Chapter Two - Pleiotropic Actions of the Incretin Hormones
Introduction
Following the discovery of secretin (Bayliss and Starling, 1902), Moore et al. (1906) proposed that a similar factor might be present in the intestinal mucosa that increased the “internal secretion” of the pancreas. They administered mucosal extracts orally to type 1 diabetes (T1DM) patients and reported successful reductions in glucosuria in some individuals. However, as pointed out by Creutzfeldt (2005), the positive responses obtained were unlikely to have been due to peptide hormones in the extracts and were probably a result of spontaneous remission. Subsequently, the effects on blood glucose of various crude secretin preparations were examined by a number of groups, with variable results (Creutzfeldt, 2005). The Belgian physiologist, Jean La Barre, was among those who found that intravenous (i.v.) administration of upper intestinal extracts produced a hypoglycemic response, and he introduced the term incrétine to describe the factor(s) responsible (La Barre, 1932). A regulatory role for the gut in glucose homeostasis was unambiguously established by two groups which determined that insulin responses to glucose delivered via gastric (Elrick et al., 1964) or jejunal (McIntyre et al., 1964) intubation were greater than when the same amount of glucose was infused intravenously. It was estimated that 50–60% of the total insulin secreted during a meal was a result of gut factors (Perley and Kipnis, 1967). The term “enteroinsular axis” was later introduced to describe the hormonal link between the gut and the endocrine pancreas (Unger and Eisentraut, 1969) and the term “incretin” was reintroduced (Creutzfeldt, 1979) to describe hormone(s) that are released from the intestine in response to glucose and stimulate insulin secretion in a glucose-dependent manner (Creutzfeldt, 1979). There is also an important neural component of the enteroinsular axis that includes both autonomic reflexes and direct enteropancreatic innervation (Kirchgessner and Gershon, 1990).
Several groups sought the factor(s) responsible for incretin activity in intestinal extracts, and the first to be identified was gastric inhibitory polypeptide (GIP), a 42 amino acid peptide originally isolated on the basis of its acid inhibitory (enterogastrone) activity in dogs (Brown, 1971, Brown & Dryburgh, 1971). It was subsequently shown to stimulate insulin secretion in a glucose-dependent manner, (Brown et al., 1975) and the name “glucose-dependent insulinotropic polypeptide” was introduced as an alternative definition of the acronym GIP (Brown and Pederson, 1976), to reflect its incretin status. Identification of a second incretin originated in the discovery by Lund and Habener that the anglerfish proglucagon gene coded for an additional glucagon-like peptide (GLP; Lund et al., 1982). Two mammalian glucagon-related sequences were subsequently identified in the mammalian proglucagon gene (Bell et al., 1983). Intestinal processing of proglucagon results in the production of GLP-17–36 amide and GLP-17–37, both of which potentiate glucose-induced insulin secretion (Holst et al., 1987, Lund, 2005, Mojsov et al., 1987), as well as GLP-2. The major circulating incretin form is GLP-17–36 amide and, by convention, combined tissue or plasma GLP-17–36 amide and GLP-17–37 levels are generally referred to as GLP-1. Although other insulinotropic hormones are synthesized in the gut, GIP and GLP-1 are the only physiological incretins identified so far.
GIP and GLP-1 are synthesized by enteroendocrine cells of the gastrointestinal tract, classified as K- and L-cells, respectively (Holst, 2007, McIntosh et al., 2009). However, subpopulations of enteroendocrine cells demonstrating colocalization of the two hormones (Mortensen et al., 2003) have been identified. Both GIP and GLP-1 are additionally synthesized in brain neurons (Nyberg et al., 2005, Tang-Christensen et al., 2001) and GLP-1 is produced in islet α-cells and in taste buds. Both hormones are released in response to a meal and exhibit almost identical insulinotropic activity (Drucker, 2006, Drucker, 2006, McIntosh et al., 2009, Meier et al., 2002b, Vahl & D'Alessio, 2003). Termination of the insulinotropic activity of both GIP and GLP-1 is performed by the prolyl endopeptidase, dipeptidyl peptidase-IV (Drucker & Nauck, 2006, McIntosh, 2008).
It is now recognized that, in addition to their incretin effects, both GIP and GLP-1 exert pleiotropic actions (Brubaker, 2006, McIntosh et al., 2005; Fig. 2.1), many of which contribute to the integration of processes involved in the regulation of food intake, and nutrient and mineral processing and storage (Abu-Hamdah et al., 2009, Drucker, 2007, McIntosh et al., 2009). This includes the regulation of physiological events underlying food intake and satiety, passage of chyme through the gastrointestinal tract, nutrient digestion and absorption, as well as intravascular transport and storage of nutrients. This is an extremely complex set of processes, our understanding of which is still rudimentary. Additionally, both hormones play key regulatory roles in the proliferation and survival of pancreatic islets. Two classes of therapeutics that take advantage of the pleiotropic actions of the incretin hormones have recently been introduced for treatment of type 2 diabetes: DPP-IV resistant analogs of GLP-1 (incretin mimetics) and DPP-IV inhibitors (incretin enhancers; Drucker & Nauck, 2006, McIntosh, 2008). In this review, we have attempted to provide an up-to-date summary of current knowledge relating to the physiological roles of GIP and GLP-1 and their modes of action.
Section snippets
GIP and GLP-1 Actions: Hormonal and Neuronal Pathways
The pleiotropic actions of GIP and GLP-1 are mediated by interaction with their cognate G protein-coupled receptors (GIP-R and GLP-1R), both of which are present in the endocrine pancreas, gastrointestinal tract, brain, and immune and vascular systems (Baggio & Drucker, 2007, Drucker, 2007, Holst, 2007, McIntosh et al., 2009). The GIP-R is also expressed in adipose tissue and bone, whereas the GLP-1R exhibits a much broader distribution, including the ANS, lungs, heart, and kidneys (Baggio &
Effects of GIP and GLP-1 on Early Events During Feeding
The majority of GIP and GLP-1 actions are initiated following digestion and absorption of the major nutrients. However, subpopulations of GLP-1 containing cells were recently identified in oral circumvallate papillae (Feng et al., 2008, Shin et al., 2008). One of the GLP-1 producing cell types also expressed α-gustducin and the TIR3 sweet taste receptor subunit, while local terminals of afferent ANS nerves expressed GLP-1 receptors, suggesting the presence of a GLP-1 regulated taste perception
Effects of GIP and GLP-1 on β-cell secretion
It is generally accepted that GIP and GLP-1 are the major, if not the sole, incretin hormones in mammals (Drucker, 2006, Holst, 2007, McIntosh et al., 2009). GIP acts directly on pancreatic β-cells and a direct mode of action for GLP-1 is supported by the presence of GLP-1Rs on β-cells (Moens et al., 1996, Thorens et al., 1993), in vitro islet responsiveness to GLP-1R agonists (Gromada et al., 1998, Moens et al., 1996), and the preserved GLP-1 stimulation of insulin secretion observed following
Effects of GLP-1 on Food Intake and Satiety
Food intake and energy expenditure are regulated by a complex interplay between peripheral hormones and autonomic and CNS neural circuits (Drucker, 2007, Huda et al., 2006, Woods & D'Alessio, 2008). GLP-1 has been shown to influence food intake and satiety in a number of species, whereas there is no strong evidence supporting a role for GIP. Intracerebroventricular administration of GLP-1 was shown to strongly inhibit feeding behavior in fasted normal weight rats (Gunn et al., 1996, Navarro et
Gastric emptying
GLP-1, administered by i.v. infusion or s.c. injection, has been shown to inhibit gastric emptying of a liquid meal in normal human volunteers (Nauck et al., 1997, Wettergren et al., 1993), as well as in obese individuals (Näslund et al., 1998b) and T2DM patients (Nauck et al., 1996, Willms et al., 1996), and reduced gastric emptying contributes significantly to the beneficial effects of incretin mimetics in T2DM (Drucker & Nauck, 2006, McIntosh, 2008, Williams, 2009). GIP has not been shown to
Cardiovascular Effects of GIP and GLP-1
There is little known regarding the regulatory effects of gastrointestinal hormones on the vascular delivery of nutrients following absorption, although early evidence suggested that GIP plays a role in regulating the hepatic and splanchnic vasculature. GIP infusion increased hepatic portal (Kogire et al., 1992) and mesenteric arterial (Fara & Salazar, 1978, Kogire et al., 1988) blood flow, whereas hepatic arterial flow was decreased (Kogire et al., 1992). Increased pancreatic islet blood flow
Effects of GIP and GLP-1 on Nutrient Storage and Flux
As a result of their islet actions, GIP and GLP-1 promote the anabolic actions of insulin. However, there is evidence that both hormones exert direct effects on the uptake, storage, and turnover of nutrients, although the literature is not without controversy.
Effects of GIP and GLP-1 on Bone
Both GIP and GLP-1 impact on bone metabolism, although the pathways by which they act differ significantly. Normal bone and osteoclast-like (SaSo2 and MG63) cell lines express GIPRs (Bollag et al., 2000, Bollag et al., 2001, Zhong et al., 2007), and GIPR activation exerts anabolic and proliferative effects on bone. Among the in vitro responses to GIP were increased alkaline phosphatase activity and collagen type 1 mRNA levels, responses associated with new bone formation (Bollag et al., 2000),
The Future
As discussed in this review, the incretin hormones exhibit a remarkable spectrum of actions, many of which are related to the regulation of nutrient and mineral assimilation and metabolism. Incretin-related drugs currently in use as T2DM therapeutics are believed to act mainly through insulinotropic and glucagonostatic actions on the pancreatic islets, as well as suppression of food intake and inhibition of gastric emptying. However, in view of the pleiotropic actions of the incretins outlined,
Acknowledgments
Studies from the authors' laboratory that are referred to in the review were generously supported by funding from the Canadian Institutes of Health Research, Canadian Diabetes Association, and the Canadian Foundation for Innovation.
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