Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.

Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake.

Adiponectin has been shown to stimulate fatty acid oxidation and enhance insulin sensitivity through the activation of AMP-activated protein kinase (AMPK) in the peripheral tissues. The effects of adiponectin in the central nervous system, however, are still poorly understood. Here, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARH. Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of adiponectin and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system.

Post-Marketing Surveillance Study of the Safety and Efficacy of Nalfurafine (Capsules 2.5 µg, Oral Dispersing Tablets 2.5 µg) in 1186 Patients with Chronic Liver Disease and Intractable Pruritus.

Background: Nalfurafine (Remitch®, Toray Industries, Inc.) is a selective κ-receptor agonist approved in Japan for the improvement of pruritus in patients with chronic liver diseases (only when existing treatments bring insufficient efficacy) in May 2015. Methods: A post-marketing Specific Drug Use Survey was conducted in Japan (March 1, 2016 to June 30, 2020) of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver disease. Results: Among 1186 cases analyzed for safety, the incidence of adverse drug reactions was 9.4% (112/1186 cases), lower than 61.4% reported in pre-marketing surveillance (297/484 cases). No specific safety issues were found and no cases of concern for drug dependence identified. Efficacy (itch improvement) was demonstrated in 73.16% (815/1114 cases; 12-week analysis set) and in 85.67% (520/607; general assessment of itch improvement at 1-year analysis set). A significant difference was found in 4 items of itch improvement at 12 weeks and 8 items of itch improvement at 1 year. No noteworthy issues were identified. Mean Visual Analog Scale (VAS) values after 12 weeks and 1 year after the first dose were significantly lower than the baseline (p < 0.0001 for both treatment durations). Mean severity scores (Kawashima's classification scheme) were significantly lower than the pretreatment score at 12 weeks and 1 year after the first dose (both p < 0.0001). No concerns were identified in the efficacy and safety of nalfurafine in patients with specific background, ie, the elderly (aged ≥ 65 years), those with renal impairment, and those on long-term treatment (≥ 365 days) compared with patients without corresponding background. Conclusion: No new safety issues of concern or cases of insufficient efficacy were identified in this Specific Drug Use Survey of the safety and efficacy of nalfurafine for the improvement of pruritus in patients with chronic liver diseases.

(3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide as a potent dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch® capsules 2.5 µg) in 3,762 hemodialysis patients with intractable pruritus.

BACKGROUND: Intractable pruritus in hemodialysis patients can significantly decrease their quality of life and is also associated with poor vital prognosis. Although combined multiple causes of intractable pruritus in these patients have been identified, no existing treatments are proven to be sufficiently effective. We conducted a post-marketing surveillance to follow-up and assess the safety and efficacy of nalfurafine, a selective κ-opioid receptor agonist, for the treatment of intractable pruritus in patients undergoing hemodialysis. PATIENTS AND METHODS: Hemodialysis patients with intractable pruritus from institutions in Japan who received oral nalfurafine hydrochloride between January 2010 and December 2013 were enrolled in the surveillance. Surveillance was completed in July 2015. Safety data during 1 year after nalfurafine treatment onset, and efficacy data of nalfurafine evaluating the first 12-week treatment period and the following period until 1 year after the initial dose of nalfurafine (using global assessment of the itch improvement by the physician, Visual Analog Scale, and the Shiratori's severity scores) were collected and analyzed. RESULTS: In total, 3,762 patients were analyzed for safety. Adverse drug reactions were experienced by 402/3,762 (10.69%) patients. The most frequent adverse drug reactions were insomnia (127/3,762 [3.38%] patients), constipation (34 [0.90%]), somnolence (32 [0.85%]), dizziness (23 [0.61%]), nausea (13 [0.35%]), and malaise (9 [0.24%]). No patients developed dependence on nalfurafine. Nalfurafine was effective in 82.50% (2,880/3,491) of patients during the first 12 weeks and in 84.95% (2,167/2,551) on treatment during the subsequent period until 1 year after nalfurafine treatment initiation. Statistically significant decreases were reported in the Visual Analog Scale and the Shiratori's severity scores (p<0.001). CONCLUSION: Oral nalfurafine hydrochloride (from 2.5 µg/day to a maximum of 5.0 µg/day) continues to be safe and effective for the treatment of intractable pruritus in hemodialysis patients in real-world clinical settings.

Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle.

In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.

Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding.

Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.