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Common variable immunodeficiency (CVID) causes granulomatous-lymphocytic interstitial lung disease (GLILD) and has a poor prognosis. We herein report a case of GLILD in a 49-year-old woman with CTLA-4 deficiency-associated CVID. The patient presented with dyspnea that had worsened over the past two years. A laboratory examination revealed hypoglobulinemia and pancytopenia. Chest computed tomography showed diffuse infiltrative and granular shadows in the bilateral interstitium. A flow cytometric analysis of blood cells and genetic testing confirmed CTLA-4 deficiency. We performed video-assisted thoracoscopic surgery for the pathological diagnosis of GLILD and to exclude infection and malignancy. Corticosteroid treatment successfully improved the condition of the patient.

Aging is believed to induce insulin resistance in humans. However, when and how insulin sensitivity changes with aging remain unclear in both humans and mice. In this study, groups of male C57BL/6N mice at 9-19 weeks (young), 34-67 weeks (mature adult), 84-85 weeks (presenile) and 107-121 weeks (aged) of age underwent hyperinsulinemic-euglycemic clamp studies with somatostatin infusion under awake and non-restrained conditions. The glucose infusion rates for maintaining euglycemia were 18.4±2.9, 5.9±1.3, 20.3±7.2 and 25.3±4.4 mg/kg/min in young, mature adult, presenile and aged mice, respectively. Thus, compared with young mice, mature adult mice exhibited the expected insulin resistance. In contrast, presenile and aged mice showed significantly higher insulin sensitivity than the mature adult mice. These age-related changes were mainly observed in glucose uptake into adipose tissue and skeletal muscle (rates of glucose disappearance were 24.3±2.0, 17.1±1.0, 25.5±5.2 and 31.8±2.9 mg/kg/min in young, mature adult, presenile and aged mice, respectively). Epididymal fat weight and hepatic triglyceride levels were higher in mature adult mice than those in young and aged mice. Our observations indicate that, in male C57BL/6N mice, insulin resistance appears at the mature adult stage of life but subsequently improves markedly. These alterations in insulin sensitivity are attributable to changes in visceral fat accumulations and age-related factors.

Cushing's disease causes numerous metabolic disorders, cognitive decline, and sarcopenia, leading to deterioration of the general health in older individuals. Cushing's disease can be treated with transsphenoidal surgery, but thus far, surgery has often been avoided in older patients. We herein report an older woman with Cushing's disease whose cognitive impairment and sarcopenia improved after transsphenoidal surgery. Although cognitive impairment and sarcopenia in most older patients show resistance to treatment, our case indicates that normalization of the cortisol level by transsphenoidal surgery can be effective in improving the cognitive impairment and muscle mass loss caused by Cushing's disease.

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake. We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. Bolus ICV SGLT2 inhibitor induced an increase in food intake. Tofogliflozin had the strongest effect among these drugs. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Intraperitoneal administration of liraglutide, a GLP-1 receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin. ICV tofogliflozin increased phosphorylation of AMPK in the lateral hypothalamus. In conclusion, SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area. Disclosure K. Takeda: None. H. Ono: None. T. Ohno: None. K. Yokote: None. Funding Japan Society for the Promotion of Science (15K09398, 18K08502, 20H00524); Japan Agency for Medical Research and Development (17GM5010002H0001, 18GM5010002H0002, 19GM5010002H0003, 20GM5010002H0004)

Objective: Insulin promotes glucose uptake, lipogenesis, cell proliferation and cell growth mainly via Akt phosphorylation. FoxO1 is a substrate of Akt, which is inactivated when phosphorylated by Akt. Via this mechanism, FoxO1 antagonizes insulin. On the other hand, constitutive activation of FoxO1 reportedly enhances Akt phosphorylation. Thus, FoxO1 activation, via Akt phosphorylation, may mimic the functions of insulin. Methods: We overexpressed constitutively-active FoxO1 (CA-FoxO1) and FoxO1Δ256, a dominant-negative mutant, in 3T3-L1 adipocytes by adenoviruses and investigated the effects of these proteins on insulin’s functions. Results: CA-FoxO1 enhanced Akt phosphorylation, glucose uptake (275%, P Conclusion: Activation of FoxO1 selectively mimics the metabolic functions of insulin, without its proliferative effects. Contrary to previously reported results, FoxO1Δ256 does not always exert a dominant negative action. Disclosure T. Ohno: None. H. Ono: None. K. Takeda: None. K. Yokote: None.

Objective: FoxO1 is a substrate of serine/threonine-kinase Akt. Although FoxO1 is phosphorylated by Akt and inactivated by insulin stimulation, constitutive activation of FoxO1 is reported to enhance Akt phosphorylation. Therefore, constitutive activation of FoxO1 may mimic insulin’s functions via Akt phosphorylation. Methods: Constitutively-active FoxO1 (CA-FoxO1) in 3T3-L1 adipocytes is overexpressed by adenovirus and Changes in insulin signaling and downstream actions was studied. Results: CA-FoxO1 induced Akt phosphorylation in differentiated 3T3-L1 adipocytes. Regarding downstream actions, CA-FoxO1 significantly enhanced glucose uptake (148.6% compared to controls, P =0.030), GLUT4 translocation (297.6%, P Conclusion: Constitutive activation of FoxO1 induced Akt phosphorylation even in differentiated 3T3-L1 adipocytes, but FoxO1 activation mimicked only metabolic functions of glucose but not proliferative or oncogenic functions of insulin. This selective mimicking of insulin by FoxO1 activation in adipocytes may improve glucose metabolism with a low risk of tumorigenesis. The mechanisms of FoxO1-Akt feedback is suggested not to be the increase in IR-β or p110α subunit of PI 3-kinase as previously reported, but to be mainly downstream of PI 3-kinase. Disclosure T. Ohno: None. H. Ono: None. K. Yokote: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker’s Bureau; Self; Abbott, Astellas Amgen, AstraZeneca K.K., Bayer Inc., FUJIFILM Pharmaceuticals U.S.A., Inc., Kaken Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.