University of Illinois at Chicago
Higher baseline levels of the bone hormone undercarboxylated osteocalcin independently predict improved islet cell transplantation outcomes
Kirstie K. Danielson1,2, Rebecca S. Monson1, Jose Oberholzer1, Tingqi Shi1.
1Division of Transplant Surgery, University of Illinois at Chicago, Chicago, IL, United States; 2Division of Epidemiology & Biostatistics, University of Illinois at Chicago, Chicago, IL, United States
Background: While islet transplant outcomes are steadily improving, recipient factors associated with transplant success remain unclear. To maximize use of scarce islets, there is a critical need to elucidate recipient factors predictive of success to inform efficacious treatment strategies (e.g., clinical care, drug delivery), and ultimately cure more people with diabetes. Recent research in mice demonstrated that bone-secreted osteocalcin (specifically the undercarboxylated [unOC], not the carboxylated [cOC] fraction) enhances β-cell insulin secretion and proliferation via a G-protein-coupled receptor. We therefore investigated in humans the longitudinal association of circulating unOC levels measured close to islet transplant with β-cell function and clinical outcomes after transplant.
Methods: The analysis includes patients in the University of Illinois at Chicago’s phase 1/2 (n=10) and phase 3 (n=12) clinical trials. We extracted data on β-cell function and clinical outcomes through 64 weeks post-first transplant, or until a second transplant if received, resulting in 298 longitudinal time points for analysis. Biomarkers were measured in serum archived pre- and at 1 and 20 weeks post-first transplant: unOC, cOC, and other endocrine factors including leptin, parathyroid hormone (PTH), and insulin-like growth factor-1 (IGF-1). Longitudinal associations of the biomarkers with β-cell function and clinical outcomes after transplant were determined using multivariable linear regression of repeated measures, adjusting for recipient age and weight, clinical trial phase, immunosuppression, number of islet equivalents (IEQs) transplanted per recipient weight (kg), islets’ glucose stimulation index, and blood draw characteristics (time fasting, month, and time of day).
Results: Recipients included 4 males and 18 females, mean age=46.4 years and BMI=23.2. While unOC alone was not associated (p=0.24), the ratio of unOC/cOC, or unOC/total OC (unOC+cOC), was positively associated with fasting C-peptide levels post-transplant (p=0.03 for both), even after adjusting for confounders. unOC/cOC was negatively associated with HbA1c post-transplant, but was nonsignificant (p=0.21) after adjustment. PTH, IGF-1, and kidney function were not associated with outcomes, nor did they confound the association of unOC/cOC with C-peptide. Investigating effect modification, a significant 3-way interaction (Figure 1; p=0.004) was discovered between recipients’ unOC/cOC and leptin levels at first transplant, and insulin use (yes/no) after transplant, on fasting C-peptide across one year post-transplant. When recipients were insulin independent, the association of unOC/cOC with fasting C-peptide was null, whereas if still insulin dependent (i.e., less than optimal islet function), there was a positive association of unOC/cOC with fasting C-peptide, which was stronger with lower leptin levels.
Conclusion: Our findings suggest that higher unOC/cOC levels close to transplant predict better islet function up to one year post-transplant. Interestingly, this positive association was strongest during insulin dependence with low leptin levels. This is consistent with leptin’s inhibition of both β-cell function and unOC formation. Islets with less than optimal function, and recipients of those islets, may therefore benefit from a hormonal environment with both high unOC/cOC and low leptin levels until islets reach a certain functional threshold.
11:00 - 12:30
|Trends and progress in clinical islet transplantation||Improvements in multiple cardiovascular biomarkers following islet cell transplantation in patients with type 1 diabetes||Plenary Room 1|
11:00 - 12:30
|Pancreas and Islet Transplantation: Imaging, Biopsies, and Biomarkers||Higher baseline levels of the bone hormone undercarboxylated osteocalcin independently predict improved islet cell transplantation outcomes||Room 110|