Free fatty acid processing diverges in human pathologic insulin resistance conditions

Area of Science:

• Metabolic pathways
• Lipid metabolism
• Gluconeogenesis

Background:

• Postreceptor insulin resistance (IR) is linked to hyperglycemia and hepatic steatosis.
• Receptor-level IR (e.g., INSR variants) causes hyperglycemia without hepatic steatosis.
• Understanding these distinct IR pathways is crucial for metabolic disease research.

Purpose of the Study:

• To investigate lipid metabolism and gluconeogenesis pathways in distinct human IR conditions.
• To differentiate the metabolic fates of free fatty acids (FFAs) in receptor vs. postreceptor IR.

Main Methods:

• Cross-sectional study comparing severe receptor IR (INSR, n=7) with severe (lipodystrophy, n=14), moderate (T2D, n=9), and mild (obesity, n=8) postreceptor IR.
• Measured lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis, hepatic triglycerides, and hepatic fat oxidation (β-hydroxybutyrate).

Main Results:

• INSR subjects exhibited significantly higher lipolysis and hepatic glucose production compared to other groups.
• Gluconeogenesis contributed more to HGP in INSR (77%) versus other groups (52-59%).
• Despite high lipolysis, INSR subjects had low hepatic triglycerides and high fat oxidation, unlike lipodystrophy patients.

Conclusions:

• Adipose tissue IR plays a key role in increasing substrate availability to the liver in both receptor and postreceptor IR.
• In receptor-level IR, FFAs are oxidized to drive gluconeogenesis.
• In postreceptor IR, FFAs contribute to both gluconeogenesis and hepatic steatosis, highlighting divergent metabolic fates.