Thumbs Up: Fructose

Also see:
Theurapeutic Honey – Cancer and Wound Healing
Carbohydrates and Bone Health
Sugar (Sucrose) Restrains the Stress Response
HFCS – More to it than we thought
Protection from Endotoxin
Lactose Intolerance: Starch, Fructose, Sucrose, & Thyroid Status
Commentary on Type 2 Diabetes
Are Happy Gut Bacteria Key to Weight Loss?
Soybean oil causes more obesity than coconut oil and fructose
The common oil that science now shows is worse than sugar

“The animal studies that are used to make the argument provided the animals an excessive amount of polyunsaturated fat, which are antagonistic to the oxidation of sugar and tend to reduce the rate of metabolism, and usually also excessive calories. The special value of fructose is that it can be oxidized even by diabetics, lacking insulin, and that it increases the metabolic rate, causing calories to be burned at a higher rate. The journals are publishing propaganda and calling it science. They are doing this to preserve the myth that cholesterol and triglycerides are the cause of heart disease, that was invented in the 1950’s and 1960s to sell vegetable oils.” -Ray Peat, PhD

Diabetes Care. 2007 Jun;30(6):1406-11. Epub 2007 Mar 23.
Orange juice or fructose intake does not induce oxidative and inflammatory response.
Ghanim H, Mohanty P, Pathak R, Chaudhuri A, Sia CL, Dandona P.
OBJECTIVE:
We have previously shown that 300 kcal from glucose intake induces a significant increase in reactive oxygen species (ROS) generation and nuclear factor-kappaB (NF-kappaB) binding in the circulating mononuclear cells in healthy normal subjects. We hypothesized that the intake of 300 calories as orange juice or fructose, the other major carbohydrate in orange juice, would induce a significantly smaller response than that of glucose.
RESEARCH DESIGN AND METHODS:
Four groups (eight subjects each) of normal-weight subjects were given a 300-cal drink of glucose (75 g), fructose (75 g), or orange juice or water sweetened with saccharin (control group) to drink, and then blood samples were collected.
RESULTS:
There was a significant increase in ROS generation by mononuclear cells (by 130 +/- 18%, P < 0.001), polymorph nuclear cells (by 95 +/- 22%, P < 0.01), and in NF-kappaB binding in mononuclear cells by 82 +/- 16% (P < 0.01) over the baseline after 2 h of glucose intake. These changes were absent following fructose, orange juice, or water intake. There was significantly lower ROS generation and NF-kappaB binding following orange juice, fructose, and water compared with glucose (P < 0.001 for all). Furthermore, incubation of mononuclear cells in vitro with 50 mmol/l of the flavonoids hesperetin or naringenin reduced ROS generation by 52 +/- 7% and 77 +/- 8% (P < 0.01), respectively, while fructose or ascorbic acid did not cause any change. CONCLUSIONS: Caloric intake in the form of orange juice or fructose does not induce either oxidative or inflammatory stress, possibly due to its flavonoids content and might, therefore, represent a potentially safe energy source.

Am J Hypertens. 2008 Jun;21(6):708-14. Epub 2008 Apr 10.
Hepatic effects of a fructose diet in the stroke-prone spontaneously hypertensive rat.
Brosnan MJ, Carkner RD.
BACKGROUND:
Feeding stroke-prone spontaneously hypertensive rats (SHRSP) a diet rich in fructose results in a profound glucose intolerance not observed in the normotensive Wistar Kyoto (WKY) strain. The aim of this study was to investigate the role of the liver in the underlying mechanisms in the SHRSP.
METHODS:
SHRSP and WKY rats were fed either 60% fructose or regular chow for 2 weeks with blood pressure being measured using tail-cuff plethysmography and radiotelemetry. Intraperitoneal glucose tolerance tests were performed and livers harvested for analysis of expression of inflammatory mediators and antioxidant proteins by western blotting and quantitative reverse transcriptase-PCR. The serum triglyceride content and fatty acid profiles were also measured.
RESULTS:
Feeding SHRSP and WKY on 60% fructose for 2 weeks resulted in glucose intolerance with no increases in levels of blood pressure. Serum triglycerides were increased in both strains of fructose-fed rats with the highest levels being observed in the SHRSP. The serum fatty acid profiles were changed with large increases in the amounts of oleic acid (18.1) and reductions in linoleic acid (18.2). Levels of expression of c-jun N-terminal kinase/stress activated protein kinase (JNK/SAPK), and nuclear factor kappaB (NF-kappaB) were shown to be unchanged between the livers of the chow and fructose-fed groups. In contrast, protein levels of the three isoforms of superoxide dismutase (SOD) were upregulated in liver of SHRSP fed on fructose while only manganese SOD (MnSOD) was upregulated in fructose-fed WKY rats.
CONCLUSIONS:
These results demonstrate that the major contribution of the liver in the early pathogenesis of metabolic syndrome may be an increased secretion of triglyceride containing altered proportions of fatty acid pools. Feeding rats a diet rich in fructose does not affect hepatic expression of inflammatory pathways and the increased hepatic SOD expression may constitute an early protective mechanism.

Am J Clin Nutr. 1989 Jun;49(6):1290-4.
Dietary fructose or starch: effects on copper, zinc, iron, manganese, calcium, and magnesium balances in humans.
Holbrook JT, Smith JC Jr, Reiser S.
A balance study was conducted to assess the effects of consuming low-copper diets, high in fructose or cornstarch. The study involved 19 apparently healthy males, aged 21-57 y. The two experimental diets averaged 0.35 mg Cu/1000 kcal and provided 20% of the calories from fructose or cornstarch. Cu, zinc, calcium, magnesium, and iron balances were determined 1 wk before the study (pretest) when the subjects consumed self-selected diets and after consuming the experimental diets for 6 wk. No major differences in mineral balances were evident between the two groups during the pretest study when the subjects ate self-selected diets. In contrast, when fed the test diets, the group consuming the low-Cu fructose diet had significantly more positive balances for all minerals studied than the group fed the low-Cu cornstarch diet. The results indicate that dietary fructose enhances mineral balance.

Anaesthesist. 1995 Nov;44(11):770-81.
[Fructose vs. glucose in total parenteral nutrition in critically ill patients].
[Article in German]
Adolph M, Eckart A, Eckart J.
Parenteral nutrition required following surgery or injury should not only meet post-aggression caloric requirements but also match the specific metabolic needs so as not to worsen the metabolic disruptions already present in this situation. The primary objective of parenteral nutrition is body protein maintenance or restoration by reduction of protein catabolism or promotion of protein synthesis or both. Whether all parenteral energy donors, ie., glucose, fructose, other polyols, and lipid emulsions, are equally capable of achieving this objective continues to be a controversial issue. The objective of the present study was to answer the following questions: (1) Do glucose and fructose differ in their effects on the metabolic changes seen following surgery or injury, the changes in glucose metabolism in particular? (2) Can the observation of poorer glucose utilization in the presence of lipids be confirmed in ICU patients?
PATIENTS, MATERIALS AND METHODS:
A prospective, randomized clinical trial has been conducted in 20 aseptic surgical ICU patients to generate an objective database along these lines by performing a detailed analysis of the metabolic responses to different parenteral nutrition protocols. The effects of a glucose solution+lipid emulsion regimen vs fructose solution+lipid emulsion regimen on a number of carbohydrate and lipid metabolism variables were evaluated for an isocaloric (carbohydrates: 0.25 g/kg body weight/h; lipids: 0.166g/kg body weight/h) and isonitrogenous (amino acids: 0.0625 g/kg body weight/h) total nutrient supply over a 10-h study period.
RESULTS:
A significantly smaller rise in blood glucose concentrations (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids n.s.) suggested that fructose had a small effect, if any at all, on glucose metabolism. Serum insulin activity showed significant differences as a function of carbohydrate regimen, i.e. infusion of fructose instead of glucose produced a less pronounced increase in insulin activity (increase from baseline: glucose+lipids P<0.001 vs fructose+lipids P<0.01). Impairment of glucose utilization by concomitant administration of lipids was observed neither in patients who first received glucose nor in those who first received fructose.
CONCLUSIONS:
As demonstrated, parenteral fructose, unlike parenteral glucose, has a significantly less adverse impact than glucose on the glucose balance, which is disrupted initially in the post-aggression state. In addition, the less pronounced increase in insulin activity during fructose infusion than during glucose infusion can be assumed to facilitate mobilization of endogenous lipid stores and lipid oxidation. Earlier workers pointed out that any rise in free fatty acid and ketone body concentrations in the serum produces inhibition of muscular glucose uptake and oxidation, and of glycolysis. These findings were recorded in a rat model and could not be confirmed in our post-aggression state patients receiving lipid doses commensurate with the usual clinical infusion rates. The serious complications that can result from hereditary fructose intolerance are completely avoidable if a careful patient history is taken before the first parenteral use of fructose. If the patient or family members and close friends, are simply asked whether he/she can tolerate fruit and sweet dishes, hereditary fructose intolerance can be ruled out beyond all reasonable doubt. Only in the extremely rare situations in which it is not possible to question either the patient or any significant other, a test dose will have to be administered to exclude fructose intolerance. The benefits of fructose-specific metabolic effects reported in the literature and corroborated by the results of our own study suggest that fructose is an important nutrient that contributes to metabolic stabilization, especially in the post-aggression phase and in septic patients.

Bone. 2008 May;42(5):960-8. Epub 2008 Feb 15.
The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats on bone mass and strength.
Tsanzi E, Light HR, Tou JC.
Consumption of sugar beverages has increased among adolescents. Additionally, the replacement of sucrose with high fructose corn syrup (HFCS) as the predominant sweetener has resulted in higher fructose intake. Few studies have investigated the effect of drinking different sugar-sweetened beverages on bone, despite suggestions that sugar consumption negatively impacts mineral balance. The objective of this study was to determine the effect of drinking different sugar-sweetened beverages on bone mass and strength. Adolescent (age 35d) female Sprague-Dawley rats were randomly assigned (n=8-9/group) to consume deionized distilled water (ddH2O, control) or ddH2O containing 13% w/v glucose, sucrose, fructose or high fructose corn syrup (HFCS-55) for 8weeks. Tibia and femur measurements included bone morphometry, bone turnover markers, determination of bone mineral density (BMD) and bone mineral content (BMC) by dual energy X-ray absorptiometry (DXA) and bone strength by three-point bending test. The effect of sugar-sweetened beverage consumption on mineral balance, urinary and fecal calcium (Ca) and phosphorus (P) was measured by inductively coupled plasma optical emission spectrometry. The results showed no difference in the bone mass or strength of rats drinking the glucose-sweetened beverage despite their having the lowest food intake, but the highest beverage and caloric consumption. Only in comparisons among the rats provided sugar-sweetened beverage were femur and tibia BMD lower in rats drinking the glucose-sweetened beverage. Differences in bone and mineral measurements appeared most pronounced between rats drinking glucose versus fructose-sweetened beverages. Rats provided the glucose-sweetened beverage had reduced femur and tibia total P, reduced P and Ca intake and increased urinary Ca excretion compared to the rats provided the fructose-sweetened beverage. The results suggested that glucose rather than fructose exerted more deleterious effects on mineral balance and bone.

Ann Nutr Aliment. 1975;29(4):305-12.
[Effects of administering diets with starch or sucrose basis on certain parameters of calcium metabolism in the young, growing rat].
[Article in French]
Artus M.
The important role of many carbohydrates on calcium metabolism has been demonstrated by FOURNIER and DUPUIS. Starch, however, neither influences the absorption nor the retention of calcium. Less is known about the effects of sucrose. In this study the influence of starch on calcium metabolsim has been compared with that of sucrose. Male weanling Wistar rats were divided into three groups according to their diets. The first group received a refined and well-balanced diet (except for the absence of vitamin D), containing 68 p. 100 of starch. The second group received the same diet except sucrose was substituted for the starch. The third group received the same diet as Group 1, with the addition of vitamin D. Plasma calcium citrate and urinary citrate and calcium were determined. At the age of 2 months after one night of fasting, each group of rats was injected intraperitoneally with a 1 ml, aqueous solution containing 1 mg calcium and 0, 6 mu Ci45Ca. Twenty-four hours later the animals were sacrificed and the calcium femur percentage, radioactivity p. 1,000 of the injected dose of 45Ca, and specific radioactivity were determined. When performance data from Group 3 were compared to Group 1 and Group 2, the following results were obtained: —Group 1 (starch diet without vitamin D) had very low plasma calcium levels; urinary calcium, plasma citrate and urinary citrate levels were lowered, and the calcium femur percentage was smaller. Bone avidity for calcium was found. –Group 2 (sucrose diet without vitamin D) had normal plasma calcium levels. Urinary calcium and citrate and plasma citrate did not show significant differences from those of animals receiving vitamin D. No significant differences were found in the specific radioactivity and radioactivity p. 1,000 of the administered dose. Contrary to starch, sucrose maintained calcium homeostasis, and apparently, normal ossification, although the femur was lighter than those of animals receiving vitamin D. Further work is necessary to determine whether the fructose component of the sucrose molecule is responsible for the increased calcium utilization and, if so, what levels of ingestion are necessary for this activity.

Carbohydr Res. 2009 Sep 8;344(13):1676-81. Epub 2009 Jun 3.
Protective role of fructose in the metabolism of astroglial C6 cells exposed to hydrogen peroxide.
Spasojević I, Bajić A, Jovanović K, Spasić M, Andjus P.
Astroglial cells represent the main line of defence against oxidative damage related to neurodegeneration. Therefore, protection of astroglia from an excess of reactive oxygen species could represent an important target of the treatment of such conditions. The aim of our study was to compare the abilities of glucose and fructose, the two monosaccharides used in diet and infusion, to protect C6 cells from hydrogen peroxide (H(2)O(2))-mediated oxidative stress. It was observed using confocal microscopy with fluorescent labels and the MTT test that fructose prevents changes of oxidative status of the cells exposed to H(2)O(2) and preserves their viability. Even more pronounced protective effects were observed for fructose 1,6-bis(phosphate). We propose that fructose and its intracellular forms prevent H(2)O(2) from participating in the Fenton reaction via iron sequestration. As fructose and fructose 1,6-bis(phosphate) are able to pass the blood-brain barrier, they could provide antioxidative protection of nervous tissue in vivo. So, in contrast to the well-known negative effects of frequent consumption of fructose under physiological conditions, acute infusion or ingestion of fructose or fructose 1,6-bis(phosphate) could be of benefit in the cytoprotective therapy of neurodegenerative disorders related to oxidative stress.

Brundin, et al. (1993) compared the effects of glucose and fructose in healthy people, and saw a greater oxygen consumption with fructose, and also an increase in the temperature of the blood, and a greater increase in carbon dioxide production. -Ray Peat, PhD

AJP – Endo April 1993 vol. 264 no. 4 E504-E513
Whole body and splanchnic oxygen consumption and blood flow after oral ingestion of fructose or glucose
T. Brundin and J. Wahren
The contribution of the splanchnic tissues to the initial 2-h rise in whole body energy expenditure after ingestion of glucose or fructose was examined in healthy subjects. Indirect calorimetry and catheter techniques were employed to determine pulmonary gas exchange, cardiac output, splanchnic blood flow, splanchnic oxygen uptake, and blood temperatures before and for 2 h after ingestion of 75 g of either fructose or glucose in water solution or of water only. Fructose ingestion was found to increase total oxygen uptake by an average of 9.5% above basal levels; the corresponding increase for glucose was 8.8% and for water only 2.5%. The respiratory exchange ratio increased from 0.84 in the basal state to 0.97 at 45 min after fructose ingestion and rose gradually after glucose to 0.86 after 120 min. The average 2-h thermic effect, expressed as percent of ingested energy, was 5.0% for fructose and 3.7% for glucose (not significant). Splanchnic oxygen consumption did not increase measurably after ingestion of either fructose or glucose. The arterial concentration of lactate rose, arterial pH fell, and PCO2 remained essentially unchanged after fructose ingestion. Glucose, but not fructose, elicited increases in cardiac output (28%) and splanchnic blood flow (56%). Fructose, but not glucose, increased arterial blood temperature significantly. It is concluded that both fructose and glucose-induced thermogenesis occurs exclusively in extrasplanchnic tissues. Compared with glucose, fructose ingestion is accompanied by a more marked rise in CO2 production, possibly reflecting an increased extrasplanchnic oxidation of lactate and an accumulation of heat in the body.

Am J Clin Nutr. 1993 Nov;58(5 Suppl):766S-770S.
Fructose and dietary thermogenesis.
Tappy L, Jéquier E.
Ingestion of nutrients increases energy expenditure above basal metabolic rate. Thermogenesis of carbohydrate comprises two distinct components: an obligatory component, which corresponds to the energy cost of carbohydrate absorption, processing, and storage; and a facultative component, which appears to be related with a carbohydrate-induced stimulation of the sympathetic nervous system, and can be inhibited by beta-adrenergic antagonists. Fructose ingestion induces a greater thermogenesis than does glucose. This can be explained by the hydrolysis of 3.5-4.5 mol ATP/mol fructose stored as glycogen, vs 2.5 mol ATP/mol glucose stored. Therefore the large thermogenesis of fructose corresponds essentially to an increase in obligatory thermogenesis. Obese individuals and obese patients with non-insulin-dependent diabetes mellitus commonly have a decrease in glucose-induced thermogenesis. These individuals in contrast display a normal thermogenesis after ingestion of fructose. This may be explained by the fact that the initial hepatic fructose metabolism is independent of insulin. This observation indicates that insulin resistance is likely to play an important role in the decreased glucose-induced thermogenesis of these individuals.

Diabetes Metab. 2005 Apr;31(2):178-88.
Consumption of carbohydrate solutions enhances energy intake without increased body weight and impaired insulin action in rat skeletal muscles.
Ruzzin J, Lai YC, Jensen J.
OBJECTIVES:
In the present study, we investigated whether replacement of tap water by fructose or sucrose solutions affect rat body weight and insulin action in skeletal muscles.
METHODS:
Rats were fed standard rodent chow ad libitum with water, or water containing fructose (10.5% or 35%) or sucrose (10.5% or 35%) for 11 weeks. Body weight and energy intake from chow and drinking solutions were measured. Urinary catecholamines secretion was determined after 50-60 days. At the end of the feeding period, soleus and epitrochlearis were removed for in vitro measurements of glucose uptake (with tracer amount of 2-[3H]-deoxy-D-glucose) and PKB Ser473 phosphorylation (assessed by Western Blot) with or without insulin.
RESULTS:
Fructose and sucrose solutions enhanced daily energy intake by about 15% without increasing rat body weight. Secretion of urinary noradrenaline was higher in rats drinking a 35% sucrose solution than in rats drinking water. In the other groups, urinary noradrenaline secretion was similar to rats consuming water. Urinary adrenaline secretion was similar in all groups. Insulin-stimulated glucose uptake and insulin-stimulated PKB phosphorylation were not reduced by intake of fructose or sucrose solution.
CONCLUSIONS:
Fructose and sucrose solutions enhanced energy intake but did not increase body weight. Although noradrenaline may regulate body weight in rats drinking 35% sucrose solution, body weight seems to be regulated by other mechanisms. Intake of fructose or sucrose solution did not impair insulin-stimulated glucose uptake or signaling in skeletal muscles.

Minerva Endocrinol. 1990 Oct-Dec;15(4):273-7.
[Postprandial thermogenesis and obesity: effects of glucose and fructose].
[Article in Italian]
Macor C, De Palo C, Vettor R, Sicolo N, De Palo E, Federspil G.
In order to check whether reduced postprandial thermogenesis, as found in obese subjects depends on insulin resistance, the study tested whether the thermogenetic response to glucose in a group of obese subjects and a group of normal weight subjects differed from that obtained using an insulin-independent monosaccharide such as fructose. Nine obese subjects and 6 control subjects were included in the study. An oral glucose tolerance and fructose tolerance test (75 g) was performed in all subjects on different days. Energy expenditure was calculated both in basal conditions and during the test (resting metabolic rate: RMR) using indirect calorimetry expressed per kg of lean weight, as assessed using bioimpedance measurement techniques. Blood samples were collected to assay glycemia and insulinemia. Results show that increased RMR induced by glucose was significantly reduced in the group of obese subjects compared to controls. In the same group of obese subjects, RMR was found to be significantly higher following fructose in comparison to the glucose response but did not differ from that in controls. Data confirm the existence of reduced thermogenesis in obese subjects induced by glucose. The fact that this phenomenon was not recorded in the same subjects following the fructose tolerance test, whose metabolism is insulin-independent, supports the hypothesis that reduced glucose-induced thermogenesis in obese subjects may depend on insulin resistance.

Many studies have found that sucrose is less fattening than starch or glucose, that is, that more calories can be consumed without gaining weight. During exercise, the addition of fructose to glucose increases the oxidation of carbohydrate by about 50% (Jentjens and Jeukendrup, 2005). -Ray Peat, PhD

Br J Nutr. 2005 Apr;93(4):485-92.
High rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged cycling exercise.
Jentjens RL, Jeukendrup AE.
A recent study from our laboratory has shown that a mixture of glucose and fructose ingested at a rate of 1.8 g/min leads to peak oxidation rates of approximately 1.3 g/min and results in approximately 55% higher exogenous carbohydrate (CHO) oxidation rates compared with the ingestion of an isocaloric amount of glucose. The aim of the present study was to investigate whether a mixture of glucose and fructose when ingested at a high rate (2.4 g/min) would lead to even higher exogenous CHO oxidation rates (>1.3 g/min). Eight trained male cyclists (VO2max: 68+/-1 ml/kg per min) cycled on three different occasions for 150 min at 50% of maximal power output (60+/-1% VO2max) and consumed either water (WAT) or a CHO solution providing 1.2 g/min glucose (GLU) or 1.2 g/min glucose+1.2 g/min fructose (GLU+FRUC). Peak exogenous CHO oxidation rates were higher (P<0.01) in the GLU+FRUC trial compared with the GLU trial (1.75 (SE 0.11) and 1.06 (SE 0.05) g/min, respectively). Furthermore, exogenous CHO oxidation rates during the last 90 min of exercise were approximately 50% higher (P<0.05) in GLU+FRUC compared with GLU (1.49 (SE 0.08) and 0.99 (SE 0.06) g/min, respectively). The results demonstrate that when a mixture of glucose and fructose is ingested at high rates (2.4 g/min) during 150 min of cycling exercise, exogenous CHO oxidation rates reach peak values of approximately 1.75 g/min.

Am J Physiol. 1987 Sep;253(3 Pt 1):G390-6.
Fructose prevents hypoxic cell death in liver.
Anundi I, King J, Owen DA, Schneider H, Lemasters JJ, Thurman RG.
Perfusion of livers from fasted rats with nitrogen-saturated buffer caused hepatocellular damage within 30 min. Lactate dehydrogenase (LDH) was released at maximal rates of approximately 300 U . g-1 . h-1 under these conditions, and virtually all cells in periportal and pericentral regions of the liver lobule were stained with trypan blue. Infusion of glucose, xylitol, sorbitol, or mannitol (20 mM) did not appreciably change the time course or extent of damage due to perfusion with nitrogen-saturated perfusate. However, fructose (20 mM) completely prevented damage assessed by LDH release, trypan blue uptake, and ultrastructural changes for at least 2 h of perfusion. Neither glucose, xylitol, sorbitol, nor mannitol (20 mM) increased lactate formation above basal levels during hypoxia. On the other hand, fructose (0.4-20 mM) caused a concentration-dependent increase in lactate formation that reached maximal rates of approximately 180 mumol . g-1 . h-1. The dose-dependent increase in glycolytic lactate production from fructose correlated well with cellular protection reflected by decreases in LDH release. ATP:ADP ratios were also increased from 0.4 to 1.8 in a dose-dependent manner by fructose. The results indicate that fructose protects the liver against hypoxic cell death by the glycolytic production of ATP in the absence of oxygen.

Biochem J. 1967 January; 102(1): 177–180.
The influence of fructose and its metabolites on ethanol metabolism in vitro
H. I. D. Thieden and F. Lundquist
1. Fructose caused an increase in the rate of ethanol oxidation by rat-liver slices, and d-glyceraldehyde was found to have a similar effect. 2. Addition of glycerol lowered the rate of ethanol oxidation if the incubation medium contained fructose and ethanol, but no such effect was found if it contained glucose and ethanol. 3. The formation of glycerol by the slices during incubation and the concentration of α-glycerophosphate in the slices were highest in medium containing fructose and ethanol. 4. In experiments without ethanol in the incubation medium, fructose strongly increased the pyruvate concentration, which resulted in a decrease of the lactate/pyruvate concentration ratio. Addition of ethanol to the medium resulted in a marked decrease in pyruvate concentration. 5. Oxygen consumption is greater in slices incubated in medium containing fructose and ethanol than in slices incubated in medium containing glucose and ethanol.

Am J Physiol Endocrinol Metab. 2005 Jun;288(6):E1160-7. Epub 2005 Jan 25.
Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog.
Shiota M, Galassetti P, Igawa K, Neal DW, Cherrington AD.
The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 microg.kg(-1).min(-1)) was given along with basal insulin (1.8 pmol.kg(-1).min(-1)) and glucagon (0.5 ng.kg(-1).min(-1)). After a control period, glucose (36.1 micromol.kg(-1).min(-1)) was continuously given intraportally for 4 h with (2.2 micromol.kg(-1).min(-1)) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from <16 to 176 +/- 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.3 to 11.2 +/- 0.6 during the first 2 h after which it remained at 11.6 +/- 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.2 to 7.4 +/- 0.6 during the first 1 h after which it decreased to 6.1 +/- 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (micromol.kg(-1).min(-1)) switched from output (8.9 +/- 1.7 and 13.3 +/- 2.8) to uptake (12.2 +/- 4.4 and 29.4 +/- 6.7) in the control and fructose groups, respectively. Average NHGU (micromol.kg(-1).min(-1)) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 +/- 3.3 and 14.5 +/- 1.4) than in the control group (15.0 +/- 4.4 and 5.9 +/- 1.8). Glucose 6-phosphate and glycogen content (micromol glucose/g) in the liver and glucose incorporation into hepatic glycogen (micromol glucose/g) were higher in the fructose (218 +/- 2, 283 +/- 25, and 109 +/- 26, respectively) than in the control group (80 +/- 8, 220 +/- 31, and 41 +/- 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised.

J Clin Endocrinol Metab. 2000 Dec;85(12):4515-9.
Acute fructose administration decreases the glycemic response to an oral glucose tolerance test in normal adults.
Moore MC, Cherrington AD, Mann SL, Davis SN.
In animal models, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to the glucose load. Therefore, we examined the effect of fructose on glucose tolerance in 11 healthy human volunteers (5 men and 6 women). Each subject underwent an oral glucose tolerance test (OGTT) on 2 separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without 7.5 g fructose (OGTT+F or OGTT-F), in random order. Arterialized blood samples were obtained from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 2 h afterward. The area under the curve (AUC) of the change in plasma glucose was 19% less in OGTT+F vs. OGTT-F (P: < 0.05). Glucose tolerance was improved by fructose in 9 subjects and worsened in 2. All 6 subjects with the largest glucose AUC during OGTT-F had a decreased response during OGTT+F (31 +/- 5% decrease). The insulin AUC did not differ between the 2 studies. Of the 9 subjects with improved glucose tolerance during the OGTT+F, 5 had smaller insulin AUC during the OGTT+F than the OGTT-F. Plasma glucagon concentrations declined similarly during OGTT-F and OGTT+F. The blood lactate response was about 50% greater during the OGTT+F (P: < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTT. In conclusion, low dose fructose improves the glycemic response to an oral glucose load in normal adults without significantly enhancing the insulin or triglyceride response. Fructose appears most effective in those normal individuals who have the poorest glucose tolerance.

Diabetes Care. 2001 Nov;24(11):1882-7.
Acute fructose administration improves oral glucose tolerance in adults with type 2 diabetes.
Moore MC, Davis SN, Mann SL, Cherrington AD.
OBJECTIVE:
In normal adults, a small (catalytic) dose of fructose administered with glucose decreases the glycemic response to a glucose load, especially in those with the poorest glucose tolerance. We hypothesized that an acute catalytic dose of fructose would also improve glucose tolerance in individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
Five adults with type 2 diabetes underwent an oral glucose tolerance test (OGTT) on two separate occasions, at least 1 week apart. Each OGTT consisted of 75 g glucose with or without the addition of 7.5 g fructose (OGTT + F or OGTT – F), in random order. Arterialized blood samples were collected from a heated dorsal hand vein twice before ingestion of the carbohydrate and every 15 min for 3 h afterward.
RESULTS:
The area under the curve (AUC) of the plasma glucose response was reduced by fructose administration in all subjects; the mean AUC during the OGTT + F was 14% less than that during the OGTT – F (P < 0.05). The insulin AUC was decreased 21% with fructose administration (P = 0.2). Plasma glucagon concentrations declined similarly during OGTT - F and OGTT + F. The incremental AUC of the blood lactate response during the OGTT - F was approximately 50% of that observed during the OGTT + F (P < 0.05). Neither nonesterified fatty acid nor triglyceride concentrations differed between the two OGTTs. CONCLUSIONS: Low-dose fructose improves the glycemic response to an oral glucose load in adults with type 2 diabetes, and this effect is not a result of stimulation of insulin secretion.

Diabet Med. 1989 Aug;6(6):506-11.
Dietary fructose as a natural sweetener in poorly controlled type 2 diabetes: a 12-month crossover study of effects on glucose, lipoprotein and apolipoprotein metabolism.
Osei K, Bossetti B.
The metabolic effects of fructose incorporated in the normal diets of 13 poorly controlled, Type 2 diabetic patients were studied in a 6-month, randomized, crossover study. Patients used 60 g day-1 of crystalline fructose in divided amounts as part of their isocaloric (1400-3900 kcal), weight-maintaining diet. During fructose supplementation, the distribution of carbohydrate-derived calories was 35% complex and 15% simple, the latter solely from fructose. This was compared with the patients’ values on their usual diabetic diet (carbohydrate 50% (mostly complex), fat 38%, and protein 12%). After 6 months of taking fructose, fasting serum glucose decreased from 12.6 +/- 1.1 (+/- SE) to 9.8 +/- 1.3 mmol l-1 (p less than 0.02), while it was unchanged on normal diet (11.0 +/- 0.1 vs 11.6 +/- 0.9 mmol l-1, NS). Glycosylated haemoglobin was also reduced from 11.3 +/- 0.4 to 9.9 +/- 0.5% (p less than 0.05) on fructose, but unchanged on the control diet (10.4 +/- 0.7 vs 11.2 +/- 0.7%, NS). No significant long-term deleterious changes were observed in the fasting serum lipids, lipoproteins, and apolipoproteins A-1 and B-100. Fructose was well tolerated without significant effects on body weight, or lactic acid and uric acid levels.

American Journal of Clinical Nutrition, Vol 59, 753S-757S
Fructose in the diabetic diet
MI Uusitupa
Fructose is an energy-yielding sweetener coming from different natural sources (fruit, berries, and vegetables) or is added to soft drinks, bakery products, and candies. The current content of fructose in the diabetic diet seems to be within recommendations. Because of the low glycemic index of fructose, fructose may be an alternative as a sweetener for those diabetic patients who like sweet foods but are liable to high postprandial glucose concentrations. In patients with mild non-insulin-dependent diabetes mellitus, fructose may result in lower postprandial glucose and insulin responses than will most other carbohydrate sources. In clinical studies, fructose has either improved metabolic control of diabetic patients or caused no significant changes. In patients susceptible to hypertriglyceridemia high doses of fructose should be avoided because of a potential hypertriglyceridemic effect. Long-term experiences about the use of fructose from large scale controlled studies on diabetic patients are lacking.

If fructose can by-pass the fatty acids’ inhibition of glucose metabolism, to be oxidized when glucose can’t, and if the metabolism of diabetes involves the oxidation of fatty acids instead of glucose, then we would expect there to be less than the normal amount of fructose in the serum of diabetics, although their defining trait is the presence of an increased amount of glucose. According to Osuagwu and Madumere (2008), that is the case. If a fructose deficiency exists in diabetes, then it is appropriate to supplement it in the diet. -Ray Peat, PhD

Nigerian Journal of Biochemistry and Molecular Biology 23 (1): 12 – 14, 2008. ISSN 0189-475
Depleted Blood Fructose in Diabetes
C. G. Osuagwu and H. E. O. Madumere
The whole blood and plasma concentrations of two hexoses, glucose and fructose, were estimated and compared in 61 non-diabetics (30 males and 31 females) and 61 diabetics (30 males and 31 females). For non-diabetics, the whole blood and plasma concentration of glucose (mg/dl) were 72.52 ± 8.90 and 87 .54 ± 12.26 while for diabetics they were 130.08 ± 34.27 and 141.03 ± 31.68, respectively. Blood and plasma fructose levels (mg/dl) for non -diabetics were 1.34 ± 0.54 and 1.34 ± 0.32, while for diabetics the values were 0.51 ± 0.33 and 0.51 ± 0.33, respectively. This finding indicates that diminished glucose utilization results to compensatory fructose utilization and depletion in diabetes. Fructose has the more stable, and same, concentrations over time in both blood and plasma than glucose. The glucose/fructose ratio for non-diabetic blood and plasma were 52.13 ± 3.30 and 65.12 ± 4.30 while the ratios for diabetics were 466.46 ± 388.76 and 501.38 ± 382.38. In all conditions considered, the differences in the blood and plasma concentrations of these hexoses between diabetics and non-diabetics were highly significant (p < 0.001). Diabetes is a hexose metabolism derangement syndrome, and not simple glucose metabolism disease. This fact should be borne in mind in diabetes management. A parameter combining glucose and fructose factors is a more efficient measure of diabetes than one of glucose alone; glucose/fructose ratio is such an index that can be employed in diagnosis.

Diabetes Care. 1980 Sep-Oct;3(5):575-82.
Effects of oral fructose in normal, diabetic, and impaired glucose tolerance subjects.
Crapo PA, Kolterman OG, Olefsky JM.
We studied the acute effects of oral ingestion of 50-g loads of dextrose, sucrose, and fructose on post-prandial serum glucose, insulin, and plasma glucagon responses in 9 normal subjects, 10 subjects with impaired glucose tolerance, and 17 non-insulin-dependent diabetic subjects. The response to each carbohydrate was quantified when the respective carbohydrate was given alone in a drink or when given in combination with protein and fat in a test meal. The data demonstrate that (1) fructose ingestion resulted in significantly lower serum glucose and insulin responses than did sucrose or dextrose ingestion in all study groups, either when given alone or in the test meal; (2) although fructose ingestion always led to the least glycemic response compared with the other hexoses, the serum glucose response to fructose was increased the more glucose intolerant the subject; (3) urinary glucose excretion during the 3 h after carbohydrate ingestion was greatest after dextrose and least after fructose in all groups. In conclusion, fructose ingestion results in markedly lower serum glucose and insulin responses and less glycosuria than either dextrose or sucrose, both when given alone or as a constituent in a test meal. However, as glucose tolerance worsens, an increasingly greater glycemic response to fructose is seen.

Am J Clin Nutr. 1982 Aug;36(2):256-61.
Comparison of the metabolic responses to fructose and sucrose sweetened foods.
Crapo PA, Scarlett JA, Kolterman OG.
We studied the acute effects of oral ingestion of fructose and sucrose sweetened cakes and ice creams on postprandial serum glucose and insulin responses in 10 normal subjects, six subjects with impaired glucose tolerance, and 10 noninsulin-dependent diabetic subjects. The data demonstrate that: 1) ingestion of fructose cakes and ice creams resulted in lower serum glucose and insulin responses than did the sucrose cakes and ice creams in all study groups; 2) when comparing cakes to ice creams, the serum glucose and insulin responses after ice cream ingestion were lower than responses after cake ingestion. In conclusion, when fructose is incorporated as a sweetener in a complex food product, it is associated with significantly lower serum glucose and insulin responses as compared to comparable sucrose sweetened foods.

Diabetes Care. 1982 Sep-Oct;5(5):512-7.
The effects of oral fructose, sucrose, and glucose in subjects with reactive hypoglycemia.
Crapo PA, Scarlett JA, Kolterman OG, Sanders LR, Hofeldt FD, Olefsky JM.
We have evaluated the acute effects of orally administered 100-g loads of fructose, sucrose, or glucose given as drinks and of 100-g loads of fructose and sucrose given in cakes on the postprandial serum glucose, insulin, and cortisol responses in seven subjects with reactive hypoglycemia. We defined reactive hypoglycemia as a serum glucose nadir of 65 mg/dl or less, symptoms compatible with hypoglycemia occurring at or after the serum glucose nadir, a hypoglycemic index of greater than 1.0, and a rise in serum cortisol to greater than 20 micrograms/dl after the serum glucose nadir. The data demonstrated that (1) pure fructose given as a drink resulted in relatively flat serum glucose and insulin responses and did not cause a hypoglycemic reaction in any of the subjects, compared with the glucose drink, which caused a hypoglycemic reaction in any of the subjects; (2) ingestion of pure sucrose as a drink elicited significantly flatter serum glucose and insulin responses than did the glucose drink and was associated with some episodes of chemical hypoglycemia and symptoms, but did not result in a hypoglycemic reaction by our definition in any patient; and (3) ingestion of fructose cake led to serum glucose and insulin responses that were lower than those caused by ingestion of sucrose cake, but ingestion of neither fructose nor sucrose cake led to a hypoglycemic reaction by our definition in any patient. In conclusion, the use of fructose as a sweetening agent given either alone, in a drink, or with other nutrients in a cake resulted in markedly flatter serum glucose and insulin responses in subjects with reactive hypoglycemia. Fructose may thus prove useful as a sweetening agent in the dietary treatment of selected patients with reactive hypoglycemia.

When rats were fed for 8 weeks on a diet with 18% fructose and 11% saturated fatty acids, the content of polyunsatured fats in the blood decreased, as they had in the Brown, et al., experiment, and their total antioxidant status was increased (Girard, et al., 2005). -Ray Peat, PhD

Nutrition. 2005 Feb;21(2):240-8.
Changes in lipid metabolism and antioxidant defense status in spontaneously hypertensive rats and Wistar rats fed a diet enriched with fructose and saturated fatty acids.
Girard A, Madani S, El Boustani ES, Belleville J, Prost J.
OBJECTIVE:
Larger doses of fructose and saturated fat have been associated with oxidative stress and development of hypertension. The effects of modest amounts of fructose and saturated fatty acids on oxidative stress are unknown.
METHODS:
To increase knowledge on this question, 10-wk-old spontaneously hypertensive rats and Wistar rats were fed for 8 wk with a control diet or an experimental diet enriched with fructose (18%) and saturated fatty acids (11%; FS diet). The total antioxidant status of organs and red blood cells was assayed by monitoring the rate of free radical-induced red blood cell hemolysis. Sensitivity of very low-density lipoprotein and low-density lipoprotein (VLDL-LDL) to copper-induced lipid peroxidation was determined as the production of thiobarbituric acid-reactive substances. Antioxidant enzymes and vitamins were also measured to establish the oxidative stress effect.
RESULTS:
The FS diet did not affect blood pressure in either strain, but it increased plasma insulin concentrations only in Wistar rats without affecting those of glucose of either strain. The FS diet significantly enhanced plasma and VLDL-LDL triacylglycerol concentrations without affecting concentrations of VLDL-LDL thiobarbituric acid-reactive substances. The decreased content of arachidonic acid and total polyunsaturated fatty acids in VLDL-LDL by the FS diet may have prevented lipid peroxidation in this fraction. Moreover, FS consumption by both strains was accompanied by a significant increase in total antioxidant capacity of adipose tissue, muscle, heart, and liver. This may have resulted from increased tissue ascorbic acid levels and glutathione peroxidase and glutathione reductase activities in tissues.
CONCLUSIONS:
These findings clearly indicate that the FS diet did not alter blood pressure of spontaneously hypertensive rats and Wistar rats. The FS diet resulted in hypertriglyceridemia but increased the total antioxidant status, which may prevent lipid peroxidation in these rats.

In 1963 and 1964, experiments (Carroll, 1964) showed that the effects of glucose and fructose were radically affected by the type of fat in the diet. Although 0.6% of calories as
polyunsaturated fat prevents the appearance of the Mead acid (which is considered to indicate a deficiency of essential fats) the “high fructose” diets consistently add 10% or more corn oil or other highly unsaturated fat to the diet. These large quantities of PUFA aren’t necessary to prevent a deficiency, but they are needed to obscure the beneficial effects of fructose. -Ray Peat, PhD

J Nutr. 1963 Jan;79:93-100.
Influences of dietary carbohydrate-fat combinations on various functions associated with glycolysis and lipogenesis in rats. I. Effects of substituting sucrose for rice starch with unsaturated and with saturated fat.
CARROLL C.
ABSTRACT Weanling rats were fed diets differing only in source of carbohydrate
and fat for 2 to 4 weeks. Livers were assayed for glucose-6-phosphatase and fructose
diphosphatase activities, and for content of glycogen and lipids. Effects on enzyme
activities of substituting fructose for glucose were similar to those observed on sub
stituting sucrose for rice starch (previous report). Feeding either hydrogenated
coconut oil (HCO) or hydrogenated peanut oil (HPO) in place of corn oil (CO)
modified the enzymatic responses to dietary fructose. Results with HPO were some what different than those with HCO. Labile phosphorus values were highest in groups
fed sucrose or fructose with CO, and lowest in those fed rice starch or glucose with
HPO. Effects of dietary carbohydrate on accumulation of lipid in liver appeared to be
a function of the type of fat fed, namely, substitution of a fructose source for a
direct glucose source resulted in the accumulation of less fat in livers of rats fed CO,
but of more fat in livers of rats fed a hydrogenated oil. Proportions of phospholipid
and cholesterol in liver lipid, and concentration of cholesterol in serum also varied with the combination of carbohydrate and fat fed.

“Sugars are probably more favorable than starches for the immune system (Harris, et al., 1999), and failure of the immune system is a common feature of cancer.” -Ray Peat, PhD

J Surg Res. 1999 Apr;82(2):339-45.
Diet-induced protection against lipopolysaccharide includes increased hepatic NO production.
Harris HW, Rockey DC, Young DM, Welch WJ.
The host response to Gram-negative infection includes the elaboration of numerous proinflammatory agents, including tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). A component of the hepatic response to infection is an elevation in serum lipids, the so-called “lipemia of sepsis,” which results from the increased production of triglyceride (TG)-rich lipoproteins by the liver. We have postulated that these lipoproteins are components of a nonadaptive, innate immune response to endotoxin [lipopolysaccharide (LPS)] and have previously demonstrated the capacity of TG-rich lipoproteins to protect against endotoxicity in rodent models of sepsis. Herein we report the capacity of a high-fructose diet to protect against LPS, most likely by inducing high circulating levels of endogenous TG-rich lipoproteins. The protective phenotype included the increased production of NO by hepatic endothelial cells. Rats, made hypertriglyceridemic by fructose feeding, experienced decreased LPS-induced mortality (P < 0.03) and systemic TNFalpha levels (P < 0.05) as compared with normolipidemic (chow-fed) controls. The increased survival was associated with elevated levels of inducible NO synthase (NOS2) mRNA levels and NO production (82 +/- 26 vs 3 +/- 3 nmol nitrite/10(6) cells, P < 0.001) by hepatic endothelial cells. Nonselective NOS inhibitors reversed the protective phenotype in vivo and readily decreased NO production by cultured endothelial cells from hypertriglyceridemic rats in vitro. This study suggests that a high-fructose diet can protect against endotoxicity in part through induction of endogenous TG-rich lipoproteins and hepatic endothelial cell NO production. This is the first report of diet-induced hyperlipoproteinemia and subsequent protection against endotoxemia.

The consumption of carbohydrate, like an increase of thyroid hormone, insulin, or progesterone, increases the retention of sodium; fructose is the most effect carbohydrate (Rebello, et al., 1983). -Ray Peat, PhD

Am J Clin Nutr. 1983 Jul;38(1):84-94.
Short-term effects of various sugars on antinatriuresis and blood pressure changes in normotensive young men.
Rebello T, Hodges RE, Smith JL.
This is a report of the effects of sugars on salt metabolism and on blood pressure. Twenty young men, none of whom had a personal or family history of hypertension, were orally hydrated after an overnight fast and required to lie recumbent for 6 h except for urinary voiding and blood pressure measurements which were performed at 1/2 h intervals. Venous blood samples were drawn at hourly intervals. The volunteers were kept constantly hydrated by giving them water to drink equivalent to the volumes of urine voided. Two hours from the start of the experiment each subject was given one of the following sugars: glucose, fructose, sucrose, galactose, lactose, or water alone. After oral hydration the subjects appeared to develop natriuresis and kaliuresis. This was quickly abolished by ingestion of either glucose, fructose, sucrose, or lactose, but not by galactose or water alone. Fructose was the most potent antinatriuretic agent. Both glucose and sucrose significantly elevated systolic blood pressure. This lasted for 2 h after glucose ingestion and 1 h after sucrose ingestion.

Ann Intern Med. 2012 Feb 21;156(4):291-304. doi: 10.1059/0003-4819-156-4-201202210-00007.
Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, Chiavaroli L, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Kendall CW, Jenkins DJ.
BACKGROUND:
The contribution of fructose consumption in Western diets to overweight and obesity in populations remains uncertain.
PURPOSE:
To review the effects of fructose on body weight in controlled feeding trials.
DATA SOURCES:
MEDLINE, EMBASE, CINAHL, and the Cochrane Library (through 18 November 2011).
STUDY SELECTION:
At least 3 reviewers identified controlled feeding trials lasting 7 or more days that compared the effect on body weight of free fructose and nonfructose carbohydrate in diets providing similar calories (isocaloric trials) or of diets supplemented with free fructose to provide excess energy and usual or control diets (hypercaloric trials). Trials evaluating high-fructose corn syrup (42% to 55% free fructose) were excluded.
DATA EXTRACTION:
The reviewers independently reviewed and extracted relevant data; disagreements were reconciled by consensus. The Heyland Methodological Quality Score was used to assess study quality.
DATA SYNTHESIS:
Thirty-one isocaloric trials (637 participants) and 10 hypercaloric trials (119 participants) were included; studies tended to be small (<15 participants), short (<12 weeks), and of low quality. Fructose had no overall effect on body weight in isocaloric trials (mean difference, -0.14 kg [95% CI, -0.37 to 0.10 kg] for fructose compared with nonfructose carbohydrate). High doses of fructose in hypercaloric trials (+104 to 250 g/d, +18% to 97% of total daily energy intake) lead to significant increases in weight (mean difference, 0.53 kg [CI, 0.26 to 0.79 kg] with fructose). LIMITATIONS: Most trials had methodological limitations and were of poor quality. The weight-increasing effect of fructose in hypercaloric trials may have been attributable to excess energy rather than fructose itself.
CONCLUSION:
Fructose does not seem to cause weight gain when it is substituted for other carbohydrates in diets providing similar calories. Free fructose at high doses that provided excess calories modestly increased body weight, an effect that may be due to the extra calories rather than the fructose.

Diabetes Care. 2012 Jul;35(7):1611-20. doi: 10.2337/dc12-0073.
Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD, Mirrahimi A, Yu ME, Carleton AJ, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Beyene J, Kendall CW, Jenkins DJ.
OBJECTIVE:
The effect of fructose on cardiometabolic risk in humans is controversial. We conducted a systematic review and meta-analysis of controlled feeding trials to clarify the effect of fructose on glycemic control in individuals with diabetes.
RESEARCH DESIGN AND METHODS:
We searched MEDLINE, EMBASE, and the Cochrane Library (through 22 March 2012) for relevant trials lasting ≥7 days. Data were aggregated by the generic inverse variance method (random-effects models) and expressed as mean difference (MD) for fasting glucose and insulin and standardized MD (SMD) with 95% CI for glycated hemoglobin (HbA(1c)) and glycated albumin. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I(2) statistic. Trial quality was assessed by the Heyland methodological quality score (MQS).
RESULTS:
Eighteen trials (n = 209) met the eligibility criteria. Isocaloric exchange of fructose for carbohydrate reduced glycated blood proteins (SMD -0.25 [95% CI -0.46 to -0.04]; P = 0.02) with significant intertrial heterogeneity (I(2) = 63%; P = 0.001). This reduction is equivalent to a ~0.53% reduction in HbA(1c). Fructose consumption did not significantly affect fasting glucose or insulin. A priori subgroup analyses showed no evidence of effect modification on any end point.
CONCLUSIONS:
Isocaloric exchange of fructose for other carbohydrate improves long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes. Generalizability may be limited because most of the trials were <12 weeks and had relatively low MQS (<8). To confirm these findings, larger and longer fructose feeding trials assessing both possible glycemic benefit and adverse metabolic effects are required.

Res Commun Chem Pathol Pharmacol. 1977 Feb;16(2):281-90.
Effects of fructose and other substances on ethanol and acetaldehyde metabolism in man.
Rawat AK.
The comparative effectiveness of oral administration of fructose, glucose sucrose and alanine has been investigated on the rates of blood alcohol clearance, and acetaldehyde removal in man. Oral administration of fructose was found to exert the most pronounced effect. It increased the rate of blood alcohol clearance by about 100%. Orally administered alanine was found to be least effective in increasing the rate of blood alcohol clearance after blood alcohol had reached peak levels, perhaps due that poor absorption of alanine. Fructose administration partially prevented the ethanol-mediated increase inlactate/pyruvate and beta-hydroxybutyrate/acetoacetate in the blood. Fructose exerted the most pronounced antiketogenic effect and the levels of circulating free fatty acids decreased in the 24-hour fasted patients upon administration of fructose with ethanol compared to ethanol alone. Oral administrations of fructose, glucose, sucrose or alanine did not significantly change the levels of acetaldehyde in the blood. Combined administration of fructose with ethanol resulted in an increase in the levels of blood sorbitol. The mechanism through which fructose exerts its stimulatory effect on the metabolism of ethanol in the liver has been discussed.

Am J Clin Nutr. 1975 Mar;28(3):254-7.
Increased rate of alcohol removal from blood with oral fructose and sucrose.
Soterakis J, Iber FL.
The effect of oral glucose, fructose and sucrose on the disappearance rate for intravenously administered alcohol was studied in eight abstinent alcoholic subjects. The three sugars were ingested on separate days in random sequence. alcohol levels were determined at hourly intervals. During sugar ingestion, the mean rates of alcohol disappearance were: 19 plus or minus 1.4 mg/100 ml per hour (plus or minus SE), with glucose, 23.9 or minus 1.4 mg/100 ml per hour with sucrose, and 25.4 plus or minus 1.4 mg/100 ml per hour with fructose. Compared to glucose both fructose and sucrose increased the rate of alcohol from the blood. The blood levels of fructose were similar after the oral dose of 2 g/kg of fructose or 4 g/kg of sucrose.

Eur J Clin Invest. 1976 Jan 30;6(1):93-102.
Effects of fructose and glucose on ethanol-induced metabolic changes and on the intensity of alcohol intoxication and hangover.
Ylikahri RH, Leino T, Huttunen MO, Pösö AR, Eriksson CJ, Nikkilä.
The effects of fructose and glucose on the metabolic changes induced by ethanol and on the intensity of alcohol intoxication and hangover were studied in 109 healthy male volunteers. After 10 hours of fasting, the subjects were given 1.75 g of ethanol per kg body wt during 3 hours under controlled laboratory conditions. Fructose or glucose were adminstered either simultaneously with ethanol or 12 hours later during the hangover period. The intensity of alcohol intoxication and hangover were estimated 10 times during the experimental period of 20 hours using subjective and objective rating scales. Sequential determinations of blood ethanol, acetaldehyde, glucose, lactate, free fatty acids, triglycerides, ketone bodies and capillary blood acid-base balance were also made during the experiment. Under these experimental conditions neither fructose nor glucose had any significant effect on the intensity of alcohol intoxication and hangover. The sugars also had no significant effect on the rate of ethanol elimination or on the blood acetaldehyde concentration during the course of the experiment. Blood glucose concentration was decreased and blood lactate, free fatty acid and ketone body concentrations were increased during the hangover period in the subjects who had been given only ethanol. These subjects also had a marked metabolic acidosis during hangover. Glucose and fructose significantly inhibited the metabolic alterations induced by ethanol. In this respect fructose was more effective than glucose. The results indicate that both fructose and glucose effectively inhibit the metabolic disturbances induced by ethanol but they do not affect the symptoms or signs of alcohol intoxication and hangover. The results support the view that hangover is not directly related to the metabolic effects of ethanol or to its metabolic products.

Biochem J. 1998 Apr 1;331 ( Pt 1):225-30.
Dietary carbohydrates enhance lactase/phlorizin hydrolase gene expression at a transcription level in rat jejunum.
Tanaka T, Kishi K, Igawa M, Takase S, Goda T.
We have previously shown that dietary sucrose stimulates the lactase/phlorizin hydrolase (LPH) mRNA accumulation along with a rise in lactase activity in rat jejunum [Goda, Yasutake, Suzuki, Takase and Koldovský (1995) Am. J. Physiol. 268, G1066-G1073]. To elucidate the mechanisms whereby dietary carbohydrates enhance the LPH mRNA expression, 7-week-old rats that had been fed a low-carbohydrate diet (5.5% of energy as starch) were given diets containing various monosaccharides or sucrose for 12h. Among carbohydrates examined, fructose, sucrose, galactose and glycerol elicited an increase in LPH mRNA accumulation along with a rise in lactase activity in the jejunum. By contrast, glucose and alpha-methylglucoside were unable to elicit a significant increase in LPH mRNA levels. To explore a transcriptional mechanism for the carbohydrate-induced increases in LPH mRNA levels, we employed two techniques currently available to estimate transcriptional rate, i.e. RNA protection assays of pre-mRNA using an intron probe, and nuclear run-on assays. Both assays revealed that fructose elicited an increase in transcription of the LPH gene, and that the transcription of LPH was influenced only slightly, if at all, by glucose intake. These results suggest that certain monosaccharides such as fructose or their metabolite(s) are capable of enhancing LPH mRNA levels in the small intestine, and that transcriptional control might play a major role in the carbohydrate-induced increase of LPH mRNA expression.

Adv Nutr March 2013 Adv Nutr vol. 4: 246-256, 2013
Challenging the Fructose Hypothesis: New Perspectives on Fructose Consumption and Metabolism
John S. White
The field of sugar metabolism, and fructose metabolism in particular, has experienced a resurgence of interest in the past decade. The “fructose hypothesis” alleges that the fructose component common to all major caloric sweeteners (sucrose, high-fructose corn syrup, honey, and fruit juice concentrates) plays a unique and causative role in the increasing rates of cardiovascular disease, hypertension, diabetes, cancer, and nonalcoholic fatty liver disease. This review challenges the fructose hypothesis by comparing normal U.S. levels and patterns of fructose intake with contemporary experimental models and looking for substantive cause-and-effect evidence from real-world diets. It is concluded that 1) fructose intake at normal population levels and patterns does not cause biochemical outcomes substantially different from other dietary sugars and 2) extreme experimental models that feature hyperdosing or significantly alter the usual dietary glucose-to-fructose ratio are not predictive of typical human outcomes or useful to public health policymakers. It is recommended that granting agencies and journal editors require more physiologically relevant experimental designs and clinically important outcomes for fructose research.

“Alcohol’s liver toxicity is associated with an increased reductive state, higher NADH/NAD, and its toxicity is prevented by agents such as fructose, which protectively lower the NADH/NAD ratio (Khan and O’Brien, 1995, Niknahad, et al., 1995). The reductive activation of iron is an important factor in the toxicity in this case (Khan and O’Brien, 1995). The fact that fructose can protect against cyanide toxicity (Niknahad, et al., 1994), seems likely to be another illustration of the important of the redox balance.” -Ray Peat, PhD

Biochim Biophys Acta. 1995 Nov 9;1269(2):153-61.
Modulating hypoxia-induced hepatocyte injury by affecting intracellular redox state.
Khan S, O’Brien PJ.
Hypoxia-induced hepatocyte injury results not only from ATP depletion but also from reductive stress and oxygen activation. Thus the NADH/NAD+ ratio was markedly increased in isolated hepatocytes maintained under 95% N2/5% CO2 in Krebs-Henseleit buffer well before plasma membrane disruption occurred. Glycolytic nutrients fructose, dihydroxyacetone or glyceraldehyde prevented cytotoxicity, restored the NADH/NAD+ ratio, and prevented complete ATP depletion. However, the NADH generating nutrients sorbitol, xylitol, glycerol and beta-hydroxybutyrate enhanced hypoxic cytotoxicity even though ATP depletion was not affected. On the other hand, NADH oxidising metabolic intermediates oxaloacetate or acetoacetate prevented hypoxic cytotoxicity but did not affect ATP depletion. Restoring the cellular NADH/NAD+ ratio with the artificial electron acceptors dichlorophenolindophenol and Methylene blue also prevented hypoxic injury and partly restored ATP levels. Ethanol which further increased the cellular NADH/NAD+ ratio increased by hypoxia also markedly increased toxicity whereas acetaldehyde which restored the normal cellular NADH/NAD+ ratio, prevented toxicity even though hypoxia induced ATP depletion was little affected by ethanol or acetaldehyde. The viability of hypoxic hepatocytes is therefore more dependent on the maintenance of normal redox homeostasis than ATP levels. GSH may buffer these redox changes as hypoxia caused cell injury much sooner with GSH depleted hepatocytes. Hypoxia also caused an intracellular release of free iron and cytotoxicity was prevented by desferoxamine. Furthermore, increasing the cellular NADH/NAD+ ratio markedly increased the intracellular release of iron. Hypoxia-induced hepatocyte injury was also prevented by oxypurinol, a xanthine oxidase inhibitor. Polyphenolic antioxidants or the superoxide dismutase mimic, TEMPO partly prevented cytotoxicity suggesting that reactive oxygen species contributed to the cytotoxicity. The above results suggests that hypoxia induced hepatocyte injury results from sustained reductive stress and oxygen activation.

Chem Biol Interact. 1995 Oct 20;98(1):27-44.
Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation.
Niknahad H, Khan S, O’Brien PJ.
By correlating lactate/pyruvate ratios and ATP levels, cytotoxicity induced by the mitochondrial respiratory inhibitors or hypoxia:reoxygenation injury can be attributed not only to ATP depletion but also to reductive stress and oxygen activation. Thus hypoxia, cyanide or antimycin markedly increases reductive stress, non-heme Fe release and H2O2 formation in hepatocytes. Cytotoxicity was partly prevented with the ferric chelator desferoxamine, the xanthine oxidase inhibitor oxypurinol and the hydrogen peroxide scavenger glutathione. No lipid peroxidation could be detected and phenolic anti-oxidants had little effect. However, polyphenolic antioxidants or the superoxide dismutase mimics TEMPO or TEMPOL partly prevented cytotoxicity. Furthermore, increasing the hepatocyte NADH/NAD+ ratio with NADH generating compounds such as ethanol, glycerol, or beta-hydroxybutyrate markedly increased cytotoxicity (prevented by desferoxamine) and further increased the intracellular release of non-heme iron. Cytotoxicity could be prevented by glycolytic substrates (eg. fructose, dihydroxyacetone, glyceraldehyde) or the NADH utilising substrates acetoacetate or acetaldehyde which decreased the reductive stress and prevented intracellular iron release. These results suggest that liver injury resulting from insufficient respiration involves reductive stress which releases intracellular Fe, converts xanthine dehydrogenase to xanthine oxidase and causes mitochondrial oxygen activation. The cell’s antioxidant defences are compromised and ATP catabolism contributes to oxygen activation.

Toxicol Appl Pharmacol. 1994 Oct;128(2):271-9.
Prevention of cyanide-induced cytotoxicity by nutrients in isolated rat hepatocytes.
Niknahad H, Khan S, Sood C, O’Brien PJ.
The effects of various glycolytic substrates and keto acid metabolites on the cytotoxic effects of cyanide have been studied with isolated rat hepatocytes. The sequence of cytotoxic events with 2 mM cyanide was an immediate inhibition of respiration followed by ATP depletion. Disruption of the plasma membrane occurred when 85-90% of ATP levels had been depleted. Fructose, dihydroxyacetone, glyceraldehyde, pyruvate, and alpha-ketoglutarate prevented cyanide-induced cytotoxicity and ATP depletion. Hepatocyte respiration was also restored by all except fructose. Fructose, unlike the others, also did not prevent cytotoxicity if added 30-60 min after cyanide. Fluoride, an inhibitor of the glycolytic enzyme enolase, prevented protection by fructose but not dihydroxyacetone or glyceraldehyde, suggesting that dihydroxyacetone and glyceraldehyde are cytoprotective by trapping cyanide, thereby restoring cytochrome oxidase activity and cellular ATP levels. Fructose, on the other hand, may be cytoprotective by supplying ATP through glycolysis. Hepatocytes isolated from fasted rats were five- to sevenfold more susceptible to cyanide-induced cytotoxicity. Furthermore, all glycogenic and gluconeogenic amino acids and carbohydrates were cytoprotective against cyanide toxicity toward fasted hepatocytes, suggesting that cellular energy stores determine their resistance to cyanide.

British Journal of Nutrition / FirstView Article, pp 1-11 Published online: 23 July 2013
Dietary intake of carbohydrates and risk of type 2 diabetes: the European Prospective Investigation into Cancer-Norfolk study
Sara Ahmadi-Abharia1 c1, Robert N. Lubena1, Natasha Powella1, Amit Bhaniania1, Rajiv Chowdhurya1, Nicholas J. Warehama2, Nita G. Forouhia2 and Kay-Tee Khawa1
In the present study, we investigated the association between dietary intake of carbohydrates and the risk of type 2 diabetes. Incident cases of diabetes (n 749) were identified and compared with a randomly selected subcohort of 3496 participants aged 40–79 years. For dietary assessment, we used 7 d food diaries administered at baseline. We carried out modified Cox proportional hazards regression analyses and compared results obtained from the different methods of adjustment for total energy intake. Dietary intakes of total carbohydrates, starch, sucrose, lactose or maltose were not significantly related to diabetes risk after adjustment for confounders. However, in the residual method for energy adjustment, intakes of fructose and glucose were inversely related to diabetes risk. The multivariable-adjusted hazard ratios (HR) of diabetes comparing the extreme quintiles of intake were 0·79 (95 % CI 0·59, 1·07; P for trend = 0·03) for glucose and 0·62 (95 % CI 0·46, 0·83; P for trend = 0·01) for fructose. In the nutrient density method, only fructose was inversely related to diabetes risk (HR 0·65, 95 % CI 0·48, 0·88). The replacement of 5 % energy intake from SFA with an isoenergetic amount of fructose was associated with a 30 % lower diabetes risk (HR 0·69, 95 % CI 0·50, 0·96). Results of the standard and energy partition methods were similar to those of the residual method. These prospective findings suggest that the intakes of starch and sucrose are not associated, but that those of fructose and glucose are inversely associated with diabetes risk. Whether the inverse associations with fructose and glucose reflect the effect of substitution of these carbohydrate subtypes with other nutrients (i.e. SFA), their net higher intake or other nutrients associated with their intake remains to be established through further investigation.

Ann Intern Med. 2012 Feb 21;156(4):291-304. doi: 10.7326/0003-4819-156-4-201202210-00007.
Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, Chiavaroli L, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Kendall CW, Jenkins DJ.
BACKGROUND:
The contribution of fructose consumption in Western diets to overweight and obesity in populations remains uncertain.
PURPOSE:
To review the effects of fructose on body weight in controlled feeding trials.
DATA SOURCES:
MEDLINE, EMBASE, CINAHL, and the Cochrane Library (through 18 November 2011).
STUDY SELECTION:
At least 3 reviewers identified controlled feeding trials lasting 7 or more days that compared the effect on body weight of free fructose and nonfructose carbohydrate in diets providing similar calories (isocaloric trials) or of diets supplemented with free fructose to provide excess energy and usual or control diets (hypercaloric trials). Trials evaluating high-fructose corn syrup (42% to 55% free fructose) were excluded.
DATA EXTRACTION:
The reviewers independently reviewed and extracted relevant data; disagreements were reconciled by consensus. The Heyland Methodological Quality Score was used to assess study quality.
DATA SYNTHESIS:
Thirty-one isocaloric trials (637 participants) and 10 hypercaloric trials (119 participants) were included; studies tended to be small (<15 participants), short (<12 weeks), and of low quality. Fructose had no overall effect on body weight in isocaloric trials (mean difference, -0.14 kg [95% CI, -0.37 to 0.10 kg] for fructose compared with nonfructose carbohydrate). High doses of fructose in hypercaloric trials (+104 to 250 g/d, +18% to 97% of total daily energy intake) lead to significant increases in weight (mean difference, 0.53 kg [CI, 0.26 to 0.79 kg] with fructose).
LIMITATIONS:
Most trials had methodological limitations and were of poor quality. The weight-increasing effect of fructose in hypercaloric trials may have been attributable to excess energy rather than fructose itself.
CONCLUSION:
Fructose does not seem to cause weight gain when it is substituted for other carbohydrates in diets providing similar calories. Free fructose at high doses that provided excess calories modestly increased body weight, an effect that may be due to the extra calories rather than the fructose.

“Fructose prevents toxin induced apoptosis in healthy cells but doesn’t prevent apoptosis of cancer cells.” -courtesy of Jannis Dittmer

J Exp Med. 2000 Jun 5;191(11):1975-85.
Metabolic depletion of ATP by fructose inversely controls CD95- and tumor necrosis factor receptor 1-mediated hepatic apoptosis.
Latta M, Künstle G, Leist M, Wendel A.
“This study demonstrates that TNF-induced hepatocyto-toxicity is prevented in vivo and in vitro after treatment with fructose. This unexpected antiapoptotic action of the sugar was exceptionally potent, as fructose completely abolished liver damage of mice even after exposure to otherwise lethal TNF doses. A similar robustness of fructose-mediated protection was also seen in vitro, because hepatocyte apoptosis was reduced by 95% over a wide range of different TNF concentrations. The effect of the sugar was exquisitely specific for nontransformed hepatocytes, which is not the case for caspase inhibitors of similar potency (8,9). Fructose neither depleted ATP nor did it protect fromapoptosis in hepatoma cells (not shown), primary neurons (23), and lymphoid cells (16). Thus, the cell type–selective effects of the sugar may be used to differentially modulate responses of tumor cells and hepatic parenchymal cells in vivo.”

Am J Clin Nutr. 2017 Aug;106(2):506-518. doi: 10.3945/ajcn.116.145151. Epub 2017 Jun 7.
Fructose replacement of glucose or sucrose in food or beverages lowers postprandial glucose and insulin without raising triglycerides: a systematic review and meta-analysis.
Evans RA, Frese M, Romero J, Cunningham JH, Mills KE.
Background: Conflicting evidence exists on the effects of fructose consumption in people with type 1 and type 2 diabetes mellitus. No systematic review has addressed the effect of isoenergetic fructose replacement of glucose or sucrose on peak postprandial glucose, insulin, and triglyceride concentrations.
Objective: The objective of this study was to review the evidence for postprandial glycemic and insulinemic responses after isoenergetic replacement of either glucose or sucrose in foods or beverages with fructose.
Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials measuring peak postprandial glycemia after isoenergetic replacement of glucose, sucrose, or both with fructose in healthy adults or children with or without diabetes. The main outcomes analyzed were peak postprandial blood glucose, insulin, and triglyceride concentrations.
Results: Replacement of either glucose or sucrose by fructose resulted in significantly lowered peak postprandial blood glucose, particularly in people with prediabetes and type 1 and type 2 diabetes. Similar results were obtained for insulin. Peak postprandial blood triglyceride concentrations did not significantly increase.
Conclusions: Strong evidence exists that substituting fructose for glucose or sucrose in food or beverages lowers peak postprandial blood glucose and insulin concentrations. Isoenergetic replacement does not result in a substantial increase in blood triglyceride concentrations.