Diabetes and artificial intelligence beyond the closed loop: a review of the landscape, promise and challenges.

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.

Continuing the quality improvement of an electronic personal health record and interactive website for people with diabetes in Scotland (My Diabetes My Way).

AIMS: eHealth applications have the potential to enable patients to take more control over managing their own health, helping to delay and prevent complications. My Diabetes My Way (MDMW) is an electronic personal health record/educational platform available to people with diabetes in Scotland. This study aims to assess user experience with respect to demographic subgroups, examine effectiveness of previous improvements made to the platform and inform its ongoing development. METHODS: All active MDMW users (22,665) were invited to take part in a questionnaire combining Likert scale and free-response items relating to system utility. Likert responses were used to generate a 'utility score'. This was used in regression analyses to determine predictors of system utility scoring. Free-response answers were analysed thematically and themes were generated. RESULTS: A total of 4713 (21%) MDMW users responded to the questionnaire. Most agreed that MDMW helps them to track changes over time, prepare for face-to-face consultations, remember information discussed in consultations and reduced the need to contact their general practitioner. Free-response answers showed that users valued earlier enhancements made to the site (e.g. linking Fitbit data), and highlighted areas needing further improvement. Evidence of the 'digital divide' was seen in respondent demographics, and some users mentioned 'lack of digital skills' as a barrier to engaging with the platform. CONCLUSIONS: User experience of MDMW was positive. Users agreed with statements that MDMW facilitates diabetes self management. Several areas of potential improvement were identified, including linking more wearable device data, and assisting/directing users to gain the digital skills required to engage fully with MDMW.

Digitising diabetes education for a safer Ramadan: Design, delivery, and evaluation of massive open online courses in Ramadan-focused diabetes education.

AIMS: Ramadan-focused diabetes education is critical to facilitate safer Ramadan fasting amongst Muslim people living with diabetes. We present the design, delivery, and evaluation of two parallel massive open online courses (MOOCs) in Ramadan-focused diabetes education for people with diabetes and HCPs. METHODS: Two Ramadan-focused diabetes education MOOCs were developed and delivered for Ramadan 2023: one for HCPs in English, and another for people with diabetes in English, Arabic and Malay. A user-centred iterative design process was adopted, informed by user feedback from a 2022 pilot MOOC. Evaluation comprised a mixed-methods evaluation of pre- and post-course user surveys. RESULTS: The platform was utilised by people with diabetes and their family, friends and healthcare professionals. Overall, a total of 1531 users registered for the platform from 50 countries, 809 started a course with a 48% subsequent completion rate among course starters. Qualitative analysis showed users found the course a user-friendly and authoritative information source. In the HCP MOOC, users reported improved post-MOOC Ramadan awareness, associated diabetes knowledge and ability to assess and advise patients in relation to their diabetes during Ramadan (p<0.01). CONCLUSIONS: We demonstrate the potential of MOOCs to deliver culturally tailored, high-quality, scalable, multilingual Ramadan-focused diabetes education to HCPs and people with diabetes.

Cost-Utility of an Online Education Platform and Diabetes Personal Health Record: Analysis Over Ten Years.

BACKGROUND AND AIMS: My Diabetes My Way (MDMW) is Scotland's interactive website and mobile app for people with diabetes and their caregivers. It contains multimedia resources for diabetes education and offers access to electronic personal health records. This study aims to assess the cost-utility of MDMW compared with routine diabetes care in people with type 2 diabetes who do not use insulin. MATERIALS AND METHODS: Analysis used the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model 2. Clinical parameters of MDMW users (n = 2576) were compared with a matched cohort of individuals receiving routine care alone (n = 11 628). Matching criteria: age, diabetes duration, sex, and socioeconomic status. Impact on life expectancy, quality-adjusted life years (QALYs), and costs of treatment and complications were simulated over ten years, including a 10% sensitivity analysis. RESULTS: MDMW cohort: 1670 (64.8%) men; average age 64.3 years; duration of diabetes 5.5 years. 906 (35.2%) women: average age 61.6 years; duration 4.7 years. The cumulative mean QALY (95% CI) gain: 0.054 (0.044-0.062) years. Mean difference in cost: -£118.72 (-£150.16 to -£54.16) over ten years. Increasing MDMW costs (10%): -£50.49 (-£82.24-£14.14). Decreasing MDMW costs (10%): -£186.95 (-£218.53 to -£122.51). CONCLUSIONS: MDMW is "dominant" over usual care (cost-saving and life improving) in supporting self-management in people with type 2 diabetes not treated with insulin. Wider use may result in significant cost savings through delay or reduction of long-term complications and improved QALYs in Scotland and other countries. MDMW may be among the most cost-effective interventions currently available to support diabetes.

User-Centered Design of A Novel Risk Prediction Behavior Change Tool Augmented With an Artificial Intelligence Engine (MyDiabetesIQ): A Sociotechnical Systems Approach.

BACKGROUND: Diabetes and its complications account for 10% of annual health care spending in the United Kingdom. Digital health care interventions (DHIs) can provide scalable care, fostering diabetes self-management and reducing the risk of complications. Tailorability (providing personalized interventions) and usability are key to DHI engagement/effectiveness. User-centered design of DHIs (aligning features to end users' needs) can generate more usable interventions, avoiding unintended consequences and improving user engagement. OBJECTIVE: MyDiabetesIQ (MDIQ) is an artificial intelligence engine intended to predict users' diabetes complications risk. It will underpin a user interface in which users will alter lifestyle parameters to see the impact on their future risks. MDIQ will link to an existing DHI, My Diabetes My Way (MDMW). We describe the user-centered design of the user interface of MDIQ as informed by human factors engineering. METHODS: Current users of MDMW were invited to take part in focus groups to gather their insights about users being shown their likelihood of developing diabetes-related complications and any risks they perceived from using MDIQ. Findings from focus groups informed the development of a prototype MDIQ interface, which was then user-tested through the "think aloud" method, in which users speak aloud about their thoughts/impressions while performing prescribed tasks. Focus group and think aloud transcripts were analyzed thematically, using a combination of inductive and deductive analysis. For think aloud data, a sociotechnical model was used as a framework for thematic analysis. RESULTS: Focus group participants (n=8) felt that some users could become anxious when shown their future complications risks. They highlighted the importance of easy navigation, jargon avoidance, and the use of positive/encouraging language. User testing of the prototype site through think aloud sessions (n=7) highlighted several usability issues. Issues included confusing visual cues and confusion over whether user-updated information fed back to health care teams. Some issues could be compounded for users with limited digital skills. Results from the focus groups and think aloud workshops were used in the development of a live MDIQ platform. CONCLUSIONS: Acting on the input of end users at each iterative stage of a digital tool's development can help to prioritize users throughout the design process, ensuring the alignment of DHI features with user needs. The use of the sociotechnical framework encouraged the consideration of interactions between different sociotechnical dimensions in finding solutions to issues, for example, avoiding the exclusion of users with limited digital skills. Based on user feedback, the tool could scaffold good goal setting, allowing users to balance their palatable future complications risk against acceptable lifestyle changes. Optimal control of diabetes relies heavily on self-management. Tools such as MDMW/ MDIQ can offer personalized support for self-management alongside access to users' electronic health records, potentially helping to delay or reduce long-term complications, thereby providing significant reductions in health care costs.

Digital Interventions Supporting Self-care in People With Type 2 Diabetes Across Greater Manchester (Greater Manchester Diabetes My Way): Protocol for a Mixed Methods Evaluation.

BACKGROUND: Type 2 Diabetes (T2D) is common, with a prevalence of approximately 7% of the population in the United Kingdom. The quality of T2D care is inconsistent across the United Kingdom, and Greater Manchester (GM) does not currently achieve the National Institute for Health and Care Excellence treatment targets. Barriers to delivery of care include low attendance and poor engagement with local T2D interventions, which tend to consist of programs of education delivered in traditional, face-to-face clinical settings. Thus, a flexible approach to T2D management that is accessible to people from different backgrounds and communities is needed. Diabetes My Way (DMW) is a digital platform that offers a comprehensive self-management and educational program that should be accessible to a wide range of people through mobile apps and websites. Building on evidence generated by a Scotland-wide pilot study, DMW is being rolled out and tested across GM. OBJECTIVE: The overarching objectives are to assess whether DMW improves outcomes for patients with T2D in the GM area, to explore the acceptability of the DMW intervention to stakeholders, and to assess the cost-effectiveness of the intervention. METHODS: A mixed methods approach will be used. We will take a census approach to recruitment in that all eligible participants in GM will be invited to participate. The primary outcomes will be intervention-related changes compared with changes observed in a matched group of controls, and the secondary outcomes will be within-person intervention-related changes. The cost-effectiveness analysis will focus on obtaining reliable estimates of how each intervention affects risk factors such as HbA1c and costs across population groups. Qualitative data will be collected via semistructured interviews and focus groups and organized using template analysis. RESULTS: As of May 10, 2021, a total of 316 participants have been recruited for the quantitative study and have successfully enrolled. A total of 278 participants attempted to register but did not have appropriate permissions set by the general practitioners to gain access to their data. In total, 10 participants have been recruited for the qualitative study (7 practitioners and 3 patients). An extension to recruitment has been granted for the quantitative element of the research, and analysis should be complete by December 2022. Recruitment and analysis for the qualitative study should be complete by December 2021. CONCLUSIONS: The findings from this study can be used both to develop the DMW system and improve accessibility and usability in more deprived populations generally, thus improving equity in access to support for T2D self-management. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/26237.

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.

Massive open online course for type 2 diabetes self-management: adapting education in the COVID-19 era.

Introduction: Type 2 diabetes self-management education is an essential component of type 2 diabetes care that is traditionally delivered in a face-to-face setting. In response to the recent COVID-19 pandemic, innovative solutions are urgently needed, allowing provision of self-management education that can be delivered in compliance with social distancing policies. Innovations that are self-service and can deliver education efficiently at low cost are particularly appealing to healthcare providers and commissioners. Methods: We aimed to evaluate user uptake, dropout, acceptability, satisfaction, perceived short-term knowledge gain and health benefits/behaviour changes in relation to a free massive open online course (MOOC) in diabetes self-management education, created and delivered during the COVID-19 pandemic. This course, focusing on addressing knowledge and self-management needs for people with type 2 diabetes, made use of online interactive content including expert and patient videos, quizzes, moderated discussion boards and live social media that encouraged personal reflection and goal setting. User expectations and experiences were explored via survey-based methods. Here, we present our experience of developing the course and describe users' experiences. Results: 1991 users registered interest in the course over a 2-week period, with 976 users starting the course and 640 (65.6%) users completing the course in full. Users engaged well, finding the course educational, user-friendly and motivating, demonstrating high completion rates and user satisfaction. A statistically significant (p<0.001) increase in self-reported self-management ability and health knowledge was observed among participants with type 2 diabetes. Discussion: MOOCs in type 2 diabetes self-management education have great potential for delivering education efficiently at scale and low cost. Although engagement can be limited by digital literacy, benefits include flexible and remote access to up-to-date, evidence-based education delivered by a multidisciplinary team of healthcare professionals.

ENDOCRINOLOGY IN THE TIME OF COVID-19: Remodelling diabetes services and emerging innovation.

The COVID-19 pandemic is a major international emergency leading to unprecedented medical, economic and societal challenges. Countries around the globe are facing challenges with diabetes care and are similarly adapting care delivery, with local cultural nuances. People with diabetes suffer disproportionately from acute COVID-19 with higher rates of serious complications and death. In-patient services need specialist support to appropriately manage glycaemia in people with known and undiagnosed diabetes presenting with COVID-19. Due to the restrictions imposed by the pandemic, people with diabetes may suffer longer-term harm caused by inadequate clinical support and less frequent monitoring of their condition and diabetes-related complications. Outpatient management need to be reorganised to maintain remote advice and support services, focusing on proactive care for the highest risk, and using telehealth and digital services for consultations, self-management and remote monitoring, where appropriate. Stratification of patients for face-to-face or remote follow-up should be based on a balanced risk assessment. Public health and national organisations have generally responded rapidly with guidance on care management, but the pandemic has created a tension around prioritisation of communicable vs non-communicable disease. Resulting challenges in clinical decision-making are compounded by a reduced clinical workforce. For many years, increasing diabetes mellitus incidence has been mirrored by rising preventable morbidity and mortality due to complications, yet innovation in service delivery has been slow. While the current focus is on limiting the terrible harm caused by the pandemic, it is possible that a positive lasting legacy of COVID-19 might include accelerated innovation in chronic disease management.

Decision Support for Diabetes in Scotland: Implementation and Evaluation of a Clinical Decision Support System.

BACKGROUND: Automated clinical decision support systems (CDSS) are associated with improvements in health care delivery to those with long-term conditions, including diabetes. A CDSS was introduced to two Scottish regions (combined diabetes population ~30 000) via a national diabetes electronic health record. This study aims to describe users' reactions to the CDSS and to quantify impact on clinical processes and outcomes over two improvement cycles: December 2013 to February 2014 and August 2014 to November 2014. METHODS: Feedback was sought via patient questionnaires, health care professional (HCP) focus groups, and questionnaires. Multivariable regression was used to analyze HCP SCI-Diabetes usage (with respect to CDSS message presence/absence) and case-control comparison of clinical processes/outcomes. Cases were patients whose HCP received a CDSS messages during the study period. Closely matched controls were selected from regions outside the study, following similar clinical practice (without CDSS). Clinical process measures were screening rates for diabetes-related complications. Clinical outcomes included HbA1c at 1 year. RESULTS: The CDSS had no adverse impact on consultations. HCPs were generally positive toward CDSS and used it within normal clinical workflow. CDSS messages were generated for 5692 cases, matched to 10 667 controls. Following clinic, the probability of patients being appropriately screened for complications more than doubled for most measures. Mean HbA1c improved in cases and controls but more so in cases (-2.3 mmol/mol [-0.2%] versus -1.1 [-0.1%], P = .003). DISCUSSION AND CONCLUSIONS: The CDSS was well received; associated with improved efficiencies in working practices; and large improvements in guideline adherence. These evidence-based, early interventions can significantly reduce costly and devastating complications.

Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men.

CONTEXT: Dietary macronutrient composition influences cardiometabolic health independently of obesity. Both dietary fat and insulin alter glucocorticoid metabolism in rodents and, acutely, in humans. However, whether longer-term differences in dietary macronutrients affect cortisol metabolism in humans and contribute to the tissue-specific dysregulation of cortisol metabolism in obesity is unknown. OBJECTIVE: The objective of the study was to test the effects of dietary macronutrients on cortisol metabolism in obese men. DESIGN: The study consisted of two randomized, crossover studies. SETTING: The study was conducted at a human nutrition unit. PARTICIPANTS: Participants included healthy obese men. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: Seventeen obese men received 4 wk ad libitum high fat-low carbohydrate (HF-LC) (66% fat, 4% carbohydrate) vs. moderate fat-moderate carbohydrate (MF-MC) diets (35% fat, 35% carbohydrate). Six obese men participated in a similar study with isocaloric feeding. Both HF-LC and MF-MC diets induced weight loss. During 9,11,12,12-[(2)H](4)-cortisol infusion, HF-LC but not MF-MC increased 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity (rates of appearance of cortisol and 9,12,12-[(2)H](3)-cortisol) and reduced urinary excretion of 5alpha- and 5beta-reduced [(2)H](4)-cortisol metabolites and [(2)H](4)-cortisol clearance. HF-LC also reduced 24-h urinary 5alpha- and 5beta-reduced endogenous cortisol metabolites but did not alter plasma cortisol or diurnal salivary cortisol rhythm. In sc abdominal adipose tissue, 11beta-HSD1 mRNA and activity were unaffected by diet. CONCLUSIONS: A low-carbohydrate diet alters cortisol metabolism independently of weight loss. In obese men, this enhances cortisol regeneration by 11beta-HSD1 and reduces cortisol inactivation by A-ring reductases in liver without affecting sc adipose 11beta-HSD1. Alterations in cortisol metabolism may be a consequence of macronutrient dietary content and may mediate effects of diet on metabolic health.

Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.

CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. OBJECTIVE: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. DESIGN AND SETTING: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. PATIENTS AND PARTICIPANTS: Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. CONCLUSIONS: Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.

Acute in vivo regulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans.

CONTEXT: Extraadrenal regeneration of cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1) is increased after a mixed meal. It is unknown which tissue is responsible and whether this reflects the complex transcriptional control of 11HSD1 or posttranscriptional control exerted by supply of reduced nicotinamide adenine dinucleotide phosphate from hexose-6-phosphate dehydrogenase. OBJECTIVE: The objective of this study was to test whether hyperinsulinemia and/or increased serum free fatty acids increase whole-body and intraadipose 11HSD1, and whether adipose 11HSD1 switches from dehydrogenase to reductase activity. METHODS: In nine healthy men, we measured whole-body cortisol regeneration (by iv infusion of 9,11,12,12-[2H]4 -cortisol) and intra-adipose interconversion of cortisol and cortisone (by sc microdialysis infusion of [3H]4 -cortisol and [3H]2 -cortisone in separate cannulae) during: 1) a hyperinsulinemic euglycemic clamp; 2) iv lipid infusion (Intralipid 20% fat emulsion); and 3) saline infusion, each for 3.5 h. RESULTS: Hyperinsulinemia increased rate of appearance of 9,12,12-[2H]3 -cortisol (19.3 +/- 0.8 vs. 16.7 +/- 1.1 nmol/min with saline, P < 0.001), indicating increased whole-body 11HSD1. Within adipose, the predominant reaction was reductase conversion of cortisone to cortisol (after 3.5 h of saline infusion, reaching 11.0 +/- 2.7% per hour reductase vs. 5.2 +/- 1.3 dehydrogenase, P < 0.02); insulin increased reductase (reaching 15.8 +/- 3.0, P < 0.05) and tended to increase dehydrogenase activity. Intralipid infusion had no effects on whole-body deuterated cortisol metabolism, but increased both dehydrogenase and reductase (reaching 16.7 +/- 1.8, P < 0.01) activities in adipose. CONCLUSIONS: Hyperinsulinemia and increased free fatty acids induce acute increases in 11HSD1 activity in adipose tissue that are not attributable to a switch from dehydrogenase to reductase. Hyperinsulinemia also increases systemic cortisol regeneration. These effects may enhance intracellular cortisol concentrations after a meal.

MyDiabetesMyWay: An Evolving National Data Driven Diabetes Self-Management Platform.

MyDiabetesMyWay (MDMW) is an award-wining national electronic personal health record and self-management platform for diabetes patients in Scotland. This platform links multiple national institutional and patient-recorded data sources to provide a unique resource for patient care and self-management. This review considers the current evidence for online interventions in diabetes and discusses these in the context of current and ongoing developments for MDMW. Evaluation of MDMW through patient reported outcomes demonstrates a positive impact on self-management. User feedback has highlighted barriers to uptake and has guided platform evolution from an education resource website to an electronic personal health record now encompassing remote monitoring, communication tools and personalized education links. Challenges in delivering digital interventions for long-term conditions include integration of data between institutional and personal recorded sources to perform big data analytics and facilitating technology use in those with disabilities, low digital literacy, low socioeconomic status and in minority groups. The potential for technology supported health improvement is great, but awareness and adoption by health workers and patients remains a significant barrier.

Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians.

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.

Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver.

In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.

11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.

11 beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing's syndrome. Transgenic mice over-expressing 11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected from these metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has been achieved in liver with carbenoxolone, which enhances hepatic insulin sensitivity. Newer selective 11HSD1 inhibitors are in development, which may achieve reduced cortisol action in adipose tissue and confer therapeutic benefit in obese patients.