Abstract
AIMS/HYPOTHESIS: Subcutaneous insulin delivery in individuals with insulin-deficient type 1 diabetes bypasses the portal circulation, disrupting the physiological porto-systemic insulin gradient and affecting postprandial hepatic glucose regulation. However, direct, non-invasive measurement of these liver-specific dynamics and their deviation from normal physiology in individuals with type 1 diabetes is challenging. To address this, we integrated metabolic imaging with whole-body tracer dilution to map postprandial glucose metabolism in both the liver and systemically in adults with type 1 diabetes and healthy control individuals. METHODS: In this cross-sectional study, ten adults with type 1 diabetes and ten healthy control individuals with similar age, BMI and gender distributions were enrolled. After an overnight fast, participants ingested 60 g [6,6'-(2)H(2)]-glucose (D-Glc); subcutaneous insulin was administered to type 1 diabetes participants according to their carbohydrate-to-insulin ratio. Interleaved deuterium metabolic imaging (DMI) and (13)C-magnetic resonance spectroscopy ((13)C-MRS) at 7 T were performed from pre-ingestion to 150 min post-ingestion to quantify hepatic D-Glc and glycogen concentrations. Blood samples were collected to measure plasma glucose, insulin and glucagon. Postprandial glucose-insulin dynamics were quantified using the single tracer oral minimal model, accounting for non-steady-state insulin exposure. RESULTS: At baseline, individuals with type 1 diabetes had significantly higher plasma glucose concentrations than control individuals (10.7±2.3 and 5.2±0.4 mmol/l, respectively; p<0.001), while preprandial glycogen levels did not differ significantly. Following D-Glc administration, hepatic D-Glc increased more markedly in the individuals with type 1 diabetes compared with the control group (peak values 4.7±2.0 and 3.0±0.8 mmol/l, respectively; p=0.02). In the postprandial period, glycogen levels did not significantly rise at 150 min in type 1 diabetes, whereas a clear increase was observed in control individuals (iAUC(0-180)=2.4 mol/l × min). Despite similar systemic insulin exposure and no significant differences in postprandial glucagon concentrations between groups, individuals with type 1 diabetes demonstrated significantly reduced suppression of endogenous glucose production (p=0.001) but similar insulin-dependent glucose disposal. Hierarchical clustering identified two distinct type 1 diabetes subgroups: Subgroup 1 exhibited a steeper increase in both hepatic and systemic D-Glc profiles, while subgroup 2 showed a divergent D-Glc trajectory and net glycogen depletion relative to accumulation in subgroup 1 (iAUC(0-180)=-3.0 vs 2.5 mol/l × min, p=0.04), despite no overt clinical differences between subgroups. CONCLUSIONS/INTERPRETATION: By integrating DMI/(13)C-MRS liver imaging with systemic stable-isotope modelling, this comparative study demonstrates significantly altered hepatic glucose metabolism in adults with well-managed type 1 diabetes vs control individuals, together with substantial phenotypic heterogeneity within the type 1 diabetes cohort. These findings highlight the potential of non-invasive metabolic phenotyping to resolve metabolic alterations and inter-individual variation in type 1 diabetes, which are essential steps towards the provision of precision medicine.