Disentangling metabolic impairment in the liver-heart axis: tissue-specific insulin sensitivity in type 2 diabetes

TL;DR

This study identifies distinct liver-heart metabolic profiles in type 2 diabetes, revealing how insulin resistance affects these organs differently and highlights a high-risk group needing targeted treatment.

Contribution

The study introduces a novel classification of liver-heart metabolic phenotypes in T2D based on tissue-specific insulin sensitivity and comorbidity risks.

Findings

A strong inverse correlation was found between liver and heart glucose uptake in T2D patients.

Three distinct liver-heart phenotypes were identified, each with different risks for MASLD and CVD.

The HepGluc[+]+mIR phenotype showed the highest risk of metabolic dysfunction and comorbidities.

Abstract

The liver-heart axis in type 2 diabetes (T2D) reflects key metabolic interactions disrupted by insulin resistance (IR). Organ-specific effects of insulin remain unclear due to challenges in measuring tissue-level IR. This study aims to define liver-heart phenotypes and their associated metabolic impairments, which relate to hepatic fat accumulation linked to metabolic dysfunction-associated steatotic liver disease (MASLD) and coronary artery calcifications (CACs) tied to cardiovascular disease (CVD).

In this cross-sectional study, 41 individuals with controlled T2D underwent biochemical tests and [18F]FDG PET/CT scans before and after a hyperinsulinemic euglycemic clamp (HEC). Tissue-specific insulin-mediated glucose uptake was derived from PET imaging, while CT provided data on radiodensity, volume, fat, and calcifications.

A strong inverse correlation was observed between myocardial and liver ΔSUV (r=-0.74, p=2×10-7), thus suggesting the liver-heart metabolic axis in T2D. Three phenotypes were determined according to increased risks of T2D comorbidities including MASLD and CVD: HepGluc[+]+mIR (high risk of MASLD and CVD), HepGluc[−]+mIR (high risk of CVD, low risk of MASLD), and HepGluc[−]+mIS (low risk of MASLD and CVD). Moreover, HOMA-IR was only reflective of organ-level dysfunction in HepGluc[+]+mIR, which was the most at-risk phenotype in terms of systemic and tissue-specific metabolic impairment, including higher inflammation, IR, liver fat, CACs, and biomarkers of MASLD and CVD.

This study explores a potential liver-heart metabolic axis in T2D, linked to insulin-mediated dysfunction that may originate in the heart and extend to the liver. The coexistence of organ-specific phenotypes suggests three possible risk profiles, with the HepGluc[+]+mIR phenotype appearing most consistent with advanced T2D progression. Careful identification of this phenotype could support improved monitoring and more personalized treatment strategies in T2D.

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