Vitamin B3 Abstracts 2

© 2010

Nicotinamide alleviates indomethacin-induced gastric ulcers: a novel antiulcer agent

            (Abdallah 2009) Download

Nicotinamide, a precursor of nicotinamide adenine dinucleotide (NAD(+)), is an essential nutrient for cell growth that participates in DNA repair and energy production. Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is an intricate process involving gastric mucus depletion, increased microvascular permeability, nitric oxide imbalance, as well as free radical production. The present study was conducted to test for the possible gastroprotective effect of nicotinamide utilizing an acute indomethacin-induced gastric ulcer model. Sucralfate possesses antiulcer/antioxidant properties; hence it was used as the reference drug. Indomethacin resulted in hemorrhagic mucosal lesions, increased microvascular permeability, and reduced the gastric mucosal contents of nitric oxide and mucus. Moreover, it produced an imbalance in the mucosal redox state as indicated by a decline of glutathione and glutathione peroxidase, which were associated with increased lipid peroxides. Comparable to sucralfate, nicotinamide markedly decreased the severity of indomethacin-induced gastric lesions and restored the levels of altered biochemical parameters. Gastroprotection afforded by nicotinamide is possibly mediated by conservation of gastric mucus, as well as nitric oxide contents, enhanced gastric microvascular permeability, and its antioxidant properties.

Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT)

            (Bingley, Mahon et al. 2008) Download

OBJECTIVE: Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers. RESEARCH DESIGN AND METHODS: The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA >or=20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis RESULTS: The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0-62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3). CONCLUSIONS: These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.

Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition

            (Bogan and Brenner 2008) Download

Although baseline requirements for nicotinamide adenine dinucleotide (NAD+) synthesis can be met either with dietary tryptophan or with less than 20 mg of daily niacin, which consists of nicotinic acid and/or nicotinamide, there is growing evidence that substantially greater rates of NAD+ synthesis may be beneficial to protect against neurological degeneration, Candida glabrata infection, and possibly to enhance reverse cholesterol transport. The distinct and tissue-specific biosynthetic and/or ligand activities of tryptophan, nicotinic acid, nicotinamide, and the newly identified NAD+ precursor, nicotinamide riboside, reviewed herein, are responsible for vitamin-specific effects and side effects. Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research.

A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX)

            (Crino, Schiaffini et al. 2004) Download

OBJECTIVE: Various adjuvant therapies have been introduced along with intensive insulin therapy in patients with recent onset type 1 diabetes. Nicotinamide (NA), administered at diagnosis of the disease, can have beneficial effects on the clinical remission rate, improve metabolic control and preserve or slightly increase beta-cell function, probably by reducing toxicity due to free oxygen radicals. Vitamin E, a known antioxidant, inhibits lipid peroxidation; this can lead to protection of islet beta cells from the combined effects of interleukin 1, tumor necrosis factor and gamma interferon. The aim of the present study was to investigate whether the addition of vitamin E to NA could improve metabolic control and the residual beta-cell function, as measured by C-peptide secretion, in children and adolescents with recent onset type 1 diabetes; patients were followed-up for 2 years after diagnosis. PATIENTS AND STUDY DESIGN: Recent onset type 1 diabetes patients (n=64, mean age 8.8 years) were recruited by participating centres of the IMDIAB group. Thirty-two patients were randomized to NA (25 mg/kg body weight) plus vitamin E (15 mg/kg body weight); 32 patients acted as controls and received NA only at the same dose as above. Intensive insulin therapy was applied to both treatment groups. RESULTS: There were three drop outs during the 2-year follow-up period. Overall, patients assigned to the NA+vitamin E group or the NA group did not significantly differ in terms of glycated hemoglobin (HbA1c) levels, insulin requirement or baseline C-peptide secretion. Patients diagnosed at an age of less than 9 years showed significantly reduced C-peptide levels compared with those aged over 9 years at diagnosis and at the 2-year follow-up but there were no differences between the NA and NA+vitamin E treated groups. However at 6 months, patients over 9 years of age treated with NA+vitamin E showed significantly higher C-peptide compared with the NA group (P<0.003). In both age groups and in the different treatment groups, C-peptide levels found at diagnosis were preserved 2 years later. CONCLUSIONS: The use of NA alone, or in combination with vitamin E, along with intensive insulin therapy is able to preserve baseline C-peptide secretion for up to 2 years after diagnosis. This finding is of particular interest for pre-pubertal children with type 1 diabetes and has never been reported before.

Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress

            (Freeman, Shimomura et al. 2006) Download

This paper reviews recent studies on the role of Nnt (nicotinamide nucleotide transhydrogenase) in insulin secretion and detoxification of ROS (reactive oxygen species). Glucose-stimulated insulin release from pancreatic beta-cells is mediated by increased metabolism. This elevates intracellular [ATP], thereby closing KATP channels (ATP-sensitive potassium channels) and producing membrane depolarization, activation of voltage-gated Ca2+ channels, Ca2+ influx and, consequently, insulin secretion. The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion, which results from a naturally occurring deletion in the Nnt gene. Transgenic expression of the wild-type Nnt gene in C57BL/6J mice rescues the phenotype. Knockdown of Nnt in the insulin-secreting cell line MIN6 with small interfering RNA dramatically reduced Ca2+ influx and insulin secretion. Similarly, mice carrying ENU (N-ethyl-N-nitrosourea)-induced loss-of-function mutations in Nnt were glucose intolerant and secreted less insulin during a glucose tolerance test. Islets isolated from these mice showed impaired insulin secretion in response to glucose, but not to the KATP channel blocker tolbutamide. This is explained by the fact that glucose failed to elevate ATP in Nnt mutant islets. Nnt is a nuclear-encoded mitochondrial protein involved in detoxification of ROS. beta-Cells isolated from Nnt mutant mice showed increased ROS production on glucose stimulation. We hypothesize that Nnt mutations enhance glucose-dependent ROS production and thereby impair beta-cell mitochondrial metabolism, possibly via activation of uncoupling proteins. This reduces ATP production and lowers KATP channel activity. Consequently, glucose-dependent electrical activity and insulin secretion are impaired.

Effect of niacin and nicotinamide on leukocytes and some urinary constituents

            (Hoffer 1956) Download

Vitamin B3 boosts neutrophil counts

            (Khanna-Gupta and Berliner 2009) Download

The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group

            (Lampeter, Klinghammer et al. 1998) Download

On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease, type 1 diabetes. The first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of nicotinamide in children at high risk for IDDM. Nicotinamide has been shown to protect beta-cells from inflammatory insults and to improve residual beta-cell function in patients after onset of IDDM. Individuals at high risk for developing IDDM within 3 years were identified by screening the siblings (age 3-12 years) of patients with IDDM for the presence of high titer (> or =20 Juvenile Diabetes Foundation [JDF] U) islet cell antibodies. Probands (n = 55) were randomized into placebo and nicotinamide (slow release, 1.2 g x m(-2) x day(-1)) receiving groups and followed prospectively in a controlled clinical trial using a sequential design. Rates of diabetes onset were similar in both groups throughout the observation period (maximum 3.8 years, median 2.1 years). This sequential design provides a 10% probability of a type II error against a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% by nicotinamide. The trial was terminated when the second sequential interim analysis after the eleventh case of diabetes showed that the trial had failed to detect a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving nicotinamide exhibited decreased first-phase insulin secretion in response to intravenous glucose (P = 0.03). No other side effects were observed. We conclude that in this subgroup of diabetes-prone individuals at very high risk and with an assumed rapid disease progression, nicotinamide treatment did not cause a major decrease or delay of diabetes development. However, the data do not exclude the possibility of a less strong, but potentially meaningful, risk reduction in this cohort, or a major clinical effect of nicotinamide in individuals with less risk of progression to IDDM than studied here.

Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited

            (Morre, Morre et al. 2009) Download

Aging-related cell-surface NADH oxidase (arNOX)-specific activities increase with age between age 30 and ages 50-65. The protein is shed and circulates. Activity correlates with a number of aging-related disorders including low-density lipoprotein (LDL) oxidation as a precondition to atherosclerosis as well as oxidation of collagen and elastin as a major contributor to skin aging. arNOX inhibitors formulated for sustained release are capable of maintaining circulating arNOX at low levels with regular use as food supplements formulated with natural compounds. Among the best sources are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox.

Nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas

            (Polo, Saibene et al. 1998) Download

Eighteen patients with non-insulin-dependent (type 2) diabetes mellitus of normal body weight [body mass index (BMI) <25 kg/m2] without signs of autoimmunity [negative for islet cell antibodies (ICA)], with secondary failure of sulphonylureas, defined as persistent hyperglycaemia in spite of maximal doses of sulphonylureas, were evaluated for C-peptide release under basal conditions and 6 min after i.v. glucagon, for glycosylated haemoglobin (HbA1C), and for fasting and mean daily blood glucose levels. They entered a 6-month, single-blind study in which they were randomly assigned to one of three treatments: (1) insulin plus nicotinamide (group 1, 0.5 g, three tablets/day); (2) insulin plus placebo (group 2, 3 tablets/day); (3) current sulphonylureas plus nicotinamide (group 3, 0.5 g, three tablets/day). They were re-evaluated for C-peptide, HbA1C, and fasting and mean daily blood glucose levels after 6 months. Compared with group 2, C-peptide release increased in both groups 1 and 3, while HbA1C, fasting and mean daily blood glucose levels improved in the three groups to the same extent. With multiple regression analysis, nicotinamide administration was the only significant factor for the improvement of C-peptide release. These data indicate that nicotinamide improves C-peptide release in type 2 diabetic patients with secondary failure of sulphonylureas, leading to a metabolic control similar to patients treated with insulin.

Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study)

            (Pozzilli, Visalli et al. 1997) Download

OBJECTIVE: Protection of residual beta cell function at the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) by intensive insulin therapy and the addition of nicotinamide (NA) has been established. The objective of this study was to evaluate the effect of a free oxygen radical scavenger such as vitamin E (Vit E) on residual beta cell function and parameters of metabolic control in patients with recent onset IDDM undergoing intensive insulin therapy. DESIGN: The effect of Vit E was compared with that of NA (control group) in a randomized multicentre trial. METHODS: Eighty-four IDDM patients between 5 and 35 years of age (mean age 15.8 +/- 8.4 (s.d.) years) entered a one year prospective study. One group of patients (n = 42) was treated with Vit E (15 mg/kg body weight/day) for one year; the other group (n = 42) received NA for one year (25 mg/kg body weight/day). All patients were under intensive insulin therapy with three to four injections a day. Basal and stimulated (1 mg i.v. glucagon) C-peptide secretion, glycosylated haemoglobin and insulin dose were evaluated at diagnosis and at three-monthly intervals up to one year. RESULTS: Preservation and slight increase of C-peptide levels at one year compared with diagnosis were obtained in the two treated patient groups. No statistically significant differences were observed in basal or stimulated C-peptide levels between the two groups of patients for up to one year after diagnosis. Glycosylated haemoglobin and insulin dose were also similar between the two groups; however patients receiving Vit E under the age of 15 years required significantly more insulin than NA-treated patients one year after diagnosis (P < 0.04). CONCLUSIONS: Our data indicate that Vit E and NA possess similar effects in protecting residual beta cell function in patients with recent onset IDDM. Since their putative mechanism of protection on beta cell cytotoxicity is different, combination of these two vitamins may be envisaged for future trials of intervention at IDDM onset.

Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans

            (Sivapirabu, Yiasemides et al. 2009) Download

BACKGROUND: Ultraviolet (UV) radiation can profoundly suppress the cutaneous immune system, thus enhancing carcinogenesis. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer. Nicotinamide (vitamin B3) prevents UV-induced immunosuppression and carcinogenesis in mice, and solar-simulated (ss) UV-induced immunosuppression in humans. Its effectiveness against different UV wavebands and mechanism of action is as yet unknown. OBJECTIVES: To determine the effects and mechanisms of topical nicotinamide on UV-induced suppression of delayed type hypersensitivity (DTH) responses in humans. METHODS: Healthy Mantoux-positive volunteers in four randomised, double-blinded studies were irradiated with solar-simulated (ss)UV (UVB + UVA) or narrowband UVB (300 nm) or UVA (385 nm). Topical nicotinamide (0.2% or 5%) or its vehicle were applied immediately after each irradiation. Mantoux testing was performed at irradiated sites and adjacent unirradiated control sites 48 h after the first irradiation and measured 72 h later. Immunosuppression was calculated as the difference in Mantoux-induced erythema and induration at test sites compared to control sites. Human keratinocyte cell cultures, with and without ssUV and nicotinamide, were used for quantitative real-time reverse transcriptase-polymerase chain reaction assessment of TP53 and enzymes that regulate oxidative phosphorylation. RESULTS: Nicotinamide cooperated with ssUV to increase enzymes involved in cellular energy metabolism and p53, and significantly protected against immunosuppression caused by UVB, longwave UVA and single and repeated ssUV exposures. CONCLUSIONS: Longwave UVA, which is poorly filtered by most sunscreens, was highly immune suppressive even at doses equivalent to 20 min of sun exposure. Nicotinamide, which protected against both UVB and UVA, is a promising agent for skin cancer prevention.

Nicotinamide induces differentiation of embryonic stem cells into insulin-secreting cells

            (Vaca, Berna et al. 2008) Download

The poly(ADP-ribose) polymerase (PARP) inhibitor, nicotinamide, induces differentiation and maturation of fetal pancreatic cells. In addition, we have previously reported evidence that nicotinamide increases the insulin content of cells differentiated from embryonic stem (ES) cells, but the possibility of nicotinamide acting as a differentiating agent on its own has never been completely explored. Islet cell differentiation was studied by: (i) X-gal staining after neomycin selection; (ii) BrdU studies; (iii) single and double immunohistochemistry for insulin, C-peptide and Glut-2; (iv) insulin and C-peptide content and secretion assays; and (v) transplantation of differentiated cells, under the kidney capsule, into streptozotocin (STZ)-diabetic mice. Here we show that undifferentiated mouse ES cells treated with nicotinamide: (i) showed an 80% decrease in cell proliferation; (ii) co-expressed insulin, C-peptide and Glut-2; (iii) had values of insulin and C-peptide corresponding to 10% of normal mouse islets; (iv) released insulin and C-peptide in response to stimulatory glucose concentrations; and (v) after transplantation into diabetic mice, normalized blood glucose levels over 7 weeks. Our data indicate that nicotinamide decreases ES cell proliferation and induces differentiation into insulin-secreting cells. Both aspects are very important when thinking about cell therapy for the treatment of diabetes based on ES cells.

Nicotinamide overload may play a role in the development of type 2 diabetes

            (Zhou, Li et al. 2009) Download

AIM: To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS: Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N(1)-methylnicotinamide on glucose metabolism, plasma H(2)O(2) levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS: Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N(1)-methylnicotinamide clearance. CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N(1)-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.


References

Abdallah, D. M. (2009). "Nicotinamide alleviates indomethacin-induced gastric ulcers: a novel antiulcer agent." Eur J Pharmacol 627(1-3): 276-80.

Bingley, P. J., J. L. Mahon, et al. (2008). "Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT)." Diabetes Care 31(1): 146-50.

Bogan, K. L. and C. Brenner (2008). "Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition." Annu Rev Nutr 28: 115-30.

Crino, A., R. Schiaffini, et al. (2004). "A randomized trial of nicotinamide and vitamin E in children with recent onset type 1 diabetes (IMDIAB IX)." Eur J Endocrinol 150(5): 719-24.

Freeman, H., K. Shimomura, et al. (2006). "Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress." Biochem Soc Trans 34(Pt 5): 806-10.

Hoffer, A. (1956). "Effect of niacin and nicotinamide on leukocytes and some urinary constituents." Can Med Assoc J 74(6): 448-51.

Khanna-Gupta, A. and N. Berliner (2009). "Vitamin B3 boosts neutrophil counts." Nat Med 15(2): 139-41.

Lampeter, E. F., A. Klinghammer, et al. (1998). "The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group." Diabetes 47(6): 980-4.

Morre, D. J., D. M. Morre, et al. (2009). "Aging-related nicotinamide adenine dinucleotide oxidase response to dietary supplementation: the French paradox revisited." Rejuvenation Res 13(2-3): 159-61.

Polo, V., A. Saibene, et al. (1998). "Nicotinamide improves insulin secretion and metabolic control in lean type 2 diabetic patients with secondary failure to sulphonylureas." Acta Diabetol 35(1): 61-4.

Pozzilli, P., N. Visalli, et al. (1997). "Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study)." Eur J Endocrinol 137(3): 234-9.

Sivapirabu, G., E. Yiasemides, et al. (2009). "Topical nicotinamide modulates cellular energy metabolism and provides broad-spectrum protection against ultraviolet radiation-induced immunosuppression in humans." Br J Dermatol 161(6): 1357-64.

Vaca, P., G. Berna, et al. (2008). "Nicotinamide induces differentiation of embryonic stem cells into insulin-secreting cells." Exp Cell Res 314(5): 969-74.

Zhou, S. S., D. Li, et al. (2009). "Nicotinamide overload may play a role in the development of type 2 diabetes." World J Gastroenterol 15(45): 5674-84.