Background/Objectives: The consumption of fructose-sweetened beverages, especially when combined with a high-fat (HF) diet, substantially contributes to obesity, diabetes, and metabolic dysfunction-associated steatotic liver disease. Ectopic fat accumulation in skeletal muscles is a critical factor in the development of insulin resistance, a key feature of these metabolic disorders. We aimed to investigate the effects of the rare sugar, d-allulose, on fructose-induced insulin resistance. Methods: Male Wistar rats were randomly assigned to fructose-free control diet (CD), HF/fructose-free diet (HF), or HF/fructose diet (HFF) groups. After 4 weeks, an intraperitoneal glucose tolerance test (IPGTT) was performed, followed by a two-step hyperinsulinemic–euglycemic clamp (HE-clamp) test at 5 weeks. Blood, skeletal muscle, and liver samples were collected after 6 weeks, and triglyceride (TG) levels were measured. Additionally, Western blot was performed on skeletal muscle samples. The same protocol was repeated for the HFF group supplemented with either 5% d-allulose or 5% cellulose. Results: Compared to the CD and HF groups, the HFF group exhibited increased blood glucose levels during the IPGTT and greater systemic and skeletal muscle insulin resistance in the HE-clamp. Furthermore, plasma, liver, and muscle TG levels were significantly elevated in the HFF group. However, d-allulose supplementation improved insulin resistance in the HFF group and reduced blood, liver, and muscle TG levels. Additionally, insulin-stimulated AKT phosphorylation and acetyl-CoA carboxylase phosphorylation were enhanced in the skeletal muscle following d-allulose administration. Conclusions: d-allulose may improve insulin resistance by reducing TG accumulation in the skeletal muscle, potentially independent of its anti-obesity properties.

We investigated whether the peripheral co-administration of leptin and liraglutide (a glucagon-like peptide-1 receptor agonist) improved glucose metabolism in a mouse model of insulin-dependent diabetes mellitus (IDDM). Twelve-week-old male C57BL/6J mice were injected intraperitoneally with a high dose of streptozotocin to induce IDDM or vehicle-treated. Mice with IDDM were divided into four groups: leptin treatment alone (LEP), liraglutide treatment alone (LIRA), co-administration of leptin and liraglutide treatment (LEP+LIRA), untreated mice (UNT). Vehicle-treated mice were the healthy controls (HC). The blood glucose (BG) levels were measured, and a glucose tolerance test (GTT) was performed to compare the five groups. Leptin was administered peripherally at 20 μg/day using an osmotic pump, while liraglutide was administered subcutaneously at 1000 μg/kg/day. Monotherapy with leptin or liraglutide significantly improved glucose metabolism, as assessed by comparing BG levels and GTTs with those of the UNT group. Mice in the LEP+LIRA group showed even greater improvements in glucose metabolism than the monotherapy groups. Notably, glucose metabolism in the LEP+LIRA group improved comparably with the HC group. Thus, the peripheral co-administration of leptin and liraglutide effectively improved glucose metabolism in mice with IDDM without the use of insulin.

Objective: In treating obesity, energy intake control is essential to avoid exceeding energy expenditure. However, excessive restriction of energy intake often leads to resting energy expenditure (REE) reduction, increasing hunger and making weight loss difficult. This study aimed to investigate whether providing nutritional guidance that considers energy expenditure based on the regular evaluation of REE and physical activity could effectively reduce body weight (BW) in patients with obesity. Methods: A single-arm, prospective interventional study was conducted on 20 patients with obesity (body mass index ≥ 25 kg/m²) at the Nagoya University Hospital for 24 weeks. REE and physical activity were regularly assessed, and the recommended energy intake was adjusted based on the values. The primary outcome was the change in BW, and the secondary outcomes included changes in REE and hunger ratings, which were assessed using a visual analog scale. Results: Eighteen participants completed the study, demonstrating a significant reduction in BW after 24 weeks (−5.34 ± 6.76%, p < 0.0001). No significant changes were observed in REE or hunger ratings. No adverse events were reported throughout the study period. Conclusions: Guidance on energy intake based on REE and physical activity was effective for reducing BW in patients with obesity without decreasing REE or increasing hunger. This approach may reduce the burden on patients with obesity while losing BW.