-
The Journal of Biological Chemistry Sep 2021The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces...
The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and reduces adiposity. Skeletal muscle contributes to preventing adiposity, by consuming nearly half the energy of a typical human. We report sexually dimorphic differences in energy metabolism and muscle function in Rdh10+/- mice. Relative to wild-type (WT) controls, Rdh10+/- males fed a high-fat diet decrease reliance on fatty-acid oxidation and experience glucose intolerance and insulin resistance. Running endurance decreases 40%. Rdh10+/- females fed this diet increase fatty acid oxidation and experience neither glucose intolerance nor insulin resistance. Running endurance increases 220%. We therefore assessed RA function in the mixed-fiber type gastrocnemius muscles (GM), which contribute to running, rather than standing, and are similar to human GM. RA levels in Rdh10+/- male GM decrease 38% relative to WT. Rdh10+/- male GM increase expression of Myog and reduce Eif6 mRNAs, which reduce and enhance running endurance, respectively. Cox5A, complex IV activity, and ATP decrease. Increased centralized nuclei reveal existence of muscle malady and/or repair in GM fibers. Comparatively, RA in Rdh10+/- female GM decreases by less than half the male decrease, from a more modest decrease in Rdh10 and an increase in the estrogen-induced retinol dehydrogenase Dhrs9. Myog mRNA decreases. Cox5A, complex IV activity, and ATP increase. Centralized GM nuclei do not increase. We conclude that Rdh10/RA affects whole body energy use and insulin resistance partially through sexual dimorphic effects on skeletal muscle gene expression, structure, and mitochondria activity.
Topics: Adiposity; Alcohol Oxidoreductases; Animals; Diet, High-Fat; Electron Transport Complex IV; Energy Metabolism; Female; Glucose Intolerance; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Muscles; Oxidation-Reduction; Physical Endurance; Running; Sex Characteristics; Sex Factors; Tretinoin
PubMed: 34419449
DOI: 10.1016/j.jbc.2021.101101 -
Neurobiology of Disease Feb 2023Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use...
Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Disease Models, Animal; Ethanol; Glucose; Hippocampus; Mice, Transgenic; Plaque, Amyloid; Presenilin-1
PubMed: 36535550
DOI: 10.1016/j.nbd.2022.105967 -
Endocrinology Jan 2023Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation...
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein-coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.
Topics: Animals; Male; Mice; Diabetes Mellitus, Type 2; Glucose; Glucose Intolerance; Lysophospholipids; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 36690339
DOI: 10.1210/endocr/bqad019 -
BMJ Open Diabetes Research & Care Mar 2023The relationship between tea consumption and glucose metabolism remains controversial. This study investigated the associations of tea consumption with impaired glucose...
INTRODUCTION
The relationship between tea consumption and glucose metabolism remains controversial. This study investigated the associations of tea consumption with impaired glucose regulation, insulin secretion and sensitivity in Shanghai High-risk Diabetic Screen project.
RESEARCH DESIGN AND METHODS
A total of 2337 Chinese subjects were enrolled in the study from 2014 to 2019. Each participant conducted a 75 g oral glucose tolerance test (OGTT) with five-point glucose and insulin level examined. They also completed a nurse-administered standard questionnaire including tea, coffee, and alcohol consumption, smoking habit, physical activity, education, sleep quality, etc. RESULTS: The result showed that tea consumption was positively associated with plasma glucose levels during OGTT after adjusting for confounder (Ps <0.05) and was associated with worsening glucose tolerance (OR 1.21, 95% CI 1.01-1.44; p=0.034). Strong tea consumption or long-term tea intake (>10 years) had an increased risk of glucose intolerance (all p<0.05). These associations did not vary in participants drinking green tea. In addition, insulin secretion indexes were decreased 7.0%-13.0% in tea consumption group. Logistic regression analysis showed that tea consumption was independently associated with lower insulin secretion (homeostasis model assessment of β-cell function (HOMA-β) (OR 0.81, 95% CI 0.68-0.97; p=0.021); Stumvoll first-phase index (OR 0.81, 95% CI 0.68-0.97; p=0.020)) in a fully adjusted model. Green tea consumption showed a negative association with insulin secretion (HOMA-β (OR 0.77, 95% CI 0.62-0.96; p=0.019)).
CONCLUSIONS
Tea intake is associated with an increased risk of glucose intolerance in a large high-risk diabetic Chinese population. Habitual tea consumption subjects might have lower pancreatic β-cell function.
Topics: Humans; Glucose Intolerance; Insulin Secretion; Diabetes Mellitus, Type 2; China; Glucose; Tea
PubMed: 36931660
DOI: 10.1136/bmjdrc-2022-003266 -
Molecular Metabolism Dec 2022Disturbances in NAD metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in...
OBJECTIVE
Disturbances in NAD metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD levels and pancreatic β-cell function in pathophysiological conditions.
METHODS
Whole body and pancreatic β-cell-specific NRK1 knockout (KO) mice were metabolically phenotyped in situations of high-fat feeding and aging. We also analyzed pancreatic β-cell function, β-cell mass and gene expression.
RESULTS
We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is abundantly expressed in pancreatic β-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised β-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, β cell dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in β-cells did not show altered glucose homeostasis.
CONCLUSIONS
This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic β-cell function in high-fat feeding or aging conditions.
Topics: Animals; Mice; Diabetes Mellitus, Type 2; Diet, High-Fat; Glucose; Mice, Knockout; NAD; Niacinamide; Pyridinium Compounds; Phosphotransferases (Alcohol Group Acceptor); Insulin-Secreting Cells; Aging
PubMed: 36165811
DOI: 10.1016/j.molmet.2022.101605 -
Drug and Alcohol Dependence Nov 2021Among people receiving residential treatment for a substance use disorder (SUD), premature treatment termination predicts poor post-treatment outcomes. We examined the... (Clinical Trial)
Clinical Trial
BACKGROUND
Among people receiving residential treatment for a substance use disorder (SUD), premature treatment termination predicts poor post-treatment outcomes. We examined the utility of the alternative model for personality disorders (AMPD) for predicting premature residential SUD treatment termination, including interactions with age and gender.
METHODS
Participants (N = 374) were receiving residential treatment for SUD and enrolled in a clinical trial with two conditions: Skills for Improving Distress Intolerance (SIDI) and Supportive Counseling (NCT01741415). Participants were assessed at intake on AMPD traits using the Personality Inventory for DSM-5 (PID-5) and tracked longitudinally. After establishing gender and age measurement invariance, we used competing risk models to predict treatment completion versus premature termination using interactions of PID-5 scores with age and gender.
FINDINGS
Disinhibition and Negative Emotionality domains and facets predicted premature treatment termination, particularly among younger, male participants. There were positive effects of SIDI on treatment completion for participants with high levels of domain and facet Negative Emotionality. A small proportion (≈ 12 %) of the PID-5 items showed differential item functioning by age or gender; however, the aggregate impact on test-level total scores was negligible.
CONCLUSIONS
Participants (particularly young men) displaying poor self-control and emotional regulation are at risk for premature termination. These findings, together with minimal aggregate differential item functioning at the scale level, suggest that the PID-5 is a practically useful, construct-valid, non-proprietary measure, aspects of which can be used for screening in residential SUD treatment. Furthermore, among those with high negative emotionality, SIDI may be effective in preventing premature treatment termination.
Topics: Diagnostic and Statistical Manual of Mental Disorders; Humans; Male; Personality; Personality Disorders; Personality Inventory; Residential Treatment
PubMed: 34521057
DOI: 10.1016/j.drugalcdep.2021.109011 -
Clinical Nutrition (Edinburgh, Scotland) Feb 2020Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation affecting >5% of the liver volume that is not explained by alcohol abuse. It is known that... (Observational Study)
Observational Study
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation affecting >5% of the liver volume that is not explained by alcohol abuse. It is known that fructose gives rise to NAFLD and it has been recently described that the ingestion of fructose in low amounts in aldolase B deficient mice is associated with the development of fatty liver. Therefore, it is reasonable that patients with HFI (Hereditary Fructose Intolerance) present fatty liver at diagnosis, but its prevalence in patients treated and with adequate follow-up is not well documented in the literature. The aim of this study is to analyze the association between HFI and NAFLD in treated patients.
METHODS
A cross-sectional observational study was conducted. The population comprised 16 genetically diagnosed HFI patients aged from 3 years to 48 and in dietary treatment of fructose, sorbitol and sacarose exclusion at least for two years. Blood samples were obtained for analytical studies and anthropometric measurements of each patient were performed.
RESULTS
Patients presented a Body Mass Index (BMI) of 17.9 ± 2.9 kg/m. The HOMA index and Quick index were in normal range for our population. The S-adenosyl-methionine (SAM)/S-adenosyl-l-homocysteine (SAH) ratio was increased in the patients in whom this analysis was performed. By imaging techniques it was observed that 9 of the 16 patients presented fatty liver (7 by hepatic MRI). Of these 9 patients, only 3 presented hepatomegaly. 7 of 9 patients affected by the c.448G > C mutation had fatty infiltration, of which three of them presented in addition hepatomegaly.
CONCLUSIONS
There is a high prevalence of fatty liver in HFI patients and it is not related to obesity and insulin resistance. The diagnosis of fatty liver in HFI patients and, above all, the identification of new therapeutic approaches, can positively impact the quality of life of these patients.
Topics: Adolescent; Adult; Child; Child, Preschool; Cross-Sectional Studies; Female; Fructose Intolerance; Humans; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Young Adult
PubMed: 30833214
DOI: 10.1016/j.clnu.2019.02.019 -
Digestive Endoscopy : Official Journal... Jan 2022High-quality bowel preparation is paramount for the diagnostic accuracy and safety of colonoscopy; however, it is often difficult for patients to adhere to high-volume... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
High-quality bowel preparation is paramount for the diagnostic accuracy and safety of colonoscopy; however, it is often difficult for patients to adhere to high-volume laxatives, which may contribute to poor bowel preparation. This review aims to assess the efficacy of bowel preparation fluids of 1 L or less (≤1 L).
METHODS
We performed a systematic review including all relevant randomized controlled trials on ultra-low volume (≤1 L) bowel preparation fluids for colonoscopy published since 2015. Primary endpoint was the percentage of adequately prepared patients. Secondary endpoints included adenoma detection rate (ADR) and safety.
RESULTS
Bowel preparation with sodium picosulfate/magnesium citrate (SPMC; 19 trials, n = 10,287), 1L-polyethylene glycol with ascorbate (PEGA; 10 trials, n = 1717), sodium phosphate (NaP; 2 trials, n = 621), and oral sulfate solution (OSS; 3 trials, n = 597) was adequate in 75.2%, 82.9%, 81.9%, and 92.1%, respectively, of patients; however, heterogeneity between studies was considerable (I range: 86-98%). Pooled ADRs were 31.1% with SPMC, 32.3% with 1L-PEGA, 30.4% with NaP, and 40.9% with OSS. Temporary electrolyte changes were seen with all ultra-low volume bowel preparation fluid solutions but without sustained effects in most patients.
CONCLUSION
Ultra-low volume bowel preparation fluids do not always meet the 90% quality standard for adequate bowel preparation as defined by current guidelines. Nonetheless, they may be considered in patients intolerant for higher-volume laxatives and without risk factors for inadequate bowel preparation or dehydration-related complications.
Topics: Adenoma; Ascorbic Acid; Cathartics; Colonoscopy; Humans; Polyethylene Glycols
PubMed: 33991373
DOI: 10.1111/den.14015 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Oct 2022To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical...
OBJECTIVE
To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options.
METHODS
The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed.
RESULTS
A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4-18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% 30.51% . 28.08%, = 20.319, < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS.
CONCLUSION
POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.
Topics: Child; Female; Humans; Male; Electrolytes; Metoprolol; Midodrine; Orthostatic Intolerance; Postural Orthostatic Tachycardia Syndrome; Retrospective Studies; Salts; Sitting Position; Syncope, Vasovagal; Tilt-Table Test
PubMed: 36241239
DOI: 10.19723/j.issn.1671-167X.2022.05.024 -
Scientific Reports Nov 2019Agonists of β adrenergic receptors (βAR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the...
Agonists of β adrenergic receptors (βAR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the activation of AR and GR, we hypothesized that the treatment of rats with relevant therapeutic doses of long acting βAR agonist (LABA; clenbuterol; CLEN) and/or GR agonist (dexamethasone; DEX) would exacerbate ozone-induced pulmonary and systemic changes. In the first study, male 12-week-old Wistar-Kyoto rats were injected intraperitoneally with vehicle (saline), CLEN (0.004 or 0.02 mg/kg), or DEX (0.02 or 0.1 mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN + DEX (each at 0.005 or 0.02 mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4 hr/day x 2-days). In air-exposed rats CLEN, DEX or CLEN + DEX did not induce lung injury or inflammation, however DEX and CLEN + DEX decreased circulating lymphocytes, spleen and thymus weights, increased free fatty acids (FFA) and produced hyperglycemia and glucose intolerance. Ozone exposure of vehicle-treated rats increased bronchoalveolar lavage fluid protein, albumin, neutrophils, IL-6 and TNF-α. Ozone decreased circulating lymphocytes, increased FFA, and induced hypeerglycemia and glucose intolerance. Drug treatment did not reverse ozone-induced ventillatory changes, however, lung effects (protein and albumin leakage, inflammation, and IL-6 increase) were exacerbated by CLEN and CLEN + DEX pre-treatment in a dose-dependent manner (CLEN > CLEN + DEX). Systemic effects induced by DEX and CLEN + DEX but not CLEN in air-exposed rats were analogous to and more pronounced than those induced by ozone. These data suggest that adverse air pollution effects might be exacerbated in people receiving LABA or LABA plus glucocorticoids.
Topics: Adrenergic beta-2 Receptor Agonists; Animals; Clenbuterol; Dexamethasone; Drug Interactions; Fatty Acids; Glucocorticoids; Glucose; Interleukin-6; Lung; Lymphocytes; Male; Ozone; Rats; Rats, Wistar; Spleen; Thymus Gland; Tumor Necrosis Factor-alpha
PubMed: 31784596
DOI: 10.1038/s41598-019-54269-w