[HTML][HTML] Free fatty acid processing diverges in human pathologic insulin resistance conditions
H Sekizkardes, ST Chung, S Chacko… - The Journal of …, 2020 - Am Soc Clin Investig
The Journal of clinical investigation, 2020•Am Soc Clin Investig
BACKGROUND Postreceptor insulin resistance (IR) is associated with hyperglycemia and
hepatic steatosis. However, receptor-level IR (eg, 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 …
hepatic steatosis. However, receptor-level IR (eg, 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 …
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.
The Journal of Clinical Investigation