Arginine Metabolism Is Altered in Adults with A-beta plus Ketosis-Prone Diabetes

Background: A-beta + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible beta cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. Objective: The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and beta cell function in KPD patients compared with control participants. Methods: Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index-matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants. Results: Arginine availability was higher in KPD patients during euglycemia [53.5 +/- 4.3 (mean +/- SEM) compared with 40.3 +/- 2.4 mu mol . kg lean body mass (LBM)(-1) . h(-1), P = 0.03] but declined more in response to hyperglycemia (Delta 10.15 +/- 2.6 compared with Delta 3.20 +/- 1.3 mu mol . kg LBM-1 . h(-1), P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 +/- 294 compared with 2584 +/- 259 min . mu mol . L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 +/- 108 compared with 926 +/- 257 min . mu U . mL(-1), P = 0.02; hyperglycemic insulin AUC 358 +/- 79 compared with 866 +/- 292 min . mu U . mL(-1), P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants. Conclusion: Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.