A free-choice high-fat high-sugar diet induces glucose intolerance and insulin unresponsiveness to a glucose load not explained by obesity

Abstract

Objectives: In diet-induced obesity, it is not clear whether impaired glucose metabolism is caused directly by the diet, or indirectly via obesity. This study examined the effects of different free-choice, high-caloric, obesity-inducing diets on glucose metabolism. In these free-choice diets, saturated fat and/or a 30% sugar solution are provided in an addition to normal chow pellets. Method: In the first experiment, male rats received a free-choice high-fat high-sugar (HFHS), free-choice high-fat (HF) or a chow diet. In a second experiment, male rats received a free-choice high-sugar (HS) diet or chow diet. For both experiments, after weeks 1 and 4, an intravenous glucose tolerance test was performed. Results: Both the HFHS and HF diets resulted in obesity with comparable plasma concentrations of free fatty acids. Interestingly, the HF diet did not affect glucose metabolism, whereas the HFHS diet resulted in hyperglycemia, hyperinsulinemia and in glucose intolerance because of a diminished insulin response. Moreover, adiposity in rats on the HF diet correlated positively with the insulin response to the glucose load, whereas adiposity in rats on the HFHS diet showed a negative correlation. In addition, total caloric intake did not explain differences in glucose tolerance. To test whether sugar itself was crucial, we next performed a similar experiment in rats on the HS diet. Rats consumed three times as much sugar when compared with rats on the HFHS diet, which resulted in obesity with basal hyperinsulinemia. Glucose tolerance, however, was not affected. Conclusion: Together, these results suggest that not only obesity or total caloric intake, but the diet content also is crucial for the glucose intolerance that we observed in rats on the HFHS diet.

Differential effects of hypercaloric choice diets on insulin sensitivity in rats

“…Moreover, the finding that fcHFHS-fed rats had significantly reduced Rd, only in comparison to the chow-fed group, further supports a role for the consumption of the combination of saturated fat and sugar water. It should be noted, however, that in contrast to earlier studies, in which we showed equal fat mass and caloric intake over the first week of exposure to a fcHF and a fcHFHS diet for one week (la Fleur et al 2010(la Fleur et al , 2011, we here observed higher caloric intake and higher total fat mass after one week on the fcHFHS diet group compared to the fcHF and the fcHS diet. We therefore cannot exclude that the rapid development of peripheral insulin resistance in the animals on a fcHFHS diet was an indirect, that is, via increased adipose mass due to increased overall intake, and not a direct effect of the fat and sugar combination of the diet.…”

“…In line with this, we observed basal hyperinsulinemia, concomitant with normal glucose tolerance and basal euglycemia in rats after 4 weeks on a fcHS diet (la Fleur et al 2011).…”

“…These data suggest that the nature of the palatable component might play a role in site-specific development of insulin resistance, whereby it seems that intake of fat is more important as opposed to sugar in the induction of hepatic insulin resistance. Furthermore, the glucose intolerance reported previously in fcHFHS-fed rats (la Fleur et al 2011) is most likely mediated, in part, by peripheral insulin resistance.…”

“…We therefore cannot exclude that the rapid development of peripheral insulin resistance in the animals on a fcHFHS diet was an indirect, that is, via increased adipose mass due to increased overall intake, and not a direct effect of the fat and sugar combination of the diet. However, the earlier shown impaired glucose tolerance in the fcHFHS-fed compared to the fcHF-fed rats despite similar 232:1 adiposity and overall intake (la Fleur et al 2011) suggests a direct effect of diet composition on insulin sensitivity independent of fat mass.…”

“…Interestingly, rats that consume a free-choice high-fat (fcHF) diet (access to a dish of pure fat in addition to chow and tap water ad libitum) accumulate fat mass and increase circulating free fatty acids (FFA) similar to rats on a fcHFHS diet, but do not develop glucose intolerance (la Fleur et al 2011). In addition, rats on a free-choice high-sugar (fcHS) diet (access to a 30% sugar solution in addition to chow and tap water ad libitum) consume more sugar water than rats on a fcHFHS diet, but do not accumulate fat mass, increase circulating FFA or become glucose intolerant (la Fleur et al 2011), suggesting that dietary composition in a hypercaloric setting is an independent determinant of glucose metabolism and body composition. The shortterm fcHFHS diet-induced glucose intolerance is not accompanied by an altered insulin response to an i.v.…”