Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #52: Incretin Physiology in Health and Disease Part 2 of 6

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #52: Incretin Physiology in Health and Disease Part 2 of 6

Nov 29, 2016

Secretion of incretin hormones

The mucosa of the intestinal tract harbors a large number of endocrine cells that give rise to various peptide hormones. These include cholecystokinin, motilin, secretin, gastrin, gastric inhibitory polypeptide (GIP, also referred to as glucose-dependent insulinotropic polypeptide), glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2, and peptide YY [15].

The abundance of endocrine cells is greatest in the small intestine and in the rectum [16]. At physiologic plasma levels, incretin activity has been demonstrated for GIP and GLP-1 [8,17,18]. Plasma concentrations of GIP rise ∼10 – 15 min after meal ingestion from baseline levels of ∼10 – 15 pmol L−1 and reach peak concentrations of ∼150 – 500 pmol L−1 , depending on meal size and composition [6,18,19]. For GLP-1, fasting concentrations range between 2 and 15 pmol L−1 , and postprandial concentration between 15 – 45 pmol L−1 have been described [18 – 21]. When GIP and GLP-1 were infused intravenously at their typical postprandial concentrations, glucose-stimulated insulin secretion was augmented in a similar fashion as seen after oral glucose ingestion, thereby suggesting that the insulinotropic activity of these hormones mediates the physiologic incretin effect to a near-total extent [18].

GIP has been demonstrated to originate from intestinal K cells, which are located throughout the small and large intestine, with a higher cell density towards the duodenum and jejunum [15]. Morphologically, L cells are characterized by a polarized shape, with an apical surface contacting the gut lumen and a basolateral membrane facing the capillary walls. Secretion of GIP is stimulated by carbohydrates, especially glucose and galactose, and certain amino acids [16]. The observation that glucose-induced GIP secretion can be abolished by the administration of the non- selective sodium-glucose co-transporter (SGLT) inhibitor phlorizin indicates that GIP secretion is linked to the absorption of glucose through the enterocytes rather than to the mere presence of nutrients inside the gut lumen [22].

Furthermore, expression of Kir6.2, Sur1, SGLT-1, GPR40, GPR119, and GPR120 was detected on rodent K cells, suggesting a potential modulation of GIP secretion through sulfonylureas and various G-protein receptor ligands [23]. However, increased GIP plasma concentrations have not been described in patients treated with sulfonylurea compounds, thereby challenging the physiologic importance of these receptors [24]. More recently, expression of somatostatin receptors (Sstrs) Sstr2, Sstr3, and Sstr5, and cannabinoid receptor type 1 (Cnr1, CB1) was detected on murine K cells, and inhibition of GIP secretion by somatostatin and the CB1 agonist methanandamide was observed in primary K cells [25]. The active peptide hormone GIP comprises 42 amino acids and an amidated C-terminus and is yielded through posttranslational processing of a larger precursor peptide (proGIP) [16]. The second incretin hormone, GLP-1, originates from intestinal L cells, which also give rise to secretion of peptide YY as well as GLP-2 and other proglucagon cleavage products. The distribution of L cells is heterogeneous throughout the different proportions of the gut with an increasing frequency of L cells being found in the distal parts of the colon and rectum [16,26]. Interestingly, co-expression of GIP and GLP-1 has been demonstrated in a substantial proportion of enteroendocrine cells [26]. The peptide GLP-1 results from proteolytic cleavage of the proglucagon precursor protein by the enzymes prohormone convertase 1/3. The peptides enteroglucagon (glicentin), GLP-2, and peptide tyrosine tyrosine (PYY) are further intestinal proglucagon cleavage products [27]. GLP-1 is secreted in two distinct forms, an amidated form GLP-1 (7-36) amide, and a glycine-extended form GLP-1 (7-37). The amidated form appears to be more abundant [27]. The biologic activity of these forms has been found to be rather similar [16].

In humans, GLP-1 secretion is enhanced by glucose, triglycerides as well as (to a lesser degree) various amino acids in vivo [16]. The mechanisms of GLP-1 secretion have been further examined in an intestinal L-cell line, called GLUTag cells, as well as in primary rodent L-cell cultures [28]. In these experimental models, expression of the sulfonylurea receptor subunits Kir6.2 and SUR1 as well as glucokinase have been detected [29]. Furthermore, stimulation of GLP-1 release through SGLT1 transporters has been suggested [29]. There is also wide evidence for a role of G-protein coupled receptors (GPRs), especially GPR 40, GPR 120, and GPR 119, in GLP-1 secretion [29]. These receptors have been demonstrated to be of particular importance for fatty acid-induced GLP-1 secretion. Stimulation of GLP-1 secretion by bile acids has also been reported in different models. These effects have been suggested to be mediated through the G protein-coupled receptor TGR5, with subsequent rises in intracellular cAMP levels [30].

Various studies in rodent models have suggested that artificial sweeteners, such as saccharin, acesulfame potassium, d-tryptophan, and sucralose, also stimulate GLP-1 release by a newly discovered group of sweet taste receptors [31]. Human studies using the sweet taste receptor T1R2/T1R3 antagonist lactisole have confirmed a physiologic role of these receptors in GLP-1 secretion [32].

There might also be a paracrine inhibitory effect of locally produced somatostatin on L-cell secretion. Finally, recent studies in rodents have suggested a stimulation of GLP-1 release by interleukin-6 (IL-6) [33].

Degradation and elimination of incretin hormones

Following their intestinal secretion, the incretin hormones GIP and GLP-1 are subject to rapid proteolytic cleavage by the enzyme dipeptidyl-peptidase 4 (DPP-4) [34]. DPP-4 can be found throughout the vascular endothelium as well as circulating in the plasma [35]. Because endogenously secreted GLP-1 enters the intestinal capillary network first and is subsequently delivered into the portal venous circulation, only a minor proportion of GLP-1 reaches the systemic circulation in its intact form GLP-1 (7-36) amide, whereas ∼85% of the total GLP-1 concentration in the peripheral circulation is found in the (largely) inactive form GLP-1 (9-36) amide [36]. Thus; ∼75% of the secreted GLP-1 are inactivated already within the gut, and an additional 40 – 50% of the remaining GLP-1 undergo degradation during the first liver passage [36].

It has also been suggested that another circulating enzyme, neutral endopeptidase 22.11, contributes to the degradation of GLP-1 to a large extent (up to 50%) [37]. While proteolytic degradation is therefore apparently the most critical step in the inactivation of GLP-1, renal filtration is driving the final elimination of the intact peptide as well as the major metabolites [38]. The mechanisms of renal handling of GLP-1 seem to involve both glomerular filtration and tubular uptake and catabolism [38]. In line with this, human studies have revealed increased plasma concentrations of GLP-1 in patients with renal impairment [38]. The plasma half-life of GLP-1 was calculated as 2.3 ± 0.4 min for the intact peptide and 3.3 ± 0.4 min for the major metabolite GLP-1 (9-36) amide. The corresponding metabolic clearance rates were 2.42 ± 0.45 L min−1 and 0.64 ± 0.16 L min−1 for intact GLP-1 and the metabolite, respectively [38].

Like GLP-1, the intact peptide GIP (1-42) is primarily inactivated through proteolytic cleavage by DPP-4, yielding the major metabolite GIP (3-42), and both the intact peptide and the metabolite are subject to renal elimination [39]. The half-life of GIP is considerably longer than that of GLP-1 and has been calculated as 5.0 ± 1.2 min for the intact peptide and 22.4 ± 3.0 min for the metabolite. The respective metabolic clearance rates were 3.18 ± 0.62 L min−1 and 1.56 ± 0.27 L min−1 [38].

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