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Whole grain foods and the prevention of type 2 diabetes mellitus Priebe-Geyersberger, G.abriele Marion
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Whole grain foods
and the prevention of type 2 diabetes mellitus
Marion Priebe-Geyersberger
Design and Lay-out LINE UP boek en media bv, Groningen Cover illustration Reinhold Geyersberger
isbn 978 90 367 4096 8
©2009 Copyright M.G. Priebe
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the author.
RIJKSUNIVERSITEIT GRONINGEN
Whole grain foods and
the prevention of type 2 diabetes mellitus
Proefschrift
ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen
op gezag van de
Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op
woensdag 16 december 2009 om 14.45 uur
door
Gabriele Marion Priebe-Geyersberger geboren op 29 juni 1956 te Nürnberg, Duitsland
Promotor: Prof. dr. R. J. Vonk
Beoordelingscommissie: Prof. dr. J. J. van Binsbergen Prof. dr. R. P. Stolk
Prof. dr. B. H. R. Wolffenbuttel
isbn: 978-90-367-4096-8
To Hermann
Paranimfen: Desiree Weening Marianne Schepers
Front cover
Rectangles from left to right:
Wheat starch granules stained with iodine (Kiselov Yuri, Wikimedia commons)
•
Structural formula of ferulic acid, as one example of the bioactive compounds in
•
whole grain
Cereal fiber: Arabinoxylan and beta-glucans in aleurone cell walls from wheat grain.
•
(reprinted from: Luc Saulnier et al, Wheat arabinoxylans: Exploiting variation in amount and composition to develop enhanced varieties, Journal of Cereal Science 46 (2007) p. 261–281 with permission from Elsevier)
Contents
Summary 9
Introduction 11
Scope of the thesis 16
Results and discussion 21
References 29
Appendix
1
Whole grain foods for the prevention of type 2 diabetes mellitus 33 Appendix
2
Starchy foods and prevention of type 2 diabetes mellitus – a systematic
review exploring the protective mechanisms 75
Appendix
3
Rate of intestinal glucose absorption is correlated with GIP plasma
concentrations in healthy men 121
Appendix
4
In vivo digestive starch charachteristics and postprandial glucose kinetics
of wholemeal wheat bread 141
Appendix
5
Low dose of acarbose dos not delay digestion of starch but reduces its
bioavailability 157
Appendix
6
Factors related to colonic fermentation of non-digestible carbohydrates of a previous evening meal increase tissue glucose uptake and moderate glucose-
associated inflammation 173
Appendix
7
Type of indigestible carbohydrate affects plasma and urine short chain
fatty acid profiles in healthy volunteers 197
Samenvatting 221
Acknowledgements 225
Curriculum vitae 233
List of publications 234
Abbreviations 236
Summary
Preventive measures are needed to hold the rapid increase in prevalence of type 2 diabetes mellitus (t2dm). Changes in life-style related factors, such as decreased physical activity and changes in dietary habits have been shown to play an important role in this rapid increase. A diet increasing the risk of development of t2dm has been defined as being high in saturated fat and energy-dense foods as well as low in fruit and vegetables. Contributing effects from starchy foods – an important component of the diet worldwide – however, have not been established well.
Starchy foods are derived mainly from tubers and cereal grains. Cereal grains either undergo a refining process (refined grain foods) or are used entirely (whole grain foods) either milled or intact. In refined-grain products, the bran and germ of the grain, which contain the major amount of micronutrients, phytochemicals and dietary fiber, have been removed and only the starchy endosperm is used.
Over the last decades, the decrease of consumption of whole grain foods occurred simultaneously with the increase of the prevalence of chronic diseases which has lead to the hypothesis that replacing whole grain foods with refined grain foods contributes to the development of t2dm.
Therefore, the first aim of this thesis was to summarize the current evidence for a protective effect of whole grain foods on the development of t2dm. In a Cochrane systematic review we have summarized the results of all prospective cohort studies conducted until now and found that the risk of the development of t2dm consistently lower was with a high intake of whole grain foods (27–30 %) or cereal fiber (28–37 %).
There are several hypotheses as to how whole grain foods might prevent t2dm.
Firstly, consumption of whole grain foods as compared to that of refined grain foods can result in a lower postprandial blood glucose response (glycemia). In view of the proposed negative effects of high glycemia on insulin sensitivity and pancreatic β-cell function, preventing these high concentrations is considered to be beneficial. Secondly, whole grain foods are rich in cereal fiber and – dependent on the processing – also rich in starch resistant to digestion in the small intestine. These non-digestible carbohydrates can be metabolised by the colonic microbiota into short-chain fatty acids (acetate, propionate and butyrate).
Possible beneficial effects could be related to these fermentation metabolites. In
addition, the presence of cereal fiber in whole grain products is associated with a high content of various micronutrients and phytochemicals of which many are potent antioxidants. Recently, oxidative stress has been related to the induction of insulin resistance. Hence, a greater capacity to cope with oxidative stress could theoretically be protective for the development of t2dm. Preventive effects of the consumption of whole grain foods could therefore be either mediated through reduced glycemia or through physiological effects associated with the presence of non-digestible carbohydrates.
The second aim of studies described in this thesis was thus to examine which food characteristics and related physiological mechanisms could be involved in the t2dm-preventive effect. In a systematic review we summarized and evaluated the results of all available experimental human trials that investigated the effect of the food characteristics in question on risk factors of t2dm. We found that the effect of reduced glycemia on risk factors of t2dm is not yet well studied. Non- digestible carbohydrates, however, have been demonstrated in several studies to have the potency to increase glucose tolerance and insulin sensitivity. In our study with healthy volunteers we showed that this effect could be mediated by short-chain fatty acids (e.g. butyrate) and propose that the relative amount of the individual short-chain fatty acids plays a more important role than their total concentrations. Further studies elucidating the underlying mechanism are needed.
In addition, we observed that whole grain foods consumed in the evening reduced the inflammatory response after an oral glucose load in the morning, which could either be related to short-chain fatty acid production or release of fiber-associated phytochemicals in the colon. This is an intriguing novel finding and opens new perspectives for research on the anti-inflammatory capacity of whole grain foods.
In conclusion, we found that whole grain foods can contribute to the prevention of t2dm. Intake of whole grain foods is already recommended as part of a healthy food pattern, but especially persons with a risk of developing t2dm could benefit from this advice. Early interventions are needed to prevent irreversible damage by unnoticed hyperglycemia, which underlines the need of development of early biomarkers of this disease. In addition, detection of subpopulations most susceptible to dietary interventions due to their genetic make-up would enable more efficient personalized dietary advice. Currently, the assortment of whole grain products is small and the consumer acceptance of whole grain foods is low. Our finding that non-digestible carbohydrates could mediate the protective effect are valuable for the development of cereal grain products with t2dm preventive potential (functional foods), which are more acceptable than traditional whole grain foods.
Introduction
Type 2 diabetes mellitus (t2dm) is the most prevalent form of diabetes worldwide. It is characterised by high fasting and high postprandial blood glucose concentrations (hyperglycemia). Chronic hyperglycemia can lead to serious damage to small blood vessels and arteries, leading to e.g. cardiovascular disease, kidney disease, eye complications and nerve damage. Even in intensively treated patients complications can still occur. The prevalence of t2dm is rapidly increasing worldwide and is thought to double in a time period of 30 years to reach 366 million in 2030 (1). Besides loss of quality of life for the individuals concerned, this poses enormous economic as well as social costs to societies, urging for preventive measures.
Pathogenesis of type 2 diabetes
In an early stage, target tissues are unable to respond to normal circulating concentrations of insulin (reduced insulin sensitivity or insulin resistance). As a consequence, the output of insulin from the pancreatic β-cells is increased (hyperinsulinaemia) to maintain normal blood glucose levels. In a later stage insulin secretion may decline as a result of β-cell dysfunction. This leads to “pre- diabetes”, which can precede overt t2dm for at least 4–7 years (2). The blood glucose concentrations in the pre-diabetes state are higher than normal but not high enough to be classified as t2dm. Persons with pre-diabetes are mostly not aware of their abnormal glycemia, because this does not cause symptoms. The prevalence of pre-diabetes in the adult population lies between 16 % and 52 % dependent on age (3). More than 30 % of persons with pre-diabetes will progress to t2dm within 5 years and they also have an increased risk of developing cardiovascular disease (3). At the moment that t2dm manifests itself with
symptoms and is diagnosed, pancreatic β-cells often have already been irreversibly damaged due to the toxic effect of hyperglycemia.
Normoglycemia → Pre-diabetes → Type 2 diabetes
Excessive weight gain and fat accumulation in de abdominal region are well established risk factors (4) of pre-diabetes and t2dm. The underlying mechanisms leading to insulin resistance and β-cell dysfunction are still subject of research.
Recently, obesity has been associated with a pro-inflammatory state in which plasma concentrations of inflammatory mediators such as tumour necrosis factor α (tnf-α), interleukin-6 (il 6) and C-reactive protein (crp) are increased. Low- grade inflammatory changes have been shown to precede t2dm by many years (5) and the potency of decreasing low-grade inflammation as strategy to prevent t2dm has been recently demonstrated with the anti-inflammatory drug salsalate (6;7).
Plasma non-esterified fatty acid (nefa) concentrations are also increased in obese persons, which leads to a reduction of glucose uptake in adipose tissue and skeletal muscles and in a stimulation of glucose output from the liver (8). In addition, it is proposed that insulin resistance is induced by increased levels of reactive oxygen species (ros) (9). Excessive macronutrient intake is one major factor associated with increased ros production. When the production of ros exceeds the capacity of the body to detoxify ros with its antioxidant defends system, oxidative
stress occurs. Various cell types have been observed to release inflammatory mediators (such as il 6 and tnf-α ) in response to elevated concentrations of glucose or nefa, which is proposed to be a consequence of oxidative stress (5;10).
Excess fat storage may also lead to alterations in the adipose tissue secretome.
Adipose tissue is known to secrete various signaling peptides – the adipokines – influencing among others insulin sensitivity, food intake and inflammation. Factors contributing to β-cell dysfunctions are toxic effects of high blood glucose and lipid concentrations as well as oxidative stress. A more detailed overview of factors implicated with the development of insulin resistance and β-cell dysfunction is given in Appendix 2.
Although genetic elements are involved in the development of pre-diabetes and t2dm, the rapid changes in incidence rates during the last decades suggest a particularly important role for life-style related factors. Besides physical activity, diet is thought to play a key role as a modifiable risk factor.
Diet as modifiable risk factor
Randomized controlled trials have shown that dietary interventions can influence the progression from pre-diabetes to t2dm (11;12). Recently, more attention is paid to differentiating between various types of the pre-diabetic state, as this may help to develop more individualized strategies for early prevention and treatment of t2dm. The three different types are isolated impaired glucose tolerance (i-igt),
isolated impaired fasting glycemia (i-ifg) or a combination of both (igt/ifg; (13)).
Definitions, underlying pathophysiology and factors influencing the development of these types are listed in Table 1.
Table 1 Main characteristic of different pre-diabetic types
Definition Pathophysiology Risk No effect of
Isolated impaired fasting glycemia (i-IFG)
Fasting plasma glucose values are above normal range but less than would qualify for T2dm
muscle insulin sensitivity unaltered Liver insulin sensitivity reduced Adipose tissue insulin sensitivity reduced
Increased by Smoking
•
Family history of
•
diabetes male sex
•
Low birth weight
•
Physical inactivity Low dietary quality Short adult stature
Isolated impaired glucose tolerance (i-IGT)
Plasma glucose values 2 h after a 75-g oral glucose tolerance test are above normal range but less than would qualify for T2dm
muscle insulin sensitivity reduced Liver insulin sensitivity unaltered Adipose tissue insulin sensitivity reduced
Increased by Physical
•
inactivity Low dietary
• quality Short adult
• stature
Low birth weight
•
decreased by male sex
•
Smoking Family history of diabetes
IFG/IGT A combination of the 2 types above
muscle insulin sensitivity reduced Liver insulin sensitivity reduced Adipose tissue insulin sensitivity – not studied yet
Smoking
Family history of diabetes
Low dietary quality Gender
Adapted from Faerch 2009 (13)
From the three pre-diabetes types especially persons with i-igt were identified to be susceptible to diet. In a 5-year intervention study it was shown that persons with normoglycemia, who later developed i-igt, consumed a diet of lower quality than those who developed i-ifg and ifg/igt (14). Another study showed that a
dietary pattern characterized by high fat and low vegetable and fruit intake affects 2-hour postprandial but not fasting glucose concentrations (15).
These data emphasise that dietary changes are capable of influencing development of pre-diabetes as well as progression to t2dm. They also indicate that a certain subpopulation would benefit more from improving dietary quality than others. Furthermore, substantial effort is currently undertaken to find differences in the genetic make-up of individuals which can predict the success or failure of specific dietary interventions. This can eventually lead to the development of personalized dietary advice for persons at risk for developing t2dm, which has the potential to be much more efficient than dietary advice for the general population. To be able to develop personalized dietary advices, information is also needed about the dietary factors that modify the risk of the development of t2dm.
Whole grain foods as part of a protective food pattern
A diet increasing the risk of development of t2dm has been defined as being high in saturated fat and energy-dense foods as well as low in fruit and vegetables. (4) Contributing effects from starchy foods – an important component of the diet worldwide – however, have not been established well. Starchy foods are derived mainly from cereal grains which either undergo a refining process (refined grain foods) or are used entirely (whole grain foods). Food products derived from cereals as wheat, rice, corn, rye, oat, and barley constitute a major part of the daily diet in many countries (16). In refined-grain products, the bran and germ of the grain, which contain the major amount
of micronutrients, phytochemicals and dietary fibre (non-digestible carbohydrates and lignin), have been removed and only the starchy endosperm (ca. 80 % of the whole grain) is used.
Whole grain foods contain either intact, flaked or broken grain kernels, coarsely ground kernels or flour that is made from whole grains. Over the last decades, the decrease of the consumption of whole grain foods occurred
simultaneously with the increase of the prevalence of chronic disease which has
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lead to the hypothesis that replacing whole grain foods with refined grain foods contributes to the development of t2dm (17;18). There are several hypotheses as to how whole grain foods might prevent t2dm. Consumption of whole grain foods as compared to that of refined grain foods results in a lower postprandial blood glucose and insulin response (19). Especially foods that contain intact, broken or coarsely ground kernels or viscous soluble fibre have been shown to have a low glycemic response and low glycemic index (gi; measure of the effect of carbohydrates on blood glucose concentration). In view of the proposed aggravating effects of high postprandial glucose and insulin concentrations on insulin sensitivity and β-cell dysfunction, preventing these high concentrations is considered to be beneficial (20;21). On the other hand, whole grain foods are rich in cereal fiber and – dependent on the processing – also rich in starch resistant to digestion in the small intestine (resistant starch). The effect of the presence of these non-digestible carbohydrates on postprandial blood glucose is expected to be little.
Possible beneficial effects of the non-digestible carbohydrates could thus be related to fermentation metabolites. Non-digestible carbohydrates can be metabolised by the colonic microbiota into the short-chain fatty acids (scfa) acetate, propionate and butyrate. Recently it became clear that scfa not only play a role in the colonic environment, but can also exert effects on adipose tissue metabolism and secretome as well as on insulin sensitivity in peripheral tissue (22;23). In addition, the presence of cereal fiber in whole grain products is associated with a high content of various micronutrients and phytochemicals, which also can potentially influence metabolic processes related to the development of t2dm.
A great number of cereal fiber-associated micronutrients and phytochemicals are for example potent antioxidants. The high antioxidant potential of whole grain cereal products has been demonstrated in various in vitro studies (24–26) and is hypothesized to improve anti-oxidant status in vivo. In view of the relationship between increased oxidative stress and induction of insulin resistance, a greater capacity to cope with oxidative stress could be theoretically protective for the development of t2dm.
Thus, whole grain foods could have the potential to reduce the risk of t2dm.
Possible preventive effects could be either mediated through reduced glycemia or through physiological effects associated with the presence of non-digestible carbohydrates.
Scope of the thesis
A number of epidemiological studies have been conducted to investigate the effect of whole grain foods on the development of t2dm itself as well as on factors implicated with the pathogenesis of t2dm. To be able to give sound dietary recommendations and to develop personalized advice for individuals at risk, all the available evidence has to be analysed. It is also of great interest to identify food characteristics involved in a beneficial effect and to understand the underlying physiological mechanisms of this effect. Based on this information, cereal grain products with enhanced health potential (functional foods) can be developed, which might be more acceptable to consumers than traditional whole grain products. Also, processing of cereal grain can be optimized and guidance to grain breeding programs can be given.
Therefore, the first aim of this thesis was to summarize the current evidence for a protective effect of whole grain foods on the development of t2dm. The second aim was to examine which food characteristics and related physiological mechanisms could be involved in a potential preventive effect.
The following specific questions were addressed:
1 What is currently known from epidemiological studies about the effect of consumption of whole grain foods on the development of t2dm?
2 What is currently known from controlled intervention trials about the relationship between specific characteristics of whole grain foods and factors implicated with the development of t2dm?
3 What are underlying physiological mechanisms related to the beneficial effects of whole grain food characteristics, derived from mechanistic studies in healthy volunteers?
To answer these questions, the following studies have been conducted:
1 Evidence from epidemiological studies for a preventive effect on the development of type 2 diabetes mellitus
We performed a Cochrane systematic review to elucidate the effect of the consumption of whole grain foods on the development of t2dm by summarizing and evaluating the results from all available prospective cohort studies,
randomized controlled trials and controlled clinical trials. Cohort studies were included that assessed the intake of whole-grain foods or cereal fiber (as marker for whole grain food intake). Clinical trials were selected that compared diets rich in whole-grain foods with diets rich in refined-grain foods. Outcome measures were incidence of t2dm as well as incidence of risk factors for t2dm, including impaired glucose tolerance, insulin resistance and overweight. (Appendix 1)
2 Information from controlled intervention trials about the relationship between specific characteristics of whole grain foods and factors implicated with the development of T2dm
Until now, it is not clear whether the reduction of the glycemic response or physiological effects associated with the presence of non-digestible carbohydrates determine the possible preventive effect of whole grain foods on the development of t2dm. We conducted a systematic review to obtain information about the relative importance of these specific characteristics of whole grain foods on factors implicated with the pathogenesis of t2dm. Based on this, the possible underlying physiological mechanisms can be further explored. Controlled intervention trials in healthy adults or adults with one or more risk factors for developing t2dm were included in the review. Dietary interventions were included that examined the effect of low versus high gi food, low versus high content of cereal fiber or resistant starch and intake of whole grain food versus intake of refined grain food. Outcome measures were glucose tolerance, insulin sensitivity, body composition, β-cell function, plasma concentrations of non-esterified fatty acids, adipokines as well as markers of inflammation and oxidative stress. Interventions were excluded that measured direct postprandial effects. (Appendix 2)
3 Information from mechanistic studies in healthy volunteers about underlying physiological mechanisms of the beneficial effects of specific characteristics of whole grain foods
Beneficial effects of whole grain foods are related to lower postprandial glycemia and increased colonic fermentation of non-digestible carbohydrates. However, it is not clear how reduced plasma glucose concentrations and increased colonic fermentation contribute to the reduced risk of developing t2dm. Therefore, a number of experimental studies were conducted in our laboratory to examine this relationship.
3.1 Does the rate of digestion of starch influence plasma concentrations of incretin hormones?
Incretin hormones influence the postprandial glucose response by potentiating glucose-induced insulin secretion. The main incretin hormones are glucagon like peptide 1 (glp-1) and glucose-dependent insulinotropic polypeptide (gip). Both hormones affect glucose and fat metabolism in adipocytes and glp-1 influences gut motility and food intake. As intraluminal glucose is one of the triggering factors for these hormones, we hypothesized that the ability to stimulate secretion of these hormones is different between rapidly and slowly digestible starches.
The effect of glucose and two starchy foods, varying in their content of rapidly and slowly digestible starch, on plasma concentrations of incretin hormones was examined in healthy men (n = 7) in a cross-over design. We assessed the rate of intestinal glucose absorption by applying the dual isotope technique and investigated whether the concentrations of these hormones are related to the rate of intestinal glucose absorption. (Appendix 3)
3.2 Does in vitro analysis of the digestive characteristics of starch in whole meal bread predict in vivo digestibility?
The blood glucose and insulin concentrations after the consumption of starchy foods are thought to be mainly determined by the rate of digestion of starch in the small intestine. In vitro analyses are available that are considered to be suitable to predict this in vivo rate of digestion. However, the predictive value of in vitro analyses for in vivo digestibility has not been evaluated yet. Therefore, we determined the in vivo digestive characteristics of starch in whole meal bread in a cross-over study in healthy men (n = 4) by applying the dual isotope technique. In addition, we assessed postprandial glucose kinetics and compared them with those of glucose. In this way, we could examine to what extent the rate of digestion of starch determines the physiological response after consumption of the wholemeal bread. (Appendix 4)
3.3 Does application of a low dose of acarbose result in incomplete digestion of starch?
Acarbose inhibits enzymes that are needed to digest carbohydrates: pancreatic α-amylase and α-glucosidases present in the brush border of the small intestine.
It is applied in the treatment of postprandial hyperglycemia of diabetic patients in doses of 50–200 mg per meal. Its expected and intended mode of action is to
delay carbohydrate digestion and absorption. In addition, it has been shown that acarbose treatment can delay the development of t2dm in persons with impaired glucose tolerance (11). We investigated whether addition of a low dose of acarbose to rapidly digestible starch can change its digestive profile to that of a slowly digestible starch without increasing the starch flux into the colon. In a cross- over study, healthy men (n = 7) ingested corn pasta with and without addition of 12.5 mg of acarbose. The dual isotope technique was applied to measure the rate of appearance of starch derived glucose, reflecting intestinal starch digestion and glucose absorption. (Appendix 5)
3.4 In what way does an evening meal rich in non-digestible carbohydrates influence glycemia after a subsequent breakfast?
Evening meals rich in non-digestible carbohydrates have been shown to have the capacity to reduce postprandial glucose concentrations after a standard high glycemic index breakfast the next morning (27–29). This phenomenon is related to colonic fermentation of non-digestible carbohydrates. We compared the glucose kinetics during an 50 g oral glucose tolerance test in the morning following either a barley kernel evening meal (rich in non-digestible carbohydrates) or a white wheat bread evening meal in a cross-over study in healthy men (n = 10). We investigated whether a) the rate of appearance of food-derived glucose in the systemic
circulation, b) the glucose production in the liver or c) glucose uptake into tissue was the cause of the reduced postprandial glucose concentrations. In addition the plasma concentrations of insulin, nefa, pro-inflammatory cytokines (il 6, tnf-α), adiponectin and products of colonic fermentation of non-digestible carbohydrates (acetate, propionate and butyrate) were analysed. (Appendix 6)
3.5 Does the type of non-digestible carbohydrate influence the production of short-chain fatty acids?
In the previous study we have shown that factors related to colonic fermentation can influence peripheral insulin sensitivity. Possible mediators of this effect could be the short-chain fatty acids (scfa), which are produced from non-digestible carbohydrates in the colon. To be able to investigate the interaction between colonic scfa production and peripheral tissue it is necessary to obtain information about the extent to which fermentation derived scfa reach the systemic
circulation. Furthermore, as different scfa can exert different or even opposing effects, information is needed as to how different fermentable substrates affect
these scfa patterns. In this study, we analyzed the colonic fermentation process of
13C-labelled barley meals, prepared from barley grown under 13co2-atmosphere.
In a cross over study, healthy volunteers (n = 5) ingested intact barley kernels (high content of dietary fiber and resistant starch) and barley porridge (high content of dietary fiber only). New analytical methods were applied to determine low-level enrichment of 13C-scfa in human plasma and urine. (Appendix 7)
Results and discussion
1 Evidence from epidemiological studies for a preventive effect of whole grain foods on the development of type 2 diabetes mellitus
In our systematic review (Appendix 1) we found one randomised controlled trial and 11 prospective cohort studies that investigated the effect of consumption of whole grain foods on the development of t2dm. The prospective studies
consistently showed a reduced risk of a high intake of whole grain foods (27–30 %) or cereal fiber (28–37 %) on the development of t2dm. We concluded that the evidence from only prospective cohort trials is too weak to be able to draw a final conclusion about the preventive effect of whole grain foods on the development of t2dm. These studies strongly suggest the preventive effect of whole grain foods but can not prove that the high consumption of whole grain foods is the cause of the reduced risk. Properly designed long-term randomised controlled trials are needed to establish a causal relationship between intake of whole grain foods and the development of t2dm. To facilitate this, relevant intermediate endpoints or biomarkers for t2dm are needed and subgroups of the population at risk have to be identified that are most susceptible to dietary intervention. In addition, plausible biological mechanisms that explain the putative protective effect would strengthen the evidence obtained from the prospective studies. Information about underlying mechanisms can be derived from experimental studies investigating the effect of specific characteristics of whole grain foods and factors involved in the pathogenesis of t2dm.
2 The role of specific characteristics of whole grain foods and underlying physiological mechanisms in the possible T2dm-preventive effect
Beneficial effects of whole grain foods are related to lower postprandial glycemia and increased content of non-digestible carbohydrates. To further investigate the possible preventive effect of whole grain foods, we examined how reduced postprandial glycemia and increased consumption of non-digestible carbohydrates influence factors implicated with an increased risk of developing t2dm. In the following paragraphs the effects of both characteristics on glucose tolerance, insulin sensitivity and markers of inflammation will be addressed.
2.1 Effects related to reduced postprandial glycemia Effect on glucose tolerance and insulin sensitivity
In our systematic review concerning the underlying mechanisms (Appendix 2) we found 9 trials that investigated the effect of interventions (20 days – 4 months) with low versus high glycemic index (gi) foods. We included only trials in which the low and high gi diets had the same amount of fat, total carbohydrates as well as mono- and disaccharides. Therefore, the reduced glycemia after ingestion of the low gi foods could not be caused by a lower glycemic load but was due to the higher content of slowly digestible starch. Only 2 trials observed a beneficial effect of a low gi diet on whole body insulin sensitivity independent of a change in body weight. None of the trials reported improved hepatic insulin sensitivity.
Effect on inflammation
Recently, studies have shown that ingestion of high gi food can result in an increase in oxidative stress and inflammation markers in the postprandial phase (30–33). The relevance of this – if exerted chronically – is not clear and needs to be investigated in long term trials. So far, only one intervention trial aimed to examine the effect of a dietary intervention with low gi foods on tnf-α and did not find any effect (Appendix 2).
Effect on plasma concentrations of incretin hormones
We found that rapidly and slowly digestible carbohydrates differ considerably in their potency to stimulate secretion of incretin hormones. Slowly available carbohydrates induced a late postprandial glp-1 response. In view of the capacity of glp-1 to slow down gastric emptying rate (34), it could be speculated that elevated glp-1 concentrations at the time point of the intake of a subsequent meal could retard nutrient delivery to the small intestine. This could result in lower glucose concentrations after the subsequent meal. Furthermore, the rate of exogenous glucose appearance was strongly correlated with the plasma concentrations of gip. (Appendix 3) The physiological consequence of this phenomenon might be important because, in addition to its insulinotropic effect, gip plays an important role in nutrient uptake into adipocytes. The presence of functional gip receptors on adipose but not on liver tissue has been documented, which suggests that gip might play an important role in glucose uptake and fat accumulation in adipocytes. Accordingly, several studies in animal models have
shown that preventing gip signaling resulted in reduced fat mass (35;36). This mechanism could play a role in the beneficial effect of low gi diets on weight reduction, which, however, remains to be elucidated.
Issues related to studying the effect of reduced glycemia – Choice of endpoint parameter and study population
In the trials investigating the effect of low versus high gi diets on insulin sensitivity (is) no effect was found with analyses of hepatic is (homeostatic model assessment). Positive results were only observed after an insulin- and glucose challenge, which are methods to obtain information about whole-body is.
(Appendix 2) As postprandial hepatic glucose uptake accounts only for 30 % of the total glucose disposal, this could imply that a low gi diet selectively improves is in peripheral tissue (mainly muscle). Accordingly, results of other studies suggest that diets in general mainly affect peripheral insulin sensitivity (13). Therefore, to be able to draw a conclusion about the effects of low gi diets, more studies are needed that investigate whole-body or peripheral is. In addition, all but one trial were conducted in volunteers with normoglycemia. Thus, information about the effect of low gi diets on glucose tolerance or is in persons with impaired glucose tolerance are lacking.
– Differentiation between the effect of dietary fiber and reduced glycemia
In trials investigating the effect of low versus high gi diets the amount of dietary fiber was often increased in the low gi dietary intervention. (Appendix 2) This means that the observed effect can also be caused by the increased fiber consumption. If this is not recognized, the effects of different foods or diets can be misinterpreted, which also hinders exploration of the underlying mechanism of the observed beneficial effects. In future trials, the dietary fiber intake should be controlled, to be able to differentiate between the effects of reduced glycemia and that of non-digestible carbohydrates.
– Determination of slowly digestible starch content
For prediction of the in vivo digestibility of starch in food products in vitro
measurements are used. We showed (Appendix 4) that whole meal bread contains starch that is partly rapidly and partly slowly digestible in vivo. In vitro analysis, however, predicted a high content of rapidly and a low content of slowly digestible
starch. This implies that in vitro techniques not necessarily predict in vivo digestive characteristics of starch correctly. In addition we showed that the glucose and insulin response after whole meal bread consumption is not only determined by the digestive characteristics of the starch – as generally expected – but also by other components of bread.
– Consequences of slowing the rate of starch digestion
In persons with impaired glucose tolerance, slowing the rate of starch digestion with the α-glucosidase inhibitor acarbose, has been shown to delay the onset of t2dm. This beneficial effect is thought to be caused by the reduction of the postprandial glucose responses. However, slowing the rate of starch digestion can also lead to incomplete starch digestion and increased colonic fermentation of starch. We showed (Appendix 5) that even a low dose of acarbose (12.5 g per meal) resulted in incomplete digestion of starch. This implies that beneficial affects observed in intervention trials with acarbose can partly be ascribed to increased fermentation of starch.
2.2 Effects related to non-digestible carbohydrates Effect on glucose tolerance and insulin sensitivity
Four interventions with a moderately increased consumption of non-digestible carbohydrates consistently improved gt and is in persons with impaired glucose tolerance and hyperinsulinema. In 2 of 6 trials in healthy volunteers a beneficial effect of increased ingestion of non-digestible carbohydrates was found. In 3 of these studies addition of non-digestible carbohydrates to the meals did not affect postprandial glycemia. This suggests that not the reduced glucose response, but factors related to increased fermentation of indigestible carbohydrates are related to the beneficial effect. (Appendix 2) In addition,10 studies examined the effect of evening meals rich in non-digestible carbohydrates on glucose tolerance following a high gi breakfast. Certain (combinations of) non-digestible carbohydrates – when ingested as evening meal – increased the glucose tolerance after the high gi breakfast. This effect was independent of the gi of the evening meal. (Appendix 2)
We found that a barley kernel evening meal (rich in non-digestible
carbohydrates) increases tissue glucose uptake the next morning. (Appendix 6) The hepatic glucose production and the postprandial insulin response were the same, which indicates improved peripheral insulin sensitivity. Hydrogen in breath,
an indicator of colonic fermentation of indigestible carbohydrate was significantly increased in the morning after the barley kernel evening meal and so was the plasma concentration of butyrate. The results of our study thus indicate that food associated factors acutely can influence peripheral insulin sensitivity, even in healthy volunteers. They also suggest that butyrate, or butyrate associated factors, could be involved in this effect.
Effect on inflammation
Whole grain foods contain a high number of micronutrients and phytochemicals as compared to refined grain foods. They are released during the small intestinal digestion as well as during colonic fermentation and have the potency to
reduce oxidative stress and inflammation (25). Results of a limited number of animal studies using polyphenol rich cereal fractions or a whole grain diet offer some support for this hypothesis (25;37;38). To date only two intervention trials investigated the effect of the intake of whole grains or cereal fiber, rich in micronutrients and phytochemicals, on markers of inflammation. They did not observe decreased inflammation. However, lower il 6 concentrations were found in one study that examined the effect of an evening meal rich in non-digestible carbohydrates on inflammation markers the next morning. (Appendix 2)
Our own studies (Appendix 6) showed that the late rise of the pro-
inflammatory cytokines il 6 and tnf-α after a glucose load in the morning was moderated by the consumption of a barley kernel evening meal, rich in non- digestible carbohydrates. Previously, it had been shown that a high glucose or meal-induced inflammatory response could be prevented by concomitant intake of antioxidants (glutathione, vitamin C) (39;40) or antioxidant rich food (olive oil, red wine) (41;42). Thus, our finding suggests that not only concomitant intake of antioxidants but also so far unknown antioxidant or anti-inflammatory factors derived from a previous evening meal can moderate meal-associated inflammation. Potential mediators of this effect could be scfa or phytochemicals released during colonic fermentation of cereal fiber.
Issues related to studying the effect of non-digestible carbohydrates – Differentiation between the effect of products of colonic fermentation of
indigestible carbohydrates and phytochemicals released during colonic fermentation The beneficial effect of indigestible carbohydrates on glucose tolerance, insulin
sensitivity and inflammation markers could be mediated by two different
mechanisms. Firstly, colonic fermentation of increased amounts of resistant starch and cereal fiber leads to increased amounts of the fermentation products scfa.
These scfa could be responsible for mediating the observed beneficial effect.
Secondly, cereal fiber deliver an increased amount of phytochemicals to the colon, which can be released during the fermentation process. Also, these phytochemicals could be responsible for the beneficial effect. To be able to distinguish between both these mechanisms, results of trials using resistant starch, which is devoid of phytochemicals, are necessary. So far, two studies (22;43) investigated the effect of rs supplementation and reported improved is. This indicates an important role for colonic scfa, which needs further confirmation. Studies in our laboratory are ongoing to investigate the possible mechanisms involved. (Appendix 2)
– Effects of different types of non-digestible carbohydrates on production of short- chain fatty acids
From our review (Appendix 2) it became clear that certain (combinations of) non-digestible carbohydrates – when ingested as an evening meal – increased the glucose tolerance after the high gi breakfast, while other combinations did not. Furthermore, the production of scfa is implicated with increased glucose tolerance or insulin sensitivity and also with reduced inflammation markers (Appendix 2 and 6). In vitro analyses have shown that fermentation of different (combinations of) non-digestible carbohydrates results in different proportions of acetate, propionate and butyrate (44;45). Thus, we tested the hypothesis that different combinations of non-digestible carbohydrates result in different scfa profiles also in vivo. We applied a newly developed analytical technique that allowed us to evaluate scfa profiles after administration of different indigestible carbohydrates in humans. The results of this study showed that meals containing dietary fiber combined with resistant starch result in altered scfa profiles as compared to meals containing dietary fiber alone (Appendix 7). The underlying mechanism of this phenomenon is, however, not clear yet.
Future perspectives
The finding that ingestion of rapidly digestible starch is correlated with increased plasma gip concentrations is interesting with regard to the beneficial effect of low gi diets on weight reduction. Assessing plasma gip concentrations in low
versus high gi intervention trials could provide valuable information about this relationship.
The predictive value of in vivo digestibility of starch with in vitro methods needs further evaluation. Reliable prediction of the digestive starch characteristics is especially important for mechanistic studies examining the metabolic effects of slowly digestible starch as well as for the evaluation of food products developed to contain more slowly digestible starch.
Our study with an evening meal rich in non-digestible carbohydrates
demonstrated the potency of factors related to colonic fermentation to increase peripheral insulin sensitivity the next morning. There are strong indications that scfa are involved in this insulin sensitizing effect and we propose that the relative amount of the individual short-chain fatty acids plays a more important role than their total concentrations. The underlying molecular mechanisms of this effect need to be explored.
The capacity of an evening meal rich in non-digestible carbohydrates to moderate meal-associated inflammation the next morning is a novel finding.
Further studies should focus on identifying factors involved in this anti- inflammatory effect.
No conclusion could be drawn about the effect of reduced glycemia on insulin sensitivity. It seems necessary that a distinction is being made between outcome measures of hepatic and peripheral insulin sensitivity. The homeostatic model assessment (homa) is easily to apply because for that model only one fasting blood sample is needed. However, insulin sensitivity assessed with homa reflects hepatic insulin sensitivity and trials comparing low with high gi food interventions using this method have not found an effect. This may be not surprising as there are indications that diet mainly affects peripheral insulin sensitivity. Therefore, to be able to draw a conclusion about the efficacy of dietary interventions, methods should be used that reflect peripheral or at least whole body insulin sensitivity.
In view of the relevance of chronic low-grade inflammation for the
development of t2dm and the potency of cereal fiber-associated phytochemicals to reduce oxidative stress and inflammation in vitro, more dietary intervention trials should explore this relationship.
Concluding remarks
Taken together the results presented in this thesis suggest that consumption of whole grain foods can contribute to the prevention of type 2 diabetes. Currently, it seems that physiological effects associated with the presence of non-digestible carbohydrates play a more important role in this preventive effect than reduction of postprandial glycemia.
Intake of whole grain foods is already recommended as part of a healthy food pattern, but especially persons with a risk of developing t2dm could benefit from this advice. Early interventions are needed to prevent irreversible damage by unnoticed hyperglycemia, which underlines the need of development of early biomarkers of this disease. In addition, detection of subpopulations most susceptible to dietary interventions due to their genetic make-up would enable more efficient personalized dietary advice. Currently, the assortment of whole grain products is small and the consumer acceptance of whole grain foods is low.
Our finding that non-digestible carbohydrates could mediate the protective effect are valuable for the development of cereal grain products with t2dm preventive potential (functional foods), which are more acceptable than traditional whole grain foods.
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Appendix
1
Whole grain foods for the prevention of type 2 diabetes mellitus
Marion G. Priebe Jaap J. van Binsbergen Rien de Vos
Roel J. Vonk
Adapted from: Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: cd006061. doi: 10.1002/14651858.cd006061
Abstract Background
Diet as one aspect of lifestyle is thought to be one of the modifiable risk factors for the development of type 2 diabetes mellitus (t2dm). Information is needed as to which components of the diet could be protective for this disease.
Objectives
To asses the effect of whole-grain foods for the prevention of t2dm.
Search strategy
We searched central, medline, embase, cinahl and amed.
Selection criteria
We selected cohort studies with a minimum duration of five years that assessed the association between intake of whole-grain foods or cereal fiber and incidence of t2dm. Randomised controlled trials lasting at least six weeks were selected that assessed the effect of a diet rich in whole-grain foods compared to a diet rich in refined grain foods on t2dm and its major risk factors.
Data collection & analysis
Two reviewers independently selected the studies, assessed study quality and extracted data. Data of studies were not pooled because of methodological diversity.
Main results
One randomised controlled trial and 11 prospective cohort studies were identified.
The randomised controlled trial, which was of low methodological quality, reported the change in insulin sensitivity in 12 obese hyperinsulinaemic subjects after six week long interventions. Intake of whole grain foods resulted in a slight improvement of insulin sensitivity and no adverse effects. Patient satisfaction, health related quality of life, total mortality and morbidity was not reported.
Four of the 11 cohort studies measured cereal fiber intake, three studies whole grain intake and two studies both. Two studies measured the change in whole grain food intake and one of them also change in cereal fiber intake. The incidence of t2dm was assessed in nine studies and changes in weight gain in two studies. The
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prospective studies consistently showed a reduced risk for high intake of whole grain foods (27–30 %) or cereal fiber (28–37 %) on the development of t2dm.
Reviewers’ conclusions
The evidence from only prospective cohort trials is considered to be too weak to be able to draw a definite conclusion about the preventive effect of whole grain foods on the development of t2dm. Properly designed long-term randomised controlled trials are needed. To facilitate this, further mechanistic research should focus on finding a set of relevant intermediate endpoints for t2dm and on identifying genetic subgroups of the population at risk that are most susceptible to dietary intervention.
Background
Diabetes mellitus is a metabolic disorder resulting from a defect in insulin
secretion, insulin action, or both. A consequence of this is chronic hyperglycaemia (i.e. elevated levels of plasma glucose) with disturbances of carbohydrate, fat and protein metabolism. Long-term complications of diabetes mellitus include retinopathy, nephropathy and neuropathy. The risk of cardiovascular disease is increased. For a detailed overview of diabetes mellitus, please see under ‘Additional information’ in the information on the Metabolic and Endocrine Disorders Group on The Cochrane Library (see ‘About the Cochrane Collaboration’, ‘Collaborative review groups-crgs’). For an explanation of methodological terms, see the main Glossary on The Cochrane Library.”
Type 2 diabetes
Type 2 diabetes is the most prevalent form of diabetes worldwide and develops as a consequence of two defects. In an early stage target tissues are unable to respond to normal circulating concentrations of insulin (insulin resistance). As a consequence the output of insulin from the pancreatic beta-cells is increased (hyperinsulinaemia) to maintain normal blood glucose levels. In a later stage insulin secretion may decline as a result of beta-cell dysfunction. This leads to impaired glucose tolerance and/or impaired fasting glycaemia (glucose values above the normal range but below those defined as diagnostic of diabetes) which is associated with an increased risk of type 2 diabetes (Unwin 2002, who 1999).
Excessive weight gain and central obesity are other well established risk factors for the development of type 2 diabetes (fao/who 2003). The incidence of obesity and
type 2 diabetes are increasing rapidly worldwide and pose enormous economic as well as social costs to societies, urging for preventive measures. Although genetic elements are involved in the pathogenesis of type 2 diabetes, the rapid changes in incidence rates suggest a particularly important role for environmental factors.
Besides physical activity, diet is thought to play a key role as a modifiable risk factor. Characteristics of a diet favouring the development of obesity and type 2 diabetes are currently defined as high in saturated fat and energy-dense foods as well as low in fruit and vegetables (fao/who 2003). The contribution of the type of starchy food – an important component of the diet worldwide – however, has not been established well. Starchy foods are derived mainly from cereal grains which undergo a refining process or will be used entirely (whole grain foods).
Whole grain foods
Food products derived from cereals as wheat, rice, corn, rye, oat, and barley constitute a major part of the daily diet in many countries (fao 1998). In refined- grain products, the bran and germ of the grain which contain the major amount of micronutrients, phytochemicals and dietary fibre (non-digestible carbohydrates and lignin), have been removed and only the starchy endosperm (ca. 80 % of the whole grain) is used. Whole grain foods contain either intact, flaked or broken grain kernels, coarsely ground kernels or flour that is made from whole grains (whole-meal flour). In epidemiological studies foods commonly are classified as whole grain as they contain more than 25 % by weight whole-grain or bran (Jacobs 1998). The Food and Drug Administration (fda 2005) has approved a health claim for whole-grain foods with a whole-grain content of more than 51 % by weight per reference amount customarily consumed and more recently has announced in a fda guidance document (draft guidelines) that it “considers ‘whole grain’ to include cereal grains that consist of the intact, ground, cracked or flaked fruit of the grains whose principal components – the starchy endosperm, germ and bran – are present in the same relative proportions as they exist in the intact grain” (fda 2006).
Changes in food patterns such as a decrease of consumption of whole grain foods which occurred simultaneously with the increase of prevalence of chronic disease over the last decades have lead to the hypothesis that constituting whole grain food by highly refined grain foods is linked to the development of type 2 diabetes and other chronic disease (Burkitt 1975, Trowell 1975). There are several hypotheses as to how whole grain foods might prevent type 2 diabetes. Beneficial effects on weight gain, for example, could be explained by the larger volume and
1
relatively low energy density of whole grain food which is due to the presence of cereal fibre. This promotes satiation and satiety thus leading to decreased energy intake (Koh-Banerjee 2003). Consumption of whole grain foods containing intact, broken or coarsely ground kernels or viscous soluble fibre results in a lower postprandial plasma glucose and insulin response as compared to refined grain foods (Slavin 2003). In view of the proposed aggravating effects of high postprandial glucose and insulin concentrations on insulin sensitivity and beta- cell failure, their suppression is considered to be beneficial (Ludwig 2002; Willett 2002). Also, the high content of antioxidants such as vitamin E, phytic acid and selenium might be advantageous (Slavin 2003) since there is emerging evidence that the pathogenesis of diabetes is associated with increased oxidative stress (Dandona 2004, Robertson 2004; Sjoholm 2005).
From observational studies there is evidence for a protective effect of whole- grain foods with regard to the development of type 2 diabetes (Fung 2002;
McKeown 2002, Meyer 2000; Montonen 2003). More recently, higher intake of whole grains was also associated with decreases in insulin resistance – a risk factor related to the development of type 2 diabetes (Liese 2003; McKeown 2004; Steffen 2003).
However, the protective effect of whole-grain foods on the development of type 2 diabetes would ideally be evaluated by randomised control trials because of their optimal control of confounding factors. To be able to observe differences in incidence of type 2 diabetes the duration of the dietary intervention would need to be very long. Alternatively persons with at least one major risk factor for type 2 diabetes could be chosen. Amelioration of the risk factor could then be used as an indication of decreased risk of development of type 2 diabetes. Still, it is likely that compliance with the whole-grain diet decreases with time, especially in persons who regard the diet as less palatable or might experience adverse effects of the intervention. The relatively high content of cereal fibre and resistant starch in the whole-grain diet might cause increased bloating and/or flatulence in sensitive persons. Due to these limitations with regard to trial duration and compliance randomised controlled trials assessing the effect of whole-grain foods on the development of type 2 diabetes are likely to be scarce.
Some reviews have been published addressing the relation between whole grain foods and the incidence of type 2 diabetes (Liu 2002; Murtaugh 2003). However, they were not systematically performed with respect to literature search and did not include quality assessment. Summarizing and evaluating the available evidence -derived from prospective cohort studies and intervention trials – concerning
the possible protective effect of whole grain foods could aid in identifying further research need and assist in defining recommendations with regard to the intake of starchy foods for the prevention of the development of type 2 diabetes.
Objectives
To asses the effect of whole-grain foods for the prevention of t2dm.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, controlled clinical trials and cohort studies were considered.
Types of participants
Randomised controlled trials or controlled clinical trials Inclusion criteria
Healthy persons and persons with at least one major risk factor for type 2 diabetes were included. Major risk factors are overweight, abdominal obesity, impaired glucose tolerance and insulin resistance. We excluded children and adolescents less than 18 years because of the well known differences in eating patterns.
Cohort studies Inclusion criteria
Free living persons (older than 18 years of age) without previously diagnosed diabetes mellitus.
Diagnostic criteria
Type 2 diabetes and impaired glucose tolerance: the diagnosis should have been established using the standard criteria valid at the time of the beginning of the trial (ada 1997; ada 1999; nddg 1979; Unwin 2002; who 1980; who 1985; who 1999).
