Free fatty acid processing diverges in human pathologic insulin resistance conditions

Authors: SEKIZKARDES, HILAL - National Institutes Of Health (NIH); CHUNG, STEPHANIE - National Institute Of Diabetes And Digestive And Kidney Diseases; CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); HAYMOND, MOREY - Children'S Nutrition Research Center (CNRC); STARTZELL, MEGAN - National Institute Of Diabetes And Digestive And Kidney Diseases; WALTER, MARY - National Institute Of Diabetes And Digestive And Kidney Diseases; WALTER, PETER - National Institute Of Diabetes And Digestive And Kidney Diseases; LIGHTBOURNE, MARISSA - National Institutes Of Health (NIH); BROWN, REBECCA - National Institute Of Diabetes And Digestive And Kidney Diseases

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/17/2020
Publication Date: 6/2/2020
Citation: Sekizkardes, H., Chung, S.T., Chacko, S., Haymond, M.W., Startzell, M., Walter, M., Walter, P.J., Lightbourne, M., Brown, R.J. 2020. Free fatty acid processing diverges in human pathologic insulin resistance conditions. Journal of Clinical Investigation. 130(7):3592-3602. https://doi.org/10.1172/JCI135431.
DOI: https://doi.org/10.1172/JCI135431

Interpretive Summary: Insulin resistance is a condition when cells in muscles, fat, and liver do not respond efficiently to insulin and are unable to easily take up glucose from circulation. In the liver, insulin suppresses glucose production and increases lipid synthesis in the presence of glucose. The objectives of this study were to investigate mechanisms by which insulin regulates glucose and triglyceride production in humans with various types of insulin resistance conditions. Scientists in Houston, Texas demonstrated that glycerol and free fatty acid availability to the liver are increased in both receptor and postreceptor insulin resistance conditions. In receptor-level insulin resistance, free fatty acid oxidation increased glucose production rather than triglyceride production. In contrast, free fatty acid contributed to both glucose and triglyceride production in postreceptor insulin resistance condition. The findings from this research provides details about glucose and fat metabolism in these insulin resistance conditions and insights for future research to find effective treatments.

Technical Abstract: Postreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptorlevel 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. 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 B-hydroxybutyrate) were measured. 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). B-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation. 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.