Structure, production, and regulation of secretion

Glucagon-like peptide-1 is cleaved from preproglucagon within the L cells of the intestinal mucosa (Donnelly 2012). GLP-1 is secreted into the circulation in two forms; GLP-11-37 and GLP-11-36 (Lockie 2013; Kieffer & Habener 1999; Neary & Batterham 2009). GLP-11-36 is the major form found in the blood (Neary & Batterham 2009), and is the form considered to be active. When in the circulation GLP-1 is rapidly broken down by DPP-IV into the inactive forms GLP-19-36 and GLP-19-37 (Lockie 2013). Due to the rapid break down of active GLP-1, most of the GLP-1 that leaves the gut is inactive, with only ~10-15% of the newly secreted GLP-1 being active in the circulation (Holst 2007). The secretion of GLP-1 is dictated by food consumption. During fasting, plasma concentrations of GLP-1 are very low, and these are seen to increase rapidly within 10 min of consuming a meal. The amount of GLP-1 released into the circulation is dependent on the size of the meal and the rate of gastric emptying (Kieffer & Habener 1999; Miholic et al. 1991; Vilsbøll et al. 2003). The release of GLP-1 is biphasic, with levels initially rising 10 min after food consumption, peaking after 30 min and remaining elevated for several hours (Orskov et al. 1996). However, the release of GLP-1 from L cells is not solely under the control of nutrients, hormones and neural inputs also play a role. This causes the biphasic pattern in GLP-1 release seen after a meal. The initial rise of GLP-1 in the 10 min after food intake is mediated both hormonally and neurally.

Whereas the later secretion of GLP-1, seen 30 min after food consumption, is caused by direct nutrient contact with the L cells in the ileum (Kieffer & Habener 1999). The release of GLP-1 into the circulation stimulates insulin secretion and inhibits glucagon secretion (Field et al. 2009; Holst 2007; Lockie 2013). This allows for increased glucose uptake and glucose clearance, which is important for the regulation of glucose (Lockie 2013). Specifically, GLP-1 is classified as an incretin hormone (Holst 2007) a collection of molecules responsible for amplifying the secretion of insulin.

secretion (Elliott et al. 1993; Herrmann-Rinke et al. 1995). However when glucose is systemically administered no rise in circulating GLP-1 is seen. This in tandem with the observation of increased GLP-1 after glucose infusion into the intestinal lumen suggests that the cells required to detect GLP-1 are distributed on the luminal side of the intestine (Kieffer

& Habener 1999). As well as glucose, fat also appears to be partially responsible for the release of GLP-1 and other proglucagon derived peptides. Consuming either mixed fats or triglycerides (TAG) in humans, causes an increase in the secretion of GLP-1. The chain length and degree of saturation of the ingested fats influences GLP-1 secretion, with monounsaturated long chain fatty acids causing a greater secretion than short chain or medium chain polyunsaturated or saturated fatty acids (Kieffer & Habener 1999). When looking at the responses to amino acids and proteins, it has been found that GLP-1 secretion does not increase in humans. However, when mixed meals containing protein are consumed GLP-1 secretion increases (Kieffer & Habener 1999).

2.3.3.3. Physiological functions and mechanisms of action

Glucagon-like peptide-1 has multiple physiological functions in the peripheral tissues (Figure 2.4), mediated through its own distinct receptor. These GLP-1 receptors are concentrated in areas closely related to appetite regulation, in particular on the beta cells of the pancreatic islets, the brain (in particular the hypothalamus), kidney, heart and GI tract (Holst 2007).

As very little active GLP-1 that leaves the L cells reaches the circulation, it has been proposed that GLP-1 may interact with afferent sensory nerve fibres as it crosses the capillary wall to induce its effects (Holst 2007). Specifically, sending impulses to the nucleus of the solitary tract, and onwards to the hypothalamus (Holst 2007).

Glucagon-like peptide-1 is suggested to be one of the most important incretin hormones (Vilsbøll & Holst, 2004). GLP-1 acts on pancreatic β cells to stimulate the release of insulin and inhibit the release of glucagon, in a glucose dependent manner (Field et al. 2009; Holst 2007). GLP-1 may also override the inhibition of insulin secretion by leptin (Kieffer &

Habener 1999). This will ensure that an adequate insulin response occurs after a meal.

Consequently, the release of GLP-1 from the gut is dependent on the quantity of glucose consumed, and will ensure that plasma glucose concentrations remain constant whatever the size of the glucose load (Holst 2007).

Figure 2.4. Physiological actions of GLP-1. Adapted from Baggio & Drucker (2007).

When those with type 2 diabetes are chronically infused with GLP-1, weight loss and improved glycaemic control are observed (Zander et al. 2002). This suggests that GLP-1 could be used in the treatment of type 2 diabetes; however, more investigation is required to determine its long term effects.

Glucagon-like peptide-1 inhibits gastric secretion and motility, gastric emptying and pancreatic secretions (Field et al. 2009; Holst 2007). This suggests that GLP-1, alongside PYY, is responsible for mediating the ‘ileal brake’ (Holst 2007). Specifically inhibiting upper gastrointestinal functions, due to the presence of unabsorbed nutrients in the ilium (Holst 2007), this effect is thought to be induced via afferent sensory neurons that are responsible for relaying impulses to the brain, in particular the hypothalamus (Holst 2007).

Glucagon-like peptide-1 has been shown to have satiating effects in humans, whereby energy intake at an ad libitum meal is reduced after acute intravenous infusion of GLP-1 (Flint et al.

1998). GLP-1 is suggested to mediate this effect by slowing gastric emptying and acting directly on the CNS (Field et al. 2009). Non-digestive effects include the inhibition of heart

fat cells, causing glucose uptake (Kieffer & Habener 1999).

2.3.3.4. Acute energy regulation

After a meal, circulating concentrations of GLP-1 show a biphasic response. Levels rise within 10 min of the meal, and peak at about 30 min, remaining elevated for several hours (Orskov et al. 1996). The magnitude of this response is determined by the nutrients consumed (Holst 2013). This pattern of secretion mirrors that of satiety and for this reason the GLP-1 is thought to have an anoeretic effect.

In rats, the acute administration of GLP-1 by injection results in decreased food intake (Turron et al. 1996). Similarly, a dose dependent reduction in food intake with GLP-1 infusion has been shown in humans (Verdich et al. 2001). Together these further imply GLP-1 has an acute role in energy regulation.

The mechanism for satiety and food intake regulation is unclear. However, both central and peripheral mechanisms could play a role (McGrath et al. 2015). Firstly, GLP-1 may transmit nutritional signals via the vagus nerve in the gastrointestinal tract (McGrath et al. 2015).

Secondly, the small amount of GLP-1 that is not broken down by DPP-IV could cross the blood brain barrier acting directly on GLP-1 receptors to induce satiation (Dailey & Moran 2013). Finally, feelings of satiation could be generated by decreased gastrointestinal motility (Holst 2007).

2.3.3.5. Chronic energy regulation

After weight loss in humans, fasting concentrations of GLP-1 have been shown to decrease (Adam et al. 2005). It has been suggested that this could increase appetite and promote weight regain during and after dieting (Neary & Batterham 2009). However, after bariatric surgery, circulating concentrations and secretions of GLP-1 are elevated and this is believed to help reduce appetite and food intake and weight loss (Ashrafian & le Roux 2009).

Together these imply GLP-1 plays a role in chronic energy balance and potentially contributes in the pathogenesis of obesity (Neary & Batterham 2009).

Similarly, by inducing supra-physiological circulating concentrations of GLP-1 through five days of prandial subcutaneous injections in obese individuals, calorie intake was reduced by 15% and 0.5 kg weight loss was seen (Näslund et al. 2004). This suggests that low

concentrations of GLP-1 could be responsible for obesity and restoration of these may increase satiety and cause weight loss.

2.3.3.6. Differences between lean and obese individuals

With regards to fasting concentrations of GLP-1 in obese and normal weight individuals, mixed findings have been reported. Some show no difference (Adam & Westerterp-Plantenga 2004; Verdich et al. 2001), whereas others report lower concentrations in the obese (Chanoine et al. 2008; Ranganath et al. 1996). Discrepancies in these findings may have been caused by recruitment of obese individuals who are losing weight or have recently lost weight (Adam et al. 2005).

In response to a meal, obese individuals have shown attenuated postprandial GLP-1 secretion in comparison to lean individuals (Adam & Westerterp-Plantenga 2005; Ranganath et al.

1996; Verdich et al. 2001). However, again some studies have reported no difference (Fukase et al. 1993).

Irrespective of these differing reports between obese and lean individuals, it has been shown that both lean and obese individuals show a dose response relationship between GLP-1 infusion and energy intake with both populations showing equal sensitivity to GLP-1 (Verdich et al. 2001). This suggests that GLP-1 or its agonists could be useful in the treatment of obesity.