Interrogating beta cell function and heterogeneity of C-peptide preservation in patients with type 1 diabetes or chronic pancreatitis

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PROJECT SUMMARY/ABSTRACT: Type 1 diabetes (T1D) is an increasing public health burden for which current therapies are focused on insulin replacement. Future T1D treatments will try to preserve endogenous pancreatic beta cell function in new onset T1D and replace beta cells via transplantation in long standing diabetes. Classically, T1D is viewed as an autoimmune disease but beta cell loss is also driven by genetic risk factors and metabolic stress. Much has been done to try to delay T1D progression from preclinical multiple autoantibody positivity to clinical disease, but progression is highly heterogenous. C-peptide preservation can improve diabetes control and decrease the risk for diabetes complications. There are a wide array of C-peptide measurements to examine endogenous beta cell function and stress and many genes have been associated with C-peptide preservation in T1D. Less is known about the influence of genetics on the preservation of endogenous beta cell function during the partial remission period (PRM) or “honeymoon” after diagnosis. These factors are also likely important for patients with chronic pancreatitis (CP) who have risk for islet loss but for whom genetic risk and metabolic stressors remain largely unexplored. Patients with CP have severe pain and progressive endocrine insufficiency due to persistent inflammation and hepatic insulin resistance. For patients with severe CP, total pancreatectomy with islet auto- transplantation (TPIAT) is an attempt to preserve a patient’s endogenous beta cell function while removing the source of their pain. Younger age and higher beta cell mass during transplantation are predictors for functional graft survival. Less is known about the role of beta cell genetics in these patients, which I will evaluate in this proposal. I am an emerging researcher with experience in basic science beta cells studies and clinical research defining heterogeneity in T1D. My goal in this career development award is to hone clinical research skills by studying the impact of genetics and markers of beta cell function in patients with newly diagnosed T1D and in a model of cell therapy (CP patients who have undergone TPIAT) with these aims: 1: Analyze if baseline markers of beta cell function and stress can predict PRM C-peptide preservation. 2: Evaluate if known pre-specified T1D SNPs are associated with PRM C-peptide preservation 3: Evaluate if pre-specified SNPs associated with C-peptide preservation predict insulin use and C-peptide in CP patients who have undergone TPIAT As part of this K23 award proposal, I outline educational, training, and scientific goals that will support my pathway to independence. I have assembled a diverse and broad mentorship/collaborator team to support this endeavor. This career development award will support my career goal to elucidate heterogeneity in beta cell (dys-)function in diabetes and to develop novel cell therapy interventions.