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  • br Competing interests br Acknowledgements br Introduction F


    Competing interests
    Introduction - Factors Regulating Glucose Tolerance Strictly speaking, the incretin effect refers to the amplification of insulin secretion, which occurs when r407 is taken in orally as compared to infused intravenously [1]. Normally, the insulin response is augmented by a factor of 2–3 after oral intake. Physiologically, this phenomenon is one of the ways whereby the organism copes with the intake of a carbohydrate load. Thus, it is one of the important mechanisms governing glucose tolerance. Glucose tolerance is usually defined as the plasma glucose profile after intake of a certain amount of carbohydrate (glucose) relative to what is seen in a group of unquestionably healthy individuals given the same carbohydrate meal. Impaired glucose tolerance therefore refers to concentrations exceeding normal boundaries of the excursions. Until recently, these boundaries were essential for a diagnosis of impaired glucose tolerance or type 2 diabetes, whereas today emphasis is on the integrated glucose levels, as reflected in the concentration of glycated haemoglobin, haemoglobin A1c. So how is glucose tolerance normally regulated? Looking at impairments in glucose metabolism, it is customary to analyse fasting glucose concentrations and postprandial glucose excursions separately, and this is reasonable since the mechanisms involved are different [2]. Of course, if fasting glucose concentrations are elevated, the postprandial glucose profile, everything else being equal, will also be shifted upwards, so that postprandial levels are also abnormal, while at the same time the gastrointestinal mechanisms for handling oral carbohydrate loads may be completely intact. An example could be patients with steatosis of the liver, where hepatic insulin resistance and hyperglucagonemia may explain fasting hyperglycemia, but have limited impact on postprandial events. Also in patients with type 2 diabetes, it is reasonable to distinguish between the postprandial and the fasting glucose levels, because the two are independently associated with cardiovascular risk [3]; thus, in subjects with well-controlled diabetes, postprandial glycemia contributes relatively more to HbA1c than fasting hyperglycemia, whereas fasting glucose contributes relatively more in subjects with dysregulated type 2 diabetes [4]. The incretin effect, the topic of the present review, is obviously one of the important determinants of the postprandial glucose excursions. Systematically, the following factors are important for postprandial glucose excursions [5]: This seems self-evident, but is nevertheless an important factor in the planning of diets for people with glucose intolerance. Only recently has it become generally accepted that low carbohydrate diets have a major beneficial effect on the course and risk of complications in patients with T2DM, with even moderate reductions resulting in significantly improved haemoglobin A1c levels and reduced liver fat (and thereby improved insulin sensitivity and increased insulin clearance) [6,7]. A related issue is the glycemic index of the ingested carbohydrates – the lower the glycemic index, the lower the postprandial glucose levels, and again it is assumed that such reductions will reduce the cardiovascular risk [7]. Once the meal is ingested, the next important factor is the gastric emptying rate. Clearly, liquid meals are emptied at faster rates than solid meals and with different kinetic patters (exponential patterns for liquids and, after a lag phase, linear for solids), but on top of that the emptying rate is strictly regulated by the meal composition to result in a rather constant transfer of nutrients to small intestine, corresponding to between 1 and 4 kcal/min [8]. The actual emptying process consists of a brief opening of the pyloric sphincter associated with a strong propulsive contraction of the antrum, resulting in a rapid ejection a bolus of gastric contents into the duodenum, where peristalsis activated by the possibly acidic bolus secures further onward transportation to more distal segments of the jejunum. In this way a rather large mucosal surface of the upper small intestine is rapidly exposed to the nutrients. Effective upper intestinal mechanisms are now activated which result in a feed-back, involving both long vago-vagal reflexes, probably also short, intramural reflexes, as well as endocrine mechanisms (cholecystokinin, secretin, perhaps also GLP-1, somatostatin?), secreted in response to both acidity, osmolarity and specific nutritional constituents (glucose, proteins, lipids), which all powerfully dampen further emptying from the stomach [5,9]. The result is an adjustment of nutrient transfer to the small intestine that depends on the composition and caloric density of the chyme delivered to the small intestine. In this way the emptying of an energy-dense meal will be spread out in time, presumably with the purpose of preventing untoward effects of rapid emptying (early and late dumping) and excessive increases in postprandial nutrient (e.g. glucose) concentrations in plasma.