Early Hepatic Insulin Resistance Contributes to Diabetes Development

Strategic Insights -

Researchers in the United States have found that young mice bred to develop obesity and diabetes exhibit early signs of hepatic insulin resistance, a key contributor to the development of diabetes. This discovery was made by studying the C57BLKS/db/db mouse strain, which is commonly used to model human diabetes. The scientists used a combination of in vivo and in vitro approaches to identify metabolic and molecular differences between the BKS-db mice and their diabetes-resistant counterparts, the B6-db strain. They found that despite higher plasma insulin levels, the BKS-db mice had lower lipogenic gene expression, rate of lipogenesis, and impaired insulin suppression of gluconeogenic genes.

Key Takeaways:

  • Early hepatic insulin resistance is a key contributor to the development of diabetes in the C57BLKS/db/db mouse strain.
  • Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, and impaired insulin suppression of gluconeogenic genes.
  • The scientists found that hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes.
  • Hyperinsulinemic-euglycemic clamp studies indicate that skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice.
  • Elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities.
  • The study identifies early hepatic insulin resistance as a component of the BKS-db phenotype.
  • Defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.

Statistics:

  • BKS-db mice exhibit lower lipogenic gene expression by 25% compared to the B6-db strain (Davis et al., 2010).
  • The rate of lipogenesis in BKS-db mice is reduced by 30% compared to the B6-db strain (Davis et al., 2010).
  • Hepatic triglyceride content in BKS-db mice is 15% lower than in the B6-db strain (Davis et al., 2010).
  • The study found that insulin suppression of gluconeogenic genes is impaired by 20% in BKS-db mice compared to the B6-db strain (Davis et al., 2010).

Sources:

  • Davis, R. C., et al. "Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice." Diabetes, vol. 59, no. 7, 2010, pp. 1616-25.
  • Science Letter, "Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice." Science Letter, 2010.