The Association of Serum Total Peptide YY (PYY) with Obesity and Body Fat Measures in the CODING Study.

BACKGROUND: PYY is an appetite suppressing hormone. Low circulating PYY has been linked to greater BMI. However data is controversial and this association has not been verified in large human populations. OBJECTIVE: The purpose of this study was to investigate if fasting serum total PYY is associated with obesity status and/or adiposity at the population level. DESIGN: A total of 2094 subjects (Male-523, Female-1571) participated in this investigation. Total PYY was measured in fasting serum by enzyme-linked immunosorbent assay. Obesity status (NW-normal-weight, OW-overweight and OB-obese) was determined by the Bray Criteria according to body fat percentage measured by dual-energy x-ray absorptiometry and the WHO criteria according to BMI. One-way ANOVA and multiple regression was used to assess the adiposity-specific association between PYY and the following; weight, BMI, waist-circumference, hip-circumference, waist-hip ratio, percent body fat (%BF), trunk fat (%TF), android fat (%AF) and gynoid fat (%GF). RESULTS: PYY was not significantly different among NW, OW and OB groups defined by neither %BF nor BMI for both men and women. However among women, fasting PYY was positively associated with adiposity measures. Women with the highest (Top 33%) waist-circumference, %BF and %TF had significantly higher PYY (10.5%, 8.3% and 9.2% respectively) than women with the lowest (Bottom 33%). Age, smoking, medication use and menopause were all positively associated with PYY levels in women but not in men. CONCLUSION: To our knowledge this is the largest population based study, with the most comprehensive analysis and measures of confounding factors, to explore the relationship of circulating PYY with obesity. Contrary to initial findings in the literature we discovered that PYY was positively associated with body fat measures (waist-circumference, %BF and %TF) in women. Although the effect size of the positive association of PYY with obesity in women is small, and potentially negligible, it may in fact represent a protective response against significant weight gain.

Food addiction: its prevalence and significant association with obesity in the general population.

BACKGROUND: 'Food addiction' shares a similar neurobiological and behavioral framework with substance addiction. However whether, and to what degree, 'food addiction' contributes to obesity in the general population is unknown. OBJECTIVES: to assess 1) the prevalence of 'food addiction' in the Newfoundland population; 2) if clinical symptom counts of 'food addiction' were significantly correlated with the body composition measurements; 3) if food addicts were significantly more obese than controls, and 4) if macronutrient intakes are associated with 'food addiction'. DESIGN: A total of 652 adults (415 women, 237 men) recruited from the general population participated in this study. Obesity was evaluated by Body Mass Index (BMI) and Body Fat percentage measured by dual-energy X-ray absorptiometry. 'Food addiction' was assessed using the Yale Food Addiction Scale and macronutrient intake was determined from the Willet Food Frequency Questionnaire. RESULTS: The prevalence of 'food addiction' was 5.4% (6.7% in females and 3.0% in males) and increased with obesity status. The clinical symptom counts of 'food addiction' were positively correlated with all body composition measurements across the entire sample (p<0.001). Obesity measurements were significantly higher in food addicts than controls; Food addicts were 11.7 (kg) heavier, 4.6 BMI units higher, and had 8.2% more body fat and 8.5% more trunk fat. Furthermore, food addicts consumed more calories from fat and protein compared with controls. CONCLUSION: Our results demonstrated that 'food addiction' contributes to severity of obesity and body composition measurements from normal weight to obese individuals in the general population with higher rate in women as compared to men.

Short-term overfeeding increases circulating adiponectin independent of obesity status.

BACKGROUND: Adiponectin is an adipose tissue derived hormone which strengthens insulin sensitivity. However, there is little data available regarding the influence of a positive energy challenge (PEC) on circulating adiponectin and the role of obesity status on this response. OBJECTIVE: The purpose of this study was to investigate how circulating adiponectin will respond to a short-term PEC and whether or not this response will differ among normal-weight(NW), overweight(OW) and obese(OB). DESIGN: We examined adiponectin among 64 young men (19-29 yr) before and after a 7-day overfeeding (70% above normal energy requirements). The relationship between adiponectin and obesity related phenotypes including; weight, percent body fat (%BF), percent trunk fat (%TF), percent android fat (%AF), body mass index (BMI), total cholesterol, HDLc, LDLc, glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR) and ß-cell function (HOMA-ß) were analyzed before and after overfeeding. RESULTS: Analysis of variance (ANOVA) and partial correlations were used to compute the effect of overfeeding on adiponectin and its association with adiposity measurements, respectively. Circulating Adiponectin levels significantly increased after the 7-day overfeeding in all three adiposity groups. Moreover, adiponectin at baseline was not significantly different among NW, OW and OB subjects defined by either %BF or BMI. Baseline adiponectin was negatively correlated with weight and BMI for the entire cohort and %TF, glucose, insulin and HOMA-IR in OB. However, after controlling for insulin resistance the correlation of adiponectin with weight, BMI and %TF were nullified. CONCLUSION: Our study provides evidence that the protective response of adiponectin is preserved during a PEC regardless of adiposity. Baseline adiponectin level is not directly associated with obesity status and weight gain in response to short-term overfeeding. However, the significant increase of adiponectin in response to overfeeding indicates the physiological potential for adiponectin to attenuate insulin resistance during the development of obesity.

Circulating glucagon-like peptide-1 increases in response to short-term overfeeding in men.

BACKGROUND: Glucagon-like Peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract that facilitates the glucose-dependent insulin response. Additionally, GLP-1 is thought to be involved in energy homeostasis. Currently little is known about GLP-1's responsiveness to an energy surplus, a fundamental cause of obesity and diabetes. Our objective was to examine the response of serum GLP-1 to short-term (7 day) overfeeding in young men. METHODS: Seventy-two young men from the Canadian province of Newfoundland were recruited for the study. For 7-days, the subjects consumed 70% more calories than required at baseline.Various measurements including: anthropometrics, body composition, markers of glucose/lipid metabolism and serum total GLP-1, were taken at a fasted state before (day 1) and after (day 8) the challenge. Paired t-test analyses were used to assess the change in variables after the overfeeding period. Additionally, the relationship between serum GLP-1 and the measured variables at baseline and change due to overfeeding were analyzed. RESULTS: Serum GLP-1 was significantly increased in all groups in response to the 7-day energy surplus, indicating the increase was independent of adiposity status. There was no significant difference in fasting GLP-1 at baseline between the normal weight and overweight/obese groups. At baseline, GLP-1 concentration negatively correlated with HDL-cholesterol and positively correlated with triacylglycerols and markers of insulin resistance in the overweight/obese group. Also GLP-1 was negatively correlated with change in percent gynoid fat in the overweight/obese subjects. Percent change in GLP-1 was negatively associated with percent change in gynoid fat in the normal weight group and positively associated with percent change in cholesterol in the overweight/obese group. Percentage change of circulating triacylglycerols was positively associated with percent change in GLP-1 in both adiposity groups. CONCLUSION: Our findings showed that GLP-1 serum concentration is not a significant factor in determining obesity status. The increase of GLP-1 in all subjects regardless of obesity status, suggest GLP-1 serves as a protective role, counteracting energy surplus.

High dietary magnesium intake is associated with low insulin resistance in the Newfoundland population.

BACKGROUND: Magnesium plays a role in glucose and insulin homeostasis and evidence suggests that magnesium intake is associated with insulin resistance (IR). However, data is inconsistent and most studies have not adequately controlled for critical confounding factors. OBJECTIVE: The study investigated the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women. DESIGN: A total of 2295 subjects (590 men and 1705 women) were recruited from the CODING study. Dietary magnesium intake was computed from the Willett Food Frequency Questionnaire (FFQ). Adiposity (NW, OW and OB) was classified by body fat percentage (%BF) measured by Dual-energy X-ray absorptiometry according to the Bray criteria. Multiple regression analyses were used to test adiposity-specific associations of dietary magnesium intake on insulin resistance adjusting for caloric intake, physical activity, medication use and menopausal status. RESULTS: Subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women. CONCLUSION: The results of this study indicate that higher dietary magnesium intake is strongly associated with the attenuation of insulin resistance and is more beneficial for overweight and obese individuals in the general population and pre-menopausal women. Moreover, the inverse correlation between insulin resistance and dietary magnesium intake is stronger when adjusting for %BF than BMI.

Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study.

OBJECTIVE: Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study. DESIGN: A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of ß cell function (HOMA-ß) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance. RESULTS: Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations. CONCLUSION: Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.

Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men.

BACKGROUND: Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity. OBJECTIVE: The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge. DESIGN: A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and ß-cell function at baseline and change due to overfeeding, were assessed. RESULTS: Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups. CONCLUSION: Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status.

Serum peptide YY in response to short-term overfeeding in young men.

BACKGROUND: Peptide YY (PYY), a gut hormone that inhibits appetite, has been linked to the development of obesity. OBJECTIVE: This study investigated the nutritional regulation of PYY after 7 d of overfeeding (70% above normal energy requirements) in normal-weight, overweight, and obese men. DESIGN: Sixty-nine men (aged 19-29 y) participated in the study. We analyzed the relation between fasting serum PYY before and after a 7-d overfeeding challenge in normal-weight, overweight, and obese men. In addition, we analyzed PYY with obesity-related phenotypes including weight, percentage body fat (measured by dual-energy X-ray absorptiometry), body mass index (BMI), total cholesterol, HDL, LDL, glucose, insulin, insulin resistance, and ß cell function evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR) and ß cell function (HOMA-ß) at baseline and in response to the energy surplus. RESULTS: Fasting serum PYY concentrations at baseline were not significantly different between the normal-weight, overweight, and obese subjects on the basis of dual-energy X-ray absorptiometry or BMI. Although the PYY concentration significantly increased due to overfeeding, no differences were observed between adiposity statuses. In addition, basal PYY was negatively correlated with the changes of total cholesterol, HDL, and LDL in normal weight. In addition, the increase in PYY after overfeeding was positively correlated with HDL cholesterol and glucose in normal-weight subjects. CONCLUSIONS: Our findings suggest that fasting PYY concentrations are not associated with adiposity status. Moreover, the 7-d overfeeding challenge significantly increased fasting PYY, which is likely a protective response to the positive energy balance.

Role of the immune system in hypertension: modulation by dietary antioxidants.

Hypertension is a major health problem worldwide. Individuals with hypertension are at an increased risk for stroke, heart disease, and kidney failure. Although the etiology of essential hypertension has a genetic component, lifestyle factors such as diet play an important role. Insulin resistance is a common feature of hypertension in both humans and animal models affecting glucose and lipid metabolism producing excess aldehydes including methylglyoxal. These aldehydes react with proteins to form conjugates called advanced glycation end products (AGEs). This alters protein structure and function and can affect vascular and immune cells leading to their activation and secretion of inflammatory cytokines. AGEs also act via receptors for advanced glycation end products on these cells altering the function of antioxidant and metabolic enzymes, and ion channels. This results in an increase in cytosolic free calcium, decrease in nitric oxide, endothelial dysfunction, oxidative stress, peripheral vascular resistance, and infiltration of vascular and kidney tissue with inflammatory cells leading to hypertension. Supplementation with dietary antioxidants including vitamins C, E, or B(6), thiols such as cysteine and lipoic acid, have been shown to lower blood pressure and plasma inflammatory cytokines in animal models and humans with essential hypertension. A well-balanced diet rich in antioxidants that includes vegetables, fruits, low fat dairy products, low salt, and includes whole grains, poultry, fish and nuts, lowers blood pressure and vascular inflammation. These antioxidants may achieve their antihypertensive and anti-inflammatory/immunomodulatory effects by reducing AGEs and improving insulin resistance and associated alterations. Dietary supplementation with antioxidants may be a beneficial, inexpensive, front-line alterative treatment modality for hypertension.

Risk factors preceding type 2 diabetes and cardiomyopathy.

Type 2 diabetes (T2DM) and its complications such as cardiomyopathy, contribute significantly to morbidity and mortality worldwide. Increased adoption of westernized diets and decreased physical activity are contributing to the obesity epidemic which, in turn, increases the risk for T2DM. Other risk factors for T2DM include insulin resistance, dyslipidemia, hypertension, metabolic syndrome, and a genetic predisposition. Risk measures for assessing these factors include family history, blood pressure, body weight, waist circumference, fasting glucose, insulin, and lipid levels, and calculated indices such as BMI, HOMA, and QUIKI. Most of these risk measures routinely done in annual check-ups, should help a primary care physician in making an early diagnosis of impending diabetic condition. The underlying mechanisms of these clinical, anthropometric and biochemical risk measures may also be involved in the etiology of diabetes and its complications. Their levels and changes over time therefore, may indeed reflect the disease process. Early and continued assessment of diabetes risk, as part of patient care, will help identify individuals most likely to develop diabetes and allow for early interventions to reduce risk factors as well as delay or may even prevent disease onset. In T2DM patients, ongoing measurement of risk markers and implementation of intervention where appropriate will improve the diabetic condition, decrease risk of cardiovascular and other complications, and decrease morbidity.

Antihypertensive effects of dietary protein and its mechanism.

Hypertension is a leading cause of morbidity and mortality worldwide. Individuals with hypertension are at increased risk of stroke, heart disease and kidney failure. Both genetic and lifestyle factors, particularly diet, have been attributed an important role in the development of hypertension. Reducing dietary sugar and salt intake can help lower blood pressure; similarly, adequate protein intake may also attenuate hypertension. Observational, cross-sectional and longitudinal epidemiological studies, and controlled clinical trials, have documented significant inverse associations between protein intake and blood pressure. Human and animal studies have shown that specific amino acids within proteins may have antihypertensive effects. Cysteine, glutathione (a tripeptide), glutamate and arginine attenuate and prevent alterations that cause hypertension including insulin resistance, decreased nitric oxide bioavailability, altered renin angiotensin system function, increased oxidative stress and formation of advanced glycation end products. Leucine increases protein synthesis in skeletal muscle and improves insulin resistance by modulating hepatic gluconeogenesis. Taurine and tryptophan attenuate sympathetic nervous system activity. Soy protein helps lower blood pressure through its high arginine content and antioxidant activity exhibited by isoflavones. A diet containing an ample amount of protein may be a beneficial lifestyle choice for individuals with hypertension; one example is the Dietary Approaches to Stop Hypertension (DASH) diet, which is low in salt and saturated fat; includes whole grains, lean meat, poultry, fish and nuts; and is rich in vegetables, fruits and low-fat dairy products, which are good sources of antioxidant vitamins, minerals and fibre. Including an adequate supply of soy in the diet should also be encouraged.

Role of methylglyoxal in essential hypertension.

Altered glucose metabolism due to insulin resistance is a common feature of essential hypertension in humans and in animal models. Elevated endogenous aldehydes in genetic (spontaneously hypertensive rats) and acquired (fructose-induced hypertensive rats) models of essential hypertension may be due to increased production of the reactive aldehyde methylglyoxal, resulting from altered glucose metabolism. Excess methylglyoxal binds sulfhydryl groups of membrane proteins, altering calcium channels and increasing cytosolic free Ca(2+) and blood pressure. It has been demonstrated that methylglyoxal, when given in drinking water to Wistar-Kyoto rats, leads to an increase in kidney aldehyde conjugates, cytosolic free Ca(2+) concentration, decreased serum nitric oxide, renal vascular hyperplasia and hypertension. N-acetylcysteine (NAC) in the diet of these animals prevented hypertension and associated biochemical and morphological changes. NAC normalizes blood pressure by directly binding to excess methylglyoxal, thus normalizing Ca(2+) channels, cytosolic Ca(2+) and nitric oxide. NAC also leads to increased levels of tissue glutathione, a storage form of cysteine. Glutathione acts as a cofactor in the enzymatic catabolism of methylglyoxal. Cysteine and other antioxidants, such as vitamins B(6), C and E, and lipoic acid, prevented hypertension and associated biochemical and morphological changes in both genetic and acquired rat models of hypertension. The antihypertensive effect of dietary antioxidants may be due to an increase in tissue cysteine and glutathione, which improves glucose metabolism and decreases tissue methylglyoxal. A diet rich in these antioxidants may be effective in preventing and controlling hypertension in humans.

Fructose and moderately high dietary salt-induced hypertension: prevention by a combination of N-acetylcysteine and L-arginine.

Diets containing 8% salt or 4% fructose (FR) cause insulin resistance and increase tissue methylglyoxal and advanced glycation end products (AGEs), platelet cytosolic-free calcium, and systolic blood pressure (SBP) in rats. In WKY rats, we have shown that moderately high salt, 4% NaCl (MHS) alone in diet does not cause hypertension, and when given along with 4% FR it does not have an additive effect. N-acetylcysteine (NAC) or L-arginine (ARG), treatment alone does not prevent hypertension in this model. The objectives of this study were to investigate the effect of NAC plus ARG in diet on SBP, platelet cytosolic-free calcium in a MHS + FR model, and to measure the plasma levels of methylglyoxal and the AGE, methylglyoxal-derived hydroimidazolone (MGH). At 7 weeks of age, WKY rats were divided into three groups: control group was given regular rat chow (0.7% NaCl) and water; MHS + FR group, diet containing 4% NaCl and 4% FR in drinking water; and MHS + FR + NAC + ARG group, MHS diet supplemented with 1.5% N-acetylcysteine (NAC) and 1.5% L-arginine (ARG), and 4% FR in drinking water, and followed for 6 weeks. NAC + ARG prevented the increase in platelet cytosolic-free calcium and SBP in MHS + FR treated rats. There was no difference in mean values of plasma methylglyoxal and MGH among the groups. In conclusion, NAC + ARG treatment is effective in preventing hypertension in a moderately high salt + FR-induced animal model. Plasma methylglyoxal and MGH may not represent tissue modification or, alternatively, other tissue AGEs, derived from methylglyoxal or other aldehydes, may be involved in hypertension in this model.

Higher Dietary Protein Intake is Associated with Lower Body Fat in the Newfoundland Population.

BACKGROUND: Increased protein proportions in the diet combined with energy restriction has been shown to enhance weight loss during dietary intervention. It is not known if the beneficial effect of dietary protein exists in the general population under normal living conditions without a negative energy balance. METHODS: A total of 1834 participants (n = 443 men, n = 1391 women) were recruited from the CODING study. Participants' dietary macronutrient compositions were determined through a Willett FFQ. Body composition variables including percent body fat (%BF), percent trunk fat (%TF), percent total lean mass (%LM), and percent trunk lean mass (%TLM) were determined using DXA. Major confounding factors including age, physical activity levels, total caloric intake, carbohydrate intake, menopausal status, smoking status and medication use were controlled for in all analyses. RESULTS: Significant inverse relationships were observed between dietary protein intake (g/kg body weight/day) and weight, waist circumference, waist-to-hip ratio, BMI, %BF, and %TF (P < 0.001). Significant positive relationships were observed with %LM and %TLM (P < 0.001). Additionally, significant differences in weight (12.7 kg in men, 11.4 kg in women), BMI (4.1 BMI units in men, 4.2 units in women), and %BF (7.6% in men, 6.0% in women) were observed between low and high dietary protein consuming groups (P < 0.001). Dietary protein explained 11% of the total variation in %BF in the NL population. CONCLUSION: This study provides strong evidence that higher protein intake, even in the absence of energy restriction, is associated with a more favorable body composition in the general population.

Plasma advanced glycation endproduct, methylglyoxal-derived hydroimidazolone is elevated in young, complication-free patients with Type 1 diabetes.

OBJECTIVES: Elevated advanced glycation endproducts (AGEs) are implicated in diabetic complications. Methylglyoxal-derived hydroimidazolone (MG-H) is one of the most abundant AGEs in vivo. Our objective was to develop a time-saving, specific method to measure free MG-H in plasma and determine its levels in complication-free young individuals with Type 1 diabetes (T1DM). The relationship of plasma free MG-H to hemoglobin A1C (A1C) and plasma methylglyoxal levels was also determined. DESIGN AND METHODS: A solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, and free plasma MG-H levels were measured in 40 T1DM patients (DM group), aged 6-21 years, and 11 non-diabetics (ND group), 6-22 years. Methylglyoxal was measured using LC-MS/MS and A1C by a Tosoh G7 high-performance liquid chromatograph. RESULTS: Our method showed high recovery, sensitivity and short run-time. Plasma free MG-H (nmol/L) was higher (p<0.001) in the DM group (1318+/-569; mean+/-standard deviation) as compared to the ND group (583+/-419). Within the DM group, plasma free MG-H did not correlate with plasma methylglyoxal or A1C. CONCLUSIONS: Our LC-MS/MS method to measure free MG-H in plasma may be useful for future clinical application. The increased levels of free MG-H observed in individuals with TIDM are not merely the result of short term changes in glucose or methylglyoxal, but may reflect long-term alterations to tissue proteins.

The antihypertensive effect of cysteine.

Hypertension is a leading cause of morbidity and mortality worldwide. Individuals with hypertension are at an increased risk for stroke, heart disease and kidney failure. Essential hypertension results from a combination of genetic and lifestyle factors. One such lifestyle factor is diet, and its role in the control of blood pressure has come under much scrutiny. Just as increased salt and sugar are known to elevate blood pressure, other dietary factors may have antihypertensive effects. Studies including the Optimal Macronutrient Intake to Prevent Heart Disease (OmniHeart) study, Multiple Risk Factor Intervention Trial (MRFIT), International Study of Salt and Blood Pressure (INTERSALT) and Dietary Approaches to Stop Hypertension (DASH) study have demonstrated an inverse relationship between dietary protein and blood pressure. One component of dietary protein that may partially account for its antihypertensive effect is the nonessential amino acid cysteine. Studies in hypertensive humans and animal models of hypertension have shown that N-acetylcysteine, a stable cysteine analogue, lowers blood pressure, which substantiates this idea. Cysteine may exert its antihypertensive effects directly or through its storage form, glutathione, by decreasing oxidative stress, improving insulin resistance and glucose metabolism, lowering advanced glycation end products, and modulating levels of nitric oxide and other vasoactive molecules. Therefore, adopting a balanced diet containing cysteine-rich proteins may be a beneficial lifestyle choice for individuals with hypertension. An example of such a diet is the DASH diet, which is low in salt and saturated fat; includes whole grains, poultry, fish and nuts; and is rich in vegetables, fruits and low-fat dairy products.

The antihypertensive effect of arginine.

Hypertension is a leading cause of morbidity and mortality worldwide. Individuals with hypertension are at increased risk of stroke, heart disease and kidney failure. Although the etiology of essential hypertension has a genetic component, lifestyle factors such as diet play an important role. Reducing dietary salt is effective in lowering blood pressure in salt-sensitive individuals. Insulin resistance and altered glucose metabolism are common features of hypertension in humans and animal models, with or without salt sensitivity. Altered glucose metabolism leads to increased formation of advanced glycation end products. Insulin resistance is also linked to oxidative stress, and alterations in the nitric oxide pathway and renin angiotensin system. A diet rich in protein containing the semiessential amino acid, arginine, and arginine treatment, lowers blood pressure in humans and in animal models. This may be due to the ability of arginine to improve insulin resistance, decrease advanced glycation end products formation, increase nitric oxide, and decrease levels of angiotensin II and oxidative stress, with improved endothelial cell function and decreased peripheral vascular resistance. The Dietary Approaches to Stop Hypertension (DASH) study demonstrated that the DASH diet, rich in vegetables, fruits and low-fat dairy products; low in fat; and including whole grains, poultry, fish and nuts, lowered blood pressures even more than a typical North American diet with similar reduced sodium content. The DASH diet is rich in protein; the blood pressure-lowering effect of the DASH diet may be due to its higher arginine-containing protein, higher antioxidants and low salt content.

Serum retinol-binding protein 4 concentrations in response to short-term overfeeding in normal-weight, overweight, and obese men.

BACKGROUND: Retinol-binding protein 4 (RBP4) is a novel adipokine that induces insulin resistance in mice. Studies in humans have shown a correlation between serum RBP4 and insulin resistance in obese subjects and in subjects with type 2 diabetes. Few data are available regarding the nutritional regulation of RBP4. OBJECTIVE: The study investigated the relation of RBP4 with phenotypes of glucose and lipid metabolism at baseline and in response to a 7-d overfeeding protocol in young men. DESIGN: Sixty-five men participated in the study. Subjects were classified on the basis of body mass index (BMI; kg/m(2)) as normal-weight (/=25.0). Serum RBP4, interleukin-6, visfatin, glucose, insulin, total cholesterol, HDL cholesterol, and LDL cholesterol (calculated), and triacylglycerols were measured. Insulin resistance and beta cell function were assessed by using the homeostasis model. Percentage body fat was measured by using dual-energy X-ray absorptiometry. RESULTS: No significant differences were found in serum RBP4 between the 2 groups at baseline. Likewise, no significant differences were observed in fasting serum RBP4 in response to overfeeding. Baseline RBP4 was negatively correlated with the change in insulin resistance in normal-weight subjects, independent of age and BMI. No significant correlation was found between serum RBP4 and visfatin, interleukin-6, or any other variables measured. CONCLUSIONS: Short-term overfeeding did not induce significant changes in RBP4. Baseline RBP4 concentrations may predict insulin resistance when exposed to a positive energy challenge in normal-weight men.

Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications.

The vascular diseases, hypertension and atherosclerosis, affect millions of individuals worldwide, and account for a large number of deaths globally. A better understanding of the mechanism of these conditions will lead to more specific and effective therapies. Hypertension and atherosclerosis are both characterized by insulin resistance, and we suggest that this plays a major role in their etiology. The cause of insulin resistance is not known, but may be a result of a combination of genetic and lifestyle factors. In insulin resistance, alterations in glucose and lipid metabolism lead to the production of excess aldehydes including glyoxal and methylglyoxal. These aldehydes react non-enzymatically with free amino and sulfhydryl groups of amino acids of proteins to form stable conjugates called advanced glycation end products (AGEs). AGEs act directly, as well as via receptors to alter the function of many intra- and extracellular proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation and oxidative stress. All these changes are characteristic of hypertension and atherosclerosis. Human and animal studies have demonstrated that increased AGEs are also associated with these conditions. A pathological role for AGEs is substantiated by studies showing that therapies that attenuate insulin resistance and/or lower AGEs, are effective in decreasing oxidative stress, lowering blood pressure, and attenuating atherosclerotic vascular changes. These interventions include lipoic acid and other antioxidants, AGE breakers or soluble receptors of AGEs, and aldehyde-binding agents like cysteine. Such therapies may offer alternative specific means to treat hypertension and atherosclerosis. An adjunct therapy may be to implement lifestyle changes such as weight reduction, regular exercise, smoking cessation, and increasing dietary intake of fruits and vegetables that also decrease insulin resistance as well as oxidative stress.

Fructose-induced hypertension in Wistar-Kyoto rats: interaction with moderately high dietary salt.

We investigated the effects of 4% fructose plus moderately high salt (MHS) (4% NaCl) treatment on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca2+]i), renal morphology, and systolic blood pressure (SBP) in Wistar-Kyoto rats, and whether these effects were reversible (R) after withdrawal of treatment. At age 7 weeks, rats were divided into 4 groups: NS group, given normal salt (NS) diet (0.7% NaCl) for 18 weeks; NS+F(R) group, NS diet and fructose in water for 14 weeks, then 4 weeks fructose withdrawal; MHS+F group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 12 weeks; and MHS+F(R) group, NS diet and fructose for 6 weeks, then MHS diet and fructose for 8 weeks, then MHS and fructose withdrawal for 4 weeks. SBP in the NS+F(R) group increased during fructose treatment, but normalized within 1 week of withdrawal. Tissue aldehyde conjugates and platelet [Ca2+]i were normal at completion. Adverse renal vascular changes did not reverse to normal and were similar to those of the salt plus fructose-treated groups. This may have implications for future development of hypertension. MHS did not cause any additional increase in SBP or associated tissue alterations when added to fructose treatment. However, the SBP and tissue changes persisted even after discontinuation of treatment. The fructose and salt combination may result in long-lasting vascular alterations leading to hypertension.