PubMed21 Apr 2026Diabetologia● 6/10i Oral glucose absorption is enhanced in early metabolic dysfunction-associated steatotic liver disease.
Tricò D, Wu T, Cimbalo N, Chiriacò M, Xie C et al.
Adults with early-stage metabolic dysfunction-associated steatotic liver disease (MASLD) absorbed 52% more glucose during oral tolerance testing compared with matched controls, with enhanced glucose absorption showing fivefold higher odds of MASLD independent of confounders. Study used stable isotope methodology in two separate cohorts measuring glucose kinetics and gastric emptying during 75g oral glucose tolerance tests. This identifies intestinal glucose absorption as a potential early driver of liver disease that precedes hepatic insulin resistance, suggesting a new therapeutic target upstream of existing MASLD interventions. The enhanced absorption occurred independently of gastric emptying rate, pointing to intestinal-specific mechanisms.
Strategic Signal
This finding positions intestinal glucose absorption modulators as potential first-in-class MASLD therapies, creating opportunity for SGLT1 inhibitors or other absorption-blocking mechanisms ahead of established metabolic pathways. The data suggests targeting glucose uptake earlier in the disease cascade could prevent progression to fibrosis, potentially shifting MASLD treatment paradigm from liver-focused interventions to gut-targeted approaches. Companies with SGLT1 assets or novel absorption inhibitors may find new indication expansion opportunities in early-stage liver disease.
Liver/NASHType 2 diabetesMechanisms
Original Abstract
AIMS/HYPOTHESIS: Hepatic glucose flux plays a crucial role in the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), promoting de novo lipogenesis, inflammation and fibrosis. This study aimed to evaluate the kinetics of oral glucose absorption and one of its key modulators, gastric emptying, in individuals with early-stage MASLD vs matched control individuals. METHODS: We quantified glucose metabolic fluxes during a 75 g OGTT using stable isotopes in individuals with MASLD without fibrosis and in healthy control individuals. In a separate cohort, we measured the gastric emptying rate using the 13C-acetate breath test during an OGTT and estimated hepatic steatosis risk. RESULTS: Compared with the control group, in the MASLD group the rate of appearance of oral ingested glucose (RaO) normalised to body weight was 34% higher at 1 h post-OGTT (+318±142 µmol/kg, p=0.031), resulting in a 52% increase in total glucose absorption (+6.4±1.8 g, p=0.001). Participants with MASLD exhibited reduced glucose clearance relative to plasma insulin levels but preserved post-load suppression of endogenous glucose production, indicating peripheral rather than hepatic insulin resistance. Among glucose metabolic fluxes, RaO showed the strongest association with prevalent MASLD, with each 1-SD increase in 1 h RaO being associated with fivefold higher odds of MASLD (OR 4.99 [95% CI 1.44, 31.57], p=0.036), independent of potential confounders. Gastric emptying rate was not associated with hepatic steatosis risk. CONCLUSIONS/INTERPRETATION: Oral glucose absorption is augmented in individuals with MASLD without fibrosis, apparently unrelated to accelerated gastric emptying. This metabolic alteration may represent an early driver of MASLD pathogenesis, preceding hepatic insulin resistance. Future research should investigate whether modulation of intestinal glucose absorption confers therapeutic benefits in MASLD.