In total, 24 studies investigating the effects of rye products in the postprandial or extended postprandial phase were found (Supplementary Table 1). Most of the studies followed a design with a breakfast meal containing a rye product or control product served after an overnight fast. Venous or capillary blood was collected at regular intervals (every 7.5–30 min) from right before the breakfast was served and for the following 3–4.5 h. Three studies covered a shorter period of only 2 h (38–40), while two studies extended over 6 and 7.8 h and included a standardized lunch in addition to the breakfast meal (41, 42). Most of the studies consisted of more than one rye product and/or more than one non-rye product (control), and thereby consisted of more than one pairwise comparison between a rye product and a control product.

From the 24 studies included in Supplementary Table 1, 72 pairwise comparisons could be extracted, and a descriptive summary of the pairs is presented in Table 1 and Figure 1. Almost all the control products were wheat based, while a few studies included barley and oat products. Most of the tested products were soft breads and the remaining could be categorized as crisp bread, cold cereal (defined as breakfast type cereals, typically eaten cold with milk, or yogurt) and porridge. The majority of the pairwise comparisons were made between the same kind of product (e.g., soft rye bread vs. soft wheat bread). However, when evaluating the processing of the cereals used in the products, most of the control products were refined endosperm-based products, whereas most of the rye products were coarser products made with whole grain rye flour or rye kernels. A large proportion of the control breads were yeast fermented breads, whereas the rye breads were a mixture of yeast and sourdough fermented breads, as well as a few unfermented breads. It should be noted that not all studies clearly report the method of fermentation of the investigated products (Table 1). Only 21 out of 72 pairwise comparisons were done between products of similar processing (e.g., endosperm wheat flour product vs. endosperm rye flour product), whereas most studies compared effects between endosperm wheat products and whole grain rye products. While rye generally has a higher dietary fiber content than other cereals (18, 43), the difference in processing has also contributed to the difference in fiber content between the rye products and the control products in the pairwise comparisons (Figure 1). The difference in available carbohydrate was low since most of the studies were standardized with regard to available carbohydrate content of the test meals. The serving size of rye products was often higher than the control product to obtain the same amount of available carbohydrate. The rye content of the rye products tested in the different studies are generally high (50–100% of cereal ingredients), except for the four bran based products, which were wheat based breads with 35% added rye bran (39, 44). Due to the higher fiber content of bran, compared to other cereal fractions, these bran-based rye breads have fiber content in similar range as the other rye-based breads (12–19 g/portion), despite the lower rye content.

While many studies investigating the acute postprandial effect of rye consumption have been conducted and in general show positive effects on postprandial glucose and insulin responses, only a few randomized intervention studies have investigated the effect of habitual rye consumption on postprandial glycemic control. Five studies investigating the effect of habitual rye consumption on markers of glycemic control were identified and are shown in Table 3. These studies consist of four randomized cross-over studies with a duration of 4–8 weeks (27, 52–54), as well as a 12-week randomized parallel study (55). The studies all included an intervention arm based on rye products, whereas the products included in the control arm(s) vary between the studies, but typically contained wheat products. The result from these studies show mixed results, with some studies showing a positive effect of rye consumption (52, 55), whereas others show no or negative effect (27, 54). Lappi et al. found a positive effect of whole grain rye bread on postprandial insulin response after 4 weeks of intervention, compared to 4 weeks intervention with refined wheat bread, whereas no such effect was found after 4 weeks of intervention with refined wheat bread with added rye bran (52). No difference in glucose response was found between either of the arms, indicating a pattern in agreement with the rye factor phenomenon. The lack of a positive effect of the rye bran-based intervention arm is in line with observations from postprandial studies, where similar types of rye bran bread did not lower postprandial insulin or glucose response and could indicate that the fiber content is not the sole explanation of the positive effects of rye consumption. However, McIntosh et al compared high fiber rye products to low fiber wheat products, as well as to high fiber wheat products, in a three armed 4-week intervention study, and found a positive effect of both high fiber rye and high fiber wheat, compared to refined wheat, but no difference between the two high fiber arms (53). On a similar note, Eriksen et al. found no difference in an oral glucose tolerance test after 4 and 8 weeks of consumption of whole grain rye products or whole grain wheat products matched for fiber content, indicating no difference between the sources of cereals under conditions where the fiber content of the two intervention diets were matched (27). On the other hand, Laaksonen et al. found reductions in insulinogenic index and insulin disposition index in an oral glucose tolerance test following a 12-week intervention with rye products and pasta, compared to 12-week intervention with oat, wheat and potato based products with a similar fiber content (55). However, there were no differences in fasting insulin and glucose, as well as AUC_{0–120 min} of glucose and insulin in the oral glucose tolerance test (55). Furthermore, it should be noted that the products included in the intervention arms included pasta and potatoes in addition to several different breads, making it hard to pin the results exclusively to the rye products (55).

In summary, there is no consistent evidence supporting a positive effect of habitual rye consumption on postprandial glycemic control, despite the predominantly positive effect found in acute meal studies. However, it should be mentioned that most of these studies evaluate the effect of the intervention on oral glucose tolerance, which may not be directly comparable to a meal tolerance test such as the ones typically used in the acute meal studies. Furthermore, the relatively large variations in study duration, outcomes assessed, and intervention products used makes it difficult to draw firm conclusions and further studies are needed to understand the potential link between the positive effects from acute meal studies and the long-term associations with improvements in glycemic control and reduced risk of type-2 diabetes.

Several mechanisms behind the rye factor phenomenon have been suggested and discussed (33). One suggested mechanism is related to structural differences in the cereal products resulting in slower glucose uptake in the gastrointestinal tract following consumption of a rye-based cereal product, compared to a non-rye control product (54, 56). If glucose uptake is slower, less insulin would be needed to maintain a similar concentration of glucose in the blood and therefore the insulin secretion is lower following consumption of the rye-based product, while the glucose response is similar to the control product. This hypothesis was tested by Östman et al. who studied the glucose kinetics using a dual tracer technique, as well as glucose and insulin response, to a rye bread and a wheat bread in a dual isotope labeling study (57). They found that the rye factor phenomenon was related to slower uptake of glucose in the intestine but not to altered disappearance or clearance of glucose in the blood stream.

Furthermore, high fiber cereals have been shown to increase the fecal energy excretion, through binding of nutrients from the food and reduce the absorption (58). Therefore, it could be theorized, that even though the studies match the rye and control products in terms of available carbohydrate, a larger amount of the available carbohydrate will be bound to the dietary fiber matrix in the fiber-rich rye products, compared to the control products which typically has a lower fiber content, and therefore the amount of carbohydrate available for absorption in the intestine will in reality be lower for rye foods, despite similar content. This could then lead to a slower and/or reduced intestinal absorption of glucose and subsequent reduced insulin secretion.

Different fermentation methods affect the structure of bread, which could in turn be thought to influence the metabolic response to bread consumption (59, 60). Two studies have tested the effects of unfermented rye crisp bread and sourdough or yeast fermented rye crisp bread on postprandial glucose and insulin response. They found lower postprandial insulin response following consumption of the unfermented crisp bread and the authors suggest that this could be due to structural differences in the unfermented breads, compared to the fermented breads (46, 47). A recent study showed that increasing the sourdough content in rye bread affected the structure of the bread and that bread with higher sourdough content resembled refined wheat bread more than a bread with lower sourdough content (61). One could hypothesize that this would lead to higher postprandial glucose and insulin response, but this remains to be tested in vivo. Additional studies investigating the effect of different fermentation methods on structural properties of bread is needed in order to fully understand the effect of fermentation on structure and potentially link it to the physiological response in vivo.

Branched chain amino acids (BCAA) have been shown to induce insulin secretion (62) and it has been speculated whether the amino acid composition and content of cereal products may influence the postprandial response (46). Generally, the content of amino acids, including BCAA, seem to be higher in the bran faction of the cereal, compared to whole grain flour and sifted flour (63), which could potentially contribute to the lack of a positive effect of bran based rye breads on postprandial insulin and glucose. However, the amino acid content is also highly affected by baking and fermentation, as well as cultivation, why more research is needed in order to understand the potential effect of cereal amino acids on postprandial response (63).

Rye contains several different bioactive compounds that have been suggested to have positive effects on various health outcomes, such as glycemic control and insulin sensitivity (33). Lignans and alkylresorcinols have been shown in in vitro and animal studies to improve insulin sensitivity (64, 65). An association between alkylresorcinols and insulin sensitivity has been confirmed in human studies (29, 66), but since alkylresorcinols may just be a marker of whole grain rye and wheat intake, it is difficult to distinguish between the effect of the alkylresorcinols and other components of whole grain products that could influence insulin sensitivity (67). Human studies on lignans and health has primarily been focused on cancer, due to the potential mild estrogenic effects of certain lignan metabolites (68). The few studies that have investigated the potential link between lignan intake and outcomes related to glycemic control and type-2 diabetes have found conflicting results (69) and as with alkylresorcinols it is difficult to distinguish between the effect of lignans and the effect of other potentially beneficial components of rye. Furthermore, it should be noted that lignans are found in relatively high amounts in other foods, such as flaxseeds, and the associations found in observational studies is not necessarily reflecting an association with lignans from rye (70).

If the mechanism behind the rye factor is mainly related to fiber content and structure, a rye factor phenomenon could likely be obtained with other cereals than rye. Eelderink et al. used a similar methodology as Östman et al. to examine the postprandial response to two wheat based breads with similar ingredients, but different structure (a standard sliced loaf bread and a flat bread; 57, 71). While glucose response was similar between the breads, insulin response was lower for the flat bread, compared to the loaf bread, and glucose kinetics revealed a slower uptake of glucose in the intestine from the flat bread, which likely explains the lower insulin response. In a similar study, comparing two different loaf type wheat breads with different structure and fiber content, Eelderink et al. found similar, but less pronounced results (72). Goletzke et al. found that a whole meal spelt bread had similar effects as two rye based breads, compared to a low fiber soft wheat pretzel (38). Liljeberg et al. found lowering of insulin, without affecting glucose, when comparing barley kernel based breads and a rye kernel based bread with a wheat kernel based bread (73). Together, these findings suggest that the rye factor phenomenon is not restricted to rye-based products. However, rye and barley have higher contents of soluble fiber than wheat, which will likely affect the structure and digestion of the cereal products and may explain the similarities in the physiological response. Bran has more insoluble fiber, and less soluble fiber, than endosperm and whole grain flour which may explain the lack of a beneficial effect of bran-based rye breads on postprandial insulin and glucose (39, 44).

In summary, limited evidence for the underlying mechanism behind the rye factor exist, but it appears that structural properties, such as particle size, viscosity, and fiber matrix, are likely the major determinants for the postprandial response to consumption of cereal products.

Amongst the studies included in this review there is a large variation in the methodology used to evaluate the postprandial response to the tested products. Some studies report the results of repeated measures models, some report AUC or iAUC over time periods varying between 2 and 5 h and some used other measures, such as peak values, glycemic index and insulin disposition index. This makes it impossible to directly compare the effect size between different studies and give an overall estimate on the magnitude of the effect across studies. While postprandial glucose response has been shown to correlate with glycated hemoglobin, which is a stronger predictor of diabetes risk, little is known about the long term implications of postprandial insulin response (74). Some studies have indicated an association between postprandial insulin response and risk of metabolic disease (75, 76), however, more evidence is needed in order to evaluate the implications of reductions in postprandial insulin response on long term disease risk.

Our understanding of the mechanism of action behind the effect of different cereals on postprandial glucose and insulin response remains suggestive, as only few studies include more mechanistic outcome measures such as measures of glucose kinetics using tracer techniques. Studies by Eelderink et al. and Östman et al. shed some light on a potential underlying mechanism by incorporating tracer-techniques, but more studies are needed to draw general conclusions (57, 71, 72).

The degree of characterization and the reporting of compositional information on products vary between studies and makes it hard to make comparisons across studies. Generally, more detailed characterization beyond nutritional values, is needed to further elucidate the effects of rye products on glycemic control as well as the underlying mechanisms. Furthermore, many studies compare rye products with a relatively high fiber content to wheat-based products with a relatively low fiber content, which makes it difficult to distinguish between the effect of fiber content and other factors, such as cereal source. However, it is important to keep in mind that the different cereals have a different fiber content and composition, even in their native form (18), why there will be differences in the fiber content, even when comparing a 100% whole grain rye product to a 100% whole grain wheat product – which underlines that fiber content and composition may explain part of the rye factor phenomenon. Moreover, one should consider the effect of different processing techniques, e.g., a milled whole grain rye flour compared with rolled whole grain rye flakes which may have very similar fiber content and composition, but at the same time express vastly different structural properties, which may in turn affect the physiological response (77).

Method of fermentation has been shown to influence the structure of bread, which could in turn influence the physiological response to consumption of the breads. However, this is often clouded by the fact that sourdough fermented rye breads are often compared to yeast fermented wheat breads, making it difficult to disentangle the effect of cereal source from the method of fermentation. From an applicational point of view it is sensible to test a yeast fermented wheat bread with a sourdough fermented rye bread, as this is the typical types of bread available on the market and consumed by consumers. However, from a mechanistic point of view studies investigating different combinations of cereal sources and methods of fermentation are needed in order to understand the underlying mechanisms and determinates for postprandial response.