Introduction. Pathogenesis of type 2 diabetes

Transcription

1 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 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 prediabetes, 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 11

2 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. Lowgrade 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. 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), 12 Introduction

3 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) Isolated impaired glucose tolerance (i-igt) Fasting plasma glucose values are above normal range but less than would qualify for T2dm Plasma glucose values 2 h after a 75-g oral glucose tolerance test are above normal range but less than would qualify for T2dm sensitivity unaltered insulin sensitivity reduced sensitivity unaltered insulin sensitivity reduced Increased by Smoking Family history of diabetes Male sex Low birth weight Increased by Physical inactivity Low dietary Short adult stature Low birth weight Decreased by Male sex Physical inactivity Low dietary Short adult stature Smoking Family history of diabetes IFG/IGT A combination of the 2 types above Smoking Family history of diabetes Low dietary Gender insulin sensitivity not studied yet 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 than those who developed i-ifg and ifg/igt (14). Another study showed that a Introduction 13

4 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 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 14 Introduction

5 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. Introduction 15