Gut Microbiome and Metabolic and Immune Indices in Males with or without Evidence of Metabolic Dysregulation.

Background: The contributions of the gut microbiota to obesity and metabolic disease represent a potentially modifiable factor that may explain variation in risk between individuals. This study aimed to explore relationships among microbial composition and imputed functional attributes, a range of soluble metabolic and immune indices, and gene expression markers in males with or without evidence of metabolic dysregulation (MetDys). Methods: This case-control study included healthy males (n=15; 41.9±11.7 years; body mass index [BMI], 22.9±1.2 kg/m2) and males with evidence of MetDys (n=14; 46.6±10.0 years; BMI, 35.1±3.3 kg/m2) who provided blood and faecal samples for assessment of a range of metabolic and immune markers and microbial composition using 16S rRNA gene sequencing. Metagenomic functions were imputed from microbial sequence data for analysis. Results: In addition to elevated values in a range of traditional metabolic, adipokine and inflammatory indices in the MetDys group, 23 immunomodulatory genes were significantly altered in the MetDys group. Overall microbial diversity did not differ between groups; however, a trend for a higher relative abundance of the Bacteroidetes (P=0.06) and a lower relative abundance of the Verrucomicrobia (P=0.09) phyla was noted in the MetDys group. Using both family- and genera-level classifications, a partial least square discriminant analysis revealed unique microbial signatures between the groups. Conclusion: These findings confirm the need for ongoing investigations in human clinical cohorts to further resolve the relationships between the gut microbiota and metabolic and immune markers and risk for metabolic disease.

Temporal trends in, and associations of, early-career general practitioner prescriptions of second-line Type 2 Diabetes medications, 2010-2018.

INTRODUCTION: Second-line pharmacotherapy for Type 2 Diabetes Mellitus ('diabetes') is necessary for optimal glycaemic control and preventing longer-term complications. We aimed to describe temporal trends in, and associations of, Australian general practitioner (GP) registrars' prescription, and initiation, of 'new' second-line oral agents (dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists) compared to sulphonylureas. MATERIALS AND METHODS: A longitudinal analysis (2010-2018) of data from the Registrar Clinical Encounters in Training project. Analysis included any diabetes problem/diagnosis that involved prescription of sulphonylureas or 'new' oral agents. Simple and multiple logistic regression models were fitted within the generalised estimating equations framework. RESULTS: 2333 registrars recorded 6064 diabetes problems/diagnoses (1.4%). 835 problems/diagnoses involved sulphonylurea or 'new' medication prescription. Of these, 61.0% [95% CI:57.4-64.4] involved 'new' medication prescription. 230 problems/diagnoses involved sulphonylurea or 'new' medication initiation, with 77% [95%CI:70.8-82.1] involving a 'new' medication. There was a significant 52% per year increase in prescribing (OR = 1.52[95% CI:1.38-1.68],p<0.001), and a 77% per (two-to-three-year) time-interval increase in initiation (OR = 1.77,[95% CI:1.30-2.43],p = <0.001) of 'new' medications compared to sulphonylureas. 'New' medications were prescribed less for non-English-speaking patients. There was some regional variation in prescribing. CONCLUSION: Registrar uptake of 'new' oral agents compared to sulphonylureas has increased rapidly.

Association Between a Low-Carbohydrate Diet, Glycemic Control, and Quality of Life in Australian Adults Living With Type 1 Diabetes: A Pilot Study.

OBJECTIVE: To examine if there is an association between a low-carbohydrate diet (LCD), glycemic control, and quality of life (QoL) in Australian adults with type 1 diabetes. METHODS: This single-group, pre-post, mixed methods (quantitative and qualitative) study was conducted in an outpatient tertiary hospital. Eligible participants were those aged ≥18 years, with type 1 diabetes for ≥1 year, and using multiple daily insulin injections. Participants followed a 12-week individualized LCD (<100 g/d). Daily glucose levels were monitored using a continuous glucose monitor. Glycated hemoglobin (HbA1c) and QoL were measured preintervention and postintervention. A post-hoc exploratory regression analysis determined whether changes in carbohydrate intake was associated with changes in HbA1c and QoL. Qualitative data collected postintervention explored participants' perceptions relating to a LCD, glycemic control, and QoL. RESULTS: Participants (n = 22) completed the 12-week LCD intervention. An LCD provided a statistically, significant improvement in HbA1c 0.83% (95% CI 0.32%-1.33%), P = .003 but did not impact QoL: estimated change 1.14 units (95% CI: -5.34 to 7.61); P = .72. The post-hoc exploratory regression analysis showed that participants with poorer baseline glycemic control were more likely to respond to an LCD resulting in significant reductions in HbA1c. Participant perceptions relating to the study variables were mixed. CONCLUSIONS: An LCD (<100 g/d) is a potentially effective and safe strategy to improve glycemic control without negatively effecting QoL in Australian adults with type 1 diabetes.

Association Between a Low Carbohydrate Diet, Quality of Life, and Glycemic Control in Australian Adults Living With Type 1 Diabetes: Protocol for a Mixed Methods Pilot Study.

BACKGROUND: Globally, the prevalence of type 1 diabetes mellitus (T1DM) is rising. In 2020, a total of 124,652 Australians had T1DM. Maintaining optimal glycemic control (hemoglobin A1c ≤7.0%, ≤53 mmol/mol) on a standard carbohydrate diet can be a challenge for people living with T1DM. The Diabetes Complications and Control Trial established that macrovascular and microvascular complications could be reduced by improving glycemic control. Recent studies have found that a very low or low carbohydrate diet can improve glycemic control. However, the overall evidence relating to an association between a very low or low carbohydrate diet and glycemic control in people living with T1DM is both limited and mixed. In addition, research has suggested that a reduced quality of life due to anxiety and depression adversely influences glycemic control. Despite a potential link between a very low or low carbohydrate diet and optimal glycemic control, to our knowledge, no research has examined an association between a low carbohydrate diet, quality of life, and glycemic control, making this study unique in its approach. OBJECTIVE: The study aims to develop a validated diabetes-specific quality of life questionnaire for use in Australian adults with T1DM and to determine if an association exists between a low carbohydrate diet, quality of life, and glycemic control in Australian adults living with T1DM. METHODS: This cross-sectional study will be conducted in a tertiary hospital outpatient setting and will consist of 3 phases: phase 1, online Australian diabetes-specific quality of life questionnaire development and piloting (25-30 adults with T1DM); phase 2, questionnaire validation (364 adults with T1DM); and phase 3, a 12-week dietary intervention to determine if an association exists between a low carbohydrate diet, quality of life, and glycemic control in adults with T1DM (16-23 adults with T1DM). The validation of the study-developed Australian diabetes-specific quality of life questionnaire, and changes in hemoglobin A1c and quality of life in adults with T1DM while undertaking a low carbohydrate diet over 12 weeks will be the primary outcomes of this study. RESULTS: Phase 1 of the study is currently open for recruitment and has recruited 12 participants to date. It is anticipated that the first results will be submitted for publication in November 2021. Presently, no results are available. CONCLUSIONS: This study is the first of its kind in that it will be the first to generate a new validated instrument, which could be used in evidence-based practice and research to understand the quality of life of Australian adults with T1DM. Second, the low carbohydrate dietary intervention outcomes could be used to inform clinicians about an alternative approach to assist T1DM adults in improving their quality of life and glycemic control. Finally, this study could warrant the development of an evidence-based low carbohydrate dietary guideline for adults living with T1DM with the potential to have a profound impact on this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04213300; https://clinicaltrials.gov/ct2/show/NCT04213300. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/25085.

A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes.

AIM: To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks followed by a 24-week, open-label extension, during which all patients received temelimab. The primary objective was the safety and tolerability of temelimab. The secondary objective was to assess the pharmacodynamics response such as C-peptide levels, insulin use, HbA1c, hypoglycaemia and autoantibodies. RESULTS: Temelimab was well tolerated without any group difference in the frequency or severity of adverse events. Concerning exploratory endpoints, there was no difference in the levels of C-peptide, insulin use or HbA1c between treatment groups at weeks 24 and 48. The frequency of hypoglycaemia events was reduced with temelimab (P = 0.0004) at week 24 and the level of anti-insulin antibodies was lower with temelimab (P < 0.01); the other autoantibodies did not differ between groups. CONCLUSIONS: Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti-insulin antibodies) under temelimab were observed. Markers of ß-cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

Appropriateness of ultrasound imaging for thyroid pathology, the standard of radiology reporting on thyroid nodules and the detection rates of thyroid malignancy: a tertiary centre retrospective audit.

BACKGROUND: The incidence of thyroid cancer is increasing worldwide without a simultaneous rise in mortality. It is thought that the incidence of non-clinically significant thyroid cancers are on the rise as a result of more sensitive diagnostic imaging. AIM: To determine the number of inappropriate requests for thyroid ultrasound (US), the quality of radiology reporting for thyroid nodules based on accepted guidelines and the resultant number of thyroid cancers identified because of these investigations. METHODS: Electronic medical records of patients who underwent thyroid US imaging and thereafter referred to the Endocrine Department at Gold Coast University Hospital, Queensland, between July 2014 and July 2017 were reviewed. Data for 251 patients who had thyroid US were analysed and the final 201 patients who were found to have thyroid nodules were evaluated using descriptive statistics. Indications for thyroid US imaging among referring clinicians were assessed and we compared both clinical management and radiology reporting practices of thyroid nodules to the published 2009 and 2015 American Thyroid Association (ATA) guidelines. RESULTS: There were 50.2% of patients with initial thyroid US imaging deemed outside of expert recommendations where 42% of these patients required further surveillance imaging and 25.4% required fine needle aspiration of their thyroid nodules. A definite recommendation whether to evaluate thyroid nodules further was provided in 44.8% of radiology reports. There were no radiology reports that described thyroid nodules findings based on patterns as recommended by the 2015 ATA guidelines. Two cases of thyroid cancer were detected including one patient with prior history of thyroid cancer and a second patient with hypothyroidism. CONCLUSION: Routine use of US thyroid imaging outside expert recommendation is common. There is lack of standardised reporting when assessing thyroid nodules on US. Limiting the initial use of US in cases of palpable neck lumps and the use of systematic reporting according to the 2017 guidelines published by the American College of Radiology Thyroid Imaging Reporting and Data System may reduce unnecessary investigations for thyroid nodules in the future.

Resources to Guide Exercise Specialists Managing Adults with Diabetes.

Exercise is an important element to optimize health and well-being, though navigating exercise safely can be challenging for exercise specialists working with people with diabetes. Measuring glucose levels before an exercise session assists in the determination of whether exercise is safe for a person with diabetes. A number of organizations have recently developed guidelines to provide exercise and diabetes recommendations based on glucose levels and other relevant factors. However, there are limited easy-to-use resources to assist exercise specialists to determine whether exercise should be started and continued by people with diabetes. The type of diabetes, pre-exercise glucose level, medications and their timing, recent food intake and general sense of wellness all warrant consideration when determining the approach to each exercise session. An expert group was convened to review the published literature and develop resources to guide exercise specialists in assessing the safety of an adult with diabetes starting exercise, and indications to cease exercise, based upon glucose levels and other factors. Contraindications to people with diabetes starting or continuing exercise are (1) glucose < 4.0 mmol/L; (2) glucose > 15.0 mmol/L with symptoms of weakness/tiredness, or with ketosis; (3) hypoglycaemic event within the previous 24 h that required assistance from another person to treat and (4) feeling unwell. To optimize diabetes and exercise safety, recommendations (stratified by pre-exercise glucose level) are provided regarding carbohydrate ingestion, glucose monitoring and medication adjustment.

BARIATRIC SURGERY FOR PRE-OPERATIVE WEIGHT REDUCTION IN A PATIENT WITH PHEOCHROMOCYTOMA.

OBJECTIVE: Obesity is a predictor of adverse outcomes in patients undergoing adrenalectomy. Pre-adrenalectomy weight reduction is becoming an increasingly common challenge in view of the rising prevalence of obesity. This case report describes the clinical course of a morbidly obese gentleman who underwent bariatric surgery prior to pheochromocytoma resection. METHODS: A morbidly obese man with a body mass index of 43 kg/m2 had an incidental finding of an 8.5 cm right-sided pheochromocytoma. Dietary and pharmacologic methods of weight loss lead to a 6 kg weight loss over a 12-month period. Multidisciplinary discussion concluded that weight loss and tumor resection were priority and the patient proceeded to laparoscopic sleeve gastrectomy with appropriate peri-operative alpha- and beta-blockade. RESULTS: Laparoscopic sleeve gastrectomy proceeded without complication and lead to a further 23 kg of weight loss and the pheochromocytoma was resected 2 months later. CONCLUSION: Bariatric surgery for pre-operative weight loss in medically prepared patients with pheochromocytoma should be considered for morbidly obese patients in whom nonsurgical weight loss is unsuccessful.

Enteroendocrine and adipokine associations with type 2 diabetes: Phenotypic risk scoring approaches.

BACKGROUND AND AIM: The contribution of gut-derived factors to the mechanisms linking obesity and metabolic disease remains under-investigated. The aim of the current study was to examine the associations between glucagon and enteroendocrine signaling and type 2 diabetes (T2D) using a derived risk score approach. To compare the relative importance of the enteroendocrine system, associations between adipokine measures and T2D were also investigated. METHODS: A total of 130 individuals with T2D and 161 individuals without T2D were included in the study. Circulating concentrations of enteroendocrine (glucagon, ghrelin, glucagon-like peptide-1, and gastric inhibitory peptide) and adipokine mediators (adiponectin, leptin, resistin, visfatin, and adipsin) were measured. Standard scores (Z-scores) were determined for each measure and enteroendocrine risk scores (ERS) and adipokine risk scores (ARS) calculated based on summation of the component measures. Associations between both the ERS and ARS and T2D status were assessed using logistic regression models. RESULTS: The ERS was significantly associated with T2D status in an adjusted model (odds ratio: 1.36; 95% confidence interval [CI]: 1.08-1.72; P = 0.009). Associations between the ARS and T2D status were not independent of age, sex, and body mass index (odds ratio: 1.21; 95%CI: 0.99-1.47; P = 0.06). Quantification of risk across ERS tertiles revealed that individuals with an ERS in the upper tertile were 10 times more likely (CI: 3.23-32.73; P < 0.001) to have T2D. CONCLUSIONS: These data support an association between enteroendocrine signaling and T2D. Use of the ERS as a potential tool for classifying individuals with metabolic syndrome as high or low risk for T2D development is being considered.

Glucose-lowering medicines for type 2 diabetes.

BACKGROUND: There is an increasing array of medicines available to improve blood glucose control in type 2 diabetes. Finding the best combination for an individual patient requires an assessment of the patient's characteristics and understanding the mechanism of action for each drug. OBJECTIVE: The aim of this article is to provide a rational approach for choosing between the various blood glucose-lowering medicines available for treatment of patients with type 2 diabetes mellitus. DISCUSSION: Metformin is the first choice of glucose-lowering medicines for most patients with type 2 diabetes. Sulphonylureas have proven benefits in long-term trials. Insulin is required in patients with symptoms of insulin deficiency. Glucagon-like peptide 1 agonists and sodium-glucose co-transporter 2 inhibitors provide some assistance in weight loss as well as improving blood glucose control. Dipeptidyl peptidase 4 inhibitors provide an alternative to metformin and sulphonylureas, especially when side effects of those drugs limit their use. Re-assessing blood glucose control after an appropriate trial period before deciding on continuing use is appropriate.

Autoimmune thyroid disease in the use of alemtuzumab for multiple sclerosis: a review.

OBJECTIVE: The monoclonal antibody alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in multiple sclerosis (MS) patients when compared to ß-interferon. The development of autoimmune diseases, including thyroid disease, has been reported in the literature with a frequency of 20 to 30%. In this article, we describe 4 cases of alemtuzumab-induced thyroid disease in patients with MS. We also performed a systematic review of the available literature. METHODS: Four patients who had received alemtuzumab for MS and subsequently developed thyroid dysfunction are presented. We compared our patients' clinical courses and outcomes to established disease patterns. We also undertook a systematic review of the published literature. RESULTS: All 4 patients presented with initial hyperthyroidism associated with elevated thyroid-stimulating hormone (TSH) receptor antibodies (TRAb). In 2 cases, hyperthyroidism did not remit after a total of 24 months of carbimazole therapy, and they subsequently underwent subtotal thyroidectomy. The third case subsequently developed biochemical hypothyroidism and required thyroxine replacement, despite having a markedly raised initial TRAb titer. Autoimmunity following alemtuzumab therapy in MS appears to occur as part of an immune reconstitution syndrome and is more likely in smokers who have a family history of autoimmune disease. CONCLUSION: Management of alemtuzumab-induced thyroid disease is similar to the management of "wild-type" Graves' disease. The use of alemtuzumab in this setting will necessitate close monitoring of thyroid function and early intervention when abnormalities are developing.

Danger of hypoglycemia due to acute tramadol poisoning.

OBJECTIVE: To report a case of prolonged hypoglycemia after acute tramadol poisoning. METHODS: We describe a patient's clinical presentation and outcome with prolonged hypoglycemia attributable to acute tramadol poisoning. In addition, the possible mechanism for the hypoglycemia is discussed, and a brief review of the pertinent literature is presented. RESULTS: A 54-year-old woman had previously undergone a partial hepatectomy because of involvement of her liver by a gastrointestinal stromal tumor. After ingestion of 3,000 mg of tramadol with suicidal intent, she developed prolonged hypoglycemia that necessitated treatment with continuous intravenous glucose infusion for 24 hours. Reports in the literature have described central nervous system depression, nausea, vomiting, tachycardia, seizures, and even death from tramadol overdoses. CONCLUSION: This report alerts clinicians to the potential danger of severe hypoglycemia in tramadol poisoning.

Extreme hypernatraemia: a case report and brief review.

A 44-year-old man presented with extreme hypernatraemia. The case is unique in three respects: the patient's plasma sodium concentration was 208mmol/L; the aetiology was multifactorial, including essential hypernatraemia, hypodipsia and high ambient temperature; and the patient survived with full neurological recovery. We briefly review various disorders of thirst and osmorecepters.