Overall and cause-specific mortality in anorexia nervosa; impact of psychiatric comorbidity and sex in a 40-year follow-up study.

OBJECTIVE: This study investigates the overall and cause-specific mortality in males and females with anorexia nervosa (AN) from 1977 to 2018, focusing on the impact of psychiatric comorbidity on mortality risk, a less explored aspect despite a high prevalence in patients with AN. METHOD: We conducted a nationwide population-based cohort study in Denmark including all patients with AN (n = 14,774) with a median follow-up time of 9.1 years and a 1:10 age- and sex-matched general population comparison cohort. Using Cox proportional hazard model, we calculated adjusted hazard ratios (aHR) for death stratified by psychiatric comorbidity, sex, and age at AN onset and evaluated the causes of death using Fine and Gray sub-distribution hazard ratios (SHR). RESULTS: In patients with AN, the weighted average aHR for all-cause mortality was 4.5 [95% CI 4.1-4.9] with up to 40 years follow-up. Psychiatric comorbidity was present in 47% of patients with AN at index date, which was associated with a 1.9-fold increase in 10-year mortality compared with patients without comorbidity and a notably four-fold increase, when diagnosed at age 6-25 years. The mortality risk was similar according to sex. 13.9% of all deaths in patients with AN were due to suicide (SHR 10.7 [8.1-14.2]). The risk of dying of natural causes was increased with a SHR of 3.8 [95% CI 3.4-4.2]. DISCUSSION: The increased mortality risk in both males and females with AN and psychiatric comorbidity, particularly when diagnosed at young age, underscores the need for comprehensive treatment addressing both AN and coexisting psychiatric conditions. PUBLIC SIGNIFICANCE: The mortality in patients with anorexia nervosa (AN) is high and we show in our study that the mortality is doubled in the presence of psychiatric comorbidity particularly the first 10 years after diagnosis seen in both sexes and with suicide as a major cause of death. These findings stress the importance of detection and treatment of psychiatric comorbidities alongside the eating disorder to prevent fatal outcome.

Glucose metabolism in brown adipose tissue determined by deuterium metabolic imaging in rats.

BACKGROUND/OBJECTIVES: Brown adipose tissue (BAT) has gained growing interest as a potential target for treatment of obesity. Currently, the most widely used technique/method for in vivo measurements of BAT activity in humans is 18FDG PET/CT. To supplement these investigations novel radiation-free methods are warranted. Deuterium metabolic imaging (DMI) is a novel modality that combines magnetic resonance spectroscopic (MRS) imaging with deuterium-labelled glucose (2H-glucose). This allows for spatio-temporal and metabolic imaging beyond glucose uptake. We aimed to evaluate if DMI could discriminate glucose metabolism in BAT of cold-acclimatised and thermoneutral rats. SUBJECTS/METHODS: Male Sprague-Dawley rats were housed in a cold environment (9 °C, n = 10) or at thermoneutrality (30 °C, n = 11) for 1 week. For imaging rats were anaesthetized, received a 2H-glucose (1 M, 1.95 g/kg) bolus and DMI was acquired at baseline followed by 20 min time intervals up to 2 h. Furthermore, Dixon MRI was performed for anatomical determination of the interscapular BAT (iBAT) depot along with dynamic contrast enhanced (DCE) MRI to evaluate perfusion. RESULTS: 2H-glucose signal was higher in cold-acclimatised rats compared with thermoneutral rats (p ≤ 0.001) indicating an overall increase in glucose uptake and metabolism. This was in line with a lower fat/water threshold, higher perfusion and increased UCP1 mRNA expression in iBAT (ninefold increment) of cold-acclimatised rats compared with thermoneutral rats. CONCLUSIONS: We find that DMI can discriminate cold-acclimatised and thermoneutral BAT in rats. This is the first study to evaluate BAT activity by DMI, which may open up for the use of the non-radioactive DMI method for BAT measurements in humans.

Hypoglycaemia and its management in primary care setting.

Hypoglycaemia is common in patients with type 1 diabetes and type 2 diabetes and constitutes a major limiting factor in achieving glycaemic control among people with diabetes. While hypoglycaemia is defined as a blood glucose level under 70 mg/dL (3.9 mmol/L), symptoms may occur at higher blood glucose levels in individuals with poor glycaemic control. Severe hypoglycaemia is defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions to assure neurologic recovery. Hypoglycaemia is the most important safety outcome in clinical studies of glucose lowering agents. The American Diabetes Association Standards of Medical Care recommends that a management protocol for hypoglycaemia should be designed and implemented by every hospital, along with a clear prevention and treatment plan. A tailored approach, using clinical and pathophysiologic disease stratification, can help individualize glycaemic goals and promote new therapies to improve quality of life of patients. Data from recent large clinical trials reported low risk of hypoglycaemic events with the use of newer anti-diabetic drugs. Increased hypoglycaemia risk is observed with the use of insulin and/or sulphonylureas. Vulnerable patients with T2D at dual risk of severe hypoglycaemia and cardiovascular outcomes show features of "frailty." Many of such patients may be better treated by the use of GLP-1 receptor agonists or SGLT2 inhibitors rather than insulin. Continuous glucose monitoring (CGM) should be considered for all individuals with increased risk for hypoglycaemia, impaired hypoglycaemia awareness, frequent nocturnal hypoglycaemia and with history of severe hypoglycaemia. Patients with impaired awareness of hypoglycaemia benefit from real-time CGM. The diabetes educator is an invaluable resource and can devote the time needed to thoroughly educate the individual to reduce the risk of hypoglycaemia and integrate the information within the entire construct of diabetes self-management. Conversations about hypoglycaemia facilitated by a healthcare professional may reduce the burden and fear of hypoglycaemia among patients with diabetes and their family members. Optimizing insulin doses and carbohydrate intake, in addition to a short warm up before or after the physical activity sessions may help avoiding hypoglycaemia. Several therapeutic considerations are important to reduce hypoglycaemia risk during pregnancy including administration of rapid-acting insulin analogues rather than human insulin, pre-conception initiation of insulin analogues, and immediate postpartum insulin dose reduction.

Effect of Roux-en-Y gastric bypass surgery on diabetes remission and complications in individuals with type 2 diabetes: a Danish population-based matched cohort study.

AIMS/HYPOTHESIS: The aim of this study was to examine the effect of Roux-en-Y gastric bypass (RYGB) surgery on diabetes remission, subsequent diabetes relapse and micro- and macrovascular complications in individuals with type 2 diabetes and obesity (BMI >35 kg/m2) in a real-world setting. METHODS: This was a population-based cohort study of 1111 individuals with type 2 diabetes treated by RYGB at hospitals in Northern Denmark (2006-2015), and 1074 matched non-operated individuals with type 2 diabetes. Diabetes remission was defined as no glucose-lowering drug use with HbA1c <48 mmol/mol (<6.5%), or metformin monotherapy with HbA1c <42 mmol/mol (<6.0%). Data on complications were ascertained from medical registries with complete follow-up. RESULTS: At 1 year of follow-up, 74% of the cohort treated by RYGB experienced diabetes remission, while 27% had relapsed after 5 years. Predictors of non-remission were age >50 years, diabetes duration >5 years, use of glucose-lowering drugs other than metformin, and baseline HbA1c >53 mmol/mol (>7.0%). Compared with the non-operated cohort using adjusted Cox regression (5.3 years follow-up), the cohort treated by RYGB had 47% lower risk of microvascular complications (HR 0.53 [95% CI 0.38, 0.73]) and a statistically non-significant 24% lower risk of macrovascular complications (HR 0.76 [95% CI 0.49, 1.18]). Diabetes remission vs non-remission at 1 year was associated with reduced HR of 0.43 (95% CI 0.25, 0.72) for microvascular complications and with HR of 0.76 (95% CI 0.40, 1.45) for macrovascular complications. CONCLUSIONS/INTERPRETATION: In routine clinical care, three out of four individuals with type 2 diabetes and obesity treated by RYGB experienced diabetes remission after 1 year, whereas 27% of these individuals had relapsed at 5 years follow-up. RYGB was associated with substantially decreased risk of microvascular complications and non-significantly fewer macrovascular complications, with early diabetes remission as a clear predictor of reduced microvascular complications.

Correction to: Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort.

The authors have discovered a coding error in the statistical analysis syntax file used for the mixed-effect model analyses in this paper. The error has led to differences (first decimal) in the estimates for the main results.

Rate of Acute Hospital Admissions Before and After Roux-en-Y Gastric Bypass Surgery: A Population-based Cohort Study.

OBJECTIVE: To examine rates of acute inpatient hospital admissions patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and a matched population-based comparison cohort. SUMMARY BACKGROUND DATA: Little is known about the admission rates before and after RYGB. METHODS: Nationwide population-based cohort study, including all 9985 patients undergoing RYGB in Denmark during 2006 to 2010, and 247,375 matched general population comparisons. We calculated cumulative incidence of surgical complications after RYGB and incidence rate ratios (RRs) of hospital admission in RYGB patients versus comparisons before and after RYGB. RESULTS: Admissions for surgical complications occurred in 3.3% (n = 328) of RYGB patients <30 days after surgery and in 23.9% (n = 2367) during entire follow-up (median 4.2 yrs). Fifteen percent (n = 1486) were admitted with abdominal pain, 5.2% (n = 518) with intestinal obstruction during follow-up. Overall admission rates in RYGB patients versus comparisons were 11.5 versus 5.9 per 100 person-years before RYGB [RR = 1.95 (95% confidence interval (CI): 1.89-2.01)], increasing to 24.9 versus 7.1 per 100 person-years after RYGB [RR = 3.38 (95% CI; 3.30, 3.47)]. RRs of cardiovascular and chronic pulmonary disease admissions decreased considerably. RRs increased for alcohol abuse [0.59 (95% CI; 0.39-0.88) to 2.17 (95% CI; 1.72-2.72)], self-harm (suicide attempts, medication overuse) [1.72 (95% CI; 1.32-2.25) to 3.61 (95% CI; 2.88-4.52)], anemia [0.84 (95% CI; 0.39-1.78) to 17.92 (95% CI; 14.94-21.48)], and osteoporosis [1.19 (95% CI; 0.93-1.53) to 1.65 (95% CI; 1.35-2.02)]. CONCLUSIONS: Short-term surgical complications occurred in 3% and long-term complications in one-fourth of RYGB patients. Compared with the general population, the RR for any inpatient admission increased after RYGB.

Effect of calcium citrate vs calcium carbonate on elevated parathyroid hormone after Roux-en-Y gastric bypass. A double-blinded, randomized trial.

OBJECTIVE: Following Roux-en-Y gastric bypass (RYGB), elevated parathyroid hormone (PTH) levels potentially harmful to bone health are commonly observed. Owing to assumed superior absorption, calcium citrate is often recommended over calcium carbonate following RYGB for the treatment of elevated PTH. We aimed to investigate the impact of either calcium carbonate or calcium citrate (1200 mg elementary calcium) in patients with elevated PTH levels following RYGB. DESIGN: Clinical, double-blinded, randomized controlled trial of a 12-week duration at a Danish University Hospital. PATIENTS AND MEASUREMENTS: Thirty-nine (no drop out) RYGB operated patients with elevated PTH levels (PTH > 6.9 pmol/L) and normal plasma levels of calcium and 25-hydroxyvitamin D were randomized to either calcium carbonate or calcium citrate (1200 mg elementary calcium/daily). We assessed change in PTH as the primary outcome. RESULTS: The effect of the two calcium formulations on change in PTH was comparable and neutral: -1.9% (calcium citrate) vs +0.9% (calcium carbonate), P = 0.680. Compared to the carbonate-treated group, the following bone turnover markers decreased significantly in the citrate-treated group: procollagen I N-terminal propeptide (-16.6% vs -3.2%, P = 0.021), osteocalcin (-17.2% vs -4.3%, P = 0.007) and bone-specific alkaline phosphatase (-5.9% vs 3.7%, P = 0.027) and remained significantly decreased after multivariable adjustment. CONCLUSION: Increasing the dose of calcium supplementation in RYGB operated patients with slightly elevated PTH levels does not normalize PTH levels, regardless of the type of supplement. Our results do not support recommending supplementation with calcium citrate over calcium carbonate in RYGB patients.

Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro.

AIMS: To test the hypothesis that brown adipose tissue (BAT) is a metformin target tissue by investigating in vivo uptake of [11 C]-metformin tracer in mice and studying in vitro effects of metformin on cultured human brown adipocytes. MATERIALS AND METHODS: Tissue-specific uptake of metformin was assessed in mice by PET/CT imaging after injection of [11 C]-metformin. Human brown adipose tissue was obtained from elective neck surgery and metformin transporter expression levels in human and murine BAT were determined by qPCR. Oxygen consumption in metformin-treated human brown adipocyte cell models was assessed by Seahorse XF technology. RESULTS: Injected [11 C]-metformin showed avid uptake in the murine interscapular BAT depot. Metformin exposure in BAT was similar to hepatic exposure. Non-specific inhibition of the organic cation transporter (OCT) protein by cimetidine administration eliminated BAT exposure to metformin, demonstrating OCT-mediated uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose-dependent manner. CONCLUSION: These results support BAT as a putative metformin target.

Evaluation of Active Brown Adipose Tissue by the Use of Hyperpolarized [1-13C]Pyruvate MRI in Mice.

The capacity to increase energy expenditure makes brown adipose tissue (BAT) a putative target for treatment of metabolic diseases such as obesity. Presently, investigation of BAT in vivo is mainly performed by fluoro-d-glucose positron emission tomography (FDG PET)/CT. However, non-radioactive methods that add information on, for example, substrate metabolism are warranted. Thus, the aim of this study was to evaluate the potential of hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging (HP-MRI) to determine BAT activity in mice following chronic cold exposure. Cold (6 °C) and thermo-neutral (30 °C) acclimated mice were scanned with HP-MRI for assessment of the interscapular BAT (iBAT) activity. Comparable mice were scanned with the conventional method FDG PET/MRI. Finally, iBAT was evaluated for gene expression and protein levels of the specific thermogenic marker, uncoupling protein 1 (UCP1). Cold exposure increased the thermogenic capacity 3⁻4 fold (p < 0.05) as measured by UCP1 gene and protein analysis. Furthermore, cold exposure as compared with thermo-neutrality increased iBAT pyruvate metabolism by 5.5-fold determined by HP-MRI which is in good agreement with the 5-fold increment in FDG uptake (p < 0.05) measured by FDG PET/MRI. iBAT activity is detectable in mice using HP-MRI in which potential changes in intracellular metabolism may add useful information to the conventional FDG PET studies. HP-MRI may also be a promising radiation-free tool for repetitive BAT studies in humans.

Changes in Prescription Drug Use After Gastric Bypass Surgery: A Nationwide Cohort Study.

OBJECTIVES: To evaluate changes over time in drug use among patients undergoing Roux-en-Y gastric bypass (RYGB) surgery and a matched population-based comparison cohort. BACKGROUND: A little is known about the prescription drug use before and after RYGB surgery. METHODS: Nationwide population-based cohort study included 9908 patients undergoing RYGB in Denmark during 2006 to 2010 and 99,080 matched general population members. We calculated prevalence ratios (PRs) comparing prescription drug use 36 months after RYGB/index date with use 6 months before this date (baseline). RESULTS: At baseline, more RYGB patients (median 40 years, 22% males) used a prescription drug (81.5% vs 49.1%). After 3 years, the use had decreased slightly among RYGB patients [PR = 0.93; 95% confidence interval (CI) = (0.91, 0.94)], but increased in the comparison cohort (PR = 1.05; 95% CI = 1.04-1.06). In the RYGB cohort, large, sustained decreases occurred for treatment of metabolic syndrome-related conditions, such as any glucose-lowering drug (PR = 0.28; 95% CI = 0.25-0.31) and lipid-modifying drugs PR = 0.50; 95% CI = 0.46-0.55). Use of inhalants for obstructive airway diseases (PR = 0.79; 95% CI = 0.74-0.85) also decreased. Use of neuropsychiatric drugs was two-fold higher at baseline in the RYGB cohort (22.8% vs 10.9%) and increased further after RYGB-that is, antidepressants (PR = 1.13; 95% CI = 1.07-1.19), antipsychotics (PR = 1.39; 95% CI = 1.21-1.60), and potential treatment of neuropathy (PR = 1.39; 95% CI = 1.28-1.51). CONCLUSIONS: Three years after RYGB surgery, we found large reductions in the use of treatment of metabolic syndrome-related conditions, inhalants for obstructive airway diseases and glucocorticoid use. In contrast, frequent use of neuropsychiatric drugs further increased after RYGB.

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction.

Brown adipose tissue thermogenesis at the cost of energy is not only important for the development of obesity, but also possesses great promise in anti-obesity treatment. Uncoupling protein 1 (UCP1) expression has been reported to be under control of the intracellular deacetylase SIRT1. Here, we investigated the effect and mechanism of inflammation and sirtuin-1 (SIRT1) activation on the induction of thermogenic genes in immortalized brown adipocytes incubated with LPS or IL1ß and mice with elevated inflammatory tone. In vitro stimulation of brown adipocytes with dibutyryl cyclic adenosine monophosthate (dbcAMP) reduced the expression of deleted in breast cancer-1 (Dbc1) (SIRT1 inhibitor) and increased the Ucp1 expression. Silencing of SIRT1 attenuated dbcAMP induction of Ucp1. In contrast, IL1ß increased the expression of Dbc1 and greatly reduced the induction of Ucp1. Similarly, in vivo studies revealed decreased expression of Ucp1 in brown adipose tissue (BAT) in mice chronically infused with LPS. Resveratrol, a known SIRT1 activator, partly rescued the Ucp1 downregulation by inflammation in both the cell cultures and mice. Here, we describe how the expression of Ucp1 in BAT is controlled via SIRT1 and is reduced under inflammation and can be rescued by SIRT1 activation by resveratrol. We suggest the reduced UCP1 expression under inflammation is mediated by the increased expression of DBC1, which inhibits SIRT1 activity.

Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort.

AIM/HYPOTHESIS: Our aim was to investigate the association between the macrophage-activation marker soluble CD163 (sCD163), adiponectin, C-reactive protein (CRP) and changes in glycaemia, insulin resistance and insulin secretion in individuals at high risk of type 2 diabetes mellitus. METHODS: This prospective study included 1014 individuals at high risk of type 2 diabetes mellitus participating in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment In PeOple with ScreeN-detected Diabetes in Primary Care (ADDITION-Europe trial) baseline examination in 2001-2006 and follow-up examination (ADDITION-Progression [ADDITION-PRO]) in 2009-2011. Baseline serum samples were analysed for sCD163, adiponectin and CRP. The associations between sCD163, adiponectin and CRP per doubling of concentration, and changes per year in HbA1c, fasting plasma glucose, 2 h glucose, fasting insulin, HOMA-IR and HOMA-ß were assessed using a mixed-effects model. RESULTS: A doubling of sCD163 concentration was positively associated with changes in fasting insulin (ß = 1.078 per year, 95% CI 0.454, 1.702) and HOMA-ß (ß = 1.313 per year, 95% CI 0.537, 2.089), and a doubling of CRP concentration was positively associated with HbA 1c (ß = 0.004 per year, 95% CI 0.001, 0.007) and fasting insulin (ß = 0.267 per year, 95% CI 0.029, 0.504) after adjustment for age and sex. A doubling of adiponectin was inversely associated with changes in fasting glucose (ß = −0.017 per year, 95% CI −0.028, −0.005), 2 h glucose (ß = −0.063 per year, 95% CI −0.107, −0.019), fasting insulin (ß = −1.558 per year, 95% CI −2.020, −1.096), HOMA-IR (ß = −0.040 per year, 95% CI −0.062, −0.019) and HOMA-ß (ß = −1.009 per year, 95% CI −1.589, −0.429) after adjustment for age and sex. The associations were robust to adjustment for baseline waist circumference and smoking. Adjustment for CRP did not change the associations for sCD163 or adiponectin. CONCLUSIONS/INTERPRETATION: Our findings indicate that mechanisms related to inflammation, including macrophage activation and adipocyte metabolism, may play a role in changes in glucose homeostasis in individuals at high risk of type 2 diabetes mellitus.

Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, PSA levels or prostate volume. A 4-month randomised trial in middle-aged men.

BACKGROUND: Resveratrol is a naturally occurring polyphenol with purported inhibitory effects on prostate growth and cancer development. A number of studies have demonstrated that resveratrol reduces prostate growth in animal models and reduces prostate cell growth in vitro. Based on these pre-clinical findings, interest in resveratrol is increasing in relation to the management of benign prostate hyperplasia (BPH) and prostate cancer. So far, no human trials have evaluated the effects of resveratrol on circulating androgens, prostate size, or biochemical markers of prostate size. METHODS: In a randomized placebo controlled clinical study using two doses of resveratrol (150 mg or 1,000 mg resveratrol daily) for 4 months, we evaluated the effects on prostate size, prostate specific antigen (PSA) and sex steroid hormones in 66 middle-aged men suffering from the metabolic syndrome(MetS). RESULTS: At baseline, prostate size and PSA were positively correlated (R = 0.34, P < 0.007) as was prostate size and age (R = 0.37, P < 0.003). Prostate size did not correlate with testosterone, free testosterone, dihydrotestosterone (DHT), or any other androgen precursor at baseline. The highest dose of resveratrol lowered the serum level of androstenedione 24% (P = 0.052), dehydroepiandrosterone (DHEA) 41% (P < 0.01), and dehydroepiandrosterone-sulphate (DHEAS) 50% (p<0.001), compared to the control group. However, prostate size and levels of PSA, testosterone, free testosterone and DHT remained unchanged. CONCLUSION: In this population of middle-aged men suffering from MetS, high dose resveratrol (1,000 mg daily) administration for 4 months significantly lowered serum levels of the androgen precursors androstenedione, DHEA and DHEAS, whereas prostate size and circulating levels of PSA, testosterone, free testosterone, and dihydrotestosterone were unaffected. The present study suggests that resveratrol does not affect prostate volume in healthy middle-aged men as measured by PSA levels and CT acquired prostate volumes. Consequently, we find no support for the use of resveratrol in the treatment of benign prostate hyperplasia.

Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome.

CONTEXT: Central obesity in polycystic ovary syndrome (PCOS) is associated with increased inflammatory markers and increased risk for type 2 diabetes. OBJECTIVE: To evaluate if improved body composition during treatment with metformin (M) vs. oral contraceptive pills (OCP) was associated with changes in circulating adiponectin, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1. PATIENTS AND INTERVENTIONS: Ninety patients with PCOS were randomized to 12-month treatment with M (2 g/day), M + OCP (150 mg desogestrel + 30 microgram ethinylestradiol) or OCP. Adiponectin, IL-6, MCP-1, whole body DXA scans, and clinical evaluations were performed before and after the intervention period in the 65 study completers. MAIN OUTCOME MEASURES: Changes in inflammatory markers and changes in total and regional fat mass estimates. RESULTS: Adiponectin, IL-6, and MCP-1 levels were unchanged during the three types of medical intervention. Treatment with M and M + OCP was superior to OCP regarding decreased regional fat mass. Baseline adiponectin and IL-6 were associated with BMI, waist, and trunk fat mass. Changes in trunk fat were significantly associated with changes in IL-6 and MCP-1 during M + OCP. CONCLUSIONS: Long-term treatment with M alone or in combination with OCP was associated with improved body composition compared to OCP, whereas inflammatory markers were unchanged. OCP was not associated with increased inflammatory markers despite a small but significant weight gain.

Risk of fractures following bariatric surgery with Roux-en-Y gastric bypass or sleeve gastrectomy: a Danish population-based cohort study.

OBJECTIVE: We examined the association between Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) and fracture risk, including major osteoporotic fractures (MOF), and the use of anti-osteoporosis medication (AOM). While RYGB is associated with impaired bone health and increased fracture risk, it remains uncertain whether SG has a similar impact and whether this risk is primarily due to MOF or any fracture. DESIGN: We conducted a nationwide cohort study covering patients treated with RYGB (n = 16 121, 10.2-year follow-up) or SG (n = 1509, 3.7-year follow-up), from 2006 to 2018, comparing them with an age- and sex-matched cohort (n = 407 580). METHODS: We computed incidence rates and adjusted hazard ratios (HRs) with 95% CIs, using Cox regression for any fracture, MOF, and use of AOM with adjustment for comorbidities. RESULTS: Compared with the general population cohort, RYGB was associated with an increased risk of any fracture (HR 1.56 [95% CI, 1.48-1.64]) and MOF (HR 1.49 [1.35-1.64]). Sleeve gastrectomy was associated with an increased risk of any fracture (HR 1.38 [1.13-1.68]), while the HR of MOF was 1.43 (0.97-2.12). The use of AOM was low but similar in all cohorts (approximately 1%). CONCLUSIONS: Bariatric surgery increased the risk of any fracture and MOF to similar extend. Risks were similar for RYGB and SG. However, SG had a shorter follow-up than RYGB, and the cohort size was rather small. More research is needed for long-term SG fracture risk assessment. The use of AOM was low in all cohorts.

Changes in Symptoms and General Well-being After Reversal of Roux-en-Y Gastric Bypass: A Questionnaire Survey.

PURPOSE: After Roux-en-Y gastric bypass (RYGB), few patients develop severe complications, which ultimately may require reversal of RYGB. We aimed to examine the effect of reversal of RYGB on symptoms and well-being. MATERIALS AND METHODS: Via contact to medical and surgical departments treating patients with RYGB, we identified 18 patients, who had undergone reversal, 2009-2019. We conducted a Danish, nationwide questionnaire survey concerning symptoms before and after reversal of the RYGB including the patients' own perceptions of their well-being. RESULTS: Fourteen patients responded to the questionnaire (86% female; median age at RYGB, 36.2 years [IQR, 30.9-38.6 years]). The median time from RYGB to reversal was 5.8 years (IQR, 5.1-7.5 years). After RYGB, 13 patients (93%) reported abdominal pain, while 12 patients still had abdominal pain after reversal. Six out of 11 patients (45%) reported complete remission of dumping/post-bariatric hypoglycemia (PBH) after reversal. Malabsorption disappeared in 10 out of 11 patients (90%). Reversal had minor effect on neuropathy. The median weight loss from RYGB was 61 kg (IQR, 56-75 kg), while the median weight regain after reversal was 30 kg (IQR, 13-46 kg). Regarding the well-being, 72 of the patients felt better or much better after reversal. CONCLUSION: In total, 72% of the patients felt better or much better after reversal of RYGB, though some still had RYGB-related symptoms. The reversal relieved dumping/PBH and malabsorption, but not abdominal pain and neuropathy. Finally, half of the weight loss was regained after reversal. Reversal of RYGB may be an option in highly selected cases.

Risk of cardiovascular disease after hospital-diagnosed overweight or obesity.

Objective: The aim was to examine the association between hospital-diagnosed overweight/obesity and incident CVD according to the time period of the overweight/obesity diagnosis. Design: This is a cohort study. Methods: From Danish national health registries, we identified all residents with a first-time hospital-based overweight/obesity diagnosis code, 1977-2018 (n = 195,221), and an age and sex-matched general population comparison cohort (n = 1,952,210). We computed adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox regression. We adjusted for comorbidities and educational level and applied 10 years of follow-up. Results: The overall incidence rate was 10.1 (95% CI 10.0-10.1) per 1000 person-years for the comparison cohort and 25.1 (95% CI 24.8-25.4) per 1000 person-years for the overweight/obesity cohort, corresponding to an aHR of 2.5 (95% CI 2.4-2.5). The aHR was elevated for all subtypes of CVD: heart failure: 3.9 (95% CI 3.7-4.1), bradyarrhythmia: 2.9 (95% CI 2.7-3.1), angina pectoris: 2.7 (95% CI 2.7-2.8), atrial fibrillation or flutter: 2.6 (95% CI 2.5-2.6), acute myocardial infarction: 2.4 (95% CI 2.3-2.4), revascularization procedure: 2.4 (95% CI 2.2-2.5), valvular heart disease: 1.7 (95% CI 1.6-1.8), ischemic stroke: 1.6 (95% CI 1.4-1.7), transient ischemic attack: 1.6 (95% CI 1.5-1.7), and cardiovascular death: 1.6 (95% CI 1.5-1.6). The 1-10-year aHR of any CVD associated with an overweight/obesity diagnosis decreased from 2.8 (95% CI 2.7-2.9) in 1977-1987 to 1.8 (95% CI 1.8-1.9) in 2008-2018. Conclusion: Patients with hospital-diagnosed overweight/obesity had high rates of ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and death, although the strength of the association decreased in recent years. Significance statement: Obesity is linked to metabolic abnormalities that predispose individuals to an increased risk of subtypes of CVD. In this population-based nationwide 40-year cohort study, we found that of 195,221 patients with an overweight/obesity diagnosis, more than 31,000 (15.9%) were admitted to hospital within 10 years because of CVD; corresponding to a 2.5-fold greater relative risk of any CVD associated with overweight/obesity than in the general population. We observed an increased risk for most CVD subtypes, including ischemic heart disease, heart failure, structural heart disease, arrhythmia, stroke, and cardiovascular death, although the strength of the association decreased in recent years. Our study emphasizes the importance of improved clinical handling of obesity and underscores the need to prevent associated complications to alleviate the burden of obesity.

Sugar-sweetened beverages and cardio-metabolic disease risks.

PURPOSE OF REVIEW: Sucrose-sweetened beverages (SSB) have for decades been implicated in cardiometabolic diseases. The purpose of this review is to summarize recent epidemiological but particularly recent human intervention studies on the metabolic effects associated/induced by SSB. RECENT FINDINGS: Recent epidemiological studies support the positive association between SSB intake and enhanced risk for metabolic syndrome, type 2 diabetes, coronary heart diseases, and stroke. From the human intervention studies rather similar results are obtained with enhanced accumulation of fat in the liver, muscle, and in the visceral fat depot induced by SSB. Moreover, SSB induces enhanced levels of circulating triglycerides and enhanced de-novo lipogenesis in the liver. The specific effect of SSB on body weigh/obesity is still not completely elucidated but SSB enhances body weight/fat mass even though not to a significant degree in all studies. Concerning the mechanisms for SSB to induce these metabolic aberrations most of the studies are in agreement with the fact that it is mainly fructose (free or as part of the sucrose molecule) that is the main driver of these metabolic aberrations presumably primarily by inducing lipid synthesis in and release from the liver. SUMMARY: There are now convincing evidences for enhanced cardiometabolic risk after higher intake of SSB where both epidemiological studies and human intervention studies are pointing in the same direction. A so-called 'well tolerated' intake of SSB is not determined. Accordingly, intake of SSB should generally be reduced as much as possible to improve the health of the population.

The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin d: results from a randomized controlled study.

Low levels of 25-hydroxyvitamin D (25OHD) are associated with increased bone turnover and risk of fractures. Plasma 25OHD is inversely related to body mass index, and vitamin D deficiency is common in obesity. We aimed to determine whether vitamin D supplementation affects bone turnover and bone mineral density (BMD) in obese subjects. Fifty-two healthy obese men and women aged 18-50 years with plasma 25OHD levels below 50 nmol/L were randomized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks. We measured plasma levels of 25OHD, parathyroid hormone (PTH), and markers of bone turnover, as well as BMD at the hip, spine, forearm, and whole body. Compared with placebo, treatment with cholecalciferol increased mean plasma 25OHD from 35 to 110 nmol/L (p < 0.00001) and significantly decreased PTH (p < 0.05). BMD increased significantly at the forearm by 1.6 ± 0.7 % (p = 0.03). The bone resorption marker C-terminal telopetide of type 1 collagen (CTX) decreased borderline significantly in the cholecalciferol group compared with the placebo group (p = 0.07). Changes in plasma 25OHD correlated inversely with changes in plasma levels of bone-specific alkaline phosphatase (r = -0.38, p = 0.01) and CTX (r = -0.33, p = 0.03). Changes in CTX correlated inversely with changes in spine BMD (r = -0.45, p = 0.04). Increasing circulating 25OHD levels by cholecalciferol treatment is of importance to bone health in young obese subjects as increased levels of 25OHD are associated with a decrease in both PTH and bone turnover and with an increase in BMD at the forearm.

Acute exercise increases circulating inflammatory markers in overweight and obese compared with lean subjects.

The primary aim of the present study was to investigate if overweight and obese compared to lean individuals displayed differences in levels of inflammatory markers in circulation, skeletal muscle (SM) and adipose tissue (AT) after acute exercise. Fifteen lean (BMI: 22.4 ± 2 kg/m(2)) and 16 overweight or obese (BMI 31.8 ± 3 kg/m(2)) individuals were included in the study. They completed 120 min of ergometer bicycling at 55-60 % of maximal heart rate. Blood samples were obtained at baseline (T = 0), after 60 (T = 60) and 120 min of exercise (T = 120), and analyzed using an ELISA method. SM and AT biopsies were obtained at T0 and T120, and mRNA expression was investigated using a Real-time RT-PCR method. Circulating IL-6, TNF-α, IL-8, and IL-15 all increased at T = 120 min (p < 0.01). Circulating IL-6 and IL-15 increased in all subjects at T = 120 min (p < 0.01), but only the increase of IL-6 was significantly higher in overweight and obese subjects (p < 0.05), and was positively correlated with body fat percentage (p < 0.01). Circulating IL-8 and TNF-α were increased in overweight and obese (p < 0.05) but not in lean subjects. Acute exercise induced an increase in IL-6 mRNA expression in SM biopsies (p < 0.05). IL-6 as well as adiponectin mRNA expression was increased in AT biopsies (p < 0.05); however, no effect of body weight was found. The findings suggest that the systemic inflammatory response to acute exercise is different in lean compared to overweight and obese subjects, with a more pronounced increase in inflammatory markers (e.g., IL-6, IL-8, and TNF-α) in overweight and obese individuals.