Background: Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D).Materials and Methods: Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders.Results: Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06–1.72), p = 0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01–1.55), p = 0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02–1.53), p = 0.022), but not osteocalcin.Conclusions: In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Context: Autoantibodies against interferon-α (AAb-IFN-α) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D). Objective: To investigate the presence and clinical relevance of the positivity to AAb-IFN-α in people with LADA compared to T1D. Research Design and Methods: Serum levels of AAb-IFN-α isoforms were measured using a cell-based approach in 41 subjects with LADA and 90 subjects with T1D. Outcomes: The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for autoantibodies (AAb) against ≥2 and against 3 interferon-α (IFN-α) isoforms, respectively. The presence and levels of AAb-IFN-α were related to clinical and biochemical features of participants with LADA. Results: Seven (17.1%) and 5 (12.2%) participants with LADA and 3 (3.3%) and 0 participants with T1D showed positivity for AAb against ≥2 and 3 IFN-α isoforms (P = .011 and P = .0025, respectively). Fasting blood glucose and hemoglobin A1c levels were numerically lower among people with LADA testing positive for AAb against ≥2 IFN-α isoforms than among those who were either negative or positive for AAb against 1 IFN-α isoform. Among LADA-positive individuals, levels of AAb-IFN-α2 isoform were inversely correlated with glutamic acid decarboxylase antibodies levels (rho = −0.513; P = .025). Conclusion: Autoimmunity against IFN-α is peculiar to autoimmune diabetes and appears to be distinctive to its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.

Osteocalcin (OCN), whose release is impaired in diabetes, is suggested to regulate the adipose tissue (AT), being potentially associated with Cardiovascular risk (CVR). We aimed at evaluating whether OCN serum levels are associated with AT health and CVR in a primary CV prevention population with AD. Body mass composition was assessed in sixty-two people with AD.Serum levels of OCN, adipokines and markers of endothelial dysfunction were measured. Regression models were used to test the association of OCN with markers of AT, endothelial dysfunction and CVR categories as determined by the Steno Type 1 Risk Engine (ST1RE) score. OCN was inversely associated with upper body fat deposition index (UBDFI) (Adj β coefficient -0.484, p value = 0.001). People in medium/high CV risk categories had higher UBFDI and lower OCN, while biomarkers of endothelial dysfunction were not different across CVR classes. A logistic binary regression for ST1RE score showed significant association of OCN with medium/high CVR category: OR [95 % CI for 1 SD increase: 0.541 [0.264--1.108], p = 0.093]. OCN is inversely associated with unhealthy AT, supporting the protective role of OCN in AT. Moreover, lower OCN levels are associated with increased CVR in AD population.

Background and Aim: Diabetic neuropathy (DN) is a recognised risk factor for fragility fractures. However, the mechanisms linking DN, bone health, and falling risk remain unclear. We aimed to assess bone health and risk of falls, with their contributing factors, in young elderly patients with type 2 diabetes (T2D) and mild‐to‐moderate DN. Methods: We enrolled 144 subjects with T2D, excluding those with severe DN (neuropathy disability score ‐NDS‐ ≥ 9) or fracture history. Clinical and biochemical data were collected, including surrogate markers of insulin resistance, such as the triglycerides/HDL (TG/HDL) ratio and triglycerides/glucose (TyG) index. Bone mineral density (BMD) and trabecular bone score (TBS) were evaluated using DXA scans. Falls were self‐recorded prospectively over 4 years using diaries. Results: Subjects with DN (27%) had higher BMI ( p = 0.036), fasting blood glucose ( p = 0.04), serum triglycerides ( p = 0.016), TG/HDL ratio ( p = 0.012) and TyG index ( p = 0.003) compared with those without DN. After adjustment for gender, age, BMI, HbA1c, TyG index and TG/HDL ratio, subjects with DN showed significantly lower BMD at the femoral neck (0.702 [0.638–0.850] g/cm ² vs. 0.789 [0.717–0.860] g/cm ² , p = 0.015) and total femur (0.890 [0.820–1.055] g/cm ² vs. 0.983 [0.889–1.076] g/cm ² , p = 0.027). No differences were observed in spine BMD or TBS. However, TBS was negatively correlated with the TG/HDL ratio ( r = −0.215, p = 0.013) and visceral adipose tissue ( r = −0.310, p < 0.001). After 4 years of follow‐up, subjects with painful neuropathy at baseline had a higher rate of falls ( p = 0.011). Conclusion: DN is associated with decreased BMD and increased risk of falls. Among factors associated with DN, insulin resistance was also associated with decreased bone quality.

We conducted a cross-sectional study to explore the interplay between β-cell function and peripheral insulin resistance in latent autoimmune diabetes in adults (LADA) compared with type 2 diabetes. Thirty-one people with LADA were matched for sex, BMI, and disease duration with 31 people with type 2 diabetes. Insulin resistance was estimated using established surrogate indexes, and serum C-peptide levels were measured by ELISA. Despite the similar BMI, the LADA group exhibited lower mean values of estimated insulin resistance compared with the type 2 diabetes group. Among individuals with similar insulin resistance, the LADA group consistently showed lower C-peptide values compared with the type 2 diabetes group. C-peptide levels showed a direct relationship with the majority of insulin resistance indexes exclusively in type 2 diabetes, but not in LADA. Our findings show that people with LADA exhibit a blunted insulin secretory capacity compared with people with type 2 diabetes, even at similar levels of insulin resistance, being unable to mount a meaningful compensatory response to insulin resistance. This discrepancy may explain the worse glycemic control often observed in people with LADA, placing these people at higher risk of suboptimal glycemic control and highlighting the importance of early and accurate classification of adult-onset diabetes and tailored therapeutic strategies. Article Highlights: The identification of differences in the relationship between insulin secretion and resistance among different diabetes types will help inform clinical decisions. The interplay between insulin secretion and resistance may distinguish latent autoimmune diabetes in adults (LADA) from type 2 diabetes. Individuals with LADA are less capable of mounting a sustained compensatory insulin secretion compared with those with type 2 diabetes, even at similar insulin resistance levels. Distinct pathophysiology characterizes LADA and type 2 diabetes. The defect in insulin secretion for similar levels of insulin resistance might contribute to the higher risk of poor glycemic control often observed in LADA, arguing for accurate diagnosis of adult-onset diabetes types.