清野 祐介

Type 1 diabetes mellitus is a major risk factor for both sarcopenia and osteoporosis, primarily due to the body's inability to utilize glucose as a result of insulin deficiency. Impairments in insulin and glucose signaling can accelerate the decline in muscle and bone health. To investigate this interaction, we examined whether insulin deficiency exacerbates muscle and bone deterioration in Chrebp knockout (KO) mice. Male wild-type (WT) and KO mice, aged 18 weeks, were intraperitoneally treated with 200 mg/kg BW streptozotocin (STZ), which selectively destroys pancreatic beta cells, thereby inducing insulin deficiency. Two weeks after STZ administration, compared with STZ-treated WT mice, STZ-treated KO mice presented significantly greater reductions in body weight and gastrocnemius muscle weight (BW: WT-vehicle vs. WT-STZ; 2.58 [-1.23, 6.39] (p = 0.21); KO-vehicle vs. KO-STZ: 8.03 [5.23, 10.82]; GA muscle: WT vehicle vs. WT STZ: 0.084 [0.047, 0.12], p < 0.0001; KO vehicle vs. KO STZ: 0.084, [0.047, 0.12], p < 0.0001). The decrease in grip strength caused by STZ administration was greater in the KO mice than in the WT mice (mean differences [95% CIs]: WT vehicle-WT STZ, 49.6. [0.9, 98.4], p = 0.046; WT STZ-KO STZ: 71.40 [29.1, 113.7], p = 0.0059; KO vehicle-KO STZ: 84.3 [51.9, 116.8], p = 0.0003). Consistent with these findings, STZ administration reduced IGF-1 expression and increased atrogin mRNA levels, with the highest levels in STZ-treated KO mice. In skeletal muscle, the changes in IGF-1 and Atrogen induced by STZ administration were significantly greater in the KO group than in the WT group (IGF-1: WT vehicle-WT STZ: 0.19 [-0.072, 0.46], p = 0.17; KO vehicle-KO STZ: 0.79 [0.53, 1.06], p < 0.0001; Atrogen: WT vehicle-WT STZ: -2.7 [-3.01, -2.29], p < 0.0001; KO vehicle-KO STZ: -3.35 [-3.71, -2.99], p < 0.0001). The BMD in the Chrebp-deficient group was greater than that in the wild-type group (WT vehicle-KO vehicle: -5.2 [-8.4, -1.9], p = 0.0014); however, the administration of STZ significantly decreased the BMD only in the KO group (WT vehicle-WT STZ: p = 0.45, KO vehicle-KO STZ: 7.2 [3.9, 10.4], p < 0.0001). These results suggest that Chrebp deficiency combined with insulin deficiency aggravates sarcopenia and osteoporosis risk. Therefore, insulin and glucose signals are important for maintaining muscle and bone mass and function. However, further studies are needed to elucidate the mechanisms by which ChREBP deletion and insulin deficiency cause osteosarcopenia.

BACKGROUND: Weight loss is a substantial non-motor feature of Parkinson's disease (PD) associated with worse clinical outcomes, but the underlying mechanisms remain poorly understood. Thus, we investigated the mechanisms of PD-related weight loss by examining the correlation between body composition and various plasma metabolites. METHODS: We enrolled 91 patients with PD and 47 healthy controls between July 2021 and October 2023. Body composition was evaluated using bioelectrical impedance analysis. Plasma metabolite profiling was conducted via mass spectrometry, including short-chain and medium-chain fatty acids, Krebs cycle intermediates, ketone bodies and phospholipids. Subsequently, alterations in body composition in PD and their association with plasma metabolites were assessed. RESULTS: Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p<0.001) compared with controls. Metabolomic analyses revealed that, in patients with PD, glycolysis and Krebs cycle markers (lactic acid and succinic acid) were reduced, while ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), amino acid catabolism-related markers (2-hydroxybutyric acid and 2-oxobutyric acid) and acetic acid were elevated. Notably, in patients with PD, acetoacetic acid and 3-hydroxybutyric acid negatively correlated with BMI. Phosphatidylcholine (40:2) was also elevated in PD and showed higher levels in individuals at more advanced Hoehn and Yahr stages. CONCLUSIONS: PD-related fat loss was accompanied by a pattern of lower glycolytic activity and higher levels of lipid and amino acid metabolism-related metabolites, consistent with a potential shift in energy utilisation. These findings highlight metabolic pathways as potential targets for interventions to mitigate weight loss in PD.

Fructose ingestion increases circulating glucagon-like peptide-1 (GLP-1) and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L-cells triggers GLP-1 secretion, which then potentiates insulin secretion and counteracts fructose-induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6-a/a) and obese diabetic (NSY.B6-Ay/a) mice, fructose elevated plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor-deficient mice (Gipr-/-) but was abolished in proglucagon-deficient mice (Gcg-/-) by pharmacological GLP-1 receptor antagonism, indicating a requirement for GLP-1, but not GIP. Across strains, fructose-induced insulin response correlated with attenuation of post-fructose glycaemia, consistent with insulin being essential for suppressing fructose-induced hyperglycaemia. To explore the mechanism underlying fructose-induced GLP-1 secretion, we combined ATP-sensitive potassium channel-deficient mice (Kcnj11-/-), the GLUTag L-cell line, and metabolic tracing of 13C-labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP/ADP ratio in L-cells, closes KATP channels and stimulates GLP-1 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP/ADP ratio were associated with elevated GLP-1 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP-1 secretion required to potentiate insulin secretion, thereby establishing a gut-pancreas axis that counter-regulates fructose-induced hyperglycaemia. KEY POINTS: Fructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. Our study demonstrates that short-term (24 h) fructose ingestion in mice elevates both insulin and glucagon-like peptide 1 (GLP-1) levels in the blood, with the plasma insulin response being GLP-1-dependent. We found that fructose metabolism in intestinal L-cells triggered GLP-1 secretion by increasing the ATP/ADP ratio and closing ATP-sensitive K+ (KATP) channels. This intestinal fructose metabolism-GLP-1-β-cell axis plays a crucial role in preventing fructose-induced hyperglycaemia, an effect that is compromised in obese diabetic mice. These insights highlight the previously unclear metabolic responses following short-term fructose ingestion and their importance in glucose homeostasis.