SAT090 Serum Ketone Levels Are Disproportionate To Beta-Oxidation In Insulin Receptor Mutation Compared Vs Lipodystrophy Patients
Authors: Klein Rachael , Chung Stephanie T , Brown Rebecca J 
Published: October 2023

Disclosure: R. Klein: None. S.T. Chung: None. R.J. Brown: None.

Introduction: Ketogenic substrates mainly derive from fatty acid (FA) metabolism via hepatic β-oxidation (βOx). βOx catabolizes FAs to acetyl-CoA, which can make ATP via the TCA cycle or ketones. Ketones are cleared peripherally by monocarboxylate transporters (MCT). Insulin is a major regulator of FA metabolism and ketogenesis. Insulin resistance (IR) is classified as receptor mediated, in which all downstream signaling is blocked (mutations of the insulin receptor, INSR), or post receptor IR where some downstream signaling pathways are decreased and others are increased (i.e. obesity and lipodystrophy, LD). Prior data showed high FA flux in INSR and LD; however, only patients with LD develop hepatosteatosis. We hypothesized that FAs in INSR are selectively directed toward βOx, and not re-esterified to triglyceride, to explain absence of hepatosteatosis. Here we assess pathways leading to βOx and ketogenesis between the two groups. Background: This was a cross-sectional study of subjects with INSR (N=30) and LD (N=30) matched for age, sex, HbA1c and pubertal stage. Untargeted lipidomic and proteomic analysis was completed on serum after an 8-12 hour fast. Analyses were conducted by t-test and Mann-Whitney. P&lt;0.05 was considered significant without adjustment for multiplicity in this hypothesis generating study. Results: Insulin was 400% higher in INSR vs LD; glucose was comparable. 36 acyl-carnitines were measured. In general, acyl-carnitines were comparable with 3% higher in INSR and 28% higher in LD. Ketoacids leucine and lysine were 126% and 114% higher in LD vs INSR. Analysis of glycolytic intermediates showed no difference in pyruvate levels, but an 9% higher hexokinase-1 (a rate limiting glycolytic enzyme) in LD. Of 10 TCA cycle intermediates, 20% were elevated in LD vs INSR, the remaining 80% were similar. Despite evidence of comparable to higher βOx intermediates in LD, the ketones acetoacetate and 3-hydroxybutyrate were 600% and 740% higher in INSR vs LD. Both monocarboxylate transporters measured, sodium-coupled MCT-1 (SCMCT-1) and MCT-4, were higher in LD vs INSR (by 34% and 1%). Conclusions: Formation of acyl-carnitines from FA is the first step in hepatic βOx, and acylcarnitine levels are typically proportional to ketones. We observed higher ketones in INSR vs LD despite evidence of comparable βOx, including acyl-carnitines and glycolytic and TCA intermediates. This suggests that elevated ketones in INSR may be due to lower clearance via monocarboxylate transporters rather than increased formation via βOx. Concentration of MCT-1, the primary transporter of ketones into muscle, was not available. However, MCT-4 and SCMCT-1 which reside in the brain and kidneys, respectively, were lower in INSR, perhaps leading to decreased ketone utilization. We hypothesize that MCTs may be negatively regulated by insulin, via a mechanism not mediated by the insulin receptor.

Presentation: Saturday, June 17, 2023