019.

Sensitivity of A1C to diagnose diabetes is decreased in high-risk older Southeast Asians.

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: <45 (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.

HbA1c may not be a sensitive determinant of diabetic status in the elderly.

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.