The recent increase in fructose consumption in industrialized nations mirrors the rise in the prevalence of hypertension, but epidemiologic studies have inconsistently linked these observations. We investigated whether increased fructose intake from added sugars associates with an increased risk for higher BP levels in US adults without a history of hypertension. We conducted a cross-sectional analysis using the data collected from the National Health and Nutrition Examination Survey (NHANES 2003 to 2006) involving 4528 adults without a history of hypertension. Median fructose intake was 74 g/d, corresponding to 2.5 sugary soft drinks each day. After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of ≥74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of ≥135/85, ≥140/90, and ≥160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.

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Increased Fructose Associates with Elevated Blood Pressure

Preclinical and clinical evidence indicates that hyperinsulinemia may play an important role in the development of colorectal cancer (1,2). Many of the established risk factors of colorectal cancer, including obesity (3,4) and physical inactivity (5), directly influence insulin levels. Other studies have observed elevated risks of colon cancer among those with a history of type 2 diabetes mellitus (6) or elevated blood insulin or plasma C-peptide levels (7–10).

Diet influences systemic insulin levels. Foods with low glucose indexes have reduced serum insulin and glucose responses, compared with foods with high indexes. The physiological response to carbohydrates can be quantified by the glycemic index, a qualitative assessment of foods calculated as a percentage of the body’s plasma glucose response to specific foods compared with the response induced by the same amount of carbohydrate from a standard carbohydrate source, usually white bread or pure glucose (11,12). The glycemic load is calculated by multiplying the carbohydrate index of each food by its glycemic index and the frequency of consumption, providing a qualitative and quantitative measurement (13). Glycemic load and other carbohydrate measures have been associated with the risk of developing colorectal cancer in some (14–17), but not all (18–21), studies.

Recent studies have found a direct association between host factors leading to hyperinsulemia and cancer recurrences and mortality in colorectal cancer survivors (22–28). In a study of stage III colon cancer patients, the highest quintile of consumption of a Western pattern diet (characterized by high intakes of meat, fat, refined grains, and sugar desserts) was associated with a three-fold increase in cancer recurrence and deaths compared with the lowest quintile (27). To further understand which component of a Western pattern diet is associated with poorer outcomes and define the impact of dietary glycemic measures on colon cancer survival, we prospectively examined the association between dietary glycemic load and index, total fructose intake, and total carbohydrates intake on cancer recurrences and survival in a cohort of stage III colon cancer patients enrolled in an adjuvant chemotherapy trial in which extensive data on dietary intake, height, weight, and physical activity were collected at the study onset prior to any subsequent events of cancer recurrence.

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Dietary Glycemic Load and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings From CALGB 89803

Objective: Dietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n 527) and African-American (n 516) children with obesity and metabolic syndrome. Methods: Participants consumed a diet for 9 days to deliver comparable percentages of protein, fat, and carbohydrate as their self-reported diet; however, dietary sugar was reduced from 28% to 10% and substituted with starch. Participants recorded daily weights, with calories adjusted for weight maintenance. Participants underwent dual-energy X-ray absorptiometry and oral glucose tolerance testing on Days 0 and 10. Biochemical analyses were controlled for weight change by repeated measures ANCOVA. Results: Reductions in diastolic blood pressure (25 mmHg; P 50.002), lactate (20.3 mmol/L; P <0.001), triglyceride, and LDL-cholesterol (246% and 20.3 mmol/L; P <0.001) were noted. Glucose tolerance and hyperinsulinemia improved (P <0.001). Weight reduced by 0.9 60.2 kg (P <0.001) and fat-free mass by 0.6 kg (P 50.04). Post hoc sensitivity analysis demonstrates that results in the subcohort that did not lose weight (n 510) were directionally consistent. Conclusions: Isocaloric fructose restriction improved surrogate metabolic parameters in children with obesity and metabolic syndrome irrespective of weight change.

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Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome

The impact of sugar-sweetened beverages (SSBs) on blood pressure (BP) has been debated, with some evidence suggesting that their increased intake is related to higher risk of developing hypertension. We conducted a systematic review exploring the relation between consumption of SSB and BP. A comprehensive search in 5 electronic databases along with a bibliography search was performed. The keywords "sugar sweetened beverages," "sugary drinks," "added sugars," "blood pressure," and "hypertension" were indexed in all combinations. Studies were included that reported the effects of intake of SSBs on BP. We excluded studies with <100 subjects and those involving subjects aged <12 years. Of 605 potentially relevant studies, a total of 12 studies (409,707 participants) met our inclusion criteria; 6 were cross sectional studies, whereas the rest were prospective cohort studies. All 12 studies showed positive relation between increased SSB intake and hypertension; however, statistical significance was reported in 10 of these studies. Of the 12 studies, 5 reported an increase in mean BP whereas 7 reported an increase in the incidence of high BP. In conclusion, our systematic review shows that the consumption of SSBs is associated with higher BP, leading to increased incidence of hypertension. Restriction on SSB consumption should be incorporated in the recommendations of lifestyle modifications for the treatment of hypertension. Interventions to reduce intake of SSBs should be an integral part of public health strategy to reduce the incidence of hypertension.

Impact of Sugar-Sweetened Beverages on Blood Pressure

Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease.

Sympathetic overactivity precedes metabolic dysfunction in a fructose model of glucose intolerance in mice

The objective of the present study was to identify metabolic, cardiovascular and autonomic changes induced by fructose overload administered in the drinking water of rats for 8 weeks. Female Wistar rats (200-220 g) were divided into 2 groups: control (N = 8) and fructose-fed rats (N = 5; 100 mg/L fructose in drinking water for 8 weeks). The autonomic control of heart rate was evaluated by pharmacological blockade using atropine (3 mg/kg) and propranolol (4 mg/kg). The animals were submitted to an intravenous insulin tolerance test (ITT) and to blood glucose measurement. The fructose overload induced a significant increase in body weight (approximately 10%) and in fasting glycemia (approximately 28%). The rate constant of glucose disappearance (KITT) during ITT was lower in fructose-fed rats (3.25 +/- 0.7%/min) compared with controls (4.95 +/- 0.3%/min, P < 0.05) indicating insulin resistance. The fructose-fed group presented increased arterial pressure compared to controls (122 +/- 3 vs 108 +/- 1 mmHg, P < 0.05) and a reduction in vagal tonus (31 +/- 9 vs 55 +/- 5 bpm in controls, P < 0.05). No changes in sympathetic tonus were observed. A positive correlation, tested by the Pearson correlation, was demonstrable between cardiac vagal tonus and KITT (r = 0.8, P = 0.02). These data provided new information regarding the role of parasympathetic dysfunction associated with insulin resistance in the development of early metabolic and cardiovascular alterations induced by a high fructose diet.

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Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159±2.2 vs SHO: 177±3.4 mmHg), as well as resting bradycardia (RTHO: 332±9.0 vs SHO: 356±5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation.

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Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats

This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin-treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 ± 2 and sedentary+simvastatin = 107 ± 2 mmHg) compared to the sedentary group (122 ± 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (≈21%) and trained+simvastatin groups (≈57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats.

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Pleiotropic effects of simvastatin in physically trained ovariectomized rats

The aim of this study was to evaluate the effects of combined exercise training in hypertensive ovariectomized rats submitted to fructose overload. Wistar and spontaneously hypertensive (SHR) rats were divided into (n=8/group): control (C), hypertensive (H), hypertensive ovariectomized (HO), hypertensive ovariectomized submitted to fructose overload sedentary (HOF) and trained (HOFT). The combined exercise training was performed on a treadmill and ladder adapted to rats in alternated days, during 8 weeks. At the end of exercise protocol, arterial pressure (AP) signals were directly recorded. Cardiovascular autonomic modulation was evaluated by spectral analysis. Oxidative stress and inflammation were measured on cardiac tissue. The association of hypertension and ovariecyomy induced an increase in arterial pressure (AP) (HO: 164±5 vs. H: 146±6 mmHg) and body weight in relation to hypertensive rats. The association of risk factors (hypertension+ovariectomy+fructose) induced an additional increase in AP (HOF: 174±4 mmHg), increased heart rate (HOF: 403±12 vs. HOS: 348±16 bpm) and blood triglycerides (HOF: 160±8 vs. HO: 125±6.4 mg/dl), promoted impairment on the insulin sensitivity, cardiovascular autonomic modulation, oxidative stress (redox ratio of glutathione: HOF: 8.94±0.8 vs. HO: 13.00±1.4) and inflammation (TNF-α- HFO: 65.8±9.9 vs. HO: 31.7±8.6 pg/mg protein) of these animals. However, the combined exercise training was able to reduce the AP (HOFTc: 158±4 mmHg) and heart rate (HOFT: 303±5 bp), to normalize the triglyceride levels (HOFT: 137±4.7 mg/dL), insulin sensitivity and vascular autonomic modulation. Moreover, this approach reduced cardiac lipoperoxidation and increased antioxidant defense and redox balance of glutathione (HOFT: 11.94 ± 1.1), reduced TNF-α (HOFT: 33.1±4.9 mg/dL) and increased IL-10. The results of this study demonstrated that the association of risk factors promoted additional impairment in metabolic, cardiovascular, autonomic, inflammatory and oxidative stress parameters and the combined exercise training was able to reduce and/or normalize these dysfunctions.

Abstract 472: Positive Role of Combined Exercise Training in a Model of Metabolic Syndrome and Menopause: Autonomic, Inflammatory and Oxidative Stress Evaluations

Janaina O Brito

Papers

Parasympathetic dysfunction is associated with insulin resistance in fructose-fed female rats

Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats

Pleiotropic effects of simvastatin in physically trained ovariectomized rats

Abstract 472: Positive Role of Combined Exercise Training in a Model of Metabolic Syndrome and Menopause: Autonomic, Inflammatory and Oxidative Stress Evaluations