Free fatty acid processing diverges in human pathologic insulin resistance conditions
Hilal Sekizkardes, … , Marissa Lightbourne, Rebecca J. Brown
Hilal Sekizkardes, … , Marissa Lightbourne, Rebecca J. Brown
Published March 19, 2020
Citation Information: J Clin Invest. 2020;130(7):3592-3602. https://doi.org/10.1172/JCI135431.
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Clinical Research and Public Health Endocrinology

Free fatty acid processing diverges in human pathologic insulin resistance conditions

Abstract

BACKGROUND Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODS Cross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma β-hydroxybutyrate) were measured.RESULTS Lipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%–0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%–17.1%], P < 0.0001). β-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSION These data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATION ClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDING National Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.

Authors

Hilal Sekizkardes, Stephanie Therese Chung, Shaji Chacko, Morey W. Haymond, Megan Startzell, Mary Walter, Peter J. Walter, Marissa Lightbourne, Rebecca J. Brown

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Figure 4

Measure of hepatic and plasma fat, and hepatic fatty acid oxidation.

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Measure of hepatic and plasma fat, and hepatic fatty acid oxidation. Hep...
Hepatic triglyceride content (A), measured using magnetic resonance spectroscopy, and plasma triglycerides (B) were normal in subjects with pathogenic variants of the insulin receptor (INSR, black squares), and elevated, consistent with nonalcoholic fatty liver disease and severe dyslipidemia, in subjects with lipodystrophy (white circles). Plasma β-hydroxybutyrate (C), a measure of hepatic FFA oxidation, was higher in subjects with INSR pathogenic variants compared with all other groups, including lipodystrophy, type 2 diabetes (gray triangles), and obesity (gray diamonds). Statistical comparisons were performed using mixed models with post hoc pairwise comparisons and Tukey’s correction for multiplicity.