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Insulin secretion in healthy subjects and patients with Type 2 diabetes – role of the gastrointestinal tract

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Postprandial glycaemia is now recognised as the major determinant of average glycaemic control in type 2 diabetes, as assessed by glycated haemoglobin. Therefore, an understanding of the factors influencing both the rise in blood glucose and insulin secretion after a meal is fundamental to the development of dietary and pharmacological approaches to optimise glycaemic control. The gastrointestinal tract regulates the rate at which carbohydrate and other nutrients are absorbed and is the source of regulatory peptides that stimulate pancreatic insulin secretion in the setting of elevated blood glucose levels. This article highlights the importance of the gastrointestinal tract in insulin secretion and glucose homeostasis and discusses potential strategies directed at modification of gastrointestinal function in order to improve glycaemic control in the management of diabetes.

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.

References (98)

  • D. Elahi et al.

    The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects

    Regulatory Peptides

    (1994)
  • D. Singh-Franco et al.

    Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus

    Clinical Therapeutics

    (2007)
  • J. Mourot et al.

    Relationship between the rate of gastric emptying and glucose and insulin responses to starchy foods in young healthy adults

    The American Journal of Clinical Nutrition

    (1988)
  • B. Ahren

    DPP-4 inhibitors

    Best Practice & Research. Clinical Endocrinology & Metabolism

    (2007)
  • T.M. Wolever

    Relationship between dietary fiber content and composition in foods and the glycemic index

    The American Journal of Clinical Nutrition

    (1990)
  • M.C. Gannon et al.

    An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes

    The American Journal of Clinical Nutrition

    (2003)
  • M.C. Gannon et al.

    The insulin and glucose responses to meals of glucose plus various proteins in type II diabetic subjects

    Metabolism

    (1988)
  • A. Karamanlis et al.

    Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects

    The American Journal of Clinical Nutrition

    (2007)
  • S. Del Prato

    In search of normoglycaemia in diabetes: controlling postprandial glucose

    International Journal of Obesity and Related Metabolic Disorders

    (2002)
  • A. Ceriello et al.

    Postprandial glucose regulation and diabetic complications

    Archives of Internal Medicine

    (2004)
  • D.M. Nathan et al.

    Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes

    The New England Journal of Medicine

    (2005)
  • The Diabetes Control and Complications Trial Research Group

    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

    The New England Journal of Medicine

    (1993)
  • UK Prospective Diabetes Study (UKPDS) Group

    Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

    Lancet

    (1998)
  • American Diabetes Association

    Postprandial blood glucose

    Diabetes Care

    (2001)
  • M.J. Perley et al.

    Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects

    The Journal of Clinical Investigation

    (1967)
  • M. Horowitz et al.

    To be or not to be–an incretin or enterogastrone?

    Gut

    (2006)
  • J. Schirra et al.

    Effects of glucagon-like peptide-1 (7–36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans

    Gut

    (2000)
  • J. Schirra et al.

    Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans

    Gut

    (2006)
  • M. Horowitz et al.

    Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects

    Diabetologia

    (1993)
  • K.L. Jones et al.

    Gastric emptying in early noninsulin-dependent diabetes mellitus

    Journal of Nuclear Medicine

    (1996)
  • S. Gonlachanvit et al.

    Effect of altering gastric emptying on postprandial plasma glucose concentrations following a physiologic meal in type-II diabetic patients

    Digestive Diseases and Sciences

    (2003)
  • M. Ishii et al.

    Altered postprandial insulin requirement in IDDM patients with gastroparesis

    Diabetes Care

    (1994)
  • A.N. Pilichiewicz et al.

    Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men

    American Journal of Physiology. Endocrinology and Metabolism

    (2007)
  • D.G. Bruce et al.

    Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes

    Diabetes

    (1988)
  • J.E. Gerich

    Pathogenesis and treatment of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM)

    Hormone and Metabolic Research

    (1996)
  • D.G. O'Donovan et al.

    Effect of variations in small intestinal glucose delivery on plasma glucose, insulin, and incretin hormones in healthy subjects and type 2 diabetes

    The Journal of Clinical Endocrinology and Metabolism

    (2004)
  • R. Chaikomin et al.

    Initially more rapid small intestinal glucose delivery increases plasma insulin, GIP, and GLP-1 but does not improve overall glycemia in healthy subjects

    American Journal of Physiology. Endocrinology and Metabolism

    (2005)
  • S.M. Duchman et al.

    Upper limit for intestinal absorption of a dilute glucose solution in men at rest

    Medicine and Science in Sports and Exercise

    (1997)
  • M.P. Schwartz et al.

    Small bowel motility affects glucose absorption in a healthy man

    Diabetes Care

    (2002)
  • H.N. Nguyen et al.

    Chyme transport patterns in human duodenum, determined by multiple intraluminal impedancometry

    The American Journal of Physiology

    (1995)
  • H. Imam et al.

    Study of intestinal flow by combined videofluoroscopy, manometry, and multiple intraluminal impedance

    The American Journal of Physiology. Gastrointestinal and Liver Physiology

    (2004)
  • R. Chaikomin et al.

    Concurrent duodenal manometric and impedance recording to evaluate the effects of hyoscine on motility and flow events, glucose absorption, and incretin release

    The American Journal of Physiology. Gastrointestinal and Liver Physiology

    (2007)
  • M. Camilleri et al.

    Abnormal intestinal motility in diabetics with the gastroparesis syndrome

    European Journal of Clinical Investigation

    (1984)
  • M. Samsom et al.

    Intestinal function

  • Y. Fujita et al.

    Increased intestinal glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in Otsuka Long-Evans Tokushima fatty rats

    Diabetologia

    (1998)
  • C.I. Cheeseman et al.

    Rapid regulation of D-glucose transport in basolateral membrane of rat jejunum

    The American Journal of Physiology

    (1989)
  • T.Z. Csaky et al.

    Induction of an intestinal epithelial sugar transport system by high blood sugar

    Experientia

    (1977)
  • T.Z. Csaky et al.

    Intestinal sugar transport in experimental diabetes

    Diabetes

    (1981)
  • E. Fischer et al.

    Effect of hyperglycaemia on sugar transport in the isolated mucosa of guinea-pig small intestine

    The Journal of Physiology

    (1984)
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