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Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

Background/Objectives: Previous studies have suggested that lifestyle intervention (LSI) therapies involving diet and exercise can modulate DNA methylation; however, whether this occurs in severely obese hypogonadal men undergoing weight loss from diet and exercise remains unclear. Methods: In this study, we investigated the effects of weight loss from diet and exercise on global DNA methylation as well as on the mRNA expression of specific demethylation enzymes, DNMT1, DNMT3A, and DNMT3B—in peripheral blood mononuclear cells (PBMCs) and DNA methylation markers in DNA of severely obese hypogonadal men. This is a secondary analysis of samples of severely obese (body mass index of ≥35 kg/m2) hypogonadal men undergoing weight loss from diet and exercise in addition to an aromatase inhibitor (anastrozole) or placebo for a total of 12 months. Results: LSI therapy significantly reduced global DNA methylation and 5-methylcytosine (5-mC) levels, decreased DNMT1, DNMT3A, and DNMT3B (p < 0.05) mRNA levels and markedly decreased CEBPα, FTO, and PPARγ mRNA expression. The reduction in global methylation was independent of aromatase inhibitor use. Conclusions: In summary, our findings suggest that LSI induces epigenetic modifications in leukocytes, possibly through the regulation of DNMT gene expression. Future studies are warranted to clarify the mechanistic pathways linking lifestyle-induced epigenetic alterations to metabolic health outcomes.

We previously reported that PRDM16 mediated the improvement in body composition in testosterone (T)-treated hypogonadal men by shifting adipogenesis to myogenesis. Previous preclinical studies suggest that Prdm16 regulates Runx2, an important osteoblastic transcription factor, expression and activity. However, the changes in PRDM16, and other genes/proteins involved in osteoblastogenesis with T therapy in hypogonadal men are unexplored. We investigated the role of PRDM16 in RUNX2 activation by measuring changes in gene expression in peripheral blood monocytes (PBMCs) and proteins in the serum of hypogonadal men after T therapy for 6 months. Likewise, we evaluated changes in the WNT10b—β-CATENIN signaling pathway by gene expression and protein analyses. We found significant increases in PRDM16 and RUNX2 expression in PBMCs together with significant increases in serum proteins at 6 months when compared to baseline. There were also increases in gene and protein expressions of WNT10b, and β-CATENIN at 6 months. Furthermore, we found a significant positive correlation between % changes in PRDM16 and WNT10b. Our results suggest that T therapy activates PRDM16, leading to enhanced signaling in the canonical WNT10b—β-CATENIN-RUNX2 pathway, the pathway involved in osteoblastogenesis. The above findings may account for the improvement in bone density and quality in hypogonadal men treated with T.

Islet cell transplantation (ITx) is an effective therapeutic approach for selected patients with type 1 diabetes with hypoglycemia unawareness and severe hypoglycemia events. In organ transplantation, human leukocyte antigen (HLA) mismatching between donor and recipient negatively impacts transplant outcomes. We aimed to determine whether HLA matching has an impact on islet allograft survival. Forty-eight patients were followed up after islet transplantation at our institution from 2000 to 2020 in a retrospective cohort. Patients underwent intrahepatic ITx or laparoscopic omental approach. Immunosuppression was dependent upon the protocol. We analyzed HLA data restricted to A, B, and DR loci on allograft survival using survival and subsequent multivariable analyses. Patients were aged 42.8 ± 8.4 years, and 64.3% were female. Diabetes duration was 28.6 ± 11.6 years. Patients matching all three HLA loci presented longer graft survival (P = 0.030). Patients with ≥1 HLA-B matching had longer graft survival compared with zero matching (P = 0.025). The number of HLA-B matching was positively associated with time of graft survival (Spearman’s rho = 0.590; P = 0.034). Analyses adjusted for confounders showed that ≥1 matching for HLA-B decreased the risk of allograft failure (P = 0.009). Our data suggest that HLA-B matching between recipients and donors improved islet allograft survival. Matching all three HLA loci (A, B, and DR) was also associated with prolonged islet allograft survival. Prospective studies and a larger sample size are warranted to validate our findings.

Abstract Disclosure: S. Bathina: None. V. Fuenmayor Lopez: None. M. Prado: None. G. Colleluori: None. D.T. Villareal: None. R.C. Villareal: None. Background: Growth Differentiation factor (GDF-15), member of TGF-β superfamily was identified as marker of aging, frailty, and metabolic disorders. Several clinical studies demonstrated an association between GDF15 with obesity and cardiovascular disease. However, information on the changes in GDF15 and its relationship to changes in metabolic and body composition parameters in the population of severely obese subjects undergoing weight loss (WL) remains lacking. Objective: The objective of this study is to evaluate the influence of WL on serum GDF15 level and its relationship to glucometabolic parameters in severely obese hypogonadal men. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention±anastrozole, aged 35-65 years old (NCT03490513) were analyzed. Hemoglobin A1C (A1C) was measured by HPLC, lipid profile by colorimetric method (except LDL was calculated), testosterone (T) and estradiol (E2) LC-MS and GDF-15 by ELISA. Body composition was measured by DXA. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At baseline, serum GDF15 positively correlated with age (r=0.25, p=0.01), fasting blood glucose (r=0.29, p=0.004) and A1C (r=0.39, p<0.001) but no correlation was found for lipid parameters and with T and E2. GDF15 was negatively correlated with total lean mass (r= -0.23, p=0.03), appendicular lean mass (r= -0.30, p=0.02), and fat-free mass (r= -0.22, p=0.03), but positively correlated with visceral adipose tissue volume (r=0.22, p=0.03). Average WL was 4.2±4.7% and 5.8±8.5% at 6months (6M) and 12 months (12M), respectively. Overall GDF15 levels increased by 9.4±84.7% at 6M and 18.4±128.0% at 12M. At 12M, changes in GDF15 levels positively correlated with changes in A1C (r= 0.26, p<0.05), and negatively with changes in total cholesterol ( r= -0.30, p=0.05), Triglycerides (r= -0.35, p=0.02) and E2 (r=-0.31, p=0.028). For LDL cholesterol changes, a negative correlation with GDF15 changes was observed at 6M (r= -0.27, p=0.047). There was no correlation between changes in GDF15 with changes in body weight and changes in body composition parameters. A comparison for those with significant WL (≥5%) vs. those with less WL showed that at 6M, GFD15 levels were reduced among those with WL of ≥5% (-19.5±42.3%) vs <5% (+19.8±93.9%), p=0.07, and at 12M (≥5% (-29.5±38.7) vs <5% (+0.61±69%), p<0.1). Conclusion: We demonstrated that changes in serum GDF15 in severely obese men undergoing WL was associated with alteration in cardiometabolic parameters. Our results show a new perspective on the potential role of GDF15 in cardiometabolic disorders associated with severe obesity. Aside from GDF15 used as a biomarker for health, it may also be used as target for drug development in modifying potential cardiometabolic complications in severe obesity. Presentation: 6/1/2024

Growth differentiation factor (GDF15) has been considered a biomarker and recently a hormonal driver for diseases in different populations. However, the role of GDF15 as a biomarker of health outcomes in obese men from different racial/ethnic background has not been evaluated. The objective of this study was to investigate the racial/ethnic differences on the relationship between GDF15 and markers of glucometabolic status, hormonal profile, body composition and bone mineral density (BMD) in obese men. One hundred ninety‐three obese men from diverse racial/ethnic backgrounds were enrolled. BMD and body composition were measured by dual energy X‐ray absorptiometry. Serum GDF15, osteocalcin, C‐terminal telopeptide, sclerostin, adiponectin, leptin, estradiol, testosterone, follicle‐stimulating hormone, luteinizing hormone, 25‐hydroxyvitamin D, lipid profile, and hemoglobin A1C (A1C) were measured. Non‐African Americans (NAA) had significantly higher GDF15 level than African Americans (AA). Level was also higher in patients with type 2 diabetes (T2DM). In both the groups GDF15 correlated with A1C and lean mass. However. GDF15 correlated  with body fat, LDL total cholesterol and femoral neck BMD only in NAA and with appendicular lean mass only in AA. Ethnicity, total cholesterol and T2DM were found to be independent predictors of GDF15. We conclude that GDF15 may influence glucometabolic status, body composition and bone parameters which may affect cardiovascular risk and osteoporosis  between races.

IntroductionType 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM.MethodsThis was a secondary analysis of baseline data from 169 male participants, aged 35–65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography.ResultsAt the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively).ConclusionPoor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality.

Abstract Disclosure: S. bathina: None. V. Fuenmayor Lopez: None. M. prado: None. S.B. Teo: None. V.S. Davila: None. R.P. Chen: None. Background: Previous clinical studies suggested the modulation of DNA methylation by lifestyle intervention (LSI) therapy by diet and exercise; however, little information is available on the effect of long-term supervised LSI in the subgroup of severely obese men with hypogonadism. Objective: The objective of this study is to evaluate the impact of long-term aerobic exercise and diet on 1) gene specific DNA methylation markers, 2) to measure Global methylation, 5-MC% (5-methylated cytosine %) and 3) on adipogenic markers by mRNA expression in PBMC in severely obese hypogonadal men undergoing LSI after 12 months. Method: Data from 116 severely obese (BMI ≥35 kg/m2) hypogonadal men participating in an ongoing clinical trial of WL from lifestyle intervention aged 35-65 years old (NCT03490513) were analyzed. Total DNA methylation and 5-MC% were analyzed using a global DNA methylation kit assay. DNA methylation enzymes (DNMT1, 3A, 3B and fat mass and obesity associated gene (FTO) and adipogenic markers (PPARγ, CEBPα) expression were examined from buffy coat by real-time quantitative PCR at BL and 12M. Results: The mean age of the participants was 51.4±7.6 years with mean BMI 41.8 ±5.4 kg/m2. At the end of 12 months, participants lost an average of 4.2±5.9% weight from baseline. LSI significantly reduced the mRNA expression of DNMT1 (BL: 3.29±1.1 Vs 12M: 0.78±0.16, p=0.038), DNMT3a (BL: 1.28±0.18 Vs 12M: 0.81±0.09, p=0.028) and DNMT3b (BL: 0.97±0.15 Vs 12M: 0.64±0.07, p=0.05) and FTO (BL: 1.47±0.27 Vs 12M: 0.86±0.09, p=0.028). LSI also decreased mRNA levels of adipogenic markers, PPARγ (BL: 1.53±0.37 Vs 12M: 0.83±0.18, p=0.08), and CEBPα (BL: 1.59±0.32 Vs 12M: 0.76±0.18, p=0.045). To confirm these epigenetic changes are at DNA level, we analyzed 64 samples at 3 timepoints, ie, BL, 6 months (6M) and 12M. We found LSI significantly reduced the 5MC % (BL: 0.16 ± 0.01 Vs 6M: 0.107 ± 0.005, p=0.0014) and (BL: 0.16 ± 0.01 Vs 12M: 0.11± 0.007, p=0.0013) and global DNA methylation (BL: 0.54 ± 0.03 Vs 6M: 0.51 ± 0.02, p=0.41) and BL: 0.54 ± 0.03 Vs 12M: ± 0.45± 0.01, p=0.045) in DNA samples. Conclusions: Our results suggest that LSI decreases global methylation by modulation of DNMTs and FTO enzymes in our subjects of severely obese hypogonadal men. This is accompanied by reduced expression of adipogenic markers. Changes in methylation may contribute to overall changes in metabolic profile in the general population of subjects undergoing LSI. Presentation: Monday, July 14, 2025

Background An emerging field of research concerns the deleterious effects of type 2 diabetes mellitus (T2DM) on bone. Our group has previously reported a hemoglobin A1c (A1c) threshold of 7% where bone impairment occurs as reflected by reduction in bone turnover markers and deterioration in bone microarchitecture and strength. However, whether poor glycemic control is also associated with underlying derangements in cellular flux remains unclear. Methods Analysis of the baseline data from 42 consecutive men aged 35-65 enrolled in a clinical trial (NCT03887936) at the Michael E DeBakey VA Medical Center, Houston, TX, who were able to provide the outcomes of interest. Inclusion criteria were average fasting morning testosterone from 2 measurements of <300 ng/dl, T2DM and BMI<35 kg/m2. The following variables were assessed: A1c by high performance liquid chromatography; testosterone and estradiol by LC/MS; bone turnover markers and sex hormone binding globulin by ELISA; quantification of osteoblast (OB) progenitors and osteoclast (OC) precursors by flow cytometry; areal bone mineral density (aBMD) and body composition by DXA; and bone microarchitecture and strength by high resolution peripheral quantitative computerized tomography. Results Participants with poorly controlled T2DM (A1c>7%) had significantly lower percent of OB progenitors in circulation than those with A1c≤7% (1.12 ± 0. 079% v 1.47 ± 0.11% of non-B non-T non-NK cells, p=0. 02) when controlling for age, duration of T2DM, free testosterone, and 25-hydroxyvitamin D levels. Higher levels of free testosterone were associated with smaller percentage of OB progenitors (r = -0.31, p = 0. 05). Although the percent of OC precursors in circulation (cells that were dual CD14CD11b+, CD14MCSFR+, or CD14CD120b+) was not significantly related to A1c, it was positively associated with percent of OB progenitors in peripheral blood (r = 0.34, p = 0. 03; r = 0.35, p = 0. 02; r = 0.39, p = 0. 01) respectively. There was a significant positive association between OB progenitors and visceral adipose tissue (VAT) volume (r=0.41, p=0. 009). Although there was no association between osteoblast progenitors and osteocalcin levels (product of mature OBs), osteocalcin negatively correlated with VAT (r=-0.47, p=0. 002). There was no association between OB progenitors and OC precursors with aBMD or bone microarchitecture parameters. Conclusions Poor glycemic control is associated with fewer circulating OB progenitors, as was higher free testosterone levels while the converse was true for VAT. It is possible that the former harms cell viability, while the latter two affect differentiation of OB progenitors into mature OB's; with testosterone promoting, and visceral adipose tissue (via unknown mediators) retarding maturation as suggested by the negative association between osteocalcin and VAT. The positive association between OB progenitors with circulating OC precursors is consistent with the physiologic crosstalk between OB and OC which appears to be preserved in patients with T2D. Presentation: No date and time listed

Disclosure: S. Bathina: None. M. Prado: None. L. Aguirre: None. G. Colleluori: None. E. Ballato: None. F. Deepika: None. V. Fuenmayor Lopez: None. D.T. Villareal: None. R.A. Villareal: None. Background: Testosterone (T) therapy increases lean mass; reduces total body and truncal fat mass and increases bone density in hypogonadal men. However, the underlying mechanisms for these changes remain unclear. In this study, we investigated the mechanisms involved for these effects of T on body composition and bone. Objective: Our aims are to evaluate the changes in 1) the gene and protein machinery involved the adipo-myogenic switch, and 2) the cellular osteogenic markers, in-vivo, in response to T therapy. Methods and Study design: Secondary analysis of specimens obtained from a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011-2016 N=105 men (40-74 years old), with average morning T <300 ng/dL who were given intramuscular T cypionate 200 mg every 2 weeks for 18 months As earlier results from our lab, effect of T therapy is maximal after 6 months, we chose to study the specimens at baseline (BL) and 6 months (6M). We measured the adipogenic transcription factors (PPARγ, CEBPa), enzymes (LPL, Adipsin) from subcutaneous fat, and myogenic lineage (Myf5, MyoD), Prdm16 and Pax7 from buffy coat by real-time quantitative PCR at BL and 6M. Serum Follistatin, PRDM16, PAX7 Myostatin, Adipsin were measured by ELISA. Changes in circulating osteogenic precursors (COP) and osteoclast precursors (OCPs) by Flow cytometry, and gene expression of osteoblastic transcription factor, Runx2, by PCR of buffy coat. OCPs in response to testosterone therapy were evaluated from samples of men participating in an ongoing clinical trial (NCT03887936). Results: T therapy decreased PPARg (BL: 2.59±2.2 vs 6M: 1.23±1.0, p=0.03); CEBPa (BL: 3.0±2.57 vs 6M: 1.7±1.2, p=0.10) LPL (BL: 2.81±2.7 vs 6M: 1.74±2.2, p=0.27) in sub-cutaneous fat tissue and increased the expression of MyoD (BL:1.34±1.6 vs 6M: 8.2±12.7, p=0.02) and Myf5 (BL: 6.1±9.7 vs 6M: 12.9±27.7, p=0.26) along with the adipo-myogenic switch, Prdm16 (BL: 1.8±1.9 vs 6M: 4.5±4.1, p< 0.01); Pax7 (BL:1.3±0.8 vs 6M: 1.9±2.0, p=0.2) in buffy coat. T therapy also increased serum Follistatin (BL:2031±1483 vs 6M: 3396 ± 1662pg/ml, p=0.009), the myogenic regulator, PAX7 (BL:21.5±1.9 vs 6M: 34±2.2ng/ml, p=0.002); and PRDM16 (BL:0.20±0.10 vs 6M: 0.49±0.26ng/ml, p=0.29) and decreased serum Myostatin (BL: 3218±738 vs 6M: 2714±62.2pg/ml, p=0.42) Adipsin (BL:15929±10209 vs 6M:12101±4865ng/ml p=0.04). COPs increased in T-treated (T) compared to Placebo (P); (P (6M): -4.3±57 vs T(6M): -20.2±44, p=0.20 & P(12M): -15.7±44.5 vs T(12M): 47.4±74.8, p=0.02)) and Runx2 expression increased (BL: 1.26±0.86 vs 6M: 2.17±1.6, p=0.03). Conclusions: Our results suggested that reciprocal effect of T-therapy on fat mass and lean mass is not only due to shift from adipogenesis to myogenesis but also due to enhanced osteogenesis. Thus, this study can provide unifying mechanism for observed effect of T in hypogonadal men. Presentation Date: Saturday, June 17, 2023