Context: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size.Objective: Our objective was to establish the health status of adults with CAH.Design and Setting: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom.Patients: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18–69) years.Main Outcome Measures: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts.Results: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.Conclusions: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.

Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem/progenitor cells from which it arises. While increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are 6 visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric and it is a subject of much debate whether these have common developmental origins and whether this differs from subcutaneous WAT. Here we show that all 6 visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue (BAT) arises from Wt1 expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1 expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated and provide several lines of evidence that Wt1 expressing mesothelium can produce adipocytes. These results: reveal a major ontogenetic difference between visceral and subcutaneous WAT; pinpoint the lateral plate mesoderm as a major source of visceral WAT; support the notion that visceral WAT progenitors are heterogeneous; and suggest that mesothelium is a source of adipocytes.

SummaryThe discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased 18fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C–17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health.

OBJECTIVE-11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) regenerates cortisol from cortisone. 11␤-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11␤-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11␤-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo. (13.5 [3.6 -23.5] and 8.0 [2.6 -13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected. RESEARCH DESIGN AND METHODS-SixCONCLUSIONS-Cortisol is released from subcutaneous adipose tissue by 11␤-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11␤-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling. Diabetes 58:46-53, 2009

Aims/hypothesis Minimal evidence supports the efficacy of flash monitoring in lowering HbA 1c . We sought to assess the impact of introducing flash monitoring in our centre. Methods We undertook a prospective observational study to assess change in HbA 1c in 900 individuals with type 1 diabetes following flash monitoring (comparator group of 518 with no flash monitoring). Secondary outcomes included changes in hypoglycaemia, quality of life, flash monitoring data and hospital admissions. Results Those with baseline HbA 1c ≥58 mmol/mol (7.5%) achieved a median −7 mmol/mol (interquartile range [IQR] −13 to −1) (0.6% [−1.2 to −0.1]%) change in HbA 1c ( p < 0.001). The percentage achieving HbA 1c <58 mmol/mol rose from 34.2% to 50.9% ( p < 0.001). Median follow-up was 245 days (IQR 182 to 330). Individuals not using flash monitoring experienced no change in HbA 1c across a similar timescale ( p = 0.508). Higher HbA 1c ( p < 0.001), younger age at diagnosis ( p = 0.003) and lower social deprivation ( p = 0.024) were independently associated with an HbA 1c fall of ≥5 mmol/mol (0.5%). More symptomatic (OR 1.9, p < 0.001) and asymptomatic (OR 1.4, p < 0.001) hypoglycaemia was reported after flash monitoring. Following flash monitoring, regimen-related and emotional components of the diabetes distress scale improved although the proportion with elevated anxiety (OR 1.2, p = 0.028) and depression (OR 2.0, p < 0.001) scores increased. Blood glucose test strip use fell from 3.8 to 0.6 per day ( p < 0.001). Diabetic ketoacidosis admissions fell significantly following flash monitoring ( p = 0.043). Conclusions/interpretation Flash monitoring is associated with significant improvements in HbA 1c and fewer diabetic ketoacidosis admissions. Higher rates of hypoglycaemia may relate to greater recognition of hitherto unrecognised events. Impact upon quality of life parameters was mixed but overall treatment satisfaction was overwhelmingly positive. Electronic supplementary material The online version of this article (10.1007/s00125-019-4894-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

SummaryCurrent understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18 F-fluorodeoxyglucose. This revealed that BMAT resists insulin-and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.

The Freestyle Libre flash glucose monitoring (FGM; Abbott Diabetes Care, Witney, UK) system was introduced in the United Kingdom in 2013. Although similar to conventional continuous glucose monitoring (CGM) systems, a few significant differences exist. FGM sensors are factory calibrated and therefore do not require calibration with blood glucose testing over their 14-day lifespan. FGM is also considerably cheaper than conventional CGM 1 but lacks alarm features and connectivity with continuous subcutaneous insulin infusion (CSII) devices, such as low-glucose suspend.2 The accuracy and usability of FGM have been validated in patients with both type 1 and type 2 diabetes. 3 We sought to prospectively assess the impact of introducing FGM to patients attending our type 1 diabetes clinic in a university teaching hospital, over a 16-week period. In particular, we assessed the impact on HbA1c, hypoglycemia (recorded and self-reported) and quality of life measures (Diabetes Distress Scale). The only inclusion criteria were a diagnosis of type 1 diabetes and a willingness to upload FGM data at least monthly. Data were analyzed as intention-to-treat.Of the 25 participants, 13 were men, and the mean age was 39.8 ± 2.0 years. Mean duration of diabetes was 19 ± 2 years. A total of 8 patients were treated with CSII, and 17 used multiple daily injections. Immediately prior to commencement of FGM, the mean HbA1c of participants was 8.0 ± 0.14%, which did not differ from the mean of the previous 4 clinic recorded HbA1c values (8.0 ± 0.2%, P = .833). Mean HbA1c fell from 8.0 ± 0.14% to 7.5 ± 0.14% (-0.48%, P = .001) following 16 weeks of FGM. The number of people with an HbA1c of 7.5% or below more than doubled after FGM use (Figure 1). The mean reduction in HbA1c was greater in those with a baseline HbA1c > 7.5%: -0.59 ± 0.15% compared to −0.2 ± 0.11% in those with HbA1c <7.5% at baseline (P = .005). Female participants had greater mean reduction in HbA1c (-0.74 ± 0.19%) compared to men (-0.23 ± 0.15%, P = .049) despite no significant difference in baseline HbA1c (8.2 ± 0.25% vs 7.8 ± 0.14%, P = .174). Of participants, 24% (6/25) achieved an HbA1c reduction of greater than 1.0%.Episodes of hypoglycemia (glucose <72 mg/dl), as determined from FGM glucose data, reduced from 17 in the first 2 weeks of use to 12 (IQR 8.5-16) in the final 2 weeks (P = .019). Significant reductions were observed in the Diabetes Distress Scale mean score (P = .006), as well as emotional burden (P = .035) and regimen-related distress subscores (P = .005). FGM use was associated with a significant increase in delivering bolus insulin 15-20 minutes in advance of meals (compared to immediately before or after meals), from 16% to 44% (P = .026).In summary, these results support the wider use of FGM to improve outcomes in people with type 1 diabetes. Benefits are realized across a number of important domains including improved HbA1c, hypoglycemia, and quality of life. Figure 1. FGM increases the proportion of patients achieving good glycemic control. Data ...