Objective: To assess how intrahepatic fat and insulin resistance relate to daily fructose and energy intake during short-term overfeeding in healthy subjects. Design and methods: The analysis of the data collected in several studies in which fasting hepatic glucose production (HGP), hepatic insulin sensitivity index (HISI), and intrahepatocellular lipids (IHCL) had been measured after both 6-7 days on a weight-maintenance diet (control, C; n ¼ 55) and 6-7 days of overfeeding with 1.5 (F1.5, n ¼ 7), 3 (F3, n ¼ 17), or 4 g fructose/kg/day (F4, n ¼ 10), with 3 g glucose/ kg/day (G3, n ¼ 11), or with 30% excess energy as saturated fat (fat30%, n ¼ 10). Results: F3, F4, G3, and fat30% all significantly increased IHCL, respectively by 113 6 86, 102 6 115, 59 6 92, and 90 6 74% as compared to C (all P < 0.05). F4 and G3 increased HGP by 16 6 10 and 8 6 11% (both P < 0.05), and F3 and F4 significantly decreased HISI by 20 6 22 and 19 6 14% (both P < 0.01). In contrast, there was no significant effect of fat30% on HGP or HISI. Conclusions: Short-term overfeeding with fructose or glucose decreases hepatic insulin sensitivity and increases hepatic fat content. This indicates short-term regulation of hepatic glucose metabolism by simple carbohydrates.

Fructose increased total carbohydrate oxidation, lactate production and oxidation, and GNG(F). Fructose oxidation was explained equally by fructose-derived lactate and glucose oxidation, most likely in skeletal and cardiac muscle. This trial was registered at clinicaltrials.gov as NCT01128647.

The increase in VLDL TAG concentration after ingestion of a high-fructose diet is more pronounced in men than in pre-menopausal women. We hypothesised that this may be due to a lower fructose-induced stimulation of de novo lipogenesis (DNL) in pre-menopausal women. To evaluate this hypothesis, nine healthy male and nine healthy female subjects were studied after ingestion of oral loads of fructose enriched with 13 C 6 fructose. Incorporation of 13 C into breath CO 2 , plasma glucose and plasma VLDL palmitate was monitored to evaluate total fructose oxidation, gluconeogenesis and hepatic DNL, respectively. Substrate oxidation was assessed by indirect calorimetry. After 13 C fructose ingestion, 44·0 (SD 3·2) % of labelled carbons were recovered in plasma glucose in males v. 41·9 (SD 2·3) % in females (NS), and 42·9 (SD 3·7) % of labelled carbons were recovered in breath CO 2 in males v. 43·0 (SD 4·5) % in females (NS), indicating similar gluconeogenesis from fructose and total fructose oxidation in males and females. The area under the curve for 13 C VLDL palmitate tracer-to-tracee ratio was four times lower in females (P,0·05), indicating a lower DNL. Furthermore, lipid oxidation was significantly suppressed in males (by 16·4 (SD 5·2), P, 0·05), but it was not suppressed in females (2 1·3 (SD 4·7) %). These results support the hypothesis that females may be protected against fructose-induced hypertriglyceridaemia because of a lower stimulation of DNL and a lower suppression of lipid oxidation. De novo lipogenesis: VLDL TAG: Endogenous glucose productionThe metabolic effects of a high-fructose diet have been widely studied in both animals and human subjects (1) . High-fructose diet is associated with the development of at least two features of the metabolic syndrome, i.e. insulin resistance and increased plasma VLDL TAG. The latter may in turn be associated with an increased production of small, dense LDL particle with high atherogenic potential (2,3) . It has been reported by several authors that a high-fructose diet increases plasma TAG less and does not reduce insulin sensitivity in both pre-menopausal women and female rodents compared with males (4 -11) . This may be due to a sex-specific difference in either fructose metabolism or adaptations to chronic fructose overfeeding. To our knowledge, whether the metabolism of an acute fructose load differs in females and males has not been specifically assessed. Fructose disposal relies mainly on the stimulation of carbohydrate oxidation (fructose oxidation in splanchnic organs and indirect oxidation of glucose and lactate synthesised from the fructose), gluconeogenesis, hepatic glycogen storage and hepatic de novo lipogenesis (DNL). The latter, although a quantitatively minor pathway for fructose disposal, may be closely linked to hepatic VLDL TAG production and synthesis of intra-hepatic lipids. Therefore, we hypothesised that fructose-induced stimulation of DNL may be blunted in pre-menopausal women.To evaluate this hypothesis, we compared the metabolic fate of i...

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