Intra-Adipose steroid metabolism in human obesity

Glucocorticoid excess causes obesity, dyslipidaemia, insulin resistance and hypertension as seen in Cushing's syndrome. In idiopathic obesity, circulating Cortisol levels are not elevated but Cortisol metabolism is altered. liphydroxysteroid dehydrogenase type 1 (11HSD1) is an intracellular enzyme that converts inactive cortisone into active Cortisol. Data from animals suggests that elevated adipose 11HSD1 may generate more glucocorticoid within adipose tissue and be an important mediator of obesity and the associated metabolic consequences (diabetes, dyslipidaemia and hypertension). This thesis addresses whether adipose IIHSD1 is elevated in human obesity, investigates if this occurs through altered transcription, and assesses the downstream impact (changes in downstream target genes and metabolic outcomes). Regulation of 11HSD1 mRNA in animal and cell models (eg by high fat feeding, insulin, and PPAR agonists), and putative control of enzyme direction by NADPH generation (via hexose-6-phosphate dehydrogenase), suggest a dynamic role for 11HSD1 in the adaptive response of adipose to altered nutrition. The importance of these potential regulators in lean and obese humans is also addressed in this thesis.In subcutaneous adipose biopsies from male and female healthy volunteers from Finland (n=19), Sweden (n=27) and USA (n=35) 11HSD1 activity (in vitro conversion of Cortisol to cortisone in presence of NADP) and mRNA (by real time PCR) was increased in association with generalised and 'central' obesity (which is most strongly associated with increased cardiovascular risk), and predicted insulin resistance. However, glucocorticoid receptor mRNA was negatively associated with obesity and insulin resistance. Adipose mRNAs for a number of key functional adipose targets (adiponectin, LPL, HSL, angiotensinogen, resistin, aromatase, PPARy) were not significantly associated with 11HSD1 expression or activity.To investigate 11HSD1 regulation, a series of randomised controlled studies in vivo in healthy male volunteers were performed to assess the regulatory effects of insulin (euglycaemic clamp) or lipid (20% Intralipid iv) over 3.5 hours and PPAR agonists (rosiglitazone or fenofibrate for 7 d). Deuterated-cortisol tracer with GCMS analysis was used to measure whole body Cortisol turnover and urinary metabolite excretion, and intra adipose microdialysis was used to assess in vivo s.c. adipose 21 11HSD1 activity and directionality. Hyperinsulinaemia increased the rate of appearance of 9,12,12-[2H]3-cortisol in plasma, indicating increased regeneration of Cortisol by 11HSD1. Within adipose tissue, the predominant reaction was conversion of cortisone to Cortisol rather than Cortisol to cortisone; both activities fell during the first hour of hyperinsulinaemia but subsequently increased. Intralipid infusion had no significant effects on deuterated Cortisol metabolism, but increased intra-adipose conversion of cortisone to Cortisol. The PPARy agonist rosiglitazone lowered adipose 11HSD1 reductase activity. The PPARa agonist fenofibrate had no effect on adipose 11HSD1 activity although urinary ratios of Cortisol/ cortisone metabolites and endogenous Cortisol clearance were reduced. These findings may be suggestive of decreased liver 5alpha-reductase activity. There were no significant changes in plasma tracer kinetics with PPAR agonists.In addition to altered glucocorticoid metabolism, changes in sex steroid metabolizing enzymes dictating oestrogen (aromatase) and androgen (AKR1C2/3) action were found to be associated with fat distribution in s.c biopsies from Swedish (n=27) and Finnish (n=19) volunteers. Further studies to determine the functional relevance of these associations are planned.These studies implicate dysregulation of 11HSD1 transcription in the pathogenesis of human obesity and the metabolic syndrome although the downstream impact of enzyme dysregulation remains unclear. They also suggest that 11HSD1 is involved in the adaptive response to nutrition, and that alteration in tissue glucocorticoids may contribute to the therapeutic action of PPAR agonists. This understanding of enzyme regulation in humans will allow further studies to dissect the basis of dysregulation in obesity. Inhibition of adipose 11HSD1 remains an intriguing target for the treatment of obesity and its metabolic complications but its physiological importance will best be determined by the development of specific adipose 11HSD1 inhibitors

Diabetes and artificial intelligence (AI) beyond the closed loop: A review of the landscape, promise and challenges for AI-supported management and self-care for all diabetes types.

The discourse amongst diabetes specialists and academics regarding technology and artificial intelligence (AI) typically centres around the 10% of people with diabetes who have type 1 diabetes, focusing on glucose sensors, insulin pumps and, increasingly, closed-loop systems. This focus is reflected in conference topics, strategy documents, technology appraisals and funding streams. What is often overlooked is the wider application of data and AI, as demonstrated through published literature and emerging marketplace products, that offers promising avenues for enhanced clinical care, health-service efficiency and cost-effectiveness. This review provides an overview of AI techniques and explores the use and potential of AI and data-driven systems in a broad context, covering all diabetes types, encompassing: (1) patient education and self-management; (2) clinical decision support systems and predictive analytics, including diagnostic support, treatment and screening advice, complications prediction; and (3) the use of multimodal data, such as imaging or genetic data. The review provides a perspective on how data- and AI-driven systems could transform diabetes care in the coming years and how they could be integrated into daily clinical practice. We discuss evidence for benefits and potential harms, and consider existing barriers to scalable adoption, including challenges related to data availability and exchange, health inequality, clinician hesitancy and regulation. Stakeholders, including clinicians, academics, commissioners, policymakers and those with lived experience, must proactively collaborate to realise the potential benefits that AI-supported diabetes care could bring, whilst mitigating risk and navigating the challenges along the way.</p

My Diabetes My Way:supporting online diabetes self-management: progress and analysis from 2016

Abstract Background My Diabetes My Way (MDMW) is the National Health Service (NHS) Scotland website for people with diabetes and their carers. It consists of an interactive information website and an electronic personal health record (ePHR) available to the 291,981 people with diabetes in Scotland. We aimed to analyse the demographic characteristics of current registrants and system usage and activity during 2016. Methods We analysed system audit trails to monitor user activity and page accesses on the information website, and logins and activity within the ePHR. The ePHR contains data from SCI-Diabetes, NHS Scotland’s flagship diabetes record, sourcing data from primary and secondary care, specialist screening services and laboratory systems. We reviewed patient registration characteristics to collate demographic data for the MWDH cohort, then compared this to aggregate data published in the 2016 Scottish Diabetes Survey. The Scottish Diabetes Survey is an annual population-based report detailing diabetes statistics for the whole diabetes population in NHS Scotland. Results The MDMW information website received an average of 101,382 page accesses per month during 2016 (56.9% increase from 2015; n = 64,607). ePHR registrants were more likely to be younger (p < 0.001) and have an ethnicity of “white” (p < 0.001) than the background diabetes population. At the end of 2016, 11,840 people with diabetes had accessed their personal clinical information (58.6% increase since end 2015; n = 7464). During 2016, an average of 1907 people accessed their records each month (48.3% increase from 2015; n = 1286). Conclusion My Diabetes My Way is a useful tool aid to diabetes self-management. The service is unique in offering records access to a national population, providing information from all relevant diabetes-related sources, rather than a single silo. MDMW supports the diabetes improvement, self-management, healthcare quality and eHealth strategies of the Scottish Government. The service also has potential to be adapted to work with other clinical systems and conditions

A Longitudinal Perspective on User Uptake of an Electronic Personal Health Record for Diabetes, With Respect To Patient Demographics

INTRODUCTION: The growing prevalence of diabetes has increased the need for scalable technologies to improve outcomes. My Diabetes My Way (MDMW) is an electronic personal health record (ePHR) available to all people with diabetes in Scotland since 2010, associated with improved clinical outcomes among users. MDMW pulls data from a national clinician-facing informatics platform and provides self-management and educational information. This study aims to describe MDMW user demographics through time with respect to the national diabetes population, with a view to addressing potential health inequalities. METHODS: Aggregate data were obtained retrospectively from the MDMW database and annual Scottish Diabetes Survey (SDS) from 2010 to 2020. Variables included diabetes type, sex, age, socioeconomic status, ethnicity, and glycemic control. Prevalence of MDMW uptake was calculated using corresponding SDS data as denominators. Comparisons between years and demographic sub-groups were made using Chi- Squared tests. RESULTS: Overall uptake of MDMW has steadily increased since implementation. By 2020, of all people with T1D or T2D in Scotland, 13% were fully enrolled to MDMW (39,881/312,326). There was proportionately greater numbers of users in younger, more affluent demographic groups (with a clear social gradient) with better glycemic control. As uptake has increased through time, so too has the observed gaps between different demographic sub-groups. CONCLUSIONS: The large number of MDMW users is encouraging, but remains a minority of people with diabetes in Scotland. There is a risk that innovations like MDMW can widen health inequalities and it is incumbent upon healthcare providers to identify strategies to prevent this