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Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes?

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We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.
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... Uric acid suppresses the production of nitric oxide, which plays an active role in glucose transport (5). It causes renal vasoconstriction, systemic hypertension, tubulointerstitial damage, decrease in nitric oxide synthase production and deterioration in afferent arteries (6)(7)(8). It suppresses nitric oxide bio-activity and insulin resistance via inflammatory factors and adipokines (9). ...
... The majority of the daily excretion (2/3) of uric acid occurs through the kidneys and 1/3 is via the gastrointestinal system (1). In normal and non-diabetic individuals, uric acid is completely filtered from the glomerulus and almost completely reabsorbed from the proximal tubules (7). In the presence of hyperuricemia, uric acid crystals accumulate in the joints and kidneys (10). ...
... Hyperuricemia is a condition seen in chronic renal failure (CRF). While there are studies stating that the level of uric acid increases mainly due to the decrease in GFR in CRF (3), there are also studies stating that hyperuricemia causes chronic kidney failure (7) and causes progression of the disease (5,6). Chonchol et al. (11) stated that the increase in serum uric acid level in CRF was mainly due to the decrease in GFR and that hyperuricemia played a minor role in the progression of the disease. ...
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Amaç: Akut böbrek yetmezliği (ABY) yoğun bakım hastalarında mortaliteyi etkileyen en önemli faktörlerden biridir. Bu çalışmanın amacı, ürik asit düzeyleri ile akut böbrek hasarı (AKI) / ABY arasında bir ilişki olup olmadığını aydınlatmaktır. Gereç ve Yöntem: Bu retrospektif çalışmamıza, önceden böbrek hastalığı olmayan ve glomerüler filtrasyon hızı (GFR) 80-120 ml/dakika olan hastanemiz yoğun bakım ünitesine kabul edilen toplam 1000 hasta dahil edildi. Yoğun bakım ünitesinde AKI gelişimi RIFLE kriterleri ile değerlendirildi. AKI gelişen hastalarda renal replasman tedavisi endikasyonu olup olmadığına bakıldı. Bilinci kapalı kişiler ve COVID-19 hastaları dahil yoğun bakım ünitesindeki tüm hastalar analize dahil edilmiştir. Bulgular: Bireylerin %27,1’inde (n=271) AKI görüldü. AKI’lı hastaların %44.3’üne (n=120) hemodiyaliz uygulanmıştı. Hemodiyaliz nedenleri olguların %36’sında iskemi, %32’sinde sepsis ve multifaktöriyel nedenler idi. Potasyum dışındaki tüm parametrelerde (üre, kreatinin, ürik asit ve sodyumda) başlangıca göre artmıştı (p
... However, paradoxically, uric acid is involved in pathological inflammatory reactions by activating the renin-angiotensin system, acting as an oxidative stressor, and decreasing the bioavailability of nitrogen oxide [5]. There is a general agreement that hyperuricemia increases the risk of (3,9) stroke and death [6], cardiovascular diseases [7], gout, insulin resistance, type 2 diabetes [8,9], and all-cause mortality [10]. Studies have shown that inflammatory cytokines are significantly higher in COVID-19 patients than in controls [11]. ...
... However, paradoxically, uric acid is involved in pathological inflammatory reactions by activating the renin-angiotensin system, acting as an oxidative stressor, and decreasing the bioavailability of nitrogen oxide [5]. There is a general agreement that hyperuricemia increases the risk of (3,9) stroke and death [6], cardiovascular diseases [7], gout, insulin resistance, type 2 diabetes [8,9], and all-cause mortality [10]. Studies have shown that inflammatory cytokines are significantly higher in COVID-19 patients than in controls [11]. ...
... Overall, patients were followed for a median of 7 days (IQR, [5][6][7][8][9][10][11][12]. During hospitalization, the lowest serum uric acid values were recorded for 93 patients. ...
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is likely to cause uric acid dysregulation, resulting in abnormal serum uric acid concentrations. In this study, we aimed to evaluate the associations between admission serum uric acid levels and demographic, clinical and laboratory features of patients hospitalized with Coronavirus disease 2019 (Covid-19) and to explore the effect of admission serum uric acid values on clinical outcomes. Methods. In this retrospective study, the demographic, clinical and laboratory data of patients with confirmed Covid-19 were collected from the electronic health records of the hospital. The study population was stratified according to the quartiles of serum uric acid; Quartile 1: ≤ 3.5 mg/dl, Quartile 2: 3.6 mg/dl to 6 mg/dl for women and 3.5 mg/dl to 7 mg/dl for men, Quartile 3: ≥ 6 mg/dl for women and ≥ 7 mg/dl for men. The outcomes were the development of acute kidney injury (AKI) and in-hospital mortality. Results. 146 patients were included in the analysis. The median age of patients was 57 (IQR, 49-65) years and 70.5% were male. The overall median serum uric acid level on admission was 4.4 (IQR, 3.5-5.9) mg/dl. Participants in the highest serum uric acid quartile were significantly more hypertensive, and diabetics and showed significantly higher estimated glomerular filtration rate (eGFR) and troponin T levels compared to patients in the lowest serum uric acid quartile. On the other hand; patients in the lowest serum uric acid quartile were admitted with more severe disease than patients with Quartile 2. During follow-up, 19 (13.1%) participants experienced AKI and 15 (10.3%) died. There were significantly positive correlations between AKI and age, hypertension, serum creatinine (SCr), hyperuricemia, C-reactive protein (CRP) and Troponin T (r=0.263, P=0.001; r=0.192, P=0.02; r=0.182, P=0.028; r=0.235, P = 0.004; r=0.219, P=0.008; r=0.236, P=0.004, respectively). A significantly negative correlation was noted between AKI and eGFR (r=-0.189, P=0.023). According to multivariate logistic regression analysis, AKI development was independently associated with CRP and hyperuricemia (OR, 1.009; 95% CI, 1.0082-1.016, P=0.009 and OR, 4.314; 95% CI, 1.190-15.633, P=0.026). The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of the concentration of serum admission uric acid was 0.693 (95% CI 0.537–0.849, P=0.006) and the cutoff value was 5.45 mg/dl (sensitivity: 68.4%; specificity: 75.6%). Conclusions. Hyperuricemia and increased CRP were independent risk factors for the development of AKI. Although patients with lower uric acid values developed more severe symptoms, mechanical ventilation and mortality rates were not found to be significantly different among patients with Covid-19 grouped based on admission serum uric values. Following the patients admitted with high uric acid levels closely in terms of renal functions would be helpful for early detection of AKI.
... However, paradoxically, uric acid is involved in pathological inflammatory reactions by activating the renin-angiotensin system, acting as an oxidative stressor, and decreasing the bioavailability of nitrogen oxide [5]. There is a general agreement that hyperuricemia increases the risk of (3,9) stroke and death [6], cardiovascular diseases [7], gout, insulin resistance, type 2 diabetes [8,9], and all-cause mortality [10]. Studies have shown that inflammatory cytokines are significantly higher in COVID-19 patients than in controls [11]. ...
... However, paradoxically, uric acid is involved in pathological inflammatory reactions by activating the renin-angiotensin system, acting as an oxidative stressor, and decreasing the bioavailability of nitrogen oxide [5]. There is a general agreement that hyperuricemia increases the risk of (3,9) stroke and death [6], cardiovascular diseases [7], gout, insulin resistance, type 2 diabetes [8,9], and all-cause mortality [10]. Studies have shown that inflammatory cytokines are significantly higher in COVID-19 patients than in controls [11]. ...
... Overall, patients were followed for a median of 7 days (IQR, [5][6][7][8][9][10][11][12]. During hospitalization, the lowest serum uric acid values were recorded for 93 patients. ...
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Russian invasion is an unprecedented test for the Ukrainian state, Ukrainian society, and the health care system. According to the Ministry of Health of Ukraine, more than 600 healthcare facilities suffered serious damage (more than 100 hospitals and 450 pharmacies were ruined, and more than 200 emergency medical vehicles were destroyed) [1]. Patients with chronic diseases in the occupied territories and war zones are deprived of medical care and support, which is a direct threat to their lives [2-4]. Chronic kidney disease (CKD) patients are one of the most vulnerable groups [5-7]. Before the war, almost 10,000 patients were treated with dialysis kidney replacement therapy (KRT) and more than 1,500 had a functioning renal graft in Ukraine [7]. The vast majority of patients with end-stage kidney disease receiving dialysis treatment were evacuated to safer regions, and some of them continued the treatment abroad [5-7]. However, the war will significantly increase the number of patients in need of kidney care. In addition to the existing number of CKD patients, there will be a large group of patients with acute kidney injury (AKI) as a result of polytrauma, bleeding, injuries, or long-term compression syndrome. Currently, we cannot predict the incidence of AKI. However, according to the previously published data (18% - 34.6% of war victims) [8], we should expect a significant increase in the population of CKD patients shortly which will require immediate changes in both organization and staffing of nephrology care. The medical community recognizes the insurmountable difficulties in providing medical support to Ukrainian citizens during the war, in particular patients receiving KRT or kidney recipients. In our opinion, special programs should be created by relevant professional associations together with the institutes of the Ministry of Health of Ukraine and the National Academy of Medical Sciences of Ukraine at both the state and regional levels in all areas. Therefore, we consider it extremely important to establish a committee for the organization of the healthcare system for CKD patients during wartime. The committee could be created within the Ukrainian Association of Nephrologists and Kidney Transplantation Specialists, for example, as the Renal Disaster Relief Task Force established by the International Association of Nephrologists [9]. The main tasks of the committee are to create a consensus of the Ukrainian Association of Nephrologists and Kidney Transplantation Specialists on the management of CKD patients and patients with AKI during the war and the post-war period. On behalf of the Editorial Board of the Ukrainian Journal of Nephrology and Dialysis, we would like to express our sincere gratitude to all health professionals who, at the risk of their own lives, continue to save patients. All members of the Ukrainian nephrological community are doing everything possible and impossible to ensure the most adequate treatment of kidney patients in wartime. Thank you again. We pray for our heroic warriors who fearlessly defend us and defend Ukraine's independence!
... Due to specificities in fructose metabolism, such as bypassing glycolytic regulatory enzyme phosphofructokinase, fructose overconsumption can cause alterations in lipid metabolism, glucose metabolism, and energy sensing [2,5,7]. Oxidative stress is considered as one of the underlying factors contributing to development of metabolic disturbances [8], and increased fructose consumption was found to affect cellular redox homeostasis and to induce low grade inflammation, thereby contributing to the pathophysiology [7,9,10]. ...
... Due to specificities in fructose metabolism, such as bypassing glycolytic regulatory enzyme phosphofructokinase, fructose overconsumption can cause alterations in lipid metabolism, glucose metabolism, and energy sensing [2,5,7]. Oxidative stress is considered as one of the underlying factors contributing to development of metabolic disturbances [8], and increased fructose consumption was found to affect cellular redox homeostasis and to induce low grade inflammation, thereby contributing to the pathophysiology [7,9,10]. In addition, fructose was found to affect absorption of redox-active transition metals including organ of copper homeostasis, while less is known about the effects of fructose, stress and their combination on renal copper metabolism. ...
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The effects of a fructose-rich diet and chronic stress on copper metabolism in the kidneys are still understudied. We investigated whether fructose and/or chronic unpredictable stress modulate copper metabolism in a way that affects redox homeostasis, thus contributing to progression of metabolic disturbances in the kidney. We determined protein level of copper transporters, chaperones, and cuproenzymes including cytochrome c oxidase, as well as antioxidant enzymes function in the kidneys of male Wistar rats subjected to 20% liquid fructose supplementation and/or chronic stress. Liquid fructose supplementation increased level of copper chaperone of superoxide dismutase and decreased metallothionein level, while rendering the level of copper importer and copper chaperones involved in copper delivery to mitochondria and trans Golgi network unaffected. Stress had no effect on renal copper metabolism. The activity and expression of renal antioxidant enzymes remained unaltered in all experimental groups. In conclusion, fructose, independently of stress, decreased renal copper level, and modulated renal copper metabolism as to preserve vital cellular function including mitochondrial energy production and antioxidative defense, at the expense of intracellular copper storage.
... The activity of fructokinase is not affected by insulin. Furthermore, fructokinase has no negative feedback mechanism (Fox and Kelley, 1972;Johnson et al., 2009;Khitan and Kim, 2013). Therefore, it is inferred that fructose ingestion causes a continuous supply to the glycolytic system. ...
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Like glucose, fructose is a monosaccharide, but the mechanisms of its absorption and metabolism in the body are very different between the two molecules. In this study, we investigated the effects of oral administration of glucose and fructose on food intake, diencephalic gene expression, and plasma metabolite concentrations in broiler chicks. The animals used in this study were 4-days-old male broiler chicks (Ross 308). They were given glucose, fructose (200 mg/ 0.5 mL/ bird) or a similar volume of distilled water orally after 6h fasting. After treatment, measurements of food intake (at 0, 30 and 60 min), and blood glucose as well as insulin concentrations were measured over time; however, diencephalic (hypothalamus) gene expression and plasma metabolites were measured at 30 min. The results showed that glucose administration suppressed food intake, but fructose administration did not suppress food intake and it was at the same level as distilled water administration. In addition, fructose administration did not increase plasma glucose and insulin levels as did glucose administration. In the diencephalon, expression levels of genes related to the melanocortin system were unaffected by the treatment, while gene expression levels related to intracellular energy regulation, such as AMP-activated protein kinase were affected by the glucose treatment in the fasted chicks. These results suggest that fructose administration does not suppress feeding behavior as a result of possible reduction in the energy levels in the diencephalon and associated energy metabolism.
... 5 Noteworthy, fructose is the only carbohydrate that generates uric acid during its metabolism 6 and a synergistic effect of fructose on uric acid levels has been suggested. 7 Fructose appears to mediate the metabolic disorders in part by raising uric acid 8 and accumulating evidence indicates that fructose-induced hyperuricemia has a key role in the development of insulin resistance. 7 Meanwhile, the importance of uric acid in reproductive diseases has been increasingly recognized, for example, serum uric acid levels are associated with increased odds of anovulation among young women. ...
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Objective To investigate the relationship between serum fructose and uric acid levels in patients with polycystic ovary syndrome (PCOS). Design A case-control study. Setting University-affiliated in vitro fertilization clinic. Population 292 patients with PCOS and 482 controls. Main Outcome Measures Serum fructose, uric acid and metabolic measurements. Results Compared with controls, serum fructose and uric acid levels were significantly increased in women with PCOS and patients with PCOS accompanied by metabolic disorders exhibited higher serum fructose and uric acid levels (P < 0.001). Restricted cubic splines indicated that serum uric acid levels linearly and positively correlated with serum fructose levels in women with PCOS (Poverall < 0.001, Pnon-linear = 0.30), whereas no correlation was found in controls (Poverall = 0.712, Pnon-linear = 0.43). Additionally, even after adjusting for confounding factors, serum fructose levels were an independent risk factor for hyperuricemia in patients with PCOS (P = 0.001; odds ratio, 1.380; 95% confidence interval, 1.207–1.577). Conclusions There was a significantly positive association of elevated uric acid levels with serum fructose levels in PCOS and was closely correlated with PCOS-related metabolic disorders, highlighting the importance of further research into the biological mechanisms of fructose and uric acid in the development of PCOS. Funding National Natural Science Foundation of China (No. 82071607 and 32100691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151039); Key Research and Development Program of Liaoning Province (No. 2018225062); Outstanding Scientific Fund of Shengjing Hospital (No. 202003). Keywords Fructose; Uric acid; PCOS; Metabolic disorder
... Numerous studies have demonstrated that an increase in fructose consumption in the modern diet is a major cause of the metabolic dysfunctions, including hypertriglyceridemia, insulin resistance, and abdominal fat accumulation, which can eventually lead to disease like obesity, type 2 diabetes, cancer, non-alcoholic fatty liver disease, and cardiovascular disease in humans and animal models (Goncalves et al., 2019;Johnson et al., 2009;Sindhunata et al., 2022;Stanhope and Havel, 2008). A better understanding of the mechanisms and regulators of disease susceptibility holds the key to counteract diet-induced metabolic disorders. ...
Preprint
The gut bacterium Akkermansia muciniphila (A. muciniphila) has been implicated in anti-obesity effects, but a systems level understanding of the molecular mechanisms is lacking. We carried out multiomics studies to investigate the molecular cascades mediating the anti-obesity effect of A. muciniphila in a fructose-induced obesity mouse model. We found that A. muciniphila colonization triggered significant shifts in gut microbiota composition, gut and plasma metabolites, and gene expression in hypothalamic neurons. Multiomics integration and network analysis prioritized the metabolite oleoyl-ethanolamide (OEA) in the gut and circulation as a regulator of gut-brain interactions that underlie the A. muciniphila anti-obesity effect. Oral administration of OEA counteracted the fructose-induced obesity through the regulation of hypothalamic anorexigenic neuropeptides such as oxytocin and arginine vasopressin. Our multiomics investigation and experimental validation elucidates the molecular regulators and pathways involved in the communication between A. muciniphila in the gut and hypothalamic neurons that counter fructose-induced obesity.
... Hypertension is also commonly associated with renal vasoconstriction which also leads to uric acid retention [21]. However, more recent studies suggest that the rise in serum uric acid also precedes these conditions and hence may not represent the underlying cause of hyperuricemia [22]. Furthermore, one study found uric acid to be minimally elevated in secondary hypertension [23], a condition in which renal vasoconstriction is also present. ...
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Both serum uric acid (SUA) and chronic kidney disease (CKD) are associated with the risk of cardiovascular disease. Hyperuricemia has been attracting attention at the clinical level as a risk factor for the progression of kidney dysfunction. Several epidemiological studies have demonstrated as association between higher serum uric acid (SUA) levels and greater risk of CKD incidence. Hyperuricemia probably causes kidney damage by a mechanism involving systemic and glomerular hypertension. Tubulointerstitial fibrosis, which might be readily associated to the direct proinammatory effects of soluble urate, is independent from the precipitation of monosodium urate crystals in the kidney. In CKD patients, higher serum uric acid levels are associated with higher degree of renal dysfunction , hypertension, diabetes, dyslipidemia, smoking, CRP, urine albuminuria, anemia, cardiovascular disease/ events and mortality. The most common cause of mortality in ckd patients with raised serum uric acid was cardiovascular disease/ events.
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Fructose-rich beverages and foods consumption correlates with the epidemic rise in cardiovascular disease, diabetes and obesity. Severity of COVID-19 has been related to these metabolic diseases. Fructose-rich foods could place people at an increased risk for severe COVID-19. We investigated whether maternal fructose intake in offspring affects hepatic and ileal gene expression of proteins that permit SARS-CoV2 entry to the cell. Carbohydrates were supplied to pregnant rats in drinking water. Adult and young male descendants subjected to water, liquid fructose alone or as a part of a Western diet, were studied. Maternal fructose reduced hepatic SARS-CoV2 entry factors expression in older offspring. On the contrary, maternal fructose boosted the Western diet-induced increase in viral entry factors expression in ileum of young descendants. Maternal fructose intake produced a fetal programming that increases hepatic viral protection and, in contrast, exacerbates fructose plus cholesterol-induced diminution in SARS-CoV2 protection in small intestine of progeny.
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Twelve carbohydrate-sensitive men selected due to their abnormally high insulin responses to a sucrose load and 12 men with normal insulin responses were fed diets containing 0, 7.5, and 15% fructose for 5 wk each in a cross-over design. The diets contained 43% total carbohydrate, 42% fat, and 15% protein. Initial fasting total cholesterol and low-density lipoprotein cholesterol were higher in the hyperinsulinemic men than in the controls. Diastolic blood pressure was not affected by diet, but systolic blood pressure was slightly higher after the men consumed the 0% fructose diet. Free fatty acids were not different. Total plasma cholesterol and low-density lipoprotein cholesterol were higher after the men consumed 7.5 and 15% fructose than when they consumed the 0% fructose diet. Plasma triglyceride increased significantly as fructose in the diets of the hyperinsulinemics increased, but was not affected in the controls. These changes in blood lipids are associated with heart disease.
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Plasma uric acid was Investigated in a population survey on diabetes and cardiovascular risk factors among Melanesians and Asian Indians in Fiji in 1980. Plasma uric acid levels were elevated in men and women with impaired glucose tolerance in both ethnic groups. The lowest plasma uric acid levels were found in diabetic patients, especially in diabetic men. Even though obesity was positively associated with plasma uric acid, it did not explain the high plasma uric acid level in persons with impaired glucose tolerance. Body mass index had a significant and independent impact on plasma uric acid levels both in nondiabetic and diabetic men and women. The strongest predictor of plasma uric acid in the multiple regression analysis in our study populations was plasma creatinlne: It alone explained 9% of the variation in men and 2% in women; and 24% in Melanesians and 5% in Asian Indians. Our findings suggest a strong renal involvement in the balance of plasma uric acid and may also reflect certain dietary patterns, such as a high intake of protein, fats, and certain local vegetables. Although the prevalence of hyperuricemia was high, 27% in both Melanesian men and women, 22% in Asian Indian men, and 11% In Asian Indian women, clinical gout was uncommon. Many predictor variables and their interactions were analyzed along with the reasons for the high plasma uric acid levels in persons with impaired glucose tolerance and for the low plasma uric acid levels in diabetic patients.
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The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined tin vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (similar to 250 mu M). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by clay 14 [mean percent maximal relaxation (E-max): 69 +/- 10% of baseline] and becomes significant by day 18 (E-max: 52 +/- 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 +/- 1 (day 28) vs. 116 +/- 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.
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INTRODUCTION Although the term, epidemiology, has in the past been applied generally, if not exclusively, to the study of communicable diseases, so far as concerns their development among groups, or their manner of transmission from the infected or the carrier to the susceptible person, the methods of such investigations can often be employed with advantage in analyzing the causes and distribution of other diseases. The essential and distinctive feature of epidemiology is the study or knowledge of that part of the natural history of a disease which determines its occurrence or distribution quantitatively and qualitatively in groups of persons, particularly as one case of sickness is related to others, by some common factor of age, sex, race, color, occupation, geographical distribution, or determining element in heredity, environment or hygiene, distinct from the study of disease as it affects the life history of the person by modifying the structures and functions