Multiple islet autoantibodies (AAb+) predict type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in just ~15% of single AAb+ (generally against glutamic acid decarboxylase, GADA+) individuals; hence the single AAb+ state may represent an early stage of T1D. We previously discovered the functional defects in suppression of glucagon secretion in non-diabetic, normoglycemic GADA+ donors which precedes the insulin secretory defect seen in T1D. This GADA+ donor alpha cell phenotype is accompanied by altered cAMP signaling and alpha cell gene expression, particularly in glycolysis and oxidative phosphorylation. The mechanism of this glucagon secretion defect in GADA+ alpha cells remains poorly understood. Therefore, the goal of the current project is to test whether the reduced or lost suppression of glucagon secretion by glucose in alpha cells during the progression of T1D is causally related to alteration of the cAMP pathway and/or bioenergetics.
This study will help to identify possible protective or pathogenic factors which may play a role in alpha cell dysfunction during development of T1D. These factors may then be used in the future for drug development to prevent or delay progression to T1D by targeting the early single AAb+ stage.