Effects of Consuming Beverages Sweetened with Fructose, Glucose, High-Fructose Corn Syrup, Sucrose, or Aspartame on OGTT-Derived Indices of Insulin Sensitivity in Young Adults.

(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.

The Dose-Response Effects of Consuming High Fructose Corn Syrup-Sweetened Beverages on Hepatic Lipid Content and Insulin Sensitivity in Young Adults.

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m2). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.

Consuming Sucrose- or HFCS-sweetened Beverages Increases Hepatic Lipid and Decreases Insulin Sensitivity in Adults.

CONTEXT: Studies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets. OBJECTIVE: To compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans. METHODS: A parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI. RESULTS: Sucrose-SB increased %hepatic lipid (absolute change: 0.6 ±â€…0.2%) compared with aspartame-SB (-0.2 ±â€…0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ±â€…0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight. CONCLUSION: Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks.

Influence of maternal and paternal pre-conception overweight/obesity on offspring outcomes and strategies for prevention.

Overweight, obesity, and their comorbidities remain global health challenges. When established early in life, overweight is often sustained into adulthood and contributes to the early onset of non-communicable diseases. Parental pre-conception overweight and obesity is a risk factor for overweight and obesity in childhood and beyond. This increased risk likely is based on an interplay of genetic alterations and environmental exposures already at the beginning of life, although mechanisms are still poorly defined. In this narrative review, potential routes of transmission of pre-conceptional overweight/obesity from mothers and fathers to their offspring as well as prevention strategies are discussed. Observational evidence suggests that metabolic changes due to parental overweight/obesity affect epigenetic markers in oocytes and sperms alike and may influence epigenetic programming and reprogramming processes during embryogenesis. While weight reduction in overweight/obese men and women, who plan to become pregnant, seems advisable to improve undesirable outcomes in offspring, caution might be warranted. Limited evidence suggests that weight loss in men and women in close proximity to conception might increase undesirable offspring outcomes at birth due to nutritional deficits and/or metabolic disturbances in the parent also affecting gamete quality. A change in the dietary pattern might be more advisable. The data reviewed here suggest that pre-conception intervention strategies should shift from women to couples, and future studies should address possible interactions between maternal and paternal contribution to longitudinal childhood outcomes. Randomized controlled trials focusing on effects of pre-conceptional diet quality on long-term offspring health are warranted.

Effects of Consuming Sugar-Sweetened Beverages for 2 Weeks on 24-h Circulating Leptin Profiles, Ad Libitum Food Intake and Body Weight in Young Adults.

Sugar-sweetened beverage (sugar-SB) consumption is associated with body weight gain. We investigated whether the changes of (Δ) circulating leptin contribute to weight gain and ad libitum food intake in young adults consuming sugar-SB for two weeks. In a parallel, double-blinded, intervention study, participants (n = 131; BMI 18-35 kg/m2; 18-40 years) consumed three beverages/day containing aspartame or 25% energy requirement as glucose, fructose, high fructose corn syrup (HFCS) or sucrose (n = 23-28/group). Body weight, ad libitum food intake and 24-h leptin area under the curve (AUC) were assessed at Week 0 and at the end of Week 2. The Δbody weight was not different among groups (p = 0.092), but the increases in subjects consuming HFCS- (p = 0.0008) and glucose-SB (p = 0.018) were significant compared with Week 0. Subjects consuming sucrose- (+14%, p < 0.0015), fructose- (+9%, p = 0.015) and HFCS-SB (+8%, p = 0.017) increased energy intake during the ad libitum food intake trial compared with subjects consuming aspartame-SB (-4%, p = 0.0037, effect of SB). Fructose-SB decreased (-14 ng/mL × 24 h, p = 0.0006) and sucrose-SB increased (+25 ng/mL × 24 h, p = 0.025 vs. Week 0; p = 0.0008 vs. fructose-SB) 24-h leptin AUC. The Δad libitum food intake and Δbody weight were not influenced by circulating leptin in young adults consuming sugar-SB for 2 weeks. Studies are needed to determine the mechanisms mediating increased energy intake in subjects consuming sugar-SB.

Synergistic effects of fructose and glucose on lipoprotein risk factors for cardiovascular disease in young adults.

BACKGROUND: Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors. METHODS: Adults (18-40 years; BMI 18-35 kg/m2) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc. FINDINGS: 145 subjects (26.0 ±â€¯5.8 years; body mass index 25.0 ±â€¯3.7 kg/m2) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [-0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [-0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340). CONCLUSION: A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption.

Effects of Dietary Glucose and Fructose on Copper, Iron, and Zinc Metabolism Parameters in Humans.

Alterations of transition metal levels have been associated with obesity, hepatic steatosis, and metabolic syndrome in humans. Studies in animals indicate an association between dietary sugars and copper metabolism. Our group has conducted a study in which young adults consumed beverages sweetened with glucose, fructose, high fructose corn syrup (HFCS), or aspartame for two weeks and has reported that consumption of both fructose- and HFCS-sweetened beverages increased cardiovascular disease risk factors. Baseline and intervention serum samples from 107 participants of this study were measured for copper metabolism (copper, ceruloplasmin ferroxidase activity, ceruloplasmin protein), zinc levels, and iron metabolism (iron, ferritin, and transferrin) parameters. Fructose and/or glucose consumption were associated with decreased ceruloplasmin ferroxidase activity and serum copper and zinc concentrations. Ceruloplasmin protein levels did not change in response to intervention. The changes in copper concentrations were correlated with zinc, but not with iron. The decreases in copper, ceruloplasmin ferroxidase activity, ferritin, and transferrin were inversely associated with the increases in metabolic risk factors associated with sugar consumption, specifically, apolipoprotein CIII, triglycerides, or post-meal glucose, insulin, and lactate responses. These findings are the first evidence that consumption of sugar-sweetened beverages can alter clinical parameters of transition metal metabolism in healthy subjects.

Dietary fructose and dyslipidemia: new mechanisms involving apolipoprotein CIII.

PURPOSE OF REVIEW: Chronic consumption of fructose and fructose-containing sugars leads to dyslipidemia. Apolipoprotein (apo) CIII is strongly associated with elevated levels of triglycerides and cardiovascular disease risk. We reviewed the effects of fructose consumption on apoCIII levels and the role of apoCIII in fructose-induced dyslipidemia. RECENT FINDINGS: Consumption of fructose increases circulating apoCIII levels compared with glucose. The more marked effects of fructose compared with glucose on apoCIII concentrations may involve the failure of fructose consumption to stimulate insulin secretion. The increase in apoCIII levels after fructose consumption correlates with increased postprandial serum triglyceride. Further, RNA interference of apoCIII prevents fructose-induced dyslipidemia in nonhuman primates. Increases in postprandial apoCIII after fructose, but not glucose consumption, are positively associated with elevated triglycerides in large triglyceride-rich lipoproteins and increased small dense LDL levels. SUMMARY: ApoCIII might be causal in the lipid dysregulation observed after consumption of fructose and fructose-containing sugars. Decreased consumption of fructose and fructose-containing sugars could be an effective strategy for reducing circulating apoCIII and subsequently lowering triglyceride levels.

Effects of Fructose or Glucose on Circulating ApoCIII and Triglyceride and Cholesterol Content of Lipoprotein Subfractions in Humans.

ApoCIII and triglyceride (TG)-rich lipoproteins (TRL), particularly, large TG-rich lipoproteins particles, have been described as important mediators of cardiovascular disease (CVD) risk. The effects of sustained consumption of dietary fructose compared with those of sustained glucose consumption on circulating apoCIII and large TRL particles have not been reported. We measured apoCIII concentrations and the TG and cholesterol content of lipoprotein subfractions separated by size in fasting and postprandial plasma collected from men and women (age: 54 ± 8 years) before and after they consumed glucose- or fructose-sweetened beverages for 10 weeks. The subjects consuming fructose exhibited higher fasting and postprandial plasma apoCIII concentrations than the subjects consuming glucose (p < 0.05 for both). They also had higher concentrations of postprandial TG in all TRL subfractions (p < 0.05, effect of sugar), with the highest increases occurring in the largest TRL particles (p < 0.0001 for fructose linear trend). Compared to glucose consumption, fructose consumption increased postprandial TG in low-density lipoprotein (LDL) particles (p < 0.05, effect of sugar), especially in the smaller particles (p < 0.0001 for fructose linear trend). The increases of both postprandial apoCIII and TG in large TRL subfractions were associated with fructose-induced increases of fasting cholesterol in the smaller LDL particles. In conclusion, 10 weeks of fructose consumption increased the circulating apoCIII and postprandial concentrations of large TRL particles compared with glucose consumption.

The Furan Fatty Acid 9M5 Acts as a Partial Ligand to Peroxisome Proliferator-Activated Receptor gamma and Enhances Adipogenesis in 3T3-L1 Preadipocytes.

A food that has been praised for its beneficial effects on overall health is fish, particularly its polyunsaturated n-3 fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). However, it has recently been suggested that minor fatty acids such as furan fatty acids are needed in combination with DHA and EPA to exert these positive effects of fish and fish oils. Only recently have furan fatty acids become available in quantities that allow the investigation of their biofunctional properties. In this study, the uptake and effect of the furan fatty acid 9-(3-methyl-5-pentylfuran-2-yl)-nonanoic acid (9M5) as a sole component and in combination with DHA and EPA on adipogenesis were analyzed using the 3T3-L1 cell model. 9M5 is taken up and metabolized into 7M5, 5M5, and 3M5 in 3T3-L1 adipocytes during a 24-h period as shown with gas chromatography with mass spectrometry (GC/MS). Furthermore, 9M5 significantly increased lipid accumulation during the differentiation process of 3T3-L1 preadipocytes into adipocytes. In addition, the combinations of DHA + 9M5 and EPA + DHA + 9M5 also exerted a significant increase compared to control adipocytes. 3T3-L1 cells incubated with 9M5 resulted in an increased protein expression of PPARγ, C/EBPα, FABP4, and adiponectin, although not to the extent that DHA as a sole component or DHA + 9M5 did. Earlier studies have shown that DHA is a natural ligand for PPARγ, thus being a potential alternative to the antidiabetic thiazolidinediones. We show that 9M5 activates a PPARγ-responsive reporter gene and could therefore be a natural ligand for PPARγ.

Expression and Characterization of Membrane-Type 4 Matrix Metalloproteinase (MT4-MMP) and its Different Forms in Melanoma.

BACKGROUND/AIMS: Membrane-type matrix metalloproteinases (MT-MMPs) are expressed on the cell surface and hydrolyze extracellular matrix components and signaling molecules by which they influence cancer cell migration and metastasis. Two of the six known MT-MMPs are anchored to the plasma membrane via a GPI anchor, one of which is MT4-MMP. Only little is known about MT4-MMP expression, synthesis, regulation and degradation. METHODS: We analyzed several human cancer cell lines as well as tissue homogenates using Western blotting and quantitative PCR for the expression of MT4-MMP. Organelles of SK-Mel-28 cells were separated using continuous Iodixanol gradients. Glycosylation of the SK-Mel-28 protein was studied via glucosidases and site directed mutagenesis of the MT4-MMP cDNA prior to transfection. RESULTS: We found the MT4-MMP highly expressed in human melanoma cell lines as well as skin and melanoma tissue samples. Three forms of MT4-MMP with molecular masses of 45 kDa, 58 kDa and 69 kDa were detected. Further, we demonstrate that the 58 kDa form is the mature protein in the cell membrane, while the 69 kDa form is its precursor found in intracellular compartments. The 69 kDa forms are processed by furin cleavage in the Golgi apparatus. Moreover, we identified Asn318 as the single N-glycosylation site of MT4-MMP. CONCLUSION: We demonstrate the novel expression of MT4-MMP in melanocytic tissues and propose a precursor/product-relationship of the different forms of MT4-MMP in melanoma cells.