Abstract
(1) Background: Disruption of insulin production by native or transplanted pancreatic islets caused by auto/allo-immunity leads to hyperglycemia, a serious health condition and important therapeutic challenge due to the lifelong need for exogeneous insulin administration. Early metabolic biomarkers can prompt timely interventions to preserve islet function, but reliable biomarkers are currently lacking. We explored the feasibility of “localized metabolomics” where initial biomarker discovery is made in aqueous humor samples for further validation in the circulation. (2) Methods: We conducted non-targeted metabolomic studies in parallel aqueous humor and plasma samples from diabetic and nondiabetic mice. Metabolite levels and associated pathways were compared in both compartments as well as to an earlier longitudinal dataset in hyperglycemia-progressor versus non-progressor non-obese diabetic (NOD) mice. (3) Results: We confirmed that aqueous humor samples can be used to assess metabolite levels. About half of the identified metabolites had well-correlated levels in the aqueous humor and plasma. Several plasma metabolites were significantly different between diabetic and nondiabetic animals and between males and females, and many of them were correlated with the aqueous humor. (4) Conclusions: This study provides proof-of-concept evidence that aqueous humor samples enriched with islet-related metabolites and representative of the immediate islet microenvironment following intraocular islet transplant can be used to assess metabolic changes that could otherwise be overlooked in the general circulation. The findings support localized metabolomics, with and without intraocular islet transplant, to identify biomarkers associated with diabetes and islet allograft rejection.
Highlights
Blood glucose levels are maintained in relatively narrow ranges that are somewhat species-specific.These narrow ranges are achieved by the fine-tuned function of the insulin-producing cells within the pancreatic islets in response to changes in systemic glucose levels [1]
We present exploratory non-targeted metabolomic studies in mice to (a) demonstrate proof-of-concept for “localized metabolomics” using small aqueous humor samples that are expected to be enriched with islet-related metabolites and representative of the immediate islet microenvironment following intraocular islet transplant, (b) explore the feasibility of initial biomarker discovery in the enriched local microenvironment for islet/diabetes-specific changes that can be measured systemically, and (c) establish the relevance of locally measured metabolites to systemic changes caused by diabetes
We previously demonstrated that aqueous humor samples are representative of the local islet microenvironment following islet transplant in the anterior chamber of the eye (ACE)
Summary
Blood glucose levels are maintained in relatively narrow ranges that are somewhat species-specific. The destruction of the insulin-producing β-cells by an immune attack, as occurs in type 1 diabetes (T1D), is a life-threating problem that leads to serious health complications associated with chronic hyperglycemia and a lifelong need for daily exogenous insulin therapy. This represents a therapeutic challenge as, far, all clinical trials with immunomodulatory approaches aimed to stop. We explore its extension in the ACE platform for the longitudinal study of autoimmune T1D and islet allograft rejection
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