Review Article: The Emerging Interplay Among the Gastrointestinal Tract, Bile Acids and Incretins in the Pathogenesis of Diabetes and Non-alcoholic Fatty Liver Disease

A. Zarrinpar; R. Loomba


Aliment Pharmacol Ther. 2012;36(10):909-921. 

In This Article

Incretin Hormones

Incretins, which are hormones released by the gastrointestinal tract in response to nutrients, augment glucose-mediated insulin secretion.[3] Their existence was suspected over a hundred years ago,[4] but was not confirmed until researchers found that the oral administration of glucose resulted in a greater increase in insulin and a more sustained response when compared with glucose administered intravenously.[5,6] An estimated 50–70% of insulin secretion after glucose ingestion is attributable to this observation, which is now known as the 'incretin effect'.[7]

To date, only two hormones fulfil the definition of an incretin hormone.[7] The first incretin hormone to be identified was gastric inhibitory polypeptide, or GIP. Initially, GIP was shown to inhibit gastric acid secretion when tested on dogs.[8] However, further work on more purified samples in humans revealed that GIP augmented insulin secretion.[9] As a result, the hormone was renamed to glucose-dependent insulinotropic polypeptide to maintain the original acronym, but to more accurately describe its function.[7] GLP-1 was discovered later, during the sequencing of mammalian genes. When mapping the proglucagon gene, it was noted that, in addition to glucagon, two more peptides were encoded.[10,11] These two peptides were largely homologous to glucagon and hence were named GLP-1 and glucagon-like peptide-2 (GLP-2). However, only GLP-1 was found to stimulate insulin release.[12] Both GIP and GLP-1 potentiate the augmentation of glucose-mediated insulin response in an additive manner and together explain the incretin effect observed in humans.[13,14]

Secretion of Incretin Hormones

Interestingly, the two incretin hormones are synthesised independently by distinct cell types that are mainly organised in two different regions of the human gut. GIP is synthesised and released from K cells located in the duodenum and proximal jejunum,[15] whereas GLP-1 is produced and released from L cells that are primarily located in the distal jejunum and ileum, although fewer numbers are found scattered throughout the small intestine.[16] They are both released in response to ingestion of nutrients, especially to glucose, carbohydrates and fats.[17–19] During fasting, the circulating levels of GIP and GLP-1 are low, but both increase rapidly with the ingestion of nutrients.[17,19] Furthermore, their release is dependent on the size of the meal, i.e. the ingestion of large meals leads to secretion of higher amounts of both GIP and GLP-1 when compared with smaller meals.[20] Neither one is affected by intravenous administration of glucose.

In humans, both fat and protein markedly stimulate GIP secretion.[21] The release of GIP is directly related to the rate of nutrient absorption rather than the presence of ingested material in the gut lumen.[7] Hence, in patients with malabsorption, serum GIP levels are low.[22] No other stimulator of GIP, besides nutrient absorption, has yet been found.

Serum levels of GLP-1 rise rapidly after ingestion of a meal, and its release occurs in a biphasic pattern.[19] Peak levels occur within approximately 5–15 min after a meal, even though the ingested material has not yet reached the L cells in the distal jejunum and ileum at that point. This phase is followed by a longer 30- to 60-min subsequent phase. The early GLP-1 response to ingested material suggests that an indirect stimulation occurs via endocrine or neural mediators. This effect has been described as a proximal-distal neuroendocrine loop that relays stimulation to ingested foods from the proximal duodenum to distally located L cells that release GLP-1.[23,24] Several studies have shown that the autonomic nervous system, through the neurotransmitters gastrin-releasing peptide (GRP) and acetylcholine, contributes to the rapid release of GLP-1.[25–27] Furthermore, in rats where the vagus nerve was severed, there was no initial peak in release of GLP-1 after a diet rich in fat.[23] Atropine, a muscarinic antagonist, diminished GLP-1 secretion in humans, further bolstering the theory that GLP-1 secretion is stimulated by neural mediators.[28] In several rat studies, GIP plays a role in GLP-1 secretion through vagal afferent-efferent pathways and the release of GRP.[23,25] However, GIP does not stimulate the secretion of GLP-1 in humans.[29] The second phase of GLP-1 release is due to the direct response of L cells to ingested food in the lumen.[30]

Biological Actions of Incretin Hormones

The incretin hormones mediate their insulinotropic effects mainly in the pancreas. However, GIP and GLP-1 have receptors in many extrapancreatic tissues that contribute to glucose homoeostasis. The GLP-1 receptor has also been found in the liver, kidney, stomach, heart, lung, intestines, skeletal muscle, adipose tissue, nodose ganglion neurons of the vagus nerve, and the brain, including the brainstem and hypothalamus.[31–35] GIP receptors are also expressed in a range of tissues in addition to the pancreas. They have been found in the stomach, small intestine, heart, lung, adipose tissue, adrenal cortex and the brain, including the cerebral cortex, hippocampus and olfactory bulb.[36] In addition, GIP has indirect effects on the liver, although no GIP receptors have been found in the liver and the mechanism for an indirect route of action has not been elucidated.[7,36] Table 1 summarises the role of the incretin hormones in various tissues.

In the pancreas, both GLP-1 and GIP stimulate glucose-dependent insulin secretion[43,44] and β-cell proliferation,[45,46] inhibit β-cell apoptosis,[47,48] and increase insulin production.[49,50] In addition, GLP-1 inhibits glucagon production,[51] whereas GIP stimulates glucagon secretion.[52] However, glucagon secretion by GIP only occurs under basal glucose concentrations, and GIP may play a role in feedback control of glucose homoeostasis, as the most profound augmentation of insulin secretion from GIP is seen under hyperglycaemic conditions.[52]

The role of the incretins in the extrapancreatic tissues is diverse. Both GLP-1 (in the liver and/or kidney) and GIP (in the liver, presumably via an indirect mechanism) inhibit glucagon-stimulated glucose production.[41,42] In the gut, GLP-1 impedes gastric emptying and hence delays the rise in glucose after eating.[53–55] In the central nervous system, GLP-1 has been shown to decrease appetite and food intake,[51] which is mediated through GLP-1 receptors found on the nodose ganglion of the afferent vagus nerve.[56] In the muscle and adipose tissue, GLP-1 and GIP stimulate glucose uptake.[35,38–40]

Although there is some understanding of the release of incretins and which organs they affect, the way in which they control glucose homoeostasis is poorly understood. In this case, GLP-1 has been better studied than GIP. There are two proposed mechanisms through which GLP-1 is hypothesised to mediate its effects: (i) the endocrine pathway; and (ii) the neural pathway.[57] In the endocrine pathway, GLP-1 is released directly into the systemic circulation after the L cells are stimulated by gut nutrients. It then binds to receptors in target organs such as the pancreas, where it increases intracellular cAMP and stimulates glucose-dependent insulin secretion.[58,59] GLP-1 also increases β-cell insulin stores through promoting insulin gene expression and stabilising transcription as well as stimulating β-cell proliferation and neogenesis.[45,46]

Neurons in the central nervous system contain GLP-1 and GLP-1 receptors – the first hint that GLP-1 has a neural pathway through which it mediates some of its actions. The predominant region of the brain that contains GLP-1 receptors is the nodose ganglion of abdominal vagal afferent nerve that terminates in the nucleus of the solitary tract.[33] GLP-1 promotes satiety and decreases food intake,[32,34,51,60] and GLP-1 agonists have led to weight loss in human studies.[61]

Given these two pathways, it may be that the GLP-1 insulin potentiation may occur as a combination of the two pathways. More than half of the GLP-1 secreted is inactivated before it reaches the systemic circulation.[62] Furthermore, GLP-1 is metabolised in the liver, leaving only a small amount that actually reaches the pancreas.[62,63] It is now presumed that GLP-1 must use local neurons as intermediaries to signal the pancreas.[64]

Incretin Hormones in Patients With T2DM

The incretin effect is severely reduced in patients with T2DM.[65] Although the cause of this is likely multifactorial, studies evaluating the secretion levels of incretins and physiological response to their exogenous administrations have shown two salient findings. There is a likely impaired secretion of GLP-1 and decreased activity of GIP.[37] In patients with T2DM, GIP secretion is normal or even increased in basal and postprandial conditions.[37] However, its insulinotropic activity has been shown to be greatly diminished in patients with T2DM, with response being 54% lower than that of normal controls.[66] In contrast to GIP, the response to GLP-1 in patients with T2DM was similar to that of controls. However, plasma levels of GLP-1 at meal time appear to be at least modestly diminished.[20,67–70] It is noteworthy to point out, however, that a few studies have demonstrated increased or unaltered levels of GLP-1.[71–74] Finally, patients with secondary DM, such as those with DM secondary to chronic pancreatitis, have similar inhibition of their incretin activity, suggesting that this is a consequence of T2DM rather than a cause of it.[75]

Synthetic GLP-1 agonists [exenatide (Amylin Pharmaceuticals, Inc., San Diego, CA, USA) and liraglutide (Novo Nordisk A/S, Bagsvaerd, Denmark)] are available for the treatment of T2DM when used as monotherapy or in combination therapy requiring subcutaneous administration.[76,77] These agents improve glycaemic control and promote weight loss, and are associated with low rates of severe hypoglycaemia.[78–80] However, there have been reports of an association between GLP-1 agonist use and acute pancreatitis in patients with T2DM.[81,82]

The major pharmaceutical target influencing incretins has been DPP-4.[83] DPP-4, which cleaves GLP-1 and GIP, is found in many tissues including the gastrointestinal tract, biliary tract, liver, spleen, lungs, pancreas, kidneys and activated T lymphocytes.[84–86] The protease resides on the surface of endothelial cells of blood vessels from the intestines; hence, it is in a perfect position to rapidly deactivate more than half of secreted incretins.[62] DPP-4 knockout mice are associated with increased GIP and GLP-1, as well as enhanced insulin secretion after oral glucose administration.[87] Interestingly, such mice are also resistant to the development of obesity induced by a high-fat diet.[88] Four DPP-4 inhibitors are currently on the market: linagliptin (Boehringer Ingelheim International GmbH, Ingelheim, Germany), saxagliptin (Bristol-Myers Squibb, Princeton, NJ, USA), sitagliptin (Merck & Co., Inc., Whitehouse Station, NJ, USA), and vildagliptin (Novartis, Basel, Switzerland; approved in various countries in Europe, Asia Pacific, Africa and Latin America). The DPP-4 inhibitors are generally well tolerated, weight neutral and not associated with hypoglycaemia,[89–92] and are associated with a rise in plasma incretins after meals.[93,94] Glucose-mediated insulin secretion was enhanced, which was consistent with improved pancreatic β-cell function.[93,94] They significantly lower blood glucose and haemoglobin A1C levels, and are used either as monotherapy or in combination therapy.[95–98]