Gastaldelli 2009: FLI Links to Insulin Resistance and CVD Risk

Background

Dr. Amalia Gastaldelli, a leading researcher in hepatic metabolism at the Italian National Research Council, published this important study examining the relationship between fatty liver, insulin resistance, and cardiovascular risk. This work helped establish the FLI as not merely a liver screening tool but a marker of systemic metabolic dysfunction.

Study Design

Population:

• •1,307 participants from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study
• •European multicenter cohort (19 centers across 14 countries)
• •Age 30-60 years, clinically healthy at enrollment
• •Comprehensive metabolic phenotyping available

Assessments:

• •FLI calculated from standard parameters
• •Euglycemic-hyperinsulinemic clamp (gold standard for insulin sensitivity)
• •Oral glucose tolerance testing (OGTT)
• •Lipid profiling including particle sizing
• •Cardiovascular risk factors and subclinical disease markers

Key Findings

FLI and Insulin Resistance: The study demonstrated strong correlation between FLI and clamp-measured insulin resistance:

FLI Category	Insulin Sensitivity (M-value)
FLI <30	7.8 mg/kg/min (highly insulin sensitive)
FLI 30-59	5.6 mg/kg/min (moderately insulin sensitive)
FLI ≥60	4.2 mg/kg/min (insulin resistant)

Relationship Strength:

• •Correlation coefficient (r) = -0.58 between FLI and M-value
• •FLI explained 34% of variance in insulin sensitivity
• •Relationship persisted after adjustment for BMI

FLI and Lipid Abnormalities: Higher FLI associated with:

• •Elevated triglycerides (223 vs 87 mg/dL)
• •Lower HDL-cholesterol (47 vs 61 mg/dL)
• •Increased small dense LDL particles
• •Higher apoB levels

FLI and Glucose Metabolism:

• •Higher FLI predicted impaired glucose tolerance
• •Fasting insulin increased across FLI tertiles
• •Beta-cell function (disposition index) decreased with higher FLI

Mechanistic Insights

The study provided crucial mechanistic understanding:

Hepatic Insulin Resistance:

1. •Fatty liver impairs insulin suppression of hepatic glucose output
2. •Results in fasting hyperglycemia and hyperinsulinemia
3. •Drives VLDL overproduction and hypertriglyceridemia

Systemic Metabolic Effects:

1. •Hepatic fat accumulation reflects systemic energy surplus
2. •Free fatty acid flux from adipose tissue overwhelms liver
3. •Lipotoxicity affects multiple metabolic pathways

Adipokine Dysregulation:

• •Higher FLI associated with elevated IL-6 and TNF-α
• •Lower adiponectin levels (protective adipokine)
• •Inflammatory milieu drives atherosclerosis

Cardiovascular Implications

FLI ≥60 was associated with:

• •Higher systolic blood pressure (+8 mmHg)
• •Elevated hsCRP (subclinical inflammation)
• •Increased carotid intima-media thickness
• •Higher Framingham risk score

Clinical Translation

This study transformed understanding of FLI:

1. •Beyond liver screening: FLI reflects systemic metabolic health
2. •Insulin resistance marker: Practical alternative to clamp studies
3. •CVD risk stratification: Identifies patients with subclinical atherosclerosis
4. •Intervention target: Improving FLI signals metabolic improvement

Metabolic Health Perspective

The Gastaldelli study provides scientific foundation for using FLI as a metabolic health metric:

Why FLI reflects metabolic dysfunction:

• •Waist circumference → visceral adiposity and adipose tissue insulin resistance
• •Triglycerides → hepatic de novo lipogenesis and VLDL overproduction
• •GGT → oxidative stress from fatty acid metabolism
• •BMI → overall energy surplus

Clinical utility:

• •FLI <30: Likely good hepatic insulin sensitivity
• •FLI ≥60: High probability of hepatic and systemic insulin resistance

For individuals optimizing metabolic health, FLI serves as an integrated marker reflecting the metabolic milieu that drives both fatty liver and cardiovascular disease. Improvements in FLI signal improvements across multiple cardiometabolic risk factors.