Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms.

This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.

Nicotinamide Protects Against Diet-Induced Body Weight Gain, Increases Energy Expenditure, and Induces White Adipose Tissue Beiging.

SCOPE: Interventions that boost NAD+ availability are of potential therapeutic interest for obesity treatment. The potential of nicotinamide (NAM), the amide form of vitamin B3 and a physiological precursor of nicotinamide adenine dinucleotide (NAD)+ , in preventing weight gain has not previously been studied in vivo. Other NAD+ precursors have been shown to decrease weight gain; however, their impact on adipose tissue is not addressed. METHODS AND RESULTS: Two doses of NAM (high dose: 1% and low dose: 0.25%) are given by drinking water to C57BL/6J male mice, starting at the same time as the high-fat diet feeding. NAM supplementation protects against diet-induced obesity by augmenting global body energy expenditure in C57BL/6J male mice. The manipulation markedly alters adipose morphology and metabolism, particularly in inguinal (i) white adipose tissue (iWAT). An increased number of brown and beige adipocyte clusters, protein abundance of uncoupling protein 1 (UCP1), mitochondrial activity, adipose NAD+ , and phosphorylated AMP-activated protein kinase (P-AMPK) levels are observed in the iWAT of treated mice. Notably, a significant improvement in hepatic steatosis, inflammation, and glucose tolerance is also observed in NAM high-dose treated mice. CONCLUSION: NAM influences whole-body energy expenditure by driving changes in the adipose phenotype. Thus, NAM is an attractive potential treatment for preventing obesity and associated complications.

Chronic Diabetes Complications: The Need to Move beyond Classical Concepts.

Chronic-diabetes-related complications simultaneously compromise both the micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.

Vitamin B3 impairs reverse cholesterol transport in Apolipoprotein E-deficient mice.

INTRODUCTION: High Density Lipoproteins (HDL) are dysfunctional in hypercholesterolemia patients. The hypothesis was tested that nicotinamide (NAM) administration will influence HDL metabolism and reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT) in a murine model of hypercholesterolemia. METHODS: Apolipoprotein E-deficient (KOE) mice were challenged with a high-fat diet for 4 weeks. The effect of different doses of NAM on cholesterol metabolism, and the ability of HDL to promote m-RCT was assessed. RESULTS: The administration of NAM to KOE mice produced an increase (∼1.5-fold; P<0.05) in the plasma levels of cholesterol, which was mainly accounted for by the non-HDL fraction. NAM produced a [3H]-cholesterol plasma accumulation (∼1.5-fold) in the m-RCT setting. As revealed by kinetic analysis, the latter was mainly explained by an impaired clearance of circulating non-HDL (∼0.8-fold). The relative content of [3H]-tracer was lowered in the livers (∼0.6-fold) and feces (>0.5-fold) of NAM-treated mice. This finding was accompanied by a significant (or trend close to significance) up-regulation of the relative gene expression of Abcg5 and Abcg8 in the liver (Abcg5: 2.9-fold; P<0.05; Abcg8: 2.4-fold; P=0.06) and small intestine (Abcg5: 2.1-fold; P=0.15; Abcg8: 1.9-fold; P<0.05) of high-dose, NAM-treated mice. CONCLUSION: The data from this study show that the administration of NAM to KOE mice impaired m-RCT in vivo. This finding was partly due to a defective hepatic clearance of plasma non-HDL.

Evaluation of efficacy, safety, pain perception and health-related quality of life of percutaneous ethanol injection as first-line treatment in symptomatic thyroid cysts.

BACKGROUND: To evaluate the efficacy, safety, pain perception and health-related quality of life (QoL) of percutaneous ethanol injection treatment (PEIT) as an alternative to thyroid surgery in symptomatic thyroid cysts. METHODS: Thirty consecutive patients (46 ± 10 years; 82% women) with symptomatic benign thyroid cysts relapsed after drainage were included. In all cases, cytology prior to treatment, maximum cyst diameter and volume were determined. PEIT was conducted using the established procedure, and the volume of fluid removed and pain perceived by the patient were assessed. In each procedure, the volume of alcohol instilled was <2 ml. After follow-up, final cyst diameter and volume were determined and the persistence of symptoms and QoL were assessed by a questionnaire (SF-36). RESULTS: Mean symptom duration was 10 ± 20 months. A single session of PEIT was required to complete the procedure in 45% of patients, two in 31% and three in 13%. Mean initial maximum cyst diameter was 3.5 ± 1.0 cm and mean extracted liquid volume 61 ± 36 ml. During PEIT, 39% of patients experienced virtually no pain, 43% mild pain and 17% moderate pain. No complications of PEIT were observed. After 12.1 ± 1.4 months of follow-up, cysts were reduced more than 70% in volume in 86.3% of patients, more than 80% in 61.9% and more than 90% in 42%. On the health-related QoL SF-36 questionnaire, patient scores 6 months post-PEIT did not differ significantly from those of the healthy Spanish population. With respect to cosmetic complaints or local symptoms of compression, PEIT-treated patients presented an initial score of 22 ± 8 and 13 ± 5 after treatment (p < 0.05). CONCLUSIONS: In our experience, percutaneous ethanol injection has prove to be an effective, safe and well-tolerated first-line treatment of symptomatic thyroid cysts.

Regulatory T cells and other lymphocyte subpopulations in patients with melanoma developing interferon-induced thyroiditis during high-dose interferon-α2b treatment.

CONTEXT: One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. OBJECTIVE: Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. DESIGN, PATIENTS AND METHODS: From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). RESULTS: Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P < 0·001). CONCLUSIONS: Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT.