We previously showed that patients with A-β+ KPD (“obese ketosis-prone type 2 diabetes”) have diminished intracellular arginine availability that may impair their ability to generate an adequate beta cell response in the face of hyperglycemia, and thus make them vulnerable to develop ketoacidosis (Mulukutla et al, J Nutr 2018). To investigate further their β cell responsiveness to exogenous arginine, we studied 9 recently diagnosed, stable, near-normoglycemic A-β+ KPD patients and 10 age-, sex- and BMI-matched nondiabetic controls with dynamic measures of insulin and C-peptide responses to glucose or arginine bolus under two conditions: in the euglycemic, fasting (basal) state and after a 5h hyperglycemic clamp. In the basal state, total and first phase insulin areas under the curve (AUC) in response to glucose were significantly greater in controls than KPD (total AUC 1756 ± 298 vs. 857 ± 126 min·µU/mL; P = 0.05); after hyperglycemia, AUC insulin response to glucose remained significantly greater in controls (total AUC 2470 ± 296 vs. 1512 ± 316 min·µU/mL; P = 0.04), and KPD patients mounted only a non-significant increase in total AUC insulin compared to the basal state (P = 0.12). In contrast, total and first phase AUC insulin in response to arginine in the basal state was similar in controls and KPD (total AUC 544 ± 85 vs. 337 ± 50 min·µU/mL; P = 0.75). After hyperglycemia, although AUC insulin response to arginine was greater in controls (total AUC 1854 ± 2227 vs. 1149 ± 207 min·µU/mL; P = 0.002), the KPD patients mounted a significant 70% increase in total AUC insulin compared to the basal state (P = 0.002). C-peptide responses mirrored those of insulin under all conditions. Thus, KPD patients exhibit a robust β cell response to arginine but not to glucose, both during fasting euglycemia and after sustained hyperglycemia. Exogenous arginine could augment insulin secretion during hyperglycemia and prevent the episodes of ketoacidosis that characterize A-β+ KPD.


J.W. Hsu: None. A.J. Cardenas: None. R. Gaba: None. M. Tosur: None. N. Ram: None. A.D. Gutierrez: Speaker’s Bureau; Self; AstraZeneca. K.M. Bohren: None. E.I. Caducoy: None. F. Jahoor: None. A. Balasubramanyam: None.


National Institutes of Health (R01DK101411)

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