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. 2024 Nov 19;5(11):101820.
doi: 10.1016/j.xcrm.2024.101820.

Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Silvia Sabatini  1 , Partho Sen  2 , Fabrizia Carli  1 , Samantha Pezzica  1 , Chiara Rosso  3 , Erminia Lembo  4 , Ornella Verrastro  5 , Ann Daly  6 , Olivier Govaere  7 , Simon Cockell  6 , Tuulia Hyötyläinen  8 , Geltrude Mingrone  9 , Elisabetta Bugianesi  3 , Quentin M Anstee  10 , Matej Orešič  11 , Amalia Gastaldelli  12
Affiliations

Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Silvia Sabatini et al. Cell Rep Med. .

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.

Keywords: MASH; MASLD; NASH; fluxomics; genome-scale metabolic modeling; gluconeogenesis; hepatic glucose production; insulin resistance; liver fibrosis; type 2 diabetes.

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Conflict of interest statement

Declaration of interests G.M. reports consulting fees from Novo Nordisk, Fractyl Inc, and Recor Inc. She is also scientific advisor of Metadeq Inc, Keyron Ltd, GHP Scientific Ltd, and Jemyll Ltd. G.M. reports receiving research grants from Metadeq Inc and Fractyl Inc. A.G. has served as a consultant for: Boehringer Ingelheim, Eli Lilly and Company, Metadeq Diagnostics, and Fractyl Health; has participated in advisory boards for Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metadeq Diagnostics, and Pfizer; and has received speaker’s honorarium and other fees from Eli Lilly and Company, Merck Sharp & Dohme, and Novo Nordisk. Q.M.A. reports grants and/or personal fees from Allergan/Tobira, E3Bio, Eli Lilly & Company Ltd, Galmed, Genfit SA, Gilead, Grunthal, Imperial Innovations, Intercept Pharma Europe Ltd, Inventiva, Janssen, Kenes, MedImmune, NewGene, Pfizer Ltd, Raptor Pharma, Novartis Pharma AG, AbbVie, BMS, GSK, NGMBio, Madrigal, Servier, EcoR1, 89Bio, Altimmune, AstraZeneca, Axcella, Blade, BNN Cardio, Celgene, Cirius, CymaBay, Genentech, HistoIndex, Indalo, IQVIA,Metacrine, North Sea Therapeutics, Novo Nordisk, Poxel, Terns, Viking Therapeutics, Glympse Bio, and PathAI, outside the submitted work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Glucose production, measured using stable isotope tracers, and insulin resistance in the EPoS-flux group (n = 80) In (A), boxplot of HGP grouping individuals according to MASL/MASH severity. In (B), (C), and (D), average HGP (mean) was reported considering the degrees of steatosis, fibrosis, and activity score (AS, inflammation + ballooning), respectively. In (E), (F), and (G), boxplots of insulin resistance in liver (Hep-IR, measured as μmol/min LBM ∗ mU/L), whole-body (HOMA-IR), and adipose tissue (Adipo-IR) in MASL/MASH groups, respectively. In (H), (I), and (J), linear associations of HGP with HOMA-IR, Adipo-IR, and lipolysis, respectively. The linear regression lines are colored in red while the area in gray indicates confidence interval at level 0.95. Dots were colored according to MASL/MASH severity. Mann-Whitney’s p value ∗<0.05, ∗∗<0.01, ∗∗∗ <0.001.
Figure 2
Figure 2
Glucose production, estimated using genome-scale metabolic models, and insulin resistance in the EPoS-transcriptomics subgroup (n = 206) In (A) and (B), boxplot of HGP in individuals without and with T2D, respectively. In (C), (D), and (E), average HGP (mean) was reported considering the degrees of steatosis (green), fibrosis (blue), and activity score (AS, inflammation + ballooning, red) in individuals with and without T2D, respectively. In (F), (G), (H), and (I), boxplots of hepatic insulin resistance (Hep-IR, as mmol/h LBM ∗ mU/L) and HOMA-IR in individuals without and with T2D, respectively. In (H) and (I), boxplots of whole-body insulin resistance (HOMA-IR) in individuals without and with T2D, respectively. In the boxplots, subjects were grouped according to MASLD histological severity. Mann-Whitney’s p value ∗<0.05, ∗∗<0.01, ∗∗∗ <0.001. In (J), linear associations of HGP with HOMA-IR were reported. The linear regression line is colored in red while the area in gray indicates confidence interval at level 0.95.
Figure 3
Figure 3
Gluconeogenesis is increased in individuals with severe fibrosis independently of T2D in the EPoS-transcriptomics group (n = 206) In (A), the schematic representation of fasting hepatic glucose metabolism, focusing on gluconeogenesis pathway and TCA cycle. In (B), the contribution of the gluconeogenesis flux to HGP expressed in μmol/min kg of LBM (GNG), estimated by genome-scale metabolic models in the EPoS-transcriptomics group. Individuals were grouped according to fibrosis stage and presence of T2D. Mann-Whitney’s test p values: ∗<0.05, ∗∗<0.01, ∗∗∗<0.001. In (C), heatmap of the estimated fluxes through the metabolic reactions in the subnetwork of (A). Each reaction in (A) is listed on the horizontal axis of the heatmap. Individuals were grouped according to fibrosis stage and T2D. Fluxes were scaled to zero mean and unit variance and reported as median within the groups. Mann-Whitney’s test p values vs. F0/F1: ∗< 0.1, ∗∗<0.05 after false discovery rate (FDR) correction, in diabetic and non-diabetic subgroups, respectively.
Figure 4
Figure 4
Hepatic expression of genes involved in insulin action but not insulin clearance is associated to advanced fibrosis, regardless of the presence of T2D in the EPoS-transcriptomics group (n = 206) In (A), (B), and (C), expression levels of IRS1, IRS2, and Akt2. Individuals were grouped according to fibrosis stage and presence of T2D. In (D), Spearman correlation matrix of the predicted fluxes through the system depicted in Figure 3A in the EPoS-transcriptomics cohort and the hepatic expression of the genes IRS1, IRS2, and Akt2. Significant correlation (p value < 0.05) were marked with ∗. In (E) and (F), expression levels of CEACAM-1 and IDE, according to the presence of advanced fibrosis and T2D. In the boxplots, Mann-Whitney’s test p values: ∗<0.05, ∗∗<0.01, ∗∗∗<0.001.
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