Kurt Højlund

Aims/hypothesis: Glycated albumin (GA) has been shown to be a moderate predictor of gestational diabetes mellitus (GDM), while evidence supporting its role in predicting adverse pregnancy outcomes remains limited. Here, we aimed to perform a comparative study of GA and haemoglobin A1c (HbA _1c ) for predicting GDM and large-for-gestational-age (LGA) infants in a prospective cohort. Methods: We developed a rapid liquid chromatography-tandem mass spectrometry method for measuring site-specific albumin glycation. GA was quantified at two glycation sites, GA (KQT) and GA (KLV), as well as their sum, GA-total. GA was measured in stored serum samples collected at 11-14 and 23-31 gestational weeks from 465 participants in the single-centre observational cohort. HbA _1c was measured routinely at each visit. Linear mixed-effects models were used to compare GA between participants with and without GDM (n=100) or LGA (n=57). Logistic regression was used to estimate odds ratios (ORs) for GDM and LGA according to GA and HbA _1c . Results: GA was lower in women who developed GDM during early pregnancy compared to non-GDM controls (GA-total; p =0.004), while in mid-late pregnancy, only GA (KQT) was lower in women with GDM ( p =0.036). In contrast, HbA _1c was higher in women with GDM at both timepoints compared to non-GDM controls ( p 1c was associated with increased odds of GDM (OR=2.20, p p p =0.032) and mid-late pregnancy (GA-total; p =0.030) and associated with increased odds of LGA (GA-total; OR=1.59, p =0.009; GA-total; OR=1.46, p =0.019, respectively). HbA _1c was not associated with LGA at either timepoint. Conclusions/interpretation: Higher GA in early and mid-late pregnancy were associated with an increased risk of LGA, whereas no significant association was observed for HbA _1c . GA may therefore provide risk assessment beyond HbA _1c for identifying pregnancies at risk of fetal overgrowth. Research in Context: What is already known about this subject?: Glycated albumin (GA) has been proposed as a biomarker for GDM, LGA, and other adverse pregnancy outcomes. HbA _1c is an established marker of chronic glycaemia outside pregnancy, but its role in the routine diagnosis and monitoring of GDM during pregnancy remains limited. Both GA and HbA _1c are markers of glycaemic exposure; however, they capture different time frames and are influenced differently by the physiological changes of pregnancy. What is the key question?: Are GA and HbA _1c measured during pregnancy associated with GDM and LGA? What are the new findings?: HbA _1c and GA showed opposing associations with GDM development. Higher GA in early and mid-late pregnancy were associated with an increased risk of LGA. HbA _1c showed limited association with LGA. How might this impact clinical practice in the foreseeable future?: GA and HbA _1c may serve as complementary biomarkers for assessing glycaemia and predicting pregnancy complications, with potential utility for improving risk stratification during pregnancy.

Aims: This study aimed to investigate the prospective associations of interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hsCRP) levels with major adverse cardiac event (MACE) and mortality in individuals recently diagnosed with type 2 diabetes and without prevalent cardiovascular disease (CVD). Methods and results: We included 7630 individuals recently diagnosed with type 2 diabetes (median duration 0.9 years) with a median age of 60 years (44% females). Individuals with prevalent CVD (n = 1390) were excluded from the primary analyses modelling Fine-Gray subdistribution hazard regressions accounting for competing risk of non-CVD death and adjusting for classical risk factors (e.g. diabetes duration, smoking, alcohol, physical activity, waist circumference, LDL cholesterol, haemoglobin A1c, systolic blood pressure, estimated glomerular filtration rate, and pharmacological treatment). Subsequently, we evaluated the predictive ability of adding low-grade inflammation to a model containing classical risk factors. Median follow-up time was 9 years. A 1-SD increase in log-IL-6 (1.98 pg/mL), log-TNF-α (1.40 pg/mL) and log-hsCRP (3.28 mg/L) was associated with HRs of 1.16 (95% CI 1.09, 1.23), 1.01 (0.95, 1.08), and 1.16 (1.09, 1.25) for MACE and 1.38 (1.31, 1.45), 1.16 (1.10, 1.22), and 1.34 (1.25, 1.43) for all-cause mortality, respectively. Prediction of both MACE and all-cause mortality was slightly improved by adding IL-6 and hsCRP to the model alongside classical risk factors. Conclusion: Low-grade inflammation was associated with MACE and all-cause mortality, independently of classical risk factors, in individuals recently diagnosed with type 2 diabetes and without prevalent CVD. Despite improved predictive ability of IL-6 and hsCRP, the absolute improvement was sparse. Lay Summary: Higher levels of chronic inflammation were associated with a higher risk of cardiovascular disease and mortality in individuals recently diagnosed with type 2 diabetes and without known cardiovascular disease.Especially, IL-6 and hsCRP were associated with a higher risk of myocardial infarction, ischaemic stroke, coronary revascularization, and heart failure hospitalizationOverall, chronic inflammation was a better predictor of mortality than non-fatal cardiovascular events

Aims: Care home admission often reflects frailty and limited life expectancy, potentially altering the benefit‐harm balance of glucose‐lowering drug (GLD) treatment for type 2 diabetes (T2D). Real‐world data on treatment patterns in this setting remain limited. We examined GLD use for T2D among Danish care home residents. Materials and Methods: We conducted a nationwide, population‐based drug utilisation study of all individuals admitted to Danish care homes between 2018 and 2023, using linked national health registries. Results: Among 88 658 residents (median age: 84 years [IQR: 78–90]; 60% women), 13% ( n = 11 101) used GLDs for T2D at admission, with 84% continuing treatment beyond 2 years. Residents using GLDs at admission had long‐standing diabetes (median duration: 12 years [IQR: 6.8–15]), relatively low glycated haemoglobin levels (median: 6.9% [IQR: 6.3–7.8]; 52 mmol/mol [45–62]) with little change around admission, and 43% used more than one GLD class, most commonly metformin (70%) and insulin (36%; basal: 30%; bolus: 16%). Use of glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors increased over time but remained limited (13% and 24%, respectively, in 2023), despite a high prevalence of cardiorenal disease (84%), and did not differ by cardiorenal disease status. Overall GLD use remained stable around admission, but initiation spiked 3 months before admission (36 initiators/10 000 residents), often following hospitalisation (63%) and primarily involved bolus insulin initiated by hospital physicians. Conclusions: GLD use for T2D among Danish care home residents is high and shows limited deintensification and potential misalignment with guideline recommendations.

Liver fibrosis is a serious complication of non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), conditions closely linked to obesity. We investigated the levels and dynamics of liver fibrosis biomarkers and liver fat content during personalized weight loss intervention in individuals with obesity, NAFLD, and concomitant MetS (n=30), with assessments at baseline, 1, and 5 months. Liver fat content decreased significantly (p < 0.0001), corresponding with complete resolution of steatosis in 36.7% of the participants, after 1 month of weight loss. Similarily, the fibrosis markers: T1 (p < 0.01), CK18 (p < 0.01), PIIINP (p < 0.0001), TIMP1 (p < 0.001), and MACK3 (p < 0.001) dropped after 1 month. CK18 (p < 0.01) and MACK3 (p < 0.001) further changed from 1 to 5 months, while FNI decreased after 5 months (p < 0.01). Except for CK18, the dynamics of these changes were more pronounced from baseline to 1 month compared with 1 to 5 months. Finally, MACK3 showed promise for explaining T1.Our study underlines the importance of weight loss in swiftly mitigating liver steatosis and supports the integration of non-invasive biomarkers to monitor fibrosis risk in individuals with obesity, NAFLD, and MetS.

Introduction: The pathogenic mitochondrial gene variant m.3243A>G disrupts oxidative phosphorylation and is associated with insulin resistance, both of which may be linked to unfavorable lipid metabolism. However, the metabolic alterations in m.3243A>G carriers, including what differentiates those with and without diabetes, remain incompletely understood. Objectives: To investigate metabolomic profiles in fasting serum and urine samples from m.3243A>G carriers compared to healthy controls. Methods: Metabolomic profiling of serum and urine samples using nuclear magnetic resonance-based metabolomics in m.3243A>G carriers ( n = 28) was compared to healthy controls matched for age and sex. Additionally, profiles from m.3243A>G carriers with diabetes ( n = 16) were compared with carriers without diabetes ( n = 12) to identify potential metabolites associated with the presence of diabetes. Results: Twenty-five metabolites in serum and 16 in urine were identified as metabolites separating m.3243A>G carriers from healthy controls. The m.3243A>G carriers presented with increased triglycerides across lipoprotein particles and altered very-low-density lipoprotein concentrations and composition. In addition, there were alterations in metabolites from a number of metabolic pathways, including glycolysis, the tricarboxylic acid cycle, glutathione, one-carbon, and nucleotide metabolism. A three metabolite-urine signature (uracil, hypoxanthine, and 1-methylnicotinamide) demonstrated discriminating potential between m.3243A>G carriers and controls in exploratory machine learning analyses (area under the curve values 0.94–0.99 and cross-validation prediction of 0.81–0.93). Among m.3243A>G carriers, branched-chain amino acids were higher in individuals with diabetes compared with carriers without diabetes. Conclusion: Dysregulated lipoprotein metabolism represents a significant metabolic fingerprint of m.3243A>G carriers. Furthermore, higher levels of branched-chain amino acids may be associated with the presence of diabetes.

Microvascular diseases (MVD) in type 2 diabetes mellitus (T2D) are associated with alterations in the bone microarchitecture, but their association with fracture risk is unclear. We investigated whether MVD (retinopathy, nephropathy, and neuropathy) are associated with higher fracture risk in persons with T2D. We identified 10491 persons with T2D, enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes cohort between 2010 and 2022. The primary outcomes were any hospital-diagnosed fracture (except facial and cranial), and major osteoporotic fractures (MOF), defined as clinical vertebral, hip, humerus, and forearm fractures, in persons with hospital-diagnosed MVD versus without MVD. We used Cox proportional hazard models to calculate crude and adjusted hazard ratios (aHRs). During a median follow-up of 7.6 years IQR (3.5; 9.7), the rates of any fracture were higher in persons with T2D and MVD versus no MVD (aHR 1.31; 95% CI [1.15; 1.51]). Similarly, MOF rate was elevated in persons with MVD (aHR 1.33 [1.09; 161]). The rates for any fracture and MOF were highest in persons with neuropathy (aHR 1.49 [1.24; 1.78] and aHR 1.54 [1.19; 1.99], respectively). Fracture risk is elevated in persons with T2D complicated by MVD, particularly in those with neuropathy.

Insulin resistance in obesity and type 2 diabetes (T2D) is characterized by reduced insulin-stimulated glucose uptake, accumulation of triacylglycerol, mitochondrial dysfunction, and altered protein metabolism in skeletal muscle. This may involve disturbed endoplasmic reticulum (ER) homeostasis, leading to alterations in the unfolded protein response (UPR) and, hence, the protein folding capacity. Here, we investigated whether markers of UPR activity are elevated in skeletal muscle in obesity and T2D and to what extent insulin regulates these UPR markers. In a case–control design, we determined mRNA expression, protein abundance, and phosphorylation of key UPR markers in skeletal muscle biopsies obtained from patients with T2D, matched to glucose-tolerant individuals with obesity and lean individuals, before and after 4-h insulin infusion during a hyperinsulinemic-euglycemic clamp. The mRNA expression or protein abundance of GRP78, the canonical ER stress sensors (ATF6, PERK, and IRE-1α), several downstream UPR markers, and related markers of mitochondrial dynamics did not differ between groups. Insulin increased the mRNA expression of ATF6, ERN1 (encoding IRE-1α), XBP1, DDIT3 (encoding CHOP), and a marker of mitochondrial fission, DNM1l (encoding DRP1), as well as eIF2α Ser51 phosphorylation in skeletal muscle in all groups (all P <0.05), with no between-group differences. Our results demonstrate that markers of UPR activity are not elevated in skeletal muscle in obesity or T2D. Interestingly, insulin increases the expression of UPR markers and activates eIF2α, which is necessary for increasing the protein folding capacity of ER in muscle, and these responses are intact in obesity and T2D.