Dr. Ron’s Research Review – November 7, 2012

This week’s research review contains a brief review of two papers proposing that chronic niacin overload causes obesity and type 2 diabetes

Two recent papers proposed that chronic niacin (from nicotinamide fortification in grains) overload is causing obesity and type 2 diabetes.

Chronic niacin overload may be involved in the increased prevalence of obesity in US children (Li, Sun et al. 2010)

Nicotinamide overload may play a role in the development of type 2 diabetes (Zhou, Li et al. 2009)

Evidence suggests that niacin-induced increase in insulin release may be a compensation of pancreatic islet beta cells in response to the insulin resistance. (Li, Sun et al. 2010)

The present study demonstrated that nicotinamide overload induced a biphasic response: insulin resistance in the early phase characterized by more insulin release due to the enhanced ROS production, and hypoglycemia in the late phase due to the different clearance rates of plasma ROS and insulin. The biphasic response may underlie the increased appetite in obesity: high nicotinamide diet may produce more ROS and decrease insulin sensitivity, which leads to more insulin release. Then, with the relative rapid fall of plasma ROS and the re-increase in insulin sensitivity, the relative high insulin level may lead to hypoglycemia, which may induce hunger, eating behavior change, and subsequent excess energy intake. (Li, Sun et al. 2010)

Dr. Ron


Review of chronic niacin overload causing obesity and type 2 diabetes

By Ronald Steriti, ND, PhD

© 2012

Two recent papers proposed that chronic niacin (from nicotinamide fortification in grains) overload is causing obesity and type 2 diabetes.

Chronic niacin overload may be involved in the increased prevalence of obesity in US children (Li, Sun et al. 2010)

In five healthy subjects, after co-administration of glucose and 300 mg nicotinamide, insulin levels (247.1 ± 129.0 pmol/L vs 452.6 ± 181.8 pmol/L, P = 0.028) were significantly higher, and the 3-h blood glucose was significantly lower (5.8 ± 1.2 mmol/L vs 4.5 ± 1.1 mmol/L, P = 0.002) after co-administration of glucose and 300 mg nicotinamide. (Li, Sun et al. 2010)

Nicotinamide overload may play a role in the development of type 2 diabetes (Zhou, Li et al. 2009)

Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. 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. 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. (Zhou, Li et al. 2009)


Excerpts

During the past few decades, one of the significant, but relatively overlooked worldwide changes in dietary composition has been the marked increase in the content of niacin (nicotinamide and nicotinic acid). (Li, Sun et al. 2010)

Obesity is characterized by increased appetite and insulin resistance, whereas niacin is a potent stimulator of appetite and niacin deficiency may lead to appetite loss. Moreover, large doses of niacin have long been known to impair glucose tolerance, induce insulin resistance and enhance insulin release. Evidence suggests that niacin- induced increase in insulin release may be a compensation of pancreatic islet β cells in response to the insulin resistance. However, whether excess niacin intake is involved in the increased appetite and the insulin resistance of obesity is unclear. Our recent study found that oxidative stress may mediate excess nicotinamide-induced insulin resistance, and that type 2 diabetic subjects have a slow de- toxification of nicotinamide. These observations suggested that type 2 diabetes may be the outcome of the association of high niacin intake and the relative low detoxification of niacin of the body. Based on these lines of evidence, we postulated that excess niacin intake may also play a role in obesity. (Li, Sun et al. 2010)

The present findings are in agreement with the hypothesis that niacin-induced increase in β-cell secretory capacity is the result of pancreatic islet adaptation to niacin-induced insulin resistance. (Li, Sun et al. 2010)

Interestingly, the present study demonstrated that nicotinamide overload induced a biphasic response: insulin resistance in the early phase characterized by more insulin release due to the enhanced ROS production, and hypoglycemia in the late phase due to the different clearance rates of plasma ROS and insulin. The biphasic response may underlie the increased appetite in obesity: high nicotinamide diet may produce more ROS and decrease insulin sensitivity, which leads to more insulin release. Then, with the relative rapid fall of plasma ROS and the re-increase in insulin sensitivity, the relative high insulin level may lead to hypoglycemia, which may induce hunger, eating behavior change, and subsequent excess energy intake. (Li, Sun et al. 2010)

As such, it is not difficult to imagine that long- term nicotinamide overload-induced insulin resistance may eventually lead to β-cell failure. From this point of view, it seems that long-term excess nicotinamide intake may be a primary cause of obesity and type 2 diabetes. (Li, Sun et al. 2010)

Type 2 diabetes generally is accepted to be a result of gene-environment interaction, although the underlying mechanism is not clear. Of the environmental factors, diet appears to play a major role. In fact, the sharp increases in the incidence of diabetes in the United States in the latter half of the 20th century and in China in the past two decades of the 20th century followed food fortification with niacin (i.e. nicotinamide and nicotinic acid) beginning in the early 1940s in the United States and in the early 1980s in China. Moreover, niacin is reported frequently to impair glucose metabolism and cause liver injury. Thus, there is the possibility that the high prevalence of type 2 diabetes in these countries in the past fewer decades may involve niacin toxicity. (Zhou, Li et al. 2009)

The pathogenesis of type 2 diabetes may be at least partially due to long- term excess nicotinamide intake, and/or slowness in N1- methylnicotinamide detoxification, and/or decrease in excess nicotinamide and N1-methylnicotinamide excretion. This may lead to high plasma N -methylnicotinamide levels, and subsequently oxidative stress and insulin resistance. Therefore, reducing nicotinamide intake and facilitating excretion of nicotinamide metabolites may be a useful preventive and therapeutic intervention in type 2 diabetes. (Zhou, Li et al. 2009)


Articles

Chronic niacin overload may be involved in the increased prevalence of obesity in US children.

         (Li, Sun et al. 2010) Download

AIM: To investigate nicotinamide's action on glucose metabolism, and the association between niacin consumption and obesity prevalence. METHODS: Dynamic nicotinamide's effect on plasma hydrogen peroxide and glucose metabolism was investigated using oral glucose tolerance tests with or without nicotinamide in the same five healthy subjects. Lag-regression analysis was used to examine the association between the niacin consumption and the obesity prevalence among US children using the data from the Economic Research Service of the US Department of Agriculture and from US Centers for Disease Control and Prevention, respectively. RESULTS: Compared with the control oral glucose tolerance test, the 1-h plasma hydrogen peroxide (1.4 +/- 0.1 micromol/L vs 1.6 +/- 0.1 micromol/L, P = 0.016) and insulin levels (247.1 +/- 129.0 pmol/L vs 452.6 +/- 181.8 pmol/L, P = 0.028) were significantly higher, and the 3-h blood glucose was significantly lower (5.8 +/- 1.2 mmol/L vs 4.5 +/- 1.1 mmol/L, P = 0.002) after co-administration of glucose and 300 mg nicotinamide. The obesity prevalence among American children increased with the increasing per capita niacin consumption, the increasing grain contribution to niacin due to niacin-fortification, and the increasing niacin-fortified ready-to-eat cereal consumption, with a 10-year lag. The regression analyses showed that the obesity prevalence in the US children of all age groups was determined by niacin consumption (R(2) = 0.814, 0.961 and 0.94 for 2-5 years, 6-11 years and 12-19 years age groups, respectively). CONCLUSION: The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.


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

Li, D., W. P. Sun, et al. (2010). "Chronic niacin overload may be involved in the increased prevalence of obesity in US children." World J Gastroenterol 16(19): 2378-87.

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.