Free fatty acid processing diverges in human pathologic insulin resistance conditions.

BACKGROUND: Post-receptor 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 four 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 post-receptor IR that was severe (lipodystrophy, n=14), moderate (type 2 diabetes [T2D], 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 beta-hydroxybutyrate) were measured. RESULTS: Lipolysis was 2-3-fold higher in INSR versus all other groups, and HGP 2-fold higher in INSR and lipodystrophy versus T2D and obesity (p<0.001) suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, ~77%, versus 52-59% in other groups (p=0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5 [0.1-0.5]), in contrast to lipodystrophy (10.6 [2.8-17.1], p<0.0001). beta-hydroxybutyrate was 2-7-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 post-receptor 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 post-receptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556; NCT00001987; NCT02457897Funding. NIDDK, USDA ARS 58-3092-5-001.