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Aims/hypothesisLifestyle modification and weight loss are cornerstones of type 2 diabetes management. However, carbohydrate restriction may have weight-independent beneficial effects on glycaemic control. This has been difficult to demonstrate because low-carbohydrate diets readily decrease body weight. We hypothesised that carbohydrate restriction enhances the beneficial metabolic effects of weight loss in type 2 diabetes.MethodsThis open-label, parallel RCT included adults with type 2 diabetes, HbA1c 48–97 mmol/mol (6.5–11%), BMI >25 kg/m2, eGFR >30 ml min−1 [1.73 m]−2 and glucose-lowering therapy restricted to metformin or dipeptidyl peptidase-4 inhibitors. Participants were randomised by a third party and assigned to 6 weeks of energy restriction (all foods were provided) aiming at ~6% weight loss with either a carbohydrate-reduced high-protein diet (CRHP, percentage of total energy intake [E%]: CH30/P30/F40) or a conventional diabetes diet (CD, E%: CH50/P17/F33). Fasting blood samples, continuous glucose monitoring and magnetic resonance spectroscopy were used to assess glycaemic control, lipid metabolism and intrahepatic fat. Change in HbA1c was the primary outcome; changes in circulating and intrahepatic triacylglycerol were secondary outcomes. Data were collected at Copenhagen University Hospital (Bispebjerg and Herlev).ResultsSeventy-two adults (CD 36, CRHP 36, all white, 38 male sex) with type 2 diabetes (mean duration 8 years, mean HbA1c 57 mmol/mol [7.4%]) and mean BMI of 33 kg/m2 were enrolled, of which 67 (CD 33, CRHP 34) completed the study. Body weight decreased by 5.8 kg (5.9%) in both groups after 6 weeks. Compared with the CD diet, the CRHP diet further reduced HbA1c (mean [95% CI] −1.9 [−3.5, −0.3] mmol/mol [−0.18 (−0.32, −0.03)%], p = 0.018) and diurnal mean glucose (mean [95% CI] −0.8 [−1.2, −0.4] mmol/l, p < 0.001), stabilised glucose excursions by reducing glucose CV (mean [95% CI] −4.1 [−5.9, −2.2]%, p < 0.001), and augmented the reductions in fasting triacylglycerol concentration (by mean [95% CI] −18 [−29, −6]%, p < 0.01) and liver fat content (by mean [95% CI] −26 [−45, 0]%, p = 0.051). However, pancreatic fat content was decreased to a lesser extent by the CRHP than the CD diet (mean [95% CI] 33 [7, 65]%, p = 0.010). Fasting glucose, insulin, HOMA2-IR and cholesterol concentrations (total, LDL and HDL) were reduced significantly and similarly by both diets.Conclusions/interpretationModerate carbohydrate restriction for 6 weeks modestly improved glycaemic control, and decreased circulating and intrahepatic triacylglycerol levels beyond the effects of weight loss itself compared with a CD diet in individuals with type 2 diabetes. Concurrent differences in protein and fat intakes, and the quality of dietary macronutrients, may have contributed to these results and should be explored in future studies.Trial registrationClinicalTrials.gov NCT03814694.FundingThe study was funded by Arla Foods amba, The Danish Dairy Research Foundation, and Copenhagen University Hospital Bispebjerg Frederiksberg.

Human obesity is a state of hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and dysfunction of the sympathetic nervous system (SNS). It is unclear whether weight loss will normalize this apparent dysfunction and if potential changes are of short -or long-term duration. In this study, we test how weight reduction following Roux-en-Y Gastric Bypass (RYGB) surgery affects the HPA-axis and SNS activity for a follow-up period of 2 years. We show that a ≈ 30% reduction in bodyweight following RYGB, is accompanied by an increase in circulating cortisol, and decrease in the concentrations of systemic metanephrines concomitant with a transient reduction in systolic blood pressure, and that the endocrine changes persist for at least 24 months post-surgery. The decrease in SNS activity was weakly, but significantly correlated with postoperative improvements in HbA1c. These findings suggests that the anatomical rearrangement of the gastrointestinal system by bariatric surgery, and the resulting marked decrease in body weight, have long-term impact on the autonomic nervous system. The biological significance of these findings is uncertain though it could be speculated that chronically elevated serum cortisol, may be involved in the development of osteoporosis, a well-known risk of bariatric surgery, as well as control of glucose and lipid metabolism. Furthermore, the chronic reduction in metanephrines observed, suggest that SNS depression may contribute to both a reduction in blood pressure and better glycemic control following surgery. We collectively demonstrate that RYGB surgery has an early and persisting impact on the HPA-axis and the sympathetic nervous system, and that this is associated with bodyweight reduction and improved glycemic control.

Background Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. Methods Seventy CAD patients, BMI 28–40 kg/m 2 and age 45–75 years were randomised to (1) 12 weeks’ aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks’ AIT twice weekly or (2) a low energy diet (LED) (800–1000 kcal/day) for 8–10 weeks followed by 40 weeks’ weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. Results Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO 2 peak 20.7 mL O 2 /kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (− 8.4; − 6.1) and waist circumference by 6.6 cm (− 7.7; − 5.5) compared to 1.7 kg (− 0.7; − 2.6) and 3.3 cm (− 5.1; − 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO 2 peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. Conclusions Both interventions were feasible. Both groups obtained improvements in VO 2 peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).

Increased oxidative stress in obesity and diabetes is associated with morbidity and mortality risks. Levels of oxidative damage to DNA and RNA can be estimated through measurement of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine. Both markers have been associated with type 2 diabetes, where especially 8-oxoGuo is prognostic for mortality risk. We hypothesized that Roux-en-Y gastric bypass (RYGB) surgery that has considerable effects on bodyweight, hyperglycemia and mortality, might be working through mechanisms that reduce oxidative stress, thereby reducing levels of the urinary markers. We used liquid chromatography coupled with tandem mass spectrometry to analyze the content of 8-oxodG and 8-oxoGuo in urinary samples from 356 obese patients treated with the RYGB-procedure. Mean age (SD) was 44.2 (9.6) years, BMI was 42.1 (5.6) kg/m 2 . Ninety-six (27%) of the patients had type 2 diabetes. Excretion levels of each marker before and after surgery were compared as estimates of the total 24-hour excretion, using a model based on glomerular filtration rate (calculated from cystatin C, age, height and weight), plasma- and urinary creatinine. The excretion of 8-oxodG increased in the first months after RYGB. For 8-oxoGuo, a gradual decrease was seen. Two years after RYGB and a mean weight loss of 35 kg, decreased hyperglycemia and insulin resistance, excretion levels of both markers were reduced by approximately 12% ( P < 0.001). For both markers, mean excretion levels were about 30% lower in the female subgroup ( P < 0.0001). Also, in this subgroup, excretion of 8-oxodG was significantly lower in patients with than without diabetes. We conclude, that oxidative damage to nucleic acids, reflected in the excretion of 8-oxodG and 8-oxoGuo, had decreased significantly two years after RYGB—indicating that reduced oxidative stress could be contributing to the many long-term benefits of RYGB-surgery in obesity and type 2 diabetes.

We assessed the association of suPAR (soluble urokinase plasminogen activator receptor) plasma levels with fibrotic and vascular manifestations in patients with systemic sclerosis (SSc). suPAR plasma levels were measured in 121 consecutive patients with SSc and correlated to pulmonary and vascular features of SSc, including interstitial lung disease as characterized by percentage of predicted CO diffusing capacity (DLco) and forced vital capacity (FVC), pulmonary fibrosis by computed tomography, and pulmonary arterial hypertension, telangiectasias, and digital ulcers. Overall, 121 SSc patients (84% females; mean age, 57 ± 12 [range: 22-79] years) were enrolled; 35% had diffuse cutaneous SSc. suPAR plasma levels ranged from 1.3-10.2 [median: 2.9 (p25-p75: 2.3-3.9)] ng/mL. Log(suPAR) levels correlated with DLco (r = -0.41, p <0.0001) and FVC (r = -0.26, p = 0.004), also when adjusted for age, sex, and pulmonary hypertension. A suPAR cut-off level of >2.5 ng/mL showed a sensitivity of 91% for identifying patients with either DLco <50% or FVC < 60% of the predicted values. Similarly, 19 (90%) had a suPAR >2.5 ng/mL among those diagnosed with pulmonary fibrosis vs. 59 (60%) among those who did not (p = 0.008). suPAR values were not associated with vascular manifestations. suPAR levels strongly correlated with pulmonary involvement in SSc. Future studies should test if suPAR estimation can be used for surveillance of severe pulmonary involvement in SSc.

This study investigates the relationship between eight free fatty acids (FFA), triglycerides (TAG), and phosphatidylcholines (PC) after Roux‐en‐Y gastric bypass (RYGB) to obtain insight into changes in lipid metabolism that might be causally related to postsurgery Type 2 diabetes remission. We measured the FFA, TAG, and PC before and up to 2 years after RYGB in three patient groups: one nondiabetes group ( n = 149), one diabetes group with postoperative remission ( n = 33), and one diabetes group with persistent diabetes after surgery ( n = 20). Pre‐ and postoperative Pearson’s correlations and linear regression models were used to assess the relationship between concentrations of individual FFA, TAG, and PC. At all timepoints, FFA explained more of the variance in PC than in TAG. The level of omega‐3 fatty acids was more strongly correlated to TAG in the group with diabetes remission compared to the nondiabetes group. The low plasma concentration of the omega‐6 fatty acid dihomo‐γ‐linolenic acid (DGLA) showed a surprisingly high correlation to both TAG and PC in all three groups. Unexpectedly, in the diabetes group without remission, a nonsignificant relation between saturated stearic acid and monounsaturated oleic acid indicates a possible impaired conversion of stearic acid to oleic acid via the enzyme delta‐9‐desaturase compared with the two other groups. We conclude that FFA might be involved in regulating the synthesis and metabolism of both TAG and especially PC. Diabetes status might influence the relationship between concentrations of FFA, TAG, and PC, and the data are suggestive of a role for the enzyme delta‐9‐desaturase in post‐RYGB diabetes remission.

Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery. Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated. The GRS for BMI was not associated with weight loss ([beta] = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center ([beta] = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI ([beta] = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss ([beta] = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25). GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.

Background Metabolic effects of empagliflozin treatment include lowered glucose and insulin concentrations, elevated free fatty acids and ketone bodies and have been suggested to contribute to the cardiovascular benefits of empagliflozin treatment, possibly through an improved cardiac function. We aimed to evaluate the influence of these metabolic changes on cardiac function in patients with T2D. Methods In a randomized cross-over design, the SGLT2 inhibitor empagliflozin (E) was compared with insulin (I) treatment titrated to the same level of glycemic control in 17 patients with type 2 diabetes, BMI of > 28 kg/m 2 , C-peptide > 500 pM. Treatments lasted 5 weeks and were preceded by 3-week washouts (WO). At the end of treatments and washouts, cardiac diastolic function was determined with magnetic resonance imaging from left ventricle early peak-filling rate and left atrial passive emptying fraction (primary and key secondary endpoints); systolic function from left ventricle ejection fraction (secondary endpoint). Coupling between cardiac function and fatty acid concentrations, was studied on a separate day with a second scan after reduction of plasma fatty acids with acipimox. Data are Mean ± standard error. Between treatment difference (ΔT: E–I) and treatments effects (ΔE: E-WO or ΔI: I -WO) were evaluated using Students’ t-test or Wilcoxon signed rank test as appropriate. Results Glucose concentrations were similar, fatty acids, ketone bodies and lipid oxidation increased while insulin concentrations decreased on empagliflozin compared with insulin treatment. Cardiac diastolic and systolic function were unchanged by either treatment. Acipimox decreased fatty acids with 35% at all visits, and this led to reduced cardiac diastolic (ΔT: −51 ± 22 ml/s (p < 0.05); ΔE: −33 ± 26 ml/s (ns); ΔI: 37 ± 26 (ns, p < 0.05 vs ΔE)) and systolic function (ΔT: -3 ± 1% (p < 0.05); ΔE: −3 ± 1% (p < 0.05): ΔI: 1 ± 2 (ns, ns vs ΔE)) under chronotropic stress during empagliflozin compared to insulin treatment. Conclusions Despite significant metabolic differences, cardiac function did not differ on empagliflozin compared with insulin treatment. Impaired cardiac function during acipimox treatment, could suggest greater cardiac reliance on lipid metabolism for proper function during empagliflozin treatment in patients with type 2 diabetes. Trial registration: EudraCT 2017-002101-35, August 2017.

Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

Background Phosphatidylcholine (PC), the most abundant of the phospholipids, has several metabolic functions in organs such as the liver and the intestine, important structural- and signaling functions in biological membranes, and might have a role in the effects of Roux-en-Y gastric bypass (RYGB), an operation known to ameliorate metabolic diseases, including type 2 diabetes. We hypothesized that serum PC, as a reflection of phospholipid metabolism, changes after RYGB, and that changes are related to weight loss and possibly to changes in glucose metabolism (reflected in the HbA1c-level) as well as to changes in serum Apo A1, Apo B and Apo B/Apo A1 ratio. Methods In a cohort of 220 RYGB patients, we studied changes in serum PC after RYGB in relation to serum Apo A1 and Apo B, the main apolipoproteins in HDL- and LDL/VLDL-particles, respectively, up to 2 years following RYGB-surgery. Results Serum PC reached its lowest levels 3 months postoperatively to later rebound to preoperative levels 24 months after RYGB. No difference was seen between patients with or without type 2 diabetes. Serum Apo A1 showed a similar pattern whereas serum Apo B concentrations stayed low after the initial decrease after RYGB. As a result, the Apo B / Apo A1 ratio constantly decreased during follow-up. There was a strong positive correlation between PC and Apo A1, and between PC and Apo B, but none between Apo A1 and Apo B. After RYGB surgery, both PC and Apo A1, but not Apo B, correlated positively to weight loss. In relation to total cholesterol, the molar ratio between serum PC and plasma cholesterol increased steadily after RYGB. Conclusions We conclude that changes in PC and apolipoproteins after RYGB are highly dynamic, reflecting a large plasticity and capability of accommodating lipid metabolism including PC-, cholesterol- and apolipoprotein metabolism imposed by RYGB surgery, independent of glucose tolerance. We suggest that after RYGB and major weight loss, PC and Apo A1 might have a special role in the altered metabolism of lipoproteins.