Melbourne Medical School Collected Works - Research Publications
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ItemNo Preview AvailableValidation of Formulae to Estimate Insulin Sensitivity in Type 1 Diabetes(American Diabetes Association, 2021-06)Introduction: The “gold standard” measure of insulin sensitivity (IS), a euglycemic hyperinsulinemic clamp, is costly, time- and labour-intensive. Several formulae, developed using clamp data estimate insulin sensitivity, expressed as estimated glucose disposal rate (eGDR) or insulin sensitivity index (eM/I or elog10M/I). Due to clamp complexity and cost these formulae often lacks independent validation. Aim: To validate several formulae estimating IS using independent euglycaemic hyperinsulinemic clamp data. Methods: Euglycemic, hyperinsulinemic clamps were performed in 108 T1D adults (age (mean±SD) 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%; 33 with microvascular complications). Measured GDR (last 30min of the clamp) ranged 0.5 - 9.6 mg/kg/min (median (LQ, UQ) 4.45 (3.04, 6.5 mg/kg/min) were compared with eGDR and eLog10M/I calculated using simple formulae by (1) Williams, (2) Zheng, (3) Dabelea and (4) and (5) (Australia (AU)) authors, all derived from routine clinical chemistry and demographics. eGDR formula (Duca) was not assessed as it includes adiponectin levels. Results: Results are in Table 1. Conclusion: Authors (AU) formulae to estimate IS, including age, sex, HDL-C, BMI, HbA1c, pulse pressure and WHR had highest correlation with measured GDR and better performance (AUROC) in detecting low IS than other formulae.
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ItemNo Preview AvailableEstimated insulin sensitivity in Type 1 diabetes adults using clinical and research biomarkers(ELSEVIER IRELAND LTD, 2020-09)AIMS: Insulin resistance in people with type 1 diabetes (T1D) is associated with increased risk of chronic complications and death. The gold standard to quantify insulin sensitivity, a euglycaemic hyperinsulinaemic clamp, is not applicable to clinical practice. We have employed clamp studies to develop a panel of formulae to estimate insulin sensitivity in adults with T1D for use in clinical practice and trials. METHODS: Clamps were conducted in 28 adults with T1D, who were also characterised with 38 clinical and research biomarkers. Exhaustive search analysis was used to derive equations correlating with clamp-quantified glucose disposal rate (GDR), GDR/plasma insulin (M/I) and log10M/I. RESULTS: Measured insulin sensitivity correlated with BMI, WHR, HDL-C, adipokines and inflammation markers on univariate analysis. Exhaustive search analysis derived three formulae correlating with clamp-derived GDR and logM/I (p < 0.0001), accounting for ≈62% of their variability. A formula using gender, age, HDL-C, pulse pressure and WHR performed as well as those containing inflammation and adipokine measures. CONCLUSIONS: The performance of formulae using routinely available parameters with/without research biomarkers in clinical studies and trials, particularly related to future complications, relevant lifestyle interventions, insulin delivery modes and insulin sensitisers is merited.
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ItemNo Preview AvailableIndependent euglycaemic hyperinsulinaemic clamp studies validate clinically applicable formulae to estimate insulin sensitivity in people with type 1 diabetes(Elsevier, 2023-01)Background and aim: Low insulin sensitivity (IS) increases Type 1 diabetes (T1D) complication risk and can be estimated by simple formulae developed from complex euglycemic hyperinsulinaemic clamp studies. We aimed to validate these formulae using independent clamp data. Methods: Clamps were performed in 104 T1D adults. Measured glucose disposal rate (GDR) was correlated with eGDR and eLog10 M/I calculated by five IS formulae. Results: Correlations ranged between 0.23–0.40. Two IS formulae (by the authors), using age, sex, HDL-C, HbA1c, pulse pressure, BMI, and waist-hip-ratio had the highest correlation with measured GDR and the best performance in detecting low IS.
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ItemNo Preview AvailableIndependent euglycaemic hyperinsulinaemic clamp studies validate clinically applicable formulae to estimate insulin sensitivity in people with type 1 diabetes (vol 17, 102691, 2023)(ELSEVIER SCI LTD, 2023-01)The authors regret that in the original article, on the second page, in the section with eGDR equations, variables “sex” and “hypertension” were missing categorical values indicators (“F = 0, M = 1”; “Yes = 1, No = 0”, respectively) required to calculate eGDR. It should be corrected by adding “F = 0, M = 1” in two instances and “Yes = 1, No = 0” in one instance. Also, please note that Miller at al. defined “hypertension” as BP ≥140/90mmHg or use of any anti-hypertensive (drug) treatment. The authors apologise for any inconvenience caused.
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ItemNo Preview AvailableInteractive Calculator to Estimate Insulin Sensitivity (IS) in Type 1 Diabetes(American Diabetes Association, 2023-06-20)Aim: To develop a free online tool to estimate IS using different metrics and existent formulae and compare estimated IS with measured glucose disposal rate (GDR) from 104 clamp studies. Methods: We prepared an online tool for calculating IS using 17 formulae. Suitable formula(e) are suggested based on available (clinical and research) data. We also compare calculated IS with measured IS (GDR) from clamp studies in 104 adults with T1D (mean±SD) age 34±7 yrs, T1D duration 10±4 yrs, HbA1c 7.7±1.5%, 33 with microvascular complications). Logistic regression was used to infer probability of calculated IS being below GDR=4.45 mg/kg/min or above GDR=6.5 mg/kg/min, which represent respectively the median and 75th percentile of measured GDR values. Results: A calculator is available at www.bit.ly/estimated-GDR and an example result in the Figure 1. Estimated IS varied widely, but results interpretation is generally consistent. Conclusion: We developed an interactive tool to estimate IS in T1D for clinical and research use.
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ItemInteractive calculator to estimate insulin sensitivity in type 1 diabetes(WILEY, 2024-05)The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic-euglycemic clamp, a time, costly, and labor-intensive research tool. A low insulin sensitivity is associated with a complication-risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated-GDR), enabling comparison of IS and its probability of IS <4.45 mg/kg/min (low) or >6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005-0.87 with agreement in detecting low and high glucose disposal rates in the range 49-93% and 89-100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user-friendly tool for individual IS calculations and also offers efficient batch processing of data for research.
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ItemMyocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.(Elsevier BV, 2024-04)Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.
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ItemDevelopment of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS(Wiley, 2024-04)AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.
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ItemDeep-PK: deep learning for small molecule pharmacokinetic and toxicity prediction(OXFORD UNIV PRESS, 2024-04-18)Evaluating pharmacokinetic properties of small molecules is considered a key feature in most drug development and high-throughput screening processes. Generally, pharmacokinetics, which represent the fate of drugs in the human body, are described from four perspectives: absorption, distribution, metabolism and excretion-all of which are closely related to a fifth perspective, toxicity (ADMET). Since obtaining ADMET data from in vitro, in vivo or pre-clinical stages is time consuming and expensive, many efforts have been made to predict ADMET properties via computational approaches. However, the majority of available methods are limited in their ability to provide pharmacokinetics and toxicity for diverse targets, ensure good overall accuracy, and offer ease of use, interpretability and extensibility for further optimizations. Here, we introduce Deep-PK, a deep learning-based pharmacokinetic and toxicity prediction, analysis and optimization platform. We applied graph neural networks and graph-based signatures as a graph-level feature to yield the best predictive performance across 73 endpoints, including 64 ADMET and 9 general properties. With these powerful models, Deep-PK supports molecular optimization and interpretation, aiding users in optimizing and understanding pharmacokinetics and toxicity for given input molecules. The Deep-PK is freely available at https://biosig.lab.uq.edu.au/deeppk/.
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ItemIdentification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation(MDPI AG, 2024)The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein–peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.