桑原 政成

Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple paradigms, including two-bottle choice, conditioned place preference and operant self-administration, alongside decreased ∆FosB expression in the nucleus accumbens. Both genetic deletion and pharmacologic inhibition of KHK-A/C suppressed ethanol intake. Hepatocyte-specific KHK-A/C knockout mice displayed partially reduced alcohol consumption, potentially linked to altered aldehyde dehydrogenase expression, while intestinal KHK-A/C deletion restored glucagon-like peptide-1 levels-a hormone known to suppress alcohol intake. Under ethanol pair-matched conditions, global and liver-specific KHK-A/C knockout mice were protected from ALD, with marked reductions in hepatic steatosis, inflammation and fibrosis. These findings identify ethanol-induced fructose metabolism as a key driver of excessive alcohol consumption and ALD pathogenesis. Given that ALD and metabolic dysfunction-associated steatotic liver disease share fructose-dependent mechanisms, targeting fructose metabolism may offer a novel therapeutic approach for treating alcohol use disorder and related liver injury.

AIM: Gut microbiota dysbiosis causes atherosclerosis. Patients with atherosclerosis and type 2 diabetes mellitus (T2D) often have low Bacteroides abundance, potentially increasing atherosclerosis risk. This study investigated the association between low Bacteroides abundance and endothelial dysfunction in patients with T2D. METHODS: The relationship between the relative Bacteroides abundance in fecal gut microbiota, assessed by 16S ribosomal RNA analysis, and the reactive hyperemia index (RHI) was investigated in 93 patients with T2D (68 men and 25 women). Clinical parameters, including plasma short-chain fatty acids and inflammatory markers, were also examined. Heatmap analysis compared lower Bacteroides group vs. upper Bacteroides group. RESULTS: Natural log-transformed RHI (Ln-RHI) was positively correlated with Ln-relative Bacteroides abundance (p < 0.05). The low Bacteroides group had a considerably lower Ln-RHI than the high group (p = 0.038). Plasma acetate content was correlated with relative Bacteroides abundance (p = 0.036) but not with Ln-RHI content. The low Bacteroides group tended to have higher high-sensitivity C-reactive protein levels than the high group (p = 0.069). No other bacterial differences between the groups were associated with the RHI. CONCLUSIONS: Low Bacteroides abundance is associated with low RHI and may be associated with the risk of atherosclerosis in patients with T2D.

INTRODUCTION: This study aimed to identify factors associated with pancreatic abnormal findings on imaging (PAI) suggesting precancerous potential between slowly progressive type 1 diabetes and acute-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: The study was designed to identify factors associated with PAI using data from a nationwide cohort, the Japanese Type 1 Diabetes Database. Clinical factors, including sex, age, type of diabetes onset, diabetes duration, body mass index, and human leucocyte antigen genotypes associated with type 1 diabetes, were evaluated. RESULTS: Among 279 patients with type 1 diabetes, 95 patients who had not undergone imaging evaluations, two patients with pancreatic lipomatosis, and 15 patients with missing data were excluded. Finally, a total of 167 patients with type 1 diabetes were analyzed. Among 13 patients who were identified as PAI positive, female sex (92.3% vs 53.2%, p=0.007), slowly progressive type 1 diabetes (69.2% vs 36.4%, p=0.034), and older age were more common compared with PAI-negative cases. The multivariable logistic regression analysis revealed that female sex (OR 13.87; 95% CI 1.6 to 120.1; p=0.017), slowly progressive type 1 diabetes (OR 5.70; 95% CI 1.46 to 22.19; p=0.012), and age (OR 1.05; 95% CI 1.002 to 1.103; p=0.043) were independently associated with PAI positivity. CONCLUSIONS: The findings indicate that slowly progressive type 1 diabetes and female sex are closely associated with PAI, along with age. These results suggest the need for increased clinical vigilance for pancreatic pathology in patients with slowly progressive type 1 diabetes.