Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men

Highlights

• If fructose influences gut–pancreas axis in obese non-diabetic males remains unknown.

• The effect of 12 week daily intake of 75 g of fructose to OGTT and mixed meal responses was analyzed.

• Daily fructose does not impair glucose tolerance or gut incretin response.

• Weight or liver fat gain during fructose is not associated with adverse glucose metabolism.

Abstract

Background and aims

Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown.

Methods and results

As many as 66 obese (BMI 26–40 kg/m²) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049).

Conclusion

In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.

Introduction

An increase in the prevalence in obesity and diabetes closely parallels the dramatic rise in sugar, especially fructose, intake due to consumption of sugar-sweetened beverages (SSBs) that accounts for nearly one-half of all added sugar intake in the U.S. [1]. Nowadays, fructose is a major sweetener in Western diets [2]. In the U.S., 50% of population consumes SSBs daily, and 25% obtains at least 200 kcal from these beverages [1].

The relationship between SSB and cardiometabolic diseases seen in epidemiological studies reflects potential combined effects of fructose and glucose or unique effects of fructose alone. The current data suggest a causative relationship between the intake of sweeteners, particularly fructose, and the increased prevalence of non-alcoholic fatty liver disease and dyslipidemia [1], [3], [4], especially postprandial plasma triglycerides (TG) [5].

Whether fructose consumption directly causes insulin resistance is much debated, and despite epidemiological evidence suggesting a link, data from intervention studies are inconsistent [4], [6], [7], [8], [9], [10], [11], [12], [13]. However, most studies included relatively small numbers of participants, a short intervention period or used only fasting insulin as a marker for insulin sensitivity. A 3-week consumption of fructose in 9 normal-weight young males impaired insulin sensitivity, measured as suppression of hepatic glucose production during a clamp, but did not change fasting insulin or glucose levels [13]. Insulin sensitivity, assessed from fasting insulin levels and deuterated glucose disposal, decreased after a 10-week fructose consumption in overweight/obese humans [12]. Studies assessing the effect of hypercaloric fructose consumption with respect to both liver fat and insulin resistance have mostly reported no change in insulin sensitivity, with varying effects on liver fat [6], [7], [8], [9], [10]. One study with 6–7 days intervention reported worsened insulin resistance together with increased liver fat [11].

Gut incretins, mainly glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), mediate the insulinotropic response to intraluminal nutrients [14]. Defects in either secretion or insulinotropic actions of GLP-1 and GIP are early signs of acquired insulin resistance characterizing the metabolic syndrome [5], [16]. Data on whether a single dose of fructose stimulates GLP-1 secretion in humans are inconsistent [17], [18], [19], whereas GIP secretion remains unaffected [17], [18], [19]. However, no data exists on the effect of longer fructose intervention on GLP-1 and GIP responses to nutritional stimuli.

Here, we test the hypothesis whether worsening of glycemic control induced by fructose consumption (75 g/day for 12 weeks served as a lemonade together with habitual ad libitum diet) may involve a gut incretin-dependent mechanism. Therefore, we studied the responses of GLP-1 and GIP in the fasting state and following a standard oral glucose tolerance test (OGTT) and the more physiological mixed meal test before and after fructose intervention in overweight male subjects who have high risk for future diabetes.