Best Practice & Research Clinical Endocrinology & Metabolism
1Insulin secretion in healthy subjects and patients with Type 2 diabetes – role of the gastrointestinal tract
Section snippets
The incretin effect
Following a meal, carbohydrate is absorbed and enters the circulation, elevating the blood glucose concentration and stimulating insulin release from the pancreatic beta cells. It has been long established that the insulin response to an oral glucose load is three- to fourfold greater than that observed after an ‘isoglycaemic’ intravenous infusion of glucose.7 This phenomenon, known as the ‘incretin effect’, led to the discovery of hormones, secreted from the gastrointestinal tract in response
Gastric emptying and its influence on blood glucose and insulin secretion
Nutrients empty from the stomach at an overall rate of about 2–3 kcal min−111, regulated predominantly by neural and hormonal feedback from the small intestine that slows further emptying by relaxing the fundus, suppressing antral and duodenal contractility and stimulating tonic and phasic contractions that are localised to the pylorus.12, 13 GLP-1 is one of the peptides involved in this feedback loop; others include cholecystokinin (CCK) and peptide YY (PYY), though not GIP.14
Although the rate
Role of the small intestine
The small intestine, being the site of glucose absorption from the external environment and the source of numerous regulatory peptides, including the incretins, is central to glucose homeostasis and postprandial insulin secretion. It is, therefore, remarkable that knowledge regarding many aspects of the small intestinal function is rudimentary.
The maximal capacity of glucose absorption from the small intestine is about 0.5 g min−1 (or 2 kcal min−1) per 30 cm.25 Therefore, it would be expected that
Gastrointestinal function and the incretin response in type 2 diabetes
Gastric emptying of solids and/or nutrient liquids is abnormally slow in 30–50% of patients with long-standing type 1 and type 2 diabetes, although the magnitude of the delay in emptying is often modest.52 Some groups have reported that gastric emptying is abnormally rapid in ‘early’ type 2 diabetes53, 54, 55, although this has not been uniformly observed.16 The only study to evaluate the natural history of gastric emptying in diabetes has demonstrated that there were no marked changes in the
The incretin effect in type 2 diabetes
Comparisons of the incretin effect in type 2 patients with that in healthy subjects have, to date, all been assessed after oral administration of nutrients, so that potential differences in the rate of gastric emptying have not been accounted for as a confounding factor. A comparison of the incretin response to intra-duodenally delivered glucose in type 2 diabetes compared to healthy controls is lacking, and represents a significant gap in current knowledge.
GIP
It has been reported that secretion of GIP is increased, decreased or normal in patients with type 2 diabetes.57 However, it appears clear that the insulinotropic action of GIP is markedly attenuated in these patients58, particularly during the ‘late phase’ of insulin secretion.59 The mechanism of this attenuated response remains uncertain, but defective expression of the GIP receptor has been observed in Zucker diabetic fatty rats.60 About 50% of glucose-tolerant, first-degree relatives of
GLP-1
Both total and active concentrations of GLP-1 following a standardised meal are lower in patients with type 2 diabetes when compared to matched controls.63 This phenomenon might contribute to impaired postprandial insulin secretion because, in contrast to GIP, the insulin response to exogenous GLP-1 is essentially intact in type 2 diabetes.45
Therapeutic strategies to optimise glycaemia involving modulation of gut function
Potential strategies to optimise postprandial glycaemia in patients with type 2 diabetes that involve dietary or pharmacological modulation of gastrointestinal function include (1) slowing gastric emptying to minimise postprandial glucose excursions, (2) inhibiting carbohydrate absorption in the small intestine, (3) augmenting incretin hormone release and (4) modifying macro-nutrient composition. It should be recognised that, in practice, many of these goals overlap (Table 1). As discussed
Slowing gastric emptying
As discussed, in patients with type 2 diabetes who are not treated with insulin, slowing the absorption of nutrients should be beneficial, as the first phase of insulin secretion is diminished. An increase in soluble fibre64, adding the non-absorbable polysaccharide, guar gum65, or combining fat with a carbohydrate-containing meal66, all improve blood glucose while lowering insulin responses. Fat is the most potent among the macro-nutrients to slow gastric emptying, a process that is mediated
Inhibiting absorption of carbohydrate
The alpha-glucosidase inhibitor, acarbose, is routinely used in the treatment of diabetes and reduces postprandial plasma glucose excursions by delaying the absorption of carbohydrate (other than monosaccharides) from the small intestine.77 In healthy volunteers, when sucrose is consumed with acarbose, the delay in absorption allows exposure of the more distal gut to carbohydrate, resulting in greater and more prolonged GLP-1 release than with sucrose alone, which probably accounts for the
Augmenting the incretin response
GLP-1 is rapidly degraded in vivo by the enzyme DPP-IV, as discussed earlier. Analogues of GLP-1 that are resistant to DPP-IV degradation, such as exenatide, have therefore been developed for therapeutic use84 and appear to retain all the anti-hyperglycaemic effects of GLP-1.85 An alternative approach to enhance circulating concentrations of endogenous active GLP-1 is to inhibit DPP-IV. These inhibitors, such as vildagliptin and sitagliptin, are available as oral formulations that are effective
Low carbohydrate and low glycaemic index diets
Lowering the carbohydrate load improves both fasting and postprandial glycaemia in type 2 patients who have failed treatment with conventional diets or sulphonylureas. Conversely, maintaining high carbohydrate ingestion, even with caloric restriction, is associated with poor glycaemic control, and higher levels of glycated haemoglobin.90 Low carbohydrate intake improves hyperglycaemia and hyperlipidaemia over follow-up of at least 12 months, compared to a conventional diet.91
The glycaemic index
Acknowledgments
The authors' research work was been supported particularly by the National Health and Medical Research Council of Australia, the Royal Adelaide Hospital/Institute of Medical and Veterinary Science Research Committee and the Rebecca L Cooper Foundation.
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2014, Surgery for Obesity and Related DiseasesCitation Excerpt :These results provide additional evidence that RYGB modify the dynamic of the beta cell secretion by promoting an earlier and accentuated release of postprandial C-peptide. In addition, our data support the hypothesis that these changes occur partly in response to the early postprandial increase of plasma glucose, because c-peptide and insulin secretion is partly regulated by the glucose available to the pancreatic beta cell [6,18,19]. A novel finding is the paradoxical increase in postprandial glucagon responses at 14 days postsurgery and reduced PP responses in the RYGB group only, changes that were not sustained 6 months after surgery.
Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice
2012, Regulatory PeptidesCitation Excerpt :Of key importance are the incretin hormones which are released after oral glucose and account for more than 50% of total insulin release after an oral glucose load compared to an isoglycemic intravenous glucose bolus [3,4]. One key incretin hormone is glucagon-like peptide-1 (GLP-1), which is secreted from intestinal L-cells [5] and potentiates glucose-stimulated insulin release [6] through GS-protein-coupled rise in intracellular cAMP [7]. Nonetheless, for the study of physiological glucose regulation, intake of pure glucose load is not physiological feeding.
Diabetic gastroparesis and its impact on glycemia
2010, Endocrinology and Metabolism Clinics of North AmericaCitation Excerpt :It is not surprising that the stomach plays a pivotal role in normal blood glucose homeostasis given that it stores ingested nutrients and empties them into the small intestine at a tightly regulated rate, where they are digested and stimulate the release of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, which stimulate insulin secretion.72 It is now recognized that the rate of gastric emptying (and probably small intestinal transit) is a major factor influencing postprandial glycemic excursions in health and in both type 1 and 2 diabetes.72 Hence, gastric emptying is both a determinant of, as well as determined by, glycemia.73
Dietary Effects on Incretin Hormone Secretion
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