Arginine Metabolism Is Significantly Different in a-ß+ Ketosis Prone Diabetes (KPD) Compared to Healthy Controls

Presentation Number: OR14-3
Date of Presentation: April 3rd, 2017

Surya Narayan Mulukutla*1, Ruchi Gaba1, Nadim Ajami2, Kurt Max Bohren3, Jean Wei-Chen Hsu2, Farook Jahoor2 and Ashok Balasubramanyam4
1Baylor College of Medicine, Houston, TX, 2Baylor College of Medicine, 3Baylor College of Medicine, TX, 4Baylor Coll of Med, Houston, TX

Abstract

Introduction: We have characterized the novel syndrome of A-B+ ketosis-prone diabetes (KPD) as a unique subset of type 2 diabetes in which obese individuals present with unprovoked diabetic ketoacidosis (DKA) despite absence of beta-cell autoimmunity and experience prolonged near-normoglycemic, insulin-independent remission. These findings imply unique and profound beta cell dysfunction of unknown etiology. Through whole body metabolomics, we have identified arginine as a possible culprit due to its role as potent insulin secretagogue.

Hypothesis: Compared to healthy subjects, KPD subjects have decreased cellular arginine availability due to increased arginine catabolism.

Methods: In 6 healthy subjects and 6 recent-onset A-B+ KPD subjects: arginine, ornithine, and citrulline metabolism was studied under fasting and hyperglycemic conditions using stable isotope tracers. Kinetic measurements and amino acid concentrations were assessed throughout, including before and after bolus arginine.

Results: No significant differences in arginine concentration were found in the fasting or hyperglycemic states between healthy controls and KPD subjects. Following an arginine bolus, healthy subjects, stressed by hyperglycemia, rapidly depleted their available pool of arginine compared to the fasting state (81.9 ± 9.3 vs 39.2 ± 12.6, p = 0.0004), despite significant decreases in the fluxes of citrulline and ornithine. However, KPD subjects similarly stressed by hyperglycemia could not match this significant decrease in arginine concentration (53.6 ± 9.8 vs 39.2 ± 12.6, p = 0.067).

Discussion: The major pathways of arginine metabolism are via hydrolysis to urea and ornithine and via oxidation to nitric oxide and citrulline. The remaining portion of arginine is then available for other actions such as promoting insulin secretion. Under fasting conditions, healthy controls showed no significant difference in arginine concentration compared to KPD subjects. Under hyperglycemic conditions, healthy controls and KPD subjects both maintained similar arginine concentrations by down-regulating the fluxes of citrulline and ornithine. However, after addition of exogenous arginine following hyperglycemia, healthy patients more quickly utilized this added source compared to KPD subjects. This implies that KPD subjects lack the dynamic ability to quickly adjust to their metabolic demands.

Conclusion: Compared to healthy subjects, KPD subjects have a higher need for arginine, preferring to maintain arginine concentrations as opposed to utilizing excess arginine. This maintenance comes at the expense of other tasks such as insulin secretion even during times of hyperglycemia. Due to the inability to adjust to the body’s metabolic demands, KPD subjects are then susceptible to persistent hyperglycemia, relative insulinopenia, and DKA.

Disclosures: NA owns shares in Diversigen, Inc.

 

Disclosure: NA: Owns shares, Diversigen, Inc.. Nothing to Disclose: SNM, RG, KMB, JWCH, FJ, AB