The intestine has garnered attention as a target organ for developing new therapies for impaired glucose tolerance. The intestine, which produces incretin hormones, is the central regulator of ...glucose metabolism. Glucagon-like peptide-1 (GLP-1) production, which determines postprandial glucose levels, is regulated by intestinal homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD
) biosynthesis in major metabolic organs such as the liver, adipose tissue, and skeletal muscle plays a crucial role in obesity- and aging-associated organ derangements. Furthermore, NAMPT-mediated NAD
biosynthesis in the intestines and its upstream and downstream mediators, adenosine monophosphate-activated protein kinase (AMPK) and NAD
-dependent deacetylase sirtuins (SIRTs), respectively, are critical for intestinal homeostasis, including gut microbiota composition and bile acid metabolism, and GLP-1 production. Thus, boosting the intestinal AMPK-NAMPT-NAD
-SIRT pathway to improve intestinal homeostasis, GLP-1 production, and postprandial glucose metabolism has gained significant attention as a novel strategy to improve impaired glucose tolerance. Herein, we aimed to review in detail the regulatory mechanisms and importance of intestinal NAMPT-mediated NAD
biosynthesis in regulating intestinal homeostasis and GLP-1 secretion in obesity and aging. Furthermore, dietary and molecular factors regulating intestinal NAMPT-mediated NAD
biosynthesis were critically explored to facilitate the development of new therapeutic strategies for postprandial glucose dysregulation.
Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide ...(NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.
Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that ...nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.
A 61-year-old woman with a 4-year history of maintenance hemodialysis due to end-stage renal disease of unknown cause was admitted because of a recurrent fever and abdominal pain lasting for 3 ...months. She had rheumatoid arthritis as a complication and had taken sulfasalazine for over 4 years. Laboratory data revealed thrombocytopenia, hypocomplementemia, a high C-reactive protein level, and positivity for antinuclear antibody and anti-double strand DNA antibody. Gallium scintigraphy showed pericarditis, pleuritis, and peritonitis. Nonscarring alopecia was also noted. She was diagnosed as having systemic lupus erythematosus (SLE). Drug-induced lupus elicited by sulfasalazine was ruled out because the symptoms did not improve even after the discontinuation of the drug upon admission. Oral prednisolone treatment markedly improved her symptoms and laboratory data. However, she later died of sepsis arising from proctitis on day 71 of admission. This report underscores the necessity of considering new-onset SLE in patients with unexplained fever and serositis, including pleuritis, peritonitis, or pericarditis, even if they are receiving maintenance dialysis.
Abstract
Background
End-of-life medical care for patients receiving maintenance hemodialysis (HD) therapy has become an increasingly important issue worldwide. Thus far, no clear indicators and/or ...biomarkers exist regarding the timing of HD therapy withdrawal.
Methods
To clarify the perimortem circumstances, we examined temporal changes in multiple clinical parameters during the last 10 serial HD sessions of 65 terminal patients with end-stage renal disease who had undergone maintenance HD and died in our hospital.
Results
The results showed that, while most of the laboratory data were unaltered, the physical parameters, such as systolic blood pressure and consciousness levels, gradually and significantly deteriorated toward the last HD session prior to death. The frequency of the use of vasopressors and O
2
inhalation tended to increase. The accumulation of such severe conditions was observed at the last HD session. Of interest, the accumulation of severe conditions at the last HD session in patients with malignancies was significantly less than those with cardiovascular diseases or infectious diseases. The accumulation of severe conditions at the last HD session did not differ between patients who withdrew HD versus those who continued HD.
Conclusion
The results of the present study suggest that predicting the timing of maintenance HD therapy withdrawal is likely to be difficult and that the timing of maintenance HD therapy termination may differ among patient groups with distinct comorbid conditions.
Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that ...nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD.sup.+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD.sup.+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD.sup.+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD.sup.+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD.sup.+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia. Key Words: NAD.sup.+, NAMPT, intestine, postprandial glucose metabolism, GLP-1, obesity Abbreviations: DMSO, dimethyl sulfoxide; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; INKO, intestinal epithelial cell-specific Nampt knockout; IPGTT, intraperitoneal glucose tolerance test; NAD.sup.+, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; OGTT, oral glucose tolerance test; RCD, regular chow diet
Nursing is a highly stressful occupation. Because nursing work involves interaction with patients and colleagues, competence in social skills may be a key issue in stress management among nurses. ...However, there are very few studies among nurses focused on social skills together with social support, both of which are important aspects of job stress. The aim of this study was to examine the interrelationships between social skills and social support with job stressors, problem-solving coping, and psychological distress among Japanese nurses. Data from a self-administered questionnaire of 1,197 female nurses who worked for 5 general hospitals in Japan were analyzed. Covariance structure analysis with structural equation modeling techniques showed that social skills and social support were positively related to each other, while they were negatively associated with psychological distress and job stressors, and positively associated with problem-solving coping. Furthermore, the direct association between social skills and psychological distress was stronger than the association between social support and psychological distress. These findings suggested that improving not only social support at work but also individual social skills is important for nurses' mental health.
The purpose of the present study was to test our hypothesis that intestinal nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD
+
) biosynthesis plays a ...pivotal role in whole-body energy and glucose metabolism. To this end, we generated a new mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. Under regular chow diet, deletion of intestinal epithelial NAMPT did not affect body weight gain, food intake, or whole-body energy expenditure, suggesting that intestinal epithelial NAMPT deficiency had no significant impacts on overall energy intake or expenditure. However, INKO mice displayed reduced early-phase insulin secretion and postprandial hyperglycemia, at least partly due to diminished glucagon-like peptide-1 (GLP-1) production. In addition, we found that diet-induced obese mice had impaired intestinal NAMPT-mediated NAD
+
biosynthesis, associated with impaired GLP-1 production and whole-body glucose metabolism, similar to the INKO mice. Finally, administration of a key NAD
+
intermediate, nicotinamide mononucleotide, to INKO and diet-induced obese mice, restored ileal NAD
+
levels and obesity-associated metabolic derangements, manifested by an impairment in GLP-1 production as well as postprandial hyperglycemia. Taken together, our study provides a new understanding of the role of intestinal NAMPT-mediated NAD
+
biosynthesis in energy and glucose metabolism, and therapeutic insights into intestinal NAD
+
biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia (Nagahisa, Yamaguchi et al. Endocrinology. 2022). A future study using INKO mice to investigate if diminished GLP-1 production is involved in obesity-associated hypertension is warranted.
Obesity is associated with dysregulation in blood pressure control and whole-body glucose metabolism, but the precise underlying mechanism(s) remain unclear. Here, we generated and characterized mice ...with vascular endothelial-cell specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD
+
), a key regulator of cellular energy metabolism. We found that vascular endothelial cell-specific
Nampt
knockout (VeNKO) mice exhibited 1) higher blood pressure (systolic blood pressure; flox/flox mice: 111 ± 2.6 mmHg, VeNKO mice: 134 ± 4.0 mmHg, p < 0.05) with cardiac hypertrophy (flox/flox mice: 5.0 mg/g-body weight, VeNKO mice: 6.1 mg/g-body weight, p < 0.05) and 2) insulin resistance with abnormal fat distribution, under high-fat diet feeding. These deleterious alterations were partially rescued by administering nicotinamide mononucleotide (NMN), a key NAD
+
intermediate. Taken together, our findings demonstrate that vascular endothelial NAMPT-mediated NAD
+
biosynthesis is involved in the regulation of blood pressure and whole-body glucose metabolism. Our study provides mechanistic and therapeutic insights into vascular endothelia NAD
+
biology related to obesity-associated hypertension and insulin resistance.
Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ ...biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.
•Reduced NMNAT1 expression was associated with impaired BAT thermogenesis.•Loss of NMNAT1 markedly decreased nuclear NAD + concentration in BAT.•Adipocyte-specific loss of NMNAT1 did not alter thermogenesis or energy metabolism.•Adipocyte-specific NMNAT1 knockout mice had normal responses to high-fat diet.
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