Low physical activity is associated with impaired endothelial function in patients with type 2 diabetes and controls after 5 years of follow-up.

BACKGROUND: The long-term association between physical activity and endothelial function has not previously been investigated in patients with type 2 diabetes. Therefore, we aimed to evaluate the relationship between physical activity and endothelial function, assessed by peripheral arterial tonometry, in patients with type 2 diabetes and non-diabetic controls after 5 years of follow-up. METHODS: We included 51 patients with newly diagnosed type 2 diabetes and 53 sex- and age matched controls. Participants underwent baseline clinical characterization including objective measurement of physical activity level using accelerometery. After 5 years of follow-up, participants were re-examined, and endothelial function was assessed as natural logarithm of reactive hyperemia index (lnRHI). RESULTS: Physical activity at baseline was associated with lnRHI after 5 years of follow-up in both patients with type 2 diabetes and controls. An increase of 1 standard deviation (SD) in daytime physical activity corresponded to a 6.7 % increase in RHI (95 % confidence interval: 1.1;12.5 %, p = 0.02). We found no difference in lnRHI between patients with diabetes and controls (0.67 ± 0.29 vs. 0.73 ± 0.31, p = 0.28). CONCLUSIONS: Daytime physical activity is associated with endothelial function after 5 years of follow-up in patients with type 2 diabetes and controls.

Cardiovascular risk in patients with and without diabetes presenting with chronic coronary syndrome in 2004-2016.

BACKGROUND: It was recently shown that new-onset diabetes patients without previous cardiovascular disease have experienced a markedly reduced risk of adverse cardiovascular events from 1996 to 2011. However, it remains unknown if similar improvements are present following the diagnosis of chronic coronary syndrome. The purpose of this study was to examine the change in cardiovascular risk among diabetes patients with chronic coronary syndrome from 2004 to 2016. METHODS: We included patients with documentation of coronary artery disease by coronary angiography between 2004 and 2016 in Western Denmark. Patients were stratified by year of index coronary angiography (2004-2006, 2007-2009, 2010-2012, and 2013-2016) and followed for two years. The main outcome was major adverse cardiovascular events (MACE) defined as myocardial infarction, ischemic stroke, or death. Analyses were performed separately in patients with and without diabetes. We estimated two-year risk of each outcome and adjusted incidence rate ratios (aIRR) using patients examined in 2004-2006 as reference. RESULTS: Among 5931 patients with diabetes, two-year MACE risks were 8.4% in 2004-2006, 8.5% in 2007-2009, and then decreased to 6.2% in 2010-2012 and 6.7% in 2013-2016 (2013-2016 vs 2004-2006: aIRR 0.70, 95% CI 0.53-0.93). In comparison, 23,540 patients without diabetes had event rates of 6.3%, 5.2%, 4.2%, and 3.9% for the study intervals (2013-2016 vs 2004-2006: aIRR 0.57, 95% CI 0.48-0.68). CONCLUSIONS: Between 2004 and 2016, the two-year relative risk of MACE decreased by 30% in patients with diabetes and chronic coronary syndrome, but slightly larger absolute and relative reductions were observed in patients without diabetes.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

The effect of renal denervation on arterial stiffness, central blood pressure and heart rate variability in treatment resistant essential hypertension: a substudy of a randomized sham-controlled double-blinded trial (the ReSET trial).

OBJECTIVES: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension. METHODS: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity FlexTM catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor®-device. RESULTS: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. -0.6 ± 1.3 (RDN) m/s), systolic C-BP (-2 ± 17 (SHAM) vs. -8 ± 16 (RDN) mmHg), diastolic C-BP (-2 ± 9 (SHAM) vs. -5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN. CONCLUSIONS: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

Improvement of mild retinopathy in type 2 diabetic patients correlates with narrowing of retinal arterioles. A prospective observational study.

PURPOSE: Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies. METHODS: Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were re-examined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened. RESULTS: At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy. CONCLUSIONS: The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy.

Feasibility of Arteriograph 24 for evaluation of 24-hour pulse wave velocity and central blood pressure in patients with type 2 diabetes and non-diabetic controls.

The objective of this study was to assess the feasibility of the Arteriograph 24 device to measure 24-hour PWV and central systolic blood pressure (cSBP) in patients with type 2 diabetes (T2DM) and non-diabetic controls and compare daytime and nighttime characteristics in the two groups. Twenty-four-hour PWV and cSBP was measured in 58 patients with T2DM (mean age: 66 ±â€…9 years, 50% women, mean duration of T2DM: 7.8 ±â€…1.5 years) and 62 age- and sex-matched controls. Seventy percent of participants (71% T2DM patients and 69% controls) had sufficient readings to generate an acceptable 24-hour report (≥14 day and ≥7 night readings). Lower nocturnal than daytime PWV and cSBP were observed in both groups. Nocturnal PWV and cSBP dipping were attenuated in T2DM patients compared to controls (PWV: -0.3 ±â€…0.9 vs. -0.7 ±â€…0.9 m/s, P  = 0.04, cSBP: -8 ±â€…14 vs. -18 ±â€…18 mmHg, P  < 0.01). No group differences in PWV or cSBP were observed during daytime (T2D vs. controls, PWV: 9.2 ±â€…1.1 vs. 9.2 ±â€…1.3 m/s, P  = 0.99, cSBP: 133 ±â€…19 vs. 137 ±â€…25 mmHg, P  = 0.42) or nighttime (PWV: 8.9 ±â€…1.3 vs. 8.4 ±â€…1.3 m/s, P  = 0.14, cSBP 124 ±â€…20 vs. 118 ±â€…27 mmHg, P  = 0.26). The study findings indicate that the nocturnal dipping of PWV and cSBP is attenuated in T2DM patients. The significant number of missing measurements raises concerns regarding the clinical utility of the Arteriograph 24 device.

From Stability to Variability: Classification of Healthy Individuals, Prediabetes, and Type 2 Diabetes Using Glycemic Variability Indices from Continuous Glucose Monitoring Data.

Objective: This study aims to investigate the continuum of glucose control from normoglycemia to dysglycemia (HbA1c ≥ 5.7%/39 mmol/mol) using metrics derived from continuous glucose monitoring (CGM). In addition, we aim to develop a machine learning-based classification model to classify dysglycemia based on observed patterns. Methods: Data from five distinct studies, each featuring at least two days of CGM, were pooled. Participants included individuals classified as healthy, with prediabetes, or with type 2 diabetes mellitus (T2DM). Various CGM indices were extracted and compared across groups. The data set was split 70/30 for training and testing two classification models (XGBoost/Logistic Regression) to differentiate between prediabetes or dysglycemia and the healthy group. Results: The analysis included 836 participants (healthy: n = 282; prediabetes: n = 133; T2DM: n = 432). Across all CGM indices, a progressive shift was observed from the healthy group to those with diabetes (P < 0.001). Statistically significant differences (P < 0.01) were noted in mean glucose, time below range, time above 140 mg/dl, mobility, multiscale complexity index, and glycemic risk index when transitioning from health to prediabetes. The XGBoost models achieved the highest receiver operating characteristic area under the curve values on the test data set ranging from 0.91 [confidence interval (CI): 0.87-0.95] (prediabetes identification) to 0.97 [CI: 0.95-0.98] (dysglycemia identification). Conclusion: Our findings demonstrate a gradual deterioration of glucose homeostasis and increased glycemic variability across the spectrum from normo- to dysglycemia, as evidenced by CGM metrics. The performance of CGM-based indices in classifying healthy individuals and those with prediabetes and diabetes is promising.

Acute hyperinsulinemia increases the contraction of retinal arterioles induced by elevated blood pressure.

Diabetic retinopathy is accompanied by disturbances in retinal blood flow, which is assumed to be related to the diabetic metabolic dysregulation. It has previously been shown that normoinsulinemic hyperglycemia has no effect on the diameter of retinal arterioles at rest and during an increase in the arterial blood pressure induced by isometric exercise. However, the influence of hyperinsulinemia on this response has not been studied in detail. In seven normal persons, the diameter response of retinal arterioles to an increased blood pressure induced by isometric exercise, to stimulation with flickering light, and to the combination of these stimuli was studied during euglycemic normoinsulinemia (protocol N) on one examination day, and euglycemic hyperinsulinemia (protocol H) on another examination day. Isometric exercise induced significant contraction of retinal arterioles at all examinations, but during a repeated examination the diameter response was significantly reduced in the test persons following the N protocol and increased in the persons following the H protocol. Flicker stimulation induced a significant dilatation of retinal arterioles at all examinations, and the response was significantly higher during a repeated examination, irrespective of the insulin level. Repeated exposure to isometric exercise reduces contraction, whereas repeated exposure to flickering light increases dilatation of retinal arterioles in vivo. Hyperinsulinemia increases contraction of retinal arterioles induced by isometric exercise.

Plasma levels of the arterial wall protein fibulin-1 are associated with carotid-femoral pulse wave velocity: a cross-sectional study.

BACKGROUND: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined. METHODS: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses. RESULTS: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 µg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 µg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 µg/mL increase in plasma fibulin-1, p<0.05), but not controls, ß = 0.021 ± 0.057 m/s per 10 µg/mL, p = 0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05. CONCLUSIONS: Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.

Adrenal incidentalomas and effectiveness of patient pathway transformation.

INTRODUCTION: A total of 10% of older individuals harbour adrenal incidentalomas and need dedicated adrenal CT to exclude malignancy and biochemical evaluation. These investigations tax medical resources, and diagnostic delay may cause anxiety for the patient. We implemented a no-need-to-see pathway (NNTS) in which low-risk patients only attend the clinic if adrenal CT or hormonal evaluation is abnormal. METHODS: We investigated the impact of a NNTS pathway on the share of patients not requiring an attendance consultation, time to malignancy and hormonal clarification, and time to end of investigation. We prospectively registered adrenal incidentaloma cases (n = 347) and compared them with historical controls (n = 103). RESULTS: All controls attended the clinic. A total of 63% of cases entered and 84% completed the NNTS pathway without seeing an endocrinologist; 53% of consultations were avoided. Time-to-event analysis revealed a shorter time to clarification of malignancy (28 days; 95% confidence interval (CI): 24-30 days versus 64 days; 95% CI: 47-117 days) and hormonal status (43 days; 95% CI: 38-48 days versus 56 days; 95% CI: 47-68 days) and a shorter time to end of pathway (47 days; 95% CI: 42-55 days versus 112 days; 95% CI: 84-131 days) in cases than controls (p ≤ 0.01). CONCLUSION: We demonstrated that NNTS pathways may be an efficient way of handling the increased burden of incidental radiological findings, avoiding 53% of attendance consultations and achieving a shorter time to end of pathway. FUNDING: Supported by a grant from Regional Hospital Central Denmark, Denmark. The study was approved by the institutional review boards of all participating hospitals. TRIAL REGISTRATION: Not relevant.

[18F]FDOPA PET/CT is superior to [68Ga]DOTATOC PET/CT in diagnostic imaging of pheochromocytoma.

BACKGROUND: Both [18F]FDOPA (FDOPA) and [68Ga]DOTATOC PET/CT (DOTATOC) are widely used for detection of pheochromocytomas/paraganglioma (PPGL). However, direct comparisons of the performance of the two tracers are only available in small series. We conducted a retrospective comparative analysis of FDOPA and DOTATOC to assess their sensitivity and accuracy in detecting PPGL when administered based on suspicion of PPGL. We consecutively included patients referred on suspicion of PPGL or PPGL recurrence who were scanned with both FDOPA and DOTATOC. Both scans were reviewed retrospectively by two experienced observers, who were blinded to the final diagnosis. The assessment was made both visually and quantitatively. The final diagnosis was primarily based on pathology. RESULTS: In total, 113 patients were included (97 suspected of primary PPGL and 16 suspected of recurrence). Of the 97 patients, 51 had pheochromocytomas (PCC) (in total 55 lesions) and 6 had paragangliomas (PGL) (in total 7 lesions). FDOPA detected and correctly localized all 55 PCC, while DOTATOC only detected 25 (sensitivity 100% vs. 49%, p < 0.0001; specificity 95% vs. 98%, p = 1.00). The negative predictive value (100% vs. 63%, p < 0.001) and diagnostic accuracy (98% vs. 70%, p < 0.01) were higher for FDOPA compared to DOTATOC. FDOPA identified 6 of 6 patients with hormone producing PGL, of which one was negative on DOTATOC. Diagnostic performances of FDOPA and DOTATOC were similar in the 16 patients with previous PPGL suspected of recurrence. CONCLUSIONS: FDOPA is superior to DOTATOC for localization of PCC. In contrast to DOTATOC, FDOPA also identified all PGL but with a limited number of patient cases.

Obstructive sleep apnea, coronary calcification and arterial stiffness in patients with diabetic kidney disease.

BACKGROUND AND AIMS: Obstructive sleep apnea (OSA) may accelerate arterial calcification, but the relation remains unexplored in diabetic kidney disease (DKD). We examined the associations between OSA, coronary calcification and large artery stiffness in patients with DKD and reduced renal function. METHODS: Patients with type 2 diabetes, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 and urine albumin-creatinine ratio (UACR) > 30 mg/g were tested for OSA quantified by the apnea-hypopnea index (AHI, events/hour). Patients without OSA (AHI< 5) were compared to patients with moderate (AHI 15-29) or severe (AHI ≥30) OSA and underwent computed tomography angiography with coronary Agatston scoring (CAS) to quantify coronary calcification. Arterial stiffness was determined as carotid-femoral pulse wave velocity (PWV). RESULTS: Among 114 patients with acceptable AHI recordings had 43 no OSA, 33 mild OSA and 38 moderate-severe OSA. Mean age of the 74 patients completing the study was 71.5 ± 9.4 years (73% males), eGFR 32.2 ± 12.3 ml/min/1.73 m2 and UACR 533 (192-1707) mg/g. CAS (ln-transformed) was significantly higher in patients with OSA compared to patients without (6.6 ± 1.7 vs. 5.6 ± 2.4, p = 0.04), and the same was observed for PWV (11.9 ± 2.7 vs. 10.5 ± 2.2 m/s, p = 0.02). In multivariable linear regression analyses adjusted for sex, age, body mass index, UACR, and mean arterial pressure, moderate-severe OSA remained significantly associated with PWV but not with CAS. Dominance analysis revealed OSA as the third and second most important factor relative to CAS and PWV respectively. CONCLUSIONS: In DKD patients, moderate-severe OSA is a significant predictor of arterial stiffness but is not independently associated with coronary calcification.

Effects of semaglutide and empagliflozin on oxygenation, vascular autoregulation, and central thickness of the retina in people with type 2 diabetes: A prespecified secondary analysis of a randomised clinical trial.

AIMS: Semaglutide and empagliflozin have shown cardiovascular protection. In SUSTAIN-6, semaglutide was associated with an increased risk of diabetic retinopathy. We investigated whether changes in retinal oxygenation, retinal vascular autoregulation, and central retinal thickness are altered by semaglutide, empagliflozin or the combination. METHODS: This study was a prespecified, secondary outcome from a randomised, 32 weeks partly placebo-controlled, partly open-label, clinical trial on the effects of semaglutide and empagliflozin on arterial stiffness and kidney oxygenation. A total of 120 participants with type 2 diabetes, established or high risk of cardiovascular disease and age ≥50 years were randomised into four parallel groups (semaglutide, empagliflozin, the combination or tablet placebo, n = 30 for each group). We primarily hypothesized that semaglutide would increase venular oxygenation. RESULTS: We found no changes in retinal arteriolar, venular or venular-arteriolar oxygenation nor in retinal vessel diameter regardless of treatment group. Semaglutide increased central retinal thickness compared to placebo with ~1 % (3.8 µm 95 % CI [0.9;6.7], p = 0.009) with no changes in the empagliflozin or combination group. CONCLUSION: Neither semaglutide, empagliflozin nor the combination alters markers of retinal function. The effect of semaglutide on central retinal thickness was small, but the clinical significance is uncertain.

Hypokalemic Paresis in a 26-Year-Old Man After Recreational Cannabis Use.

BACKGROUND Hypokalemia (serum potassium level below 3.5 mmol/L) is present in approximately 11% of patients admitted to emergency departments. Hypokalemia can be a manifestation of many underlying causes and if untreated can be fatal. A careful approach to work-up and management is required in hypokalemic patients. CASE REPORT Here we report a 26-year-old previously healthy male patient who was admitted to the Emergency Department with rapidly progressing paresis of the lower and upper extremities. Initial laboratory results revealed severe hypokalemia of 2.1 mmol/l, which aggravated to 1.6 mmol/l before receiving treatment with intravenous potassium chloride supplementation. In addition, the patient developed rhabdomyolysis secondary to prolonged paralysis and immobilization induced by hypokalemia. Following this treatment, the patient's symptoms eased rapidly, and his potassium concentration was normalized. The patient admitted to smoking cannabis the day before admission. In this case report, we systematically elaborate and exclude the causes of hypokalemia in this otherwise healthy young adult, including medication, gastrointestinal symptoms, licorice consumption, and genetical testing. Cannabis has been associated with hypokalemia, proposedly through activation of the cannabinoid receptor 1 (CB1)-mediated activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. CONCLUSIONS This case report emphasizes that hypokalemia can cause paralysis and cannabis should be included in the diagnostic mindset.

The Socioeconomic Consequences of Cushing's Syndrome: A Nationwide Cohort Study.

CONTEXT: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown. OBJECTIVE: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery. DESIGN: Nationwide register-based cohort study. METHODS: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression. RESULTS: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression. CONCLUSION: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess.

Outcome and prognosis after adrenal metastasectomy: nationwide study.

BACKGROUND: Data regarding adrenal metastasectomy are limited. Here, clinical outcomes, safety, and prognostic factors in patients undergoing adrenal metastasectomy were evaluated in a large nationwide study. METHODS: Patients undergoing adrenal metastasectomy between 2000 and 2018 were identified in the Danish National Pathology Registry. Medical records were reviewed to confirm eligibility and to collect clinical data. The primary outcome was overall survival (OS). Cox multivariable regression analyses were? adjusted for baseline factors. RESULTS: In total, 435 patients underwent adrenal metastasectomy; the primary cancer origins were renal (n = 195, 45 per cent), lung (n = 121, 28 per cent), colorectal (n = 50, 11 per cent), and other (n = 69, 16 per cent). The median (interquartile range; i.q.r.) age was 66 (59-71) years, and 280 (64 per cent) were men. The 5-year OS was 31 per cent. The 30-day mortality was 1.8 per cent. Complications were more frequent and severe in patients who underwent open surgery compared with laparoscopic surgery (Clavien-Dindo III-V, 31.5 per cent versus 11.8 per cent respectively, P < 0.001). Factors associated with poor survival included non-radical pR2 resection (hazard ratio (HR) 3.57, 95 per cent c.i. 1.96 to 6.48), tumour size more than 50 mm (HR 1.79, 95 per cent c.i. 1.26 to 2.52), lung cancer origin (HR 1.77, 95 per cent c.i. 1.31 to 2.40), open surgical approach (HR 1.33, 95 per cent c.i. 1.04 to 1.71), presence of extra-adrenal metastases (HR 1.31, 95 per cent c.i. 1.01 to 1.71), and increasing Charlson co-morbidity index factors (HR 1.14 per one-point increase, 95 per cent c.i. 1.03 to 1.27). CONCLUSION: Adrenal metastasectomy is safe and may result in long-term survival in a subset of patients. Non-radical resection, large tumour size, lung cancer origin, open approach, presence of extra-adrenal metastases, and co-morbidity were associated with inferior outcomes.

Glucose variability and low bone turnover in people with type 2 diabetes.

INTRODUCTION: Type 2 diabetes (T2D) is related to an increased fracture risk and low bone turnover. However, the mechanisms are not elucidated. In the present study we investigate the association between glycemic variability and bone turnover markers. METHODS: 100 participants with T2D and 100 age and gender matched controls were included in this cross-sectional study. All participants with T2D were equipped with a continuous glucose monitoring (CGM) sensor for 3 days (CGMS iPro Continuous Glucose Recorder; Medtronic MiniMed). The dawn glucose levels were defined as a morning period starting 1 h before breakfast ending 1 h post ingestion. On all participants serum (s)-C-terminal cross-linked telopeptide of type-I collagen (CTX), s-procollagen type 1 amino terminal propeptide (P1NP), and s-sclerostin were measured. RESULTS: Participants with T2D displayed significantly lower levels of the bone resorption marker s-CTX and the bone formation marker s-P1NP compared to controls. S-CTX was significantly negatively associated with the mean amplitude of glycemic excursions (MAGE) and the dawn glucose levels whereas s-P1NP only was significantly negatively associated with the dawn glucose levels while it was borderline significantly associated with MAGE (p = 0.05). S-CTX and s-P1NP were significantly lower among the 50% with the highest dawn glucose levels compared to the 50% lowest dawn glucose levels also after adjustment for age, gender, glycated hemoglobin A1c (HbA1c), and body mass index (BMI). CONCLUSION: We observed that the amplitude of glycemic excursions and rise in dawn glucose was negatively associated with bone turnover markers. Future research is needed to determine whether reduction of the amplitude of glycemic excursions increase bone turnover markers.

Effect of 12-week continuous positive airway pressure therapy on glucose levels assessed by continuous glucose monitoring in people with type 2 diabetes and obstructive sleep apnoea; a randomized controlled trial.

Aim: Obstructive sleep apnoea (OSA) is frequent in type 2 diabetes (T2D). The aim was to investigate the effect of a 12-week treatment with continuous positive airway pressure (CPAP) on glycaemic control assessed by continuous glucose monitoring (CGM), HbA1c and fasting blood glucose in patients with T2D and newly detected OSA. Methods: In a randomized controlled multicentre study, 72 participants with T2D and moderate to severe OSA (78% male, age 62 ± 7, AHI 35 ± 15) were recruited from outpatient clinics in three Danish hospitals and were randomized to CPAP intervention or control. The main outcome was glycaemic control assessed by 6 days CGM at baseline and after 12-week therapy, as well as by HbA1c and fasting blood glucose. Results: No significant changes were found in average glucose levels, time in glucose range, time with hypoglycaemia, time with hyperglycaemia or coefficient of variability. HbA1c decreased 0.7 mmol/mol (0.07%; P = .8) in the CPAP group and increased 0.8 mmol/mol (0.08%; P = .6) in the control group (intergroup difference, P = .6). Fasting blood glucose increased by 0.2 mmol/L (P = .02) in the CPAP group and by 0.4 mmol/L (P = .01) in the control group (intergroup difference, P = .7). In a prespecified subgroup analysis comparing participants with high adherence (minimum usage of four hours/night for 70% of all nights) to CPAP to the control group, no significant changes were observed either, although these participants had a tendency towards better glycaemic indices. Conclusions: CPAP treatment for 12 weeks does not significantly change glycaemic control in patients with type 2 diabetes and OSA.

Incidence and Clinical Presentation of Pheochromocytoma and Sympathetic Paraganglioma: A Population-based Study.

CONTEXT: Pheochromocytoma and sympathetic paraganglioma (PPGL) are rare catecholamine-secreting tumors but recent studies suggest increasing incidence. Traditionally, PPGL are described to present with paroxysmal symptoms and hypertension, but existing data on clinical presentation of PPGL come from referral centers. OBJECTIVE: We aimed to describe time trends in clinical presentation and incidence of PPGL in a population-based study. METHODS: We conducted a nationwide retrospective cohort study of a previously validated cohort of 567 patients diagnosed with PPGL in Denmark 1977-2015. We collected clinical data from medical records of a geographic subcohort of 192 patients. We calculated age-standardized incidence rates (SIRs) and prevalence for the nationwide cohort and descriptive statistics on presentation for the subset with clinical data. RESULTS: SIRs increased from 1.4 (95% CI 0.2-2.5) per million person-years in 1977 to 6.6 (95% CI 4.4-8.7) per million person-years in 2015, corresponding to a 4.8-fold increase. The increase was mainly due to incidentally found tumors that were less than 4 cm and diagnosed in patients older than 50 years with no or limited paroxysmal symptoms of catecholamine excess. On December 31, 2015, prevalence of PPGL was 64.4 (CI 95% 57.7-71.2) per million inhabitants. Of 192 patients with clinical data, 171 (89.1%) had unilateral pheochromocytoma, while unilateral paraganglioma (n = 13, 6.8%) and multifocal PPGL (n = 8, 4.2%) were rare. CONCLUSION: Incidence of PPGL has increased 4.8-fold from 1977 to 2015 due to a "new" group of older patients presenting with smaller incidentally found PPGL tumors and few or no paroxysmal symptoms.