Petersen 2018: Mechanisms of Insulin Action and Insulin Resistance

Background

Drs. Max C. Petersen and Gerald I. Shulman from Yale University published this comprehensive review in Physiological Reviews (PMID: 30067154), detailing the molecular mechanisms of insulin action and resistance.

Study Design

State-of-the-art review synthesizing decades of research on insulin signaling, from receptor binding to metabolic effects, and how these pathways become impaired in insulin resistance.

Key Findings

Normal insulin signaling cascade:

1. •Insulin binds receptor → autophosphorylation
2. •IRS-1/2 recruitment and phosphorylation
3. •PI3K activation → PIP3 generation
4. •Akt activation
5. •Metabolic effects (glucose uptake, glycogen synthesis, lipogenesis)

Primary mechanism of insulin resistance:

Tissue	Key Defect
Liver	DAG-PKCε impairs insulin receptor kinase
Muscle	DAG-PKCθ impairs IRS-1 signaling
Both	Ectopic lipid accumulation is the trigger

Key insight: Diacylglycerol (DAG) accumulation from ectopic lipid activates protein kinase C isoforms that impair insulin signaling.

Mechanistic Insights

Why does ectopic fat cause insulin resistance?

1. •Excess energy intake → lipid overflow
2. •Fat stored in liver/muscle (not just adipose)
3. •DAG accumulates in membranes
4. •PKC activation impairs insulin signaling
5. •Compensatory hyperinsulinemia develops

Clinical Implications

Targeting ectopic fat reverses insulin resistance:

• •Weight loss reduces liver/muscle fat
• •Carbohydrate restriction decreases hepatic de novo lipogenesis
• •Exercise improves muscle fat oxidation

Metabolic Health Perspective

This review provides the molecular explanation for why metabolic interventions work: they reduce ectopic fat → lower DAG → restore insulin signaling. Liver fat reduction (measurable by FLI) is a key therapeutic target.