Hepatic glucose metabolism in the steatotic liver

Scoditti, Egeria; Sabatini, Silvia; Carli, Fabrizia; Gastaldelli, Amalia

doi:10.1038/s41575-023-00888-8

Cited by 7 publications

(1 citation statement)

References 197 publications

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“…This leads to an increase in gluconeogenesis and de novo lipogenesis from the increasingly insulin resistant and steatotic hepatocytes in the liver. The progression of MASLD leads to increased production of several hepatokines, that worsen insulin resistance [28][29][30][31] and, along with the resulting hyperglycemia and increased serum free fatty acids (FFA), cause glucolipotoxicity that worsens β-cell function, in a vicious cycle. Thus, crosstalk between the liver and the islets is critical to the onset and perpetuation of T2DM.…”

Section: Introductionmentioning

confidence: 99%

A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

Aleman,

Ravikumar,

Wiegand

et al. 2024

Preprint

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Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in pancreatic islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with primary islets on a chip (PANIS) enabling MASLD progression and islet dysfunction to be quantitatively assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF), under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion (GSIS) response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived secreted factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying complex disease mechanisms, and advancing precision medicine.

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Section: Introductionmentioning

confidence: 99%