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Parallel epidemic of diabetes and sugar consumption. Sugar intake has been increasing steadily over the last 200 yr (33, 310, 318 –319). In parallel, there has been a rise in diabetes (first described based on death certificates of diabetes-related deaths per 100,000 population) (4) and later by diabetes prevalence rates (268). The data showing sugar consumption are adapted with permission from R.J. Johnson, et al.: Am J Clin Nutr 86:899 –906, 2007 (27) © The American Society for Nutrition.  

Parallel epidemic of diabetes and sugar consumption. Sugar intake has been increasing steadily over the last 200 yr (33, 310, 318 –319). In parallel, there has been a rise in diabetes (first described based on death certificates of diabetes-related deaths per 100,000 population) (4) and later by diabetes prevalence rates (268). The data showing sugar consumption are adapted with permission from R.J. Johnson, et al.: Am J Clin Nutr 86:899 –906, 2007 (27) © The American Society for Nutrition.  

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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 excessiv...

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... drinks also increase the risk for nonalcoholic fatty liver dis- ease (53). Figure 4 shows the remarkable association of sugar intake with diabetes over the last two centuries. ...

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... 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.
... 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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... 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. ...
Preprint
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. ...
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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.
... 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.
... 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!
... 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.
... Fructose has been reported to be related to obesity and metabolic syndrome. Experimental studies have demonstrated that fructose is able to induce leptin resistance and bring about metabolic syndrome in rats [18,19]. ...
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Objective To investigate the association of fasting serum fructose concentrations and the incidence of GDM. Research design and methods Five hundred twenty six pregnant women who attended the obstetric clinic of Xinhua Hospital, Chongming Branch were recruited prospectively from September 2019 to November 2020. Fasting serum fructose concentrations were measured by a validated liquid chromatography–tandem mass spectrometry method. GDM was diagnosed according to the criteria of the IADPSG. Independent sample t-test was used to compare the differences between groups. Multiple stepwise regression analysis was used to estimate the associations of serum fructose and other variables. Multivariate logistic regression models were adopted to evaluate the odds ratios (ORs) for GDM. Results Of the 526 pregnant women, 110 were diagnosed with GDM. Fasting fructose concentrations were increased significantly in GDM patients compared to those without GDM (1.30 ug/ml vs 1.16 ug/ml, p<0.001). Fasting fructose concentration was independently associated with GDM after adjusting the potential confounders, 1 ug/ml increase in fasting serum fructose level was associated with an 81.1% increased risk of GDM (1.811, [1.155-2.840]). Taking fructose <1.036 ug/ml as the reference, the OR for GDM was significantly higher in fructose ≥1.036 ug/ml group (OR, 1.669; 95% CI, 1.031–2.701) after all the potential confounders were adjusted. Conclusions Increased fasting serum fructose levels were independently associated with the incidence of GDM.
... Moreover, fructose metabolic pathway differs from that of glucose, and previous studies suggest that high fructose intake decreases insulin sensitivity [15][16][17]. Although fructose is present in sucrose, the association of exclusive fructose consumption with T2D has not been established. ...
Article
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We aimed to investigate the association between sugar or starch intake and the risk of type 2 diabetes (T2D) in middle-aged Japanese adults. Participants comprised 27,797 men and 36,880 women aged 45–75 years with no history of diabetes and critical illness before the second survey in the Japan Public Health Center-based Prospective Study. We calculated sugar (total sugar, total fructose, and sugar subtypes) and starch intakes (% energy/d) using a validated 147-item food frequency questionnaire, to estimate the average dietary intake over the previous year. T2D onset was defined by validated self-reports. ORs adjusted for potential confounders were estimated using multiple logistic regression with categorical and cubic spline models. During the 5-year follow-up, 690 men and 500 women were identified with T2D. In women, the quartiles of total sugar or total fructose intakes were not significantly associated with T2D risk; however, the spline curves showed an increased risk at extremely high intake levels (ORs [95% CI]: 1.88 [1.07–3.31] at 30% energy/d for total sugar and 1.87 [1.10–3.16] at 14% energy/d for total fructose). Starch intake was positively associated with T2D risk among women in the categorical and spline models (ORs [95% CI]: 1.55 [1.13–2.12] at 50% energy/d). In men, sugar and starch intakes were not associated with T2D risk. In this large-scale population-based cohort study, starch intake was associated with an increased T2D risk in Japanese women. An increased risk with extremely high intake of total sugar or total fructose among women cannot be disregarded.
... Abbreviations: ASC, Apoptosis-associated speck-like protein containing caspase recruitment domain; Caspase-1, Cysteinyl aspartate specific proteinase-1; CRP, C-reactive protein; FBG, Fasting blood glucose; FINS, Fasting serum insulin; Fru, Fructose; HFCS, High-fructose corn syrup; HOMA-IR, Homeostasis model of assessment for IR index; HOMA-ISI, Homeostasis model of assessment for insulin sensitivity index; HOMA-β%, Homeostasis model of assessment for islet β-cell function; GDM, Gestational Diabetes Mellitus; IL-1β, Interleukin-1β; IL-6, Interleukin-6; IL-17, Interleukin-17; IR, Insulin resistance; ITT, Insulin tolerance tests; LPS, Lipopolysaccharide; NF-κB p65, Nuclear factor-κB p65; NLRP3, Nucleotide binding oligomerization domain-like receptors; OGTT, Oral glucose tolerance tests; T2DM, Type 2 diabetes; TNF-α, Tumor necrosis factor α. Fructose (Fru) is a type of sugar found in fruits and honey. It is mainly available as a component of the disaccharide sucrose, which is degraded by intestinal enzymes to release free Fru and glucose (14). High-fructose corn syrup (HFCS), which is used as a sweetener in soft drinks, pastries, desserts, and various processed foods, is another major source of Fru (14). ...
... It is mainly available as a component of the disaccharide sucrose, which is degraded by intestinal enzymes to release free Fru and glucose (14). High-fructose corn syrup (HFCS), which is used as a sweetener in soft drinks, pastries, desserts, and various processed foods, is another major source of Fru (14). Large increases in the HFCS consumption worldwide have led to sharp spikes in the global prevalence of both diabetes mellitus and obesity (15). ...
Article
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Background Insulin resistance (IR), which is affected by dietary factors, is the main pathology underlying of gestational diabetes mellitus (GDM). Fructose (Fru), a sugar found in fruits, honey, and food sweeteners, has been reported to induce IR and inflammation. This study explored the effects and mechanisms of Fru on IR of GDM in pregnant and postpartum mice and their offspring. Methods The 6-week-old female C57BL/6J mice were randomly divided into control (Chow) and fructose (Fru) groups, with the latter receiving 20% (w/v) Fru in drinking water from 2 weeks before pregnancy to the end of pregnancy. The effects of Fru on IR and inflammation were determined using serum parameters, glucose metabolism tests, immunohistochemistry, and western blotting. Results Compared with the Chow group mice, pregnant mice treated with Fru exhibited greater gestational weight gain, higher fasting blood glucose and insulin concentrations, and a higher homeostasis model of assessment (HOMA) for IR index, but a lower HOMA for insulin sensitivity index. Treatment with Fru also increased the concentrations of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-17, and C-reactive protein in sera and the expression of IL-6, TNF-α, IL-17, and IL-1β mRNA in liver tissues of pregnant mice. Both CD68 and IL-1β positive cell were increased in Fru-treated mice compared with in Chow mice. Fru treatment also promoted IR and inflammation in mice at 4 weeks after delivery and in offspring mice. Mechanistically, Fru promoted the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 to activate the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Conclusions Exposure to Fru before and during pregnancy induced IR in pregnant mice, which continued at 4 weeks postpartum and affected the offspring. The effects of Fru may be associated with activation of the NF-κB–NLRP3 pathway.