Arginine Metabolism Is Altered in Adults with A-β + Ketosis-Prone Diabetes

Abstract

Background: A-β + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible β 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 β 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 μmol · kg lean body mass (LBM)-1 · h-1, P = 0.03] but declined more in response to hyperglycemia (Δ 10.15 ± 2.6 compared with Δ 3.20 ± 1.3 μmol · 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 · μmol · 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 · μU · mL-1, P = 0.02; hyperglycemic insulin AUC 358 ± 79 compared with 866 ± 292 min · μU · 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.

FIGURE 1

Available arginine under euglycemic and hyperglycemic conditions (A) and the change in available arginine between the euglycemic and hyperglycemic conditions (B) in 6 recent-onset KPD patients and 6 age-, gender-, and BMI-matched control participants. Values are means ± SEMs. (A) Means were compared by repeated-measures 2-factor ANOVA. Significant interaction between group and glycemic state (P < 0.05), significant main effect of glycemic state and group (P < 0.05). Post hoc comparisons: ^asignificantly different from control group in corresponding clinical condition, P < 0.05 (post hoc Sidak multiple comparison test); ^bsignificantly different from corresponding group in euglycemic condition, P < 0.05 (post hoc Sidak multiple comparison test); ^csignificantly different from control group, P < 0.05 (t test). KPD, ketosis-prone diabetes; LBM, lean body mass.

FIGURE 2

Plasma ornithine AUC from 0 to 56 min following intravenous arginine bolus in 6 recent-onset KPD patients and 6 age-, gender-, and BMI-matched control participants under euglycemic and hyperglycemic conditions. Values are means ± SEM, n = 6. ^aSignificantly different from corresponding group in euglycemic condition, P < 0.05 (paired t test); ^bsignificantly different from control group in corresponding clinical condition, P < 0.10 (nonpaired t test). KPD, ketosis-prone diabetes.

FIGURE 3

Plasma insulin concentrations (secretory response) (A, B), first-phase plasma insulin AUC (C, D), and total plasma insulin AUC (E, F) after glucose bolus (A, C, E) and after arginine bolus (B, D, F) in recent-onset KPD patients and age-, gender-, and BMI-matched control participants, following euglycemic and hyperglycemic conditions. Values are means ± SEMs, n = 4 for control participants and n = 5 for KPD. ^aSignificantly different from control group in corresponding clinical condition: ^aP < 0.05; ^bP < 0.10 (t test). KPD, ketosis-prone diabetes.

FIGURE 4

Mean of 3 peak insulin values during first-phase insulin secretion in response to glucose bolus (AIR-gluc), arginine bolus (AIR-arg), and glucose + arginine (GPAIS), in 6 recent-onset KPD patients and 3 control participants. Values are means ± SEMs. ^aSignificantly different from control group, P < 0.05 (t test). AIR, acute insulin response; GPAIS, glucose potentiation of arginine-induced insulin secretion; KPD, ketosis-prone diabetes.

FIGURE 5

Relative abundance of Bacteroidetes and Firmicutes within the intestinal microbiome of 6 recent-onset KPD patients and 6 age-, gender-, and BMI-matched control participants. Values are individuals with mean (–). ^a,bSignificantly different from the control group: ^aP < 0.05; ^bP < 0.10 (paired t test). KPD, ketosis-prone diabetes.

FIGURE 6

Correlation of bacterial richness using OTUs (A), bacterial evenness using SDI (B), Bacteroidetes relative abundance (C), and Firmicutes relative abundance (D) with ornithine flux in all 12 study participants [6 recent-onset KPD patients and 6 age-, gender-, and BMI-matched control participants]. KPD, ketosis-prone diabetes; LBM, lean body mass; OTU, organizational taxonomic unit; SDI, Shannon diversity index.