Metabolic-associated fatty liver disease is characterized by a post-oral glucose load hyperinsulinemia in individuals with mild metabolic alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remain unclear. We compared the glucose metabolism, insulin resistance, insulin secretion, and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a body mass index (BMI) between 25 and 40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3 h 75 g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percent of participants had MAFLD. Median age (IQR) [57 (45-65) vs. 57 (44-63) yr] and sex (60% vs. 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (P < 0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity, and first-phase pancreatic ß-cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (P < 0.02). Among individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance while exhibiting lower first phase ß-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede T2D.NEW & NOTEWORTHY Using an oral glucose tolerance test, we found hyperinsulinemia, lower insulin sensitivity, lower insulin clearance, and lower first-phase pancreatic ß-cell function in individuals with MAFLD. This may explain part of the increased risk of incident type 2 diabetes in this population. These data also highlight implications of hyperinsulinemia and impaired insulin clearance in the progression of MAFLD to type 2 diabetes.

Tissue pleiotropic effect of biotin and prebiotic supplementation in established obesity.

Combination therapies targeting multiple organs and metabolic pathways are promising therapeutic options to combat obesity progression and/or its comorbidities. The alterations in the composition of the gut microbiota initially observed in obesity have been extended recently to functional alterations. Bacterial functions involve metabolites synthesis that may contribute to both the gut microbiota and the host physiology. Among them are B vitamins, whose metabolism at the systemic, tissue or microbial level are dysfunctional in obesity. We previously reported that the combination of oral supplementation of a prebiotic (fructo-oligosaccharides, FOS) and vitamin B7/B8 (biotin) impedes fat mass accumulation and hyperglycemia in mice with established obesity. This was associated with an attenuation of dysbiosis with improved microbial vitamin metabolism. We now extend this study by characterizing whole-body energy metabolism along with adipose tissue transcriptome and histology in this mouse model. We observed that FOS resulted in increased caloric excretion in parallel with down-regulation of genes and proteins involved in jejunal lipid transport. The combined treatments also strongly inhibited the accumulation of subcutaneous fat mass, with a reduced adipocyte size and expression of lipid metabolism genes. Down-regulation of inflammatory and fibrotic genes and proteins was also observed in both visceral and brown adipose tissues and liver by combined FOS and biotin supplementation. In conclusion, oral administration of a prebiotic and biotin has a beneficial impact on the metabolism of key organs involved in the pathophysiology of obesity, which could have promising translational applications.

Deep phenotyping and biomarkers of various dairy fat intakes in an 8-week randomized clinical trial and 2-year swine study.

Health effects of dairy fats (DF) are difficult to evaluate, as DF intakes are hard to assess epidemiologically and DF have heterogeneous compositions that influence biological responses. We set out to find biomarkers of DF intake and assess biological response to a summer DF diet (R2), a winter DF diet (R3), and a R3 supplemented with calcium (R4) compared to a plant-fat-based diet (R1) in a randomized clinical trial (n=173) and a 2-year study in mildly metabolically disturbed downsized pigs (n=32). Conventional clinical measures were completed by LC/MS plasma metabolomics/lipidomics. The measured effects were modeled as biological functions to facilitate interpretation. DF intakes in pigs specifically induced a U-shaped metabolic trajectory, reprogramming metabolism to close to its initial status after a one-year turnaround. Twelve lipid species repeatably predicted DF intakes in both pigs and humans (6.6% errors). More broadly, in pigs, quality of DF modulated the time-related biological response (R2: 30 regulated functions, primarily at 6 months; R3: 26 regulated functions, mostly at 6-12 months; R4: 43 regulated functions, mostly at 18 months). Despite this heterogeneity, 9 functions overlapped under all 3 DF diets in both studies, related to a restricted area of amino acids metabolism, cofactors, nucleotides and xenobiotic pathways and the microbiota. In conclusion, over the long-term, DF reprograms metabolism to close to its initial biological status in metabolically-disrupted pigs. Quality of the DF modulates its metabolic influence, although some effects were common to all DF. A resilient signature of DF consumption found in pigs was validated in humans.