Abstract
Insulin resistance is associated with high circulating level of complement factor C3. Animal studies suggest that improper complement activation mediates high-fat-diet-induced insulin resistance. Individuals born with low birth weight (LBW) are at increased risk of developing insulin resistance. We hypothesized that high-fat overfeeding (HFO) increase circulating C3 and induce complement activation in a birth weight differential manner. Twenty LBW and 26 normal birth weight (NBW) young men were studied using a randomised crossover design. Insulin resistance was measured after a control-diet and after 5-days HFO by a hyperinsulinemic-euglycemic-clamp. Circulating C4, C3, ficolins, mannose-binding-lectin, complement activation products C3bc, terminal complement complex (TCC) and complement activation capacity were determined using turbidimetry and ELISA. HFO induced peripheral insulin resistance in LBW individuals only, while both groups had the same degree of hepatic insulin resistance after HFO. Viewing all individuals circulating levels of C4, C3, C3bc, TCC and complement activation capacity decreased paradoxically along the development of insulin resistance after HFO (P = 0.0015, P < 0.0001, P = 0.01, P < 0.0001, P = 0.0002, P < 0.0001, P = 0.0006). Birth weight did not influence these results. This might reflect a hitherto unrecognized down-regulatory mechanism of the complement system. More human studies are needed to understand the underlying physiology and the potential consequences of these findings.
Highlights
Affecting more than 170 million people worldwide, diabetes constitutes a major threat to human health across the world[1], with type 2 diabetes (T2D) accounting for more than 90% of all cases[2]
In order to examine if the complement dampening effect of high-fat overfeeding (HFO) was transient or more profound we found, in the 24 individuals who received the control diet first followed by the HFO diet 6–8 weeks after, that C4, C3 and terminal complement complex (TCC) decreased significantly after HFO (p = 0.0004, p < 0.0001 and p = 0.0008, respectively) (Fig. 2A,C and G), as did the functional capacity of the classical, alternative and lectin pathway (P = 0.0004, P < 0.0001 and P = 0.0027 respectively) (Fig. 3A,C,E)
In this study we aimed to investigate whether insulin resistance induced by a high-fat diet might influence the complement system, and circulating C3 level and complement activation
Summary
Affecting more than 170 million people worldwide, diabetes constitutes a major threat to human health across the world[1], with type 2 diabetes (T2D) accounting for more than 90% of all cases[2]. Subclinical inflammation and improper immune activation may mediate or influence the impact of a high-fat diet on the development of insulin resistance[8]. The complement system consists of tree distinct pathways of proteolytic cascades, namely the classical, alternative and lectin pathway These pathways generate C3 convertases efficiently cleaving C3 into C3a and C3b11. Several animal studies suggest that improper complement activation mediates high-fat-diet-induced insulin resistance through the action of www.nature.com/scientificreports/. In this study we hypothesized that high-fat overfeeding would increase C3 and induce complement activation in a potential different manner in people with and without LBW. We investigated circulating levels of C3 and the complement activation products C3bc and TCC after a control diet and after short term high-fat overfeeding in a group of healthy young men with either NBW or LBW. We aimed to explore whether the association between C3 and insulin resistance may be due to an association to hepatic or peripheral insulin resistance
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