Major adverse cardiovascular events among patients with type-2 diabetes, a nationwide cohort study comparing primary metabolic and bariatric surgery to GLP-1 receptor agonist treatment.

BACKGROUND: Glucagon-like Peptide-1 receptor agonists (GLP-1 RA) and metabolic and bariatric surgery (MBS) both improve cardiovascular outcomes in patients with severe obesity and type-2 diabetes (T2D). The aim of the present study was to assess the impact of MBS on major cardiovascular adverse events (MACE) in patients with severe obesity and T2D compared to patients with T2D treated with GLP-1 RA. SUBJECTS AND METHODS: In this propensity score matched cohort study on nationwide data, patients with T2D and severe obesity who underwent MBS in Sweden from 2007 until 2019 were identified from the Scandinavian Obesity Surgery Registry and matched to a non-surgical group with T2D treated with GLP-1 RA (81.7% liraglutide, 9.0% dulaglutide, 6.0% exenatide, 1.6% lixisenatide and 0.8% semaglutide) from the general population using generalized linear model. Major outcome was MACE (hospitalization for acute coronary syndrome or cerebrovascular event or all-cause death), evaluated with multivariable Cox regression. RESULTS: In total 2161 patients (obesity class I (10.2%), class II (40.3%), class III (49.5%)) were matched to 2161 non-surgical patients (mean age 51.1 ± 9.29 vs 51.5 ± 8.92 years, 64.8% vs. 64.4% women, with mean number of diabetes drugs of 2.5 ± 0.89 vs 2.6 ± 0.87, a mean duration of diabetes of 6.0 ± 4.15 vs 6.0 ± 4.51 years with 44.2% vs. 42.8% being treated with insulin at baseline). During the study period, 113 patients (8-year cumulative incidence 9.3%) compared to 130 non-surgical patients (8-year cumulative incidence 11.3%) suffered from MACE or all-cause mortality (HR 0.76, 95%CI 0.59-0.98), and 69 patients (8-year cumulative incidence 5.1%) compared to 92 non-surgical patients (8-year cumulative incidence 7.6%) suffered from a non-fatal MACE (HR 0.68, 95%CI 0.49-0.93). CONCLUSION: In this matched cohort study, MBS was associated with lower risk for MACE compared to treatment with early GLP-1 RA in patients with T2D.

Oxygen saturation in intraosseous sternal blood measured by CO-oximetry and evaluated non-invasively during hypovolaemia and hypoxia - a porcine experimental study.

PURPOSE: This study intended to determine, and non-invasively evaluate, sternal intraosseous oxygen saturation (SsO2) and study its variation during provoked hypoxia or hypovolaemia. Furthermore, the relation between SsO2 and arterial (SaO2) or mixed venous oxygen saturation (SvO2) was investigated. METHODS: Sixteen anaesthetised male pigs underwent exsanguination to a mean arterial pressure of 50 mmHg. After resuscitation and stabilisation, hypoxia was induced with hypoxic gas mixtures (air/N2). Repeated blood samples from sternal intraosseous cannulation were compared to arterial and pulmonary artery blood samples. Reflection spectrophotometry measurements by a non-invasive sternal probe were performed continuously. RESULTS: At baseline SaO2 was 97.0% (IQR 0.2), SsO2 73.2% (IQR 19.6) and SvO2 52.3% (IQR 12.4). During hypovolaemia, SsO2 and SvO2 decreased to 58.9% (IQR 16.9) and 38.1% (IQR 12.5), respectively, p < 0.05 for both, whereas SaO2 remained unaltered (p = 0.44). During hypoxia all saturations decreased; SaO2 71.5% (IQR 5.2), SsO2 39.0% (IQR 6.9) and SvO2 22.6% (IQR 11.4) (p < 0.01), respectively. For hypovolaemia, the sternal probe red/infrared absorption ratio (SQV) increased significantly from baseline (indicating a reduction in oxygen saturation) + 5.1% (IQR 7.4), p < 0.001 and for hypoxia + 19.9% (IQR 14.8), p = 0.001, respectively. CONCLUSION: Sternal blood has an oxygen saturation suggesting a mixture of venous and arterial blood. Changes in SsO2 relate well with changes in SvO2 during hypovolaemia or hypoxia. Further studies on the feasibility of using non-invasive measurement of changes in SsO2 to estimate changes in SvO2 are warranted.

Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study.

BACKGROUND: The number of patients with myocardial infarction and severe obesity is increasing and there is a lack of evidence how these patients should be treated. The aim of this study was to investigate the association between metabolic surgery (Roux-en-Y gastric bypass and sleeve gastrectomy) and major adverse cardiovascular events in patients with previous myocardial infarction (MI) and severe obesity. METHODS: Of 566 patients with previous MI registered in the SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) undergoing metabolic surgery and registered in the nationwide Scandinavian Obesity Surgery Registry, 509 patients (Roux-en-Y gastric bypass n=465; sleeve gastrectomy n=44) could be matched 1:1 to a control with MI from SWEDEHEART, but no subsequent metabolic surgery regarding sex, age (±3 years), year of MI (±3 years), and body mass index (±3). The 2 groups were well matched, except for a lower proportion of reduced ejection fraction after MI (7% versus 12%), previous heart failure (10% versus 19%), atrial fibrillation (6% versus 10%), and chronic obstructive pulmonary disease (4% versus 7%) in patients undergoing metabolic surgery. RESULTS: The median (interquartile range) follow-up time was 4.6 (2.7-7.1) years. The 8-year cumulative probability of major adverse cardiovascular events was lower in patients undergoing metabolic surgery (18.7% [95% CI, 15.9-21.5%] versus 36.2% [33.2-39.3%], adjusted hazard ratio, 0.44 [95% CI, 0.32-0.61]). Patients undergoing metabolic surgery had also a lower risk of death (adjusted HR, 0.45 [95% CI, 0.29-0.70]; MI, 0.24 [0.14-0.41]) and new onset heart failure, but there were no significant differences regarding stroke (0.91 [0.38-2.20]) and new onset atrial fibrillation (0.56 [0.31-1.01]). CONCLUSIONS: In severely obese patients with previous MI, metabolic surgery is associated with a low risk for serious complications, lower risk of major adverse cardiovascular events, death, new MI, and new onset heart failure. These findings need to be confirmed in a randomized, controlled trial.

Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity.

BACKGROUND AND AIMS: Oxidative stress plays a key role in the development of metabolic complications associated with obesity, including insulin resistance and the most common chronic liver disease worldwide, nonalcoholic fatty liver disease. We have recently discovered that the microRNA miR-144 regulates protein levels of the master mediator of the antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2). On miR-144 silencing, the expression of NRF2 target genes was significantly upregulated, suggesting that miR-144 controls NRF2 at the level of both protein expression and activity. Here we explored a mechanism whereby hepatic miR-144 inhibited NRF2 activity upon obesity via the regulation of the tricarboxylic acid (TCA) metabolite, fumarate, a potent activator of NRF2. METHODS: We performed transcriptomic analysis in liver macrophages (LMs) of obese mice and identified the immuno-responsive gene 1 (Irg1) as a target of miR-144. IRG1 catalyzes the production of a TCA derivative, itaconate, an inhibitor of succinate dehydrogenase (SDH). TCA enzyme activities and kinetics were analyzed after miR-144 silencing in obese mice and human liver organoids using single-cell activity assays in situ and molecular dynamic simulations. RESULTS: Increased levels of miR-144 in obesity were associated with reduced expression of Irg1, which was restored on miR-144 silencing in vitro and in vivo. Furthermore, miR-144 overexpression reduces Irg1 expression and the production of itaconate in vitro. In alignment with the reduction in IRG1 levels and itaconate production, we observed an upregulation of SDH activity during obesity. Surprisingly, however, fumarate hydratase (FH) activity was also upregulated in obese livers, leading to the depletion of its substrate fumarate. miR-144 silencing selectively reduced the activities of both SDH and FH resulting in the accumulation of their related substrates succinate and fumarate. Moreover, molecular dynamics analyses revealed the potential role of itaconate as a competitive inhibitor of not only SDH but also FH. Combined, these results demonstrate that silencing of miR-144 inhibits the activity of NRF2 through decreased fumarate production in obesity. CONCLUSIONS: Herein we unravel a novel mechanism whereby miR-144 inhibits NRF2 activity through the consumption of fumarate by activation of FH. Our study demonstrates that hepatic miR-144 triggers a hyperactive FH in the TCA cycle leading to an impaired antioxidant response in obesity.

Lipolysis defect in people with obesity who undergo metabolic surgery.

OBJECTIVE: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome. DESIGN/METHODS: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist). RESULTS: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007). CONCLUSION: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass.

Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes.

AIMS/HYPOTHESIS: Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. METHODS: Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation. RESULTS: Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37-56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. CONCLUSIONS/INTERPRETATION: Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent.

Three weeks of interrupting sitting lowers fasting glucose and glycemic variability, but not glucose tolerance, in free-living women and men with obesity.

We aimed to determine whether interrupting prolonged sitting improves glycemic control and the metabolic profile of free-living adults with obesity. Sixteen sedentary individuals {10 women/6 men; median [interquartile range (IQR)] age 50 (44-53) yr, body mass index (BMI) 32 (32-35.8) kg/m2} were fitted with continuous glucose and activity monitors for 4 wk. After a 1-wk baseline period, participants were randomized into habitual lifestyle (Control) or frequent activity breaks from sitting (FABS) intervention groups. Each day, between 0800 and 1800 h, FABS received smartwatch notifications to break sitting with 3 min of low-to-moderate-intensity physical activity every 30 min. Glycemic control was assessed by oral glucose tolerance test (OGTT) and continuous glucose monitoring. Blood samples and vastus lateralis biopsies were taken for assessment of clinical chemistry and the skeletal muscle lipidome, respectively. Compared with baseline, FABS increased median steps by 744 [IQR (483-951)] and walking time by 10.4 [IQR (2.2-24.6)] min/day. Other indices of activity/sedentary behavior were unchanged. Glucose tolerance and average 24-h glucose curves were also unaffected. However, mean (±SD) fasting glucose levels [-0.34 (±0.37) mmol/L] and daily glucose variation [%CV; -2% (±2.2%)] reduced in FABS, suggesting a modest benefit for glycemic control that was most robust at higher volumes of daily activity. Clinical chemistry and the skeletal muscle lipidome were largely unperturbed, although two long-chain triglycerides increased 1.25-fold in FABS, postintervention. All parameters remained stable in control. Under free-living conditions, FABS lowered fasting glucose and glucose variability. Larger volumes of activity breaks from sitting may be required to promote greater health benefits.NEW & NOTEWORTHY Under free-living conditions, breaking sitting modestly increased activity behavior. Breaking sitting was insufficient to modulate glucose tolerance or the skeletal muscle lipidome. Activity breaks reduced fasting blood glucose levels and daily glucose variation compared with baseline, with a tendency to also decrease fasting LDLc. This intervention may represent the minimal dose for breaking sedentary behavior, with larger volumes of activity possibly required to promote greater health benefits.

Remission, relapse, and risk of major cardiovascular events after metabolic surgery in persons with hypertension: A Swedish nationwide registry-based cohort study.

BACKGROUND: Several studies have shown that metabolic surgery is associated with remission of diabetes and hypertension. In terms of diabetes, factors such as duration, insulin use, weight loss, and age have been shown to contribute to the likelihood of remission. Such factors have not been determined for hypertension. The aim of this study was to evaluate factors associated with the remission and relapse of hypertension after metabolic surgery, as well as the risk for major adverse cardiovascular event (MACE) and mortality in patients with and without remission. METHODS AND FINDINGS: All adults who underwent metabolic surgery between January 2007 and June 2016 were identified in the nationwide Scandinavian Obesity Surgery Registry (SOReg). Through cross-linkage with the Swedish Prescribed Drug Register, Patient Register, and Statistics Sweden, individual data on prescriptions, inpatient and outpatient diagnoses, and mortality were retrieved. Of the 15,984 patients with pharmacologically treated hypertension, 6,286 (39.3%) were in remission at 2 years. High weight loss and male sex were associated with higher chance of remission, while duration, number of antihypertensive drugs, age, body mass index (BMI), cardiovascular disease, and dyslipidemia were associated with lower chance. After adjustment for age, sex, BMI, comorbidities, and education, the cumulative probabilities of MACEs (2.8% versus 5.7%, adjusted odds ratio (OR) 0.60, 95% confidence interval (CI) 0.47 to 0.77, p < 0.001) and all-cause mortality (4.0% versus 8.0%, adjusted OR 0.71, 95% CI 0.57 to 0.88, p = 0.002) were lower for patients being in remission at 2 years compared with patients not in remission, despite relapse of hypertension in 2,089 patients (cumulative probability 56.3%) during 10-year follow-up. The main limitations of the study were missing information on nonpharmacological treatment for hypertension and the observational study design. CONCLUSIONS: In this study, we observed an association between high postoperative weight loss and male sex with better chance of remission, while we observed a lower chance of remission depending on disease severity and presence of other metabolic comorbidities. Patients who achieved remission had a halved risk of MACE and death compared with those who did not. The results suggest that in patients with severe obesity and hypertension, metabolic surgery should not be delayed.

Prevention of hemorrhage-induced renal vasoconstriction and hypoxia by angiotensin II type 1 receptor antagonism in pigs.

Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg-1·h-1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of <50 mmHg for 30 min. Plasma ANG II levels, hemodynamics and oxygenation were assessed 60 min prehemorrhage, 30-min after the start of hemorrhage, and 60 min posthemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma ANG II levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, ANG II antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.

Influence of obesity, weight loss, and free fatty acids on skeletal muscle clock gene expression.

The molecular circadian clock plays a role in metabolic homeostasis. We tested the hypothesis obesity and systemic factors associated with insulin resistance affect skeletal muscle clock gene expression. We determined clock gene expression in skeletal muscle of obese women (n = 5) and men (n = 18) before and 6 mo after Roux-en-Y gastric bypass (RYGB) surgery and normal-weight controls (women n = 6, men n = 8). Skeletal muscle clock gene expression was affected by obesity and weight loss. CRY1 mRNA (P = 0.05) was increased and DBP mRNA (P < 0.05) was decreased in obese vs. normal weight women and restored to control levels after RYGB-induced weight loss. CLOCK, CRY1, CRY2, and DBP mRNA (P < 0.05) was decreased in obese men compared with normal weight men. Expression of all other clock genes was unaltered by obesity or weight loss in both cohorts. We correlated clock gene expression with clinical characteristics of the participants. Among the genes studied, DBP and PER3 expression was inversely correlated with plasma lipids in both cohorts. Circadian time-course studies revealed that core clock genes oscillate over time (P < 0.05), with BMAL1, CIART, CRY2, DBP, PER1, and PER3 expression profiles altered by palmitate treatment. In conclusion, skeletal muscle clock gene expression and function is altered by obesity, coincident with changes in plasma lipid levels. Palmitate exposure disrupts clock gene expression in myotubes, indicating that dyslipidemia directly alters the circadian program. Strategies to reduce lipid overload and prevent elevations in nonesterified fatty acid and cholesterol levels may sustain circadian clock signals in skeletal muscle.

Association between metabolic surgery and cardiovascular outcome in patients with hypertension: A nationwide matched cohort study.

BACKGROUND: Hypertension, together with obesity, is a leading cause of mortality and disability. Whilst metabolic surgery offers remission of several metabolic comorbidities, the effect for patients with hypertension remains controversial. The objective of the present study was to evaluate the effect of metabolic surgery on cardiovascular events and mortality on patients with morbid obesity (body mass index [BMI] ≥ 35 kg/m2) and hypertension. METHODS AND FINDINGS: We conducted a matched cohort study of 11,863 patients with morbid obesity and pharmacologically treated hypertension operated on with metabolic surgery and a matched non-operated-on control group of 26,199 subjects with hypertension (matched by age, sex, and area of residence) of varied matching ratios from 1:1 to 1:9, using data from the Scandinavian Obesity Surgery Register (SOReg), the Swedish National Patient Registers (NPR) for in-hospital and outpatient care, the Swedish Prescribed Drug Register, and Statistics Sweden. The main outcome was major adverse cardiovascular event (MACE), defined as first occurrence of acute coronary syndrome (ACS) event, cerebrovascular event, fatal cardiovascular event, or unattended sudden cardiac death. The mean age in the study group was 52.1 ± 7.46 years, with 65.8% being women (n = 7,810), and mean BMI was 41.9 ± 5.43 kg/m2. MACEs occurred in 379 operated-on patients (3.2%) and 1,125 subjects in the control group (4.5%). After adjustment for duration of hypertension, comorbidities, and education, a reduction in risk was seen in the metabolic surgery group (adjusted hazard ratio [HR] 0.73, 95% confidence intervals [CIs] 0.64-0.84, P < 0.001). The surgery group had lower risk for ACS events (adjusted HR 0.52, 95% CI 0.41-0.66, P < 0.001) and a tendency towards lower risk for cerebrovascular events (adjusted HR 0.81, 95% CI 0.63-1.01, P = 0.060) compared with controls. The main limitations with the study were the lack of information on BMI and history of smoking in the control group and the nonrandomised study design. CONCLUSION: Metabolic surgery on patients with morbid obesity and pharmacologically treated hypertension was associated with lower risk for MACEs and all-cause mortality compared with age- and sex-matched controls with hypertension from the general population.

The association between socioeconomic factors and weight loss 5 years after gastric bypass surgery.

INTRODUCTION: Patients with low socioeconomic status have been reported to have poorer outcome than those with a high socioeconomic status after several types of surgery. The influence of socioeconomic factors on weight loss after bariatric surgery remains unclear. The aim of the present study was to evaluate the association between socioeconomic factors and postoperative weight loss. MATERIALS AND METHODS: This was a retrospective, nationwide cohort study with 5-year follow-up data for 13,275 patients operated with primary gastric bypass in Sweden between January 2007 and December 2012 (n = 13,275), linking data from the Scandinavian Obesity Surgery Registry, Statistics Sweden, the Swedish National Patient Register, and the Swedish Prescribed Drugs Register. The assessed socioeconomic variables were education, profession, disposable income, place of residence, marital status, financial aid and heritage. The main outcome was weight loss 5 years after surgery, measured as total weight loss (TWL). Linear regression models, adjusted for age, preoperative body mass index (BMI), sex and comorbid diseases were constructed. RESULTS: The mean TWL 5 years after surgery was 28.3 ± 9.86%. In the adjusted model, first-generation immigrants (%TWL, B -2.4 [95% CI -2.9 to -1.9], p < 0.0001) lost significantly less weight than the mean, while residents in medium-sized (B 0.8 [95% CI 0.4-1.2], p = 0.0001) or small towns (B 0.8 [95% CI 0.4-1.2], p < 0.0001) lost significantly more weight. CONCLUSIONS: All socioeconomic groups experienced improvements in weight after bariatric surgery. However, as first-generation immigrants and patients residing in larger towns (>200,000 inhabitants) tend to have inferior weight loss compared to other groups, increased support in the pre- and postoperative setting for these two groups could be of value. The remaining socioeconomic factors appear to have a weaker association with postoperative weight loss.

Nondigestible Carbohydrates Affect Metabolic Health and Gut Microbiota in Overweight Adults after Weight Loss.

BACKGROUND: The composition of diets consumed following weight loss (WL) can have a significant impact on satiety and metabolic health. OBJECTIVE: This study was designed to test the effects of including a nondigestible carbohydrate to achieve weight maintenance (WM) following a period of WL. METHODS: Nineteen volunteers [11 females and 8 males, aged 20-62 y; BMI (kg/m2): 27-42] consumed a 3-d maintenance diet (15%:30%:55%), followed by a 21-d WL diet (WL; 30%:30%:40%), followed by 2 randomized 10-d WM diets (20%:30%:50% of energy from protein:fat:carbohydrate) containing either resistant starch type 3 (RS-WM; 22 or 26 g/d for females and males, respectively) or no RS (C-WM) in a within-subject crossover design without washout periods. The primary outcome, WM after WL, was analyzed by body weight. Secondary outcomes of fecal microbiota composition and microbial metabolite concentrations and gut hormones were analyzed in fecal samples and blood plasma, respectively. All outcomes were assessed at the end of each dietary period. RESULTS: Body weight was similar after the RS-WM and C-WM diets (90.7 and 90.8 kg, respectively), with no difference in subjectively rated appetite. During the WL diet period plasma ghrelin increased by 36% (P < 0.001), glucose-dependent insulinotropic polypeptide (GIP) decreased by 33% (P < 0.001), and insulin decreased by 46% (P < 0.001), but no significant differences were observed during the RS-WM and C-WM diet periods. Fasting blood glucose was lower after the RS-WM diet (5.59 ± 0.31 mmol/L) than after the C-WM diet [5.75 ± 0.49 mmol/L; P = 0.015; standard error of the difference between the means (SED): 0.09]. Dietary treatments influenced the fecal microbiota composition (R2 = 0.054, P = 0.031) but not diversity. CONCLUSIONS: The metabolic benefits, for overweight adults, from WL were maintained through a subsequent WM diet with higher total carbohydrate intake. Inclusion of resistant starch in the WM diet altered gut microbiota composition positively and resulted in lower fasting glucose compared with the control, with no apparent change in appetite. This trial was registered at clinicaltrials.gov as NCT01724411.

Measuring arterial oxygen saturation from an intraosseous photoplethysmographic signal derived from the sternum.

Photoplethysmography performed on the peripheral extremities or the earlobes cannot always provide sufficiently rapid and accurate calculation of arterial oxygen saturation. The purpose of this study was to evaluate a novel photoplethysmography prototype to be fixed over the sternum. Our hypotheses were that arterial oxygen saturation can be determined from an intraosseous photoplethysmography signal from the sternum and that such monitoring detects hypoxemia faster than pulse oximetry at standard sites. Sixteen healthy male volunteers were subjected to incremental hypoxemia using different gas mixtures with decreasing oxygen content. The sternal probe was calibrated using arterial haemoglobin CO-oximetry (SaO2%). Sternal probe readings (SRHO2%) were then compared to SaO2% at various degrees of hypoxia. The time to detect hypoxemia was compared to measurements from standard finger and ear pulse oximeters. A significant association from individual regression between SRHO2% and SaO2% was found (r2 0.97), Spearman R ranged between 0.71 and 0.92 for the different inhaled gas mixtures. Limits of agreement according to Bland-Altman plots had a increased interval with decreasing arterial oxygen saturation. The sternal probe detected hypoxemia 28.7 s faster than a finger probe (95% CI 20.0-37.4 s, p < 0.001) and 6.6 s faster than an ear probe (95% CI 5.3-8.7 s, p < 0.001). In an experimental setting, arterial oxygen saturation could be determined using the photoplethysmography signal obtained from sternal blood flow after calibration with CO-oximetry. This method detected hypoxemia significantly faster than pulse oximetry performed on the finger or the ear.

Short-term low-calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults.

Diet intervention in obese adults is the first strategy to induce weight loss and improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. Eight obese, insulin-resistant, nondiabetic adults were recruited to participate in a 3-wk low-calorie diet intervention cohort study (1,000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. Body weight was reduced, insulin sensitivity [measured by homeostatic model assessment of insulin resistance, (HOMA-IR)] was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL, and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that biosynthesis of unsaturated fatty acid was among the most enriched pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD1 decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced. Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity.

Duration of type 2 diabetes and remission rates after bariatric surgery in Sweden 2007-2015: A registry-based cohort study.

BACKGROUND: Although bariatric surgery is an effective treatment for type 2 diabetes (T2D) in patients with morbid obesity, further studies are needed to evaluate factors influencing the chance of achieving diabetes remission. The objective of the present study was to investigate the association between T2D duration and the chance of achieving remission of T2D after bariatric surgery. METHODS AND FINDINGS: We conducted a nationwide register-based cohort study including all adult patients with T2D and BMI ≥ 35 kg/m2 who received primary bariatric surgery in Sweden between 2007 and 2015 identified through the Scandinavian Obesity Surgery Registry. The main outcome was remission of T2D, defined as being free from diabetes medication or as complete remission (HbA1c < 42 mmol/mol without medication). In all, 8,546 patients with T2D were included. Mean age was 47.8 ± 10.1 years, mean BMI was 42.2 ± 5.8 kg/m2, 5,277 (61.7%) were women, and mean HbA1c was 58.9 ± 17.4 mmol/mol. The proportion of patients free from diabetes medication 2 years after surgery was 76.6% (n = 6,499), and 69.9% at 5 years (n = 3,765). The chance of being free from T2D medication was less in patients with longer preoperative duration of diabetes both at 2 years (odds ratio [OR] 0.80/year, 95% CI 0.79-0.81, p < 0.001) and 5 years after surgery (OR 0.76/year, 95% CI 0.75-0.78, p < 0.001). Complete remission of T2D was achieved in 58.2% (n = 2,090) at 2 years, and 46.6% at 5 years (n = 681). The chance of achieving complete remission correlated negatively with the duration of diabetes (adjusted OR 0.87/year, 95% CI 0.85-0.89, p < 0.001), insulin treatment (adjusted OR 0.25, 95% CI 0.20-0.31, p < 0.001), age (adjusted OR 0.94/year, 95% CI 0.93-0.95, p < 0.001), and HbA1c at baseline (adjusted OR 0.98/mmol/mol, 95% CI 0.97-0.98, p < 0.001), but was greater among males (adjusted OR 1.57, 95% CI 1.29-1.90, p < 0.001) and patients with higher BMI at baseline (adjusted OR 1.07/kg/m2, 95% CI 1.05-1.09, p < 0.001). The main limitations of the study lie in its retrospective nature and the low availability of HbA1c values at long-term follow-up. CONCLUSIONS: In this study, we found that remission of T2D after bariatric surgery was inversely associated with duration of diabetes and was highest among patients with recent onset and those without insulin treatment.

Gastric Bypass Surgery Reduces De Novo Cases of Type 2 Diabetes to Population Levels: A Nationwide Cohort Study From Sweden.

OBJECTIVE: The aim of this study was to determine long-term changes in pharmacological treatment of type 2 diabetes after primary Roux-en-Y gastric bypass (RYGB) surgery, in patients with and without pharmacological treatment of diabetes preoperatively. SUMMARY OF BACKGROUND DATA: Several studies have shown that gastric bypass has good effect on diabetes, at least in the short-term. This study is a nationwide cohort study using Swedish registers, with basically no patients lost to follow-up during up to 7 years after surgery. METHODS: The effect of RYGB on type 2 diabetes drug treatment was evaluated in this nationwide matched cohort study. Participants were 22,047 adults with BMI ≥30 identified in the nationwide Scandinavian Surgical Obesity Registry, who underwent primary RYGB between 2007 and 2012. For each individual, up to 10 general population comparators were matched on birth year, sex, and place of residence. Prescription data were retrieved from the nationwide Swedish Prescribed Drug Register through September 2015. Incident use of pharmacological treatment was analyzed using Cox regression. RESULTS: Sixty-seven percent of patients with pharmacological treatment of type 2 diabetes before surgery were not using diabetes drugs 2 years after surgery and 61% of patients were not pharmacologically treated up to 7 years after surgery. In patients not using diabetes drugs at baseline, there were 189 new cases of pharmacological treatment of type 2 diabetes in the surgery group and 2319 in the matched general population comparators during a median follow-up of 4.6 years (incidence: 21.4 vs 27.9 per 10,000 person-years; adjusted hazard ratio 0.77, 95% confidence interval 0.67-0.89; P < 0.001). CONCLUSIONS: Gastric bypass surgery not only induces remission of pharmacological treatment of type 2 diabetes but also protects from new onset of pharmacological diabetes treatment. The effect seems to persist in most, but not all, patients over 7 years of follow-up.

FAK tyrosine phosphorylation is regulated by AMPK and controls metabolism in human skeletal muscle.

AIMS/HYPOTHESIS: Insulin-mediated signals and AMP-activated protein kinase (AMPK)-mediated signals are activated in response to physiological conditions that represent energy abundance and shortage, respectively. Focal adhesion kinase (FAK) is implicated in insulin signalling and cancer progression in various non-muscle cell types and plays a regulatory role during skeletal muscle differentiation. The role of FAK in skeletal muscle in relation to insulin stimulation or AMPK activation is unknown. We examined the effects of insulin or AMPK activation on FAK phosphorylation in human skeletal muscle and the direct role of FAK on glucose and lipid metabolism. We hypothesised that insulin treatment and AMPK activation would have opposing effects on FAK phosphorylation and that gene silencing of FAK would alter metabolism. METHODS: Human muscle was treated with insulin or the AMPK-activating compound 5-aminoimadazole-4-carboxamide ribonucleotide (AICAR) to determine FAK phosphorylation and glucose transport. Primary human skeletal muscle cells were used to study the effects of insulin or AICAR treatment on FAK signalling during serum starvation, as well as to determine the metabolic consequences of silencing the FAK gene, PTK2. RESULTS: AMPK activation reduced tyrosine phosphorylation of FAK in skeletal muscle. AICAR reduced p-FAKY397 in isolated human skeletal muscle and cultured myotubes. Insulin stimulation did not alter FAK phosphorylation. Serum starvation increased AMPK activation, as demonstrated by increased p-ACCS222, concomitant with reduced p-FAKY397. FAK signalling was reduced owing to serum starvation and AICAR treatment as demonstrated by reduced p-paxillinY118. Silencing PTK2 in primary human skeletal muscle cells increased palmitate oxidation and reduced glycogen synthesis. CONCLUSIONS/INTERPRETATION: AMPK regulates FAK signalling in skeletal muscle. Moreover, siRNA-mediated FAK knockdown enhances lipid oxidation while impairing glycogen synthesis in skeletal muscle. Further exploration of the interaction between AMPK and FAK may lead to novel therapeutic strategies for diabetes and other chronic conditions associated with an altered metabolic homeostasis.

IL6 and LIF mRNA expression in skeletal muscle is regulated by AMPK and the transcription factors NFYC, ZBTB14, and SP1.

Adenosine monophosphate-activated protein kinase (AMPK) controls glucose and lipid metabolism and modulates inflammatory responses to maintain metabolic and inflammatory homeostasis during low cellular energy levels. The AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-4-ribofuranoside (AICAR) interferes with inflammatory pathways in skeletal muscle, but the mechanisms are undefined. We hypothesized that AMPK activation reduces cytokine mRNA levels by blocking transcription through one or several transcription factors. Three skeletal muscle models were used to study AMPK effects on cytokine mRNA: human skeletal muscle strips obtained from healthy men incubated in vitro, primary human muscle cells, and rat L6 cells. In all three skeletal muscle systems, AICAR acutely reduced cytokine mRNA levels. In L6 myotubes treated with the transcriptional blocker actinomycin D, AICAR addition did not further reduce Il6 or leukemia inhibitory factor ( Lif) mRNA, suggesting that AICAR modulates cytokine expression through regulating transcription rather than mRNA stability. A cross-species bioinformatic approach identified novel transcription factors that may regulate LIF and IL6 mRNA. The involvement of these transcription factors was studied after targeted gene-silencing by siRNA. siRNA silencing of the transcription factors nuclear transcription factor Y subunit c ( Nfyc), specificity protein 1 ( Sp1), and zinc finger and BTB domain containing 14 ( Zbtb14), or AMPK α1/α2 subunits, increased constitutive levels of Il6 and Lif. Our results identify novel candidates in the regulation of skeletal muscle cytokine expression and identify AMPK, Nfyc, Sp1, and Zbtb14 as novel regulators of immunometabolic signals from skeletal muscle.

Screening of potential adipokines identifies S100A4 as a marker of pernicious adipose tissue and insulin resistance.

BACKGROUND: Adipokines are peptides secreted from white adipose tissue (WAT), which have been linked to WAT dysfunction and metabolic complications of obesity. We set out to identify novel adipokines in subcutaneous WAT (sWAT) linked to insulin resistance (IR). METHODS: Gene expression was determined by microarray and qPCR in obese and non-obese subjects with varying degree of IR. WAT-secreted and circulating protein levels were measured by ELISA. RESULTS: In sWAT of 80 obese women discordant for IR, 44 genes encoding potential adipose-secreted proteins were differentially expressed. Among these, merely two proteins, S100A4 and MXRA5 were released from sWAT in a time-dependent manner (criterion for true adipokines) but only the circulating levels of S100A4 were higher in IR. In two additional cohorts (n = 29 and n = 56), sWAT S100A4 secretion was positively and BMI-independently associated with IR (determined by clamp or HOMA-IR), ATP-III risk score and adipocyte size (hypertrophy). In non-obese (n = 20) and obese subjects before and after bariatric surgery (n = 21), circulating and sWAT-secreted levels were highest in the obese and normalized following weight loss. Serum S100A4 concentrations were higher in subjects with type 2 diabetes. S100A4 sWAT expression associated positively with genes involved in inflammation/extracellular matrix formation and inversely with genes in metabolic pathways. Although S100A4 was expressed in both stromal cells and adipocytes, only the expression in adipocytes associated with BMI. CONCLUSIONS: S100A4 is a novel adipokine associated with IR and sWAT inflammation/adipocyte hypertrophy independently of BMI. Its value as a circulating marker for dysfunctional WAT and IR needs to be validated in larger cohorts.