In a new study, long chain fatty acid oxidation disorders (LCFAOD) prevented Intralipid-induced insulin resistance in the liver but did not prevent insulin resistance in peripheral tissue. LCFAOD also did not prevent intramyocellular lipid (IMCL) accumulation in the periphery.
The results were presented during the International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Conference by Melanie Gillingham, PhD, RD, LD, associate professor of Molecular and Medical Genetics, School of Medicine, at Oregon Health and Science University in Portland. In her talk, she shed light on the possible mechanisms of insulin resistance.
During the trial, 16 LCFAOD patients and 16 matched controls underwent 5-hour hyperinsulinemic-euglycemic clamps. During the clamps, participants received either an infusion of Intralipid or a control solution containing small amounts of glycerol. All patients completed the procedure twice on different days, once with the control solution and once with Intralipid, in a randomized order.
During the glycerol infusion testing, the respiratory quotient (RQ) was similar between both the LCFAOD and healthy control groups. The RQs of both groups decreased during Intralipid infusion. However, the RQs of the control group were significantly lower than the LCFAOD patients, indicating that the patients oxidized less fat and more glucose than the controls.
Analysis of the liver revealed no difference in endogenous glucose production basal between groups prior to the initiation of infusions. Intralipid infusion increased endogenous glucose production clamp in controls as expected, but the same was not seen in LCFAOD patients, despite both groups showing increased levels of intrahepatic lipids. These results indicated that liver cells of the LCFAOD patients remained insulin-responsive.
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“So if you take this all together, under high insulin conditions, with a concomitant rise of free fatty acids due to Intralipid, we were able to demonstrate that patients with a long-chain fatty acid oxidation disorder had decreased whole-body fatty acid oxidation and accumulation of intrahepatic lipid,” Dr. Gillingham summarized. “And yet remained responsive to insulin under these conditions, with a diminution of endogenous glucose production, similar to the glycerol condition.”
“We do not know, however, what happened with the diacylglycerol or ceramide concentrations in the hepatocytes,” she said.
The study also found that glucose disposal in peripheral tissues was not significantly different between groups (P =.1) but was different based on treatment with glycerol vs Intralipid (P <.0001). Intralipid infusion was found to decrease glucose uptake in both groups.
IMCL showed a slight increase in controls when on Intralipid compared to minimal change among LCFAOD patients. There was a treatment (P <.009) and interaction effect (P =.035) seen in a mixed-effects model.
In both groups, plasma-free fatty acids levels decreased during the glycerol clamp. In contrast, the fatty acid levels steadily increased in both groups during Intralipid infusion, however, the LCFAOD patients increased faster than controls. This result indicated that more of the fatty acids were staying in the plasma of LCFAOD patients.
Further analysis showed a slight, but significant, increase in lipid droplet accumulation in control patients during the Intralipid trials, compared to no change in accumulation for the LCFAOD patients. These results suggested a decrease in lipid uptake in the muscle of LCFAOD patients.
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A previous study had seen an increased amount of glycolytic fibers in LCFAOD patients, which might have accounted for some of the difference in lipid uptake, but additional testing found no differences in the fiber types of the vastus lateralis muscles between the control or LCFAOD patients. Data did suggest a possible downregulation of CD36 expression, which would have led to decreased lipid uptake in peripheral cells.
Of the 16 patients who participated in the trial, 6 had carnitine palmitoyltransferase 2 deficiency (CPT2D), 4 had very long-chain acyl-CoA dehydrogenase deficiency (LVCADD), and 6 had long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).
After a 10 hour fast, patients began an infusion of dideuterated glucose and underwent magnetic resonance spectroscopy (MRS) to measure body lipid content at 6 am. At 8 am, researchers began administering a constant infusion of insulin along with either a control solution of 2.5% glycerol or a 20% solution of Intralipid for 5 hours. Glucose levels were measured every 5 minutes and an infusion of 20% dextrose was adjusted to keep glucose levels at 90 mg/dl.
At the end of the 5-hour clamp, tissue samples were collected from the vastus lateralis muscle and adipose tissue from the umbilicus. At this point, the infusions were turned off and patients were given lunch before returning for another MRS scan to estimate the change in muscle and liver lipid content.
Fatty acid oxidation and insulin sensitivity: revisiting the Randle cycle. Presented at: International Network for Fatty Acid Oxidation Research and Management (INFORM) Virtual Meeting: October 27, 2021; Virtual.