Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.

Background: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin.Methods: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen’s Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects.Results: In total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76–1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73–1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49–0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis.Conclusion: In our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.

Background: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin.Methods: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator.Results: In total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses.Conclusion: These results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

Background: Coffee consumption is inversely associated with type 2 diabetes. Cafestol, a bioactive compound in coffee, has demonstrated glucose-lowering and insulin-secretory properties in cell and animal studies. The acute effects of cafestol on glucose metabolism in humans have only been briefly investigated, and longer-term effects have not been explored. This study aimed to assess the effects of purified cafestol on insulin sensitivity and other metabolic parameters in healthy individuals with increased waist circumference at risk of developing type 2 diabetes. Methods: A 12-week randomized, placebo-controlled, parallel trial was conducted with 40 participants. Insulin suppression tests, mixed meal tests, and MRI scans were performed before and after the intervention. Results: Administering 6 mg of cafestol twice daily did not alter insulin sensitivity or glucose tolerance but led to significant reductions in body weight (2%), visceral fat volume (5%), and gamma-glutamyl transferase levels (15%) compared to the placebo. Conclusions: Cafestol may hold promise for weight and visceral fat reduction. Cafestol did not improve insulin sensitivity or glucose tolerance in this study but might still contribute to the observed inverse association between coffee consumption and type 2 diabetes. Future research should explore higher dosages and longer treatment durations, particularly in individuals with impaired glucose metabolism and type 2 diabetes.

Type 2 diabetes mellitus (T2DM) and osteoporosis are two major public health concerns worldwide, contributing to morbidity and mortality in the elderly. Aging is one of the most significant risk factors for low bone mass, bone fragility, and fractures. Among the several comorbidities that affect the elderly with diabetes, increased fracture risk is a relatively recently discovered complication. Generally, individuals with T2DM exhibit higher bone mineral density, which complicates the assessment of fracture risk. Despite the growing evidence for an association between T2DM and increased fracture risk, especially among the elderly, the underlying mechanism has not yet been fully uncovered, and proper evaluation of bone health in individuals with T2DM remains a challenge. The present review includes 125 articles investigating the effects of T2DM on bone health in the elderly. A systematic literature search was performed in PubMed, Embase, and CINAHL for articles containing terms corresponding to ‘elderly’ and ‘type 2 diabetes mellitus’ along with ‘bone fracture’, ‘osteoporosis’, or ‘bone turnover’. Articles investigating the effects of T2DM and disease severity, duration, or complications on bone parameters – i.e. fracture risk, structure, and turnover – were selected for inclusion in the present review. Overall, the evidence indicated reduced bone turnover in individuals with T2DM, accompanied by an increased bone mineral density (BMD) and an inefficient distribution of bone mass with accumulated trabecular bone and diminished cortical bone. These structural alterations in bone tissues result in bone fragility and overall increased fracture risk in elderly individuals with T2DM. However, measurement of BMD does not adequately predict the increased fracture risk in T2DM. Therefore, identification and application of more precise predictors of fracture risk in individuals with T2DM are required. Furthermore, a better understanding of the pathophysiological mechanisms involved may assist in developing effective treatments of bone disease in individuals with diabetes. The present review introduces current candidates for improved measures of bone quality and fracture risk along with the current knowledge on the pathophysiology of diabetic bones.