Metabolic profiling of galectin-1 and galectin-3: a cross-sectional, multi-omics, association study.

OBJECTIVES: Experimental studies indicate a role for galectin-1 and galectin-3 in metabolic disease, but clinical evidence from larger populations is limited. METHODS: We measured circulating levels of galectin-1 and galectin-3 in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study, participants (n = 502, all aged 50 years) and characterized the individual association profiles with metabolic markers, including clinical measures, metabolomics, adipose tissue distribution (Imiomics) and proteomics. RESULTS: Galectin-1 and galectin-3 were associated with fatty acids, lipoproteins and triglycerides including lipid measurements in the metabolomics analysis adjusted for body mass index (BMI). Galectin-1 was associated with several measurements of adiposity, insulin secretion and insulin sensitivity, while galectin-3 was associated with triglyceride-glucose index (TyG) and fasting insulin levels. Both galectins were associated with inflammatory pathways and fatty acid binding protein (FABP)4 and -5-regulated triglyceride metabolic pathways. Galectin-1 was also associated with several proteins related to adipose tissue differentiation. CONCLUSIONS: The association profiles for galectin-1 and galectin-3 indicate overlapping metabolic effects in humans, while the distinctly different associations seen with fat mass, fat distribution, and adipose tissue differentiation markers may suggest a functional role of galectin-1 in obesity.

Loading enhances glucose uptake in muscles, bones, and bone marrow of lower extremities in humans.

CONTEXT: Increased standing time has been associated with improved health, but the underlying mechanism is unclear. OBJECTIVES: We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities. METHODS: In this single-center clinical trial with randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index (BMI) between 30 and 35 kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography (PET/CT) imaging. The primary endpoint was the change in GU ratio between loaded bones (i.e. femur and tibia) and non-loaded bones (i.e. humerus). RESULTS: High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (e.g. femur/humerus ratio increased by 19%, p = 0.029), muscles (e.g. m. quadriceps femoris/m. triceps brachii ratio increased by 28%, p = 0.014) and in certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, p = 0.041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load. CONCLUSIONS: Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.

Cardiorespiratory fitness and the association with galectin-1 in middle-aged individuals.

Galectin-1 plays a functional role in human metabolism and the levels are altered in obesity and type 2 diabetes (T2D). This study investigates the association of cardiorespiratory fitness (CRF) with galectin-1 and the interconnection with body fatness. Cross-sectional data from the Swedish CArdioPulmonary bioImage Study (SCAPIS) pilot was analyzed, including a sample of 774 middle-aged individuals. A submaximal cycle ergometer test was used to estimate CRF as an indirect measure of the physical activity (PA) level. Serum-galectin-1 concentration was determined from venous blood collected after an overnight fast. Body mass index (BMI) was used as an indirect measure of body fatness. CRF was significantly associated with galectin-1, when controlled for age and sex (regression coefficient (regr coeff) = -0.29, p<0.001). The strength of the association was attenuated when BMI was added to the regression model (regr coeff = -0.09, p = 0.07), while the association between BMI and galectin-1 remained strong (regr coeff = 0.40, p<0.001). CRF was associated with BMI (regr coeff = -0.50, p<0.001). The indirect association between CRF and galectin-1 through BMI (-0.50 x 0.40) contributed to 69% of total association (mediation analysis). In group comparisons, individuals with low CRF-high BMI had the highest mean galectin-1 level (25 ng/ml), while individuals with high CRF-low BMI had the lowest level (21 ng/ml). Intermediate levels of galectin-1 were found in the low CRF-low BMI and high CRF-high BMI groups (both 22 ng/ml). The galectin-1 level in the low CRF-high BMI group was significantly different from the other three groups (P<0.001). In conclusion, galectin-1 is associated with CRF as an indirect measure of the PA level through interconnection with body fatness. The size of the association is of clinical relevance.

Galectin-1 correlates with inflammatory markers and T regulatory cells in children with type 1 diabetes and/or celiac disease.

Type 1 diabetes (T1D) and celiac disease (CeD) are common autoimmune diseases in children where the pathophysiology is not fully characterized. The autoimmune process involves a complex scenario of both inflammatory and regulatory features. Galectin-1 (GAL-1) has a wide range of biological activities e.g. interaction with immune cells. We examined the relationship between GAL-1 and soluble immune markers and T-cell subsets in a cohort of children with T1D and/or CeD relative to healthy children. GAL-1, together with several soluble immune markers [e.g. interleukins (IL)], tumor necrosis factor (TNF), acute phase proteins, and matrix metalloproteinases (MMP) were measured in sera from children with T1D and/or CeD by fluorochrome (Luminex) technique using children without these diseases as a reference. Subgroups of T cells, including T-regulatory (Treg) cells, were analysed by flow cytometry. Association between GAL-1, pro-inflammatory markers, and Treg cells differed depending on which illness combination was present. In children with both T1D and CeD, GAL-1 correlated positively with pro-inflammatory markers (IL-1ß, IL-6, and TNF-α). Composite scores increased the strength of correlation between GAL-1 and pro-inflammatory markers, Th1-associated interferon (IFN)-γ, and T1D-associated visfatin. Contrary, in children diagnosed with exclusively T1D, GAL-1 was positively correlated to CD25hi and CD25hiCD101+ Treg cells. For children with only CeD, no association between GAL-1 and other immune markers was observed. In conclusion, the association observed between GAL-1, soluble immune markers, and Treg cells may indicate a role for GAL-1 in the pathophysiology of T1D and, to some extent, also in CeD.

The dual hypothesis of homeostatic body weight regulation, including gravity-dependent and leptin-dependent actions.

Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the gravitostat and proposed that there are two components of the gravitostat. First, an obvious mechanism involves increased energy consumption in relation to body weight when working against gravity on land. In addition, we propose that there exists a component, involving sensing of the body weight by osteocytes in the weight-bearing bones, resulting in a feedback regulation of energy metabolism and body weight. The gravity-dependent homeostatic regulation is mainly active in obese mice. We, herein, propose the dual hypothesis of body weight regulation, including gravity-dependent actions (= gravitostat) at the upper end and leptin-dependent actions at the lower end of the body weight spectrum. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Feasibility of high-dose tadalafil and effects on insulin resistance in well-controlled patients with type 2 diabetes (MAKROTAD): a single-centre, double-blind, randomised, placebo-controlled, cross-over phase 2 trial.

Background: Phosphodiesterase-5 inhibitors exert positive vascular and metabolic effects in type 2 diabetes (T2D), but the effect on insulin resistance in T2D is unclear. Methods: This randomised, double blind, placebo-controlled, two-period crossover trial was conducted at Sahlgrenska University Hospital (Gothenburg, Sweden). Men without apparent erectile dysfunction (age 40-70 years) and women (age 55-70 years, post-menopause) diagnosed with T2D between 3 months and 10 years, haemoglobin A1c (HbA1c) < 60 mmol/mol and a body mass index (BMI) 27-40 kg/m2 were enrolled. Participants were randomly assigned to one period of oral tadalafil 20 mg once a day and one period of placebo for 6 weeks, separated by an 8-week wash-out period. Placebo and tadalafil tablets were made visually indistinguishable and delivered randomized in two separate boxes for each participant. Both treatment periods ended with a glucose clamp, and measurements of body composition and metabolic markers in blood, subcutaneous and muscular interstitial fluid. The primary aim was to assess difference in whole-body insulin resistance after 6-weeks of treatment, determined after completion of the two study arms, and secondary aims were to study effects of tadalafil on pathophysiology of T2D as well as tolerability of high-dose tadalafil in T2D. Primary analysis was performed in participants with full analysis set (FAS) and safety analysis in all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT02601989), and EudraCT (2015-000573). Findings: Between January 22nd, 2016, and January 31st, 2019, 23 participants with T2D were enrolled, of whom 18 were included in the full analysis set. The effect of tadalafil on insulin resistance was neutral compared with placebo. However, tadalafil decreased glycaemia measured as HbA1c (mean difference -2.50 mmol/mol, 95% confidence interval (CI), -4.20; -0.78, p = 0.005), and, further, we observed amelioration of endothelial function and markers of liver steatosis and glycolysis, whereas no statistically significant differences of other clinical phenotyping were shown. Muscle pain, dyspepsia, and headache were more frequent in participants on high-dose tadalafil compared with placebo (p < 0.05) but no difference between treatments appeared for serious adverse events. Interpretation: High-dose tadalafil does not decrease whole-body insulin resistance, but increases microcirculation, induces positive effects in the liver and in intermediate metabolites, in parallel with an improved metabolic control measured as HbA1c. High-dose tadalafil is moderately well tolerated, warranting larger trials to define the optimal treatment regimen in T2D. Funding: The Swedish Research Council, Swedish Diabetes Foundation, Novo Nordisk Foundation, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, Sahlgrenska University Hospital funds, Gothenburg Society of Medicine, Eli Lilly & Company, USA, and Eli Lilly & Company, Sweden AB.

Galectin-1 in Obesity and Type 2 Diabetes.

Galectin-1 is a carbohydrate-binding protein expressed in many tissues. In recent years, increasing evidence has emerged for the role of galectin-1 in obesity, insulin resistance and type 2 diabetes. Galectin-1 has been highly conserved through evolution and is involved in key cellular functions such as tissue maturation and homeostasis. It has been shown that galectin-1 increases in obesity, both in the circulation and in the adipose tissue of human and animal models. Several proteomic studies have independently identified an increased galectin-1 expression in the adipose tissue in obesity and in insulin resistance. Large population-based cohorts have demonstrated associations for circulating galectin-1 and markers of insulin resistance and incident type 2 diabetes. Furthermore, galectin-1 is associated with key metabolic pathways including glucose and lipid metabolism, as well as insulin signalling and inflammation. Intervention studies in animal models alter animal weight and metabolic profile. Several studies have also linked galectin-1 to the progression of complications in diabetes, including kidney disease and retinopathy. Here, we review the current knowledge on the clinical potential of galectin-1 in obesity and type 2 diabetes.

Performance of Dexcom G5 and FreeStyle Libre sensors tested simultaneously in people with type 1 or 2 diabetes and advanced chronic kidney disease.

BACKGROUND: Advanced chronic kidney disease (CKD) is a common complication for people with type 1 and 2 diabetes and can often lead to glucose instability. Continuous glucose monitoring (CGM) helps users monitor and stabilize their glucose levels. To date, CGM and intermittent scanning CGM are only approved for people with diabetes but not for those with advanced CKD. AIM: To compare the performance of Dexcom G5 and FreeStyle Libre sensors in adults with type 1 or 2 diabetes and advanced CKD. METHODS: This was a non-randomized clinical trial that took place in two outpatient clinics in western Sweden. All patients with type 1 or 2 diabetes and an estimated glomerular filtration rate (eGFR) of < 30 mL/min per 1.73 m2 were invited to participate. Forty patients (full analysis set = 33) carried the Dexcom G5 sensor for 7 d and FreeStyle Libre sensor for 14 d simultaneously. For referencing capillary blood glucose (SMBG) was measured with a high accuracy glucose meter (HemoCue®) during the study period. At the end of the study, all patients were asked to answer a questionnaire on their experience using the sensors. RESULTS: The mean age was 64.1 (range 41-77) years, hemoglobin A1c was 7.0% [standard deviation (SD) 3.2], and diabetes duration was 28.5 (SD 14.7) years. A total of 27.5% of the study population was on hemodialysis and 22.5% on peritoneal dialysis. The mean absolute relative difference for Dexcom G5 vs SMBG was significantly lower than that for FreeStyle Libre vs SMBG [15.2% (SD 12.2) vs 20.9% (SD 8.6)], with a mean difference of 5.72 [95% confidence interval (CI): 2.11-9.32; P = 0.0036]. The mean absolute difference was also significantly lower for Dexcom G5 than for FreeStyle Libre, 1.21 mmol/L (SD 0.78) and 1.76 mmol/L (SD 0.78), with a mean diffrenec of 0.55 (95%CI: 0.27-0.83; P = 0.0004).The mean difference (MD) was -0.107 mmol/L and -1.10 mmol/L (P = 0.0002), respectively. In all, 66% of FreeStyle Libre values were in the no risk zone on the surveillance error grid compared to 82% of Dexcom G5 values. CONCLUSION: Dexcom G5 produces more accurate sensor values than FreeStyle Libre in people with diabetes and advanced CKD and is likely safe to be used by those with advanced CKD.

Somatic ablation of IKKß in liver and leukocytes is not tolerated in obese mice but hepatic IKKß deletion improves fatty liver and insulin sensitivity.

The kinase IKKß controls pro-inflammatory gene expression, and its activity in the liver and leukocytes was shown to drive metabolic inflammation and insulin resistance in obesity. However, it was also proposed that liver IKKß signaling protects obese mice from insulin resistance and endoplasmic reticulum (ER) stress by increasing XBP1s protein stability. Furthermore, mice lacking IKKß in leukocytes display increased lethality to lipopolysaccharides. This study aims at improving our understanding of the role of IKKß signaling in obesity. We induced IKKß deletion in hematopoietic cells and liver of obese mice by Cre-LoxP recombination, using an INF-inducible system, or a liver-specific IKKß deletion in obese mice by adenovirus delivery of the Cre recombinase. The histopathological, immune, and metabolic phenotype of the mice was characterized. IKKß deletion in the liver and hematopoietic cells was not tolerated in mice with established obesity exposed to the TLR3 agonist poly(I:C) and exacerbated liver damage and ER-stress despite elevated XBP1s. By contrast, liver-specific ablation of IKKß in obese mice reduced steatosis and improved insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of de-novo lipogenesis genes. We conclude that IKKß blockage in liver and leukocytes is not tolerated in obese mice exposed to TLR3 agonists. However, selective hepatic IKKß ablation improves fatty liver and insulin sensitivity in association with increased XBP1s protein abundance and reduced expression of lipogenic genes.