The role of gut hormones in glucose homeostasis (original) (raw)

Proglucagon-derived peptides (PGDPs) are generated by differential posttranslational processing of the precursor proglucagon in the pancreas, intestine, and brain. Although glucagon is the principal PGDP produced in α cells of the islets, prohormone convertase 1 (PC1) generates glicentin, oxyntomodulin, GLP1, and GLP2 from proglucagon in enteroendocrine L cells. The importance of PC1 processing of proglucagon in enteroendocrine L cells is illustrated by the phenotype of PC1-deficient mice, which exhibit multiple defects in prohormone processing, including a lack of substantial amounts of mature bioactive GLP1 and GLP2. Although most PGDP-expressing cells are located in the distal bowel and colon, there are also cells in the more proximal regions of the small bowel that produce both GLP1 and GIP.

Nutrient ingestion potently upregulates intestinal expression of the gene encoding proglucagon and the secretion of PGDPs, and a high-fiber diet (26), protein hydrolysates, and short-chain fatty acids increase levels of mRNA encoding proglucagon in enteroendocrine L cells (27, 28). Intestinal injury and resection are both associated with elevated circulating levels of PGDPs and increased levels of proglucagon mRNA in the remnant intestine (29, 30). PGDP secretion by enteroendocrine L cells is stimulated by neural signals, peptide hormones such as GIP (in rodents but not humans), and direct nutrient contact (31).

GLP1. GLP1 circulates as 2 equipotent forms, GLP17-37 and GLP17-36amide (32–34), but most circulating GLP1 in humans is GLP17-36amide (35). Plasma levels of full-length GLP1 are typically within the 5- to 10-pM range in the fasting state and increase to approximately 50 pM after meal ingestion (35, 36). A small, but detectable, defect in meal-stimulated GLP1 secretion has been observed in subjects with obesity or T2DM about 60–120 minutes after food consumption (36). Clearance of GLP1 has received considerable attention because of the therapeutic potential of the peptide. The half-life of circulating native bioactive GLP1 is less than 2 minutes (37, 38), mostly because it is cleared by the kidney and degraded by DPP4.

GLP1 exerts multiple physiological actions leading to control of energy intake and nutrient assimilation (1) (Table 1). The original physiological role described for GLP1 was that of an incretin hormone that stimulates insulin secretion in a glucose-dependent manner (39–41). GLP1 also increases transcription of the gene encoding insulin and enhances both the stability of the mRNA encoding insulin and biosynthesis of insulin by mechanisms that involve pathways that are both dependent on and independent of cAMP and protein kinase A, as well as pathways that increase the intracellular concentration of Ca2+ (Table 1). GLP1 also improves β cell function by inducing increased expression of sulfonylurea receptor and inwardly rectifying K+ channel (KIR6.2) in β cells. It also prevents the downregulation of mRNA encoding KIR6.2 and the downregulation of ATP-sensitive K+ channel activity induced by high levels of glucose.

The physiological importance of endogenous GLP1 has been demonstrated using GLP1R antagonists, immunoneutralizing antisera, and_Glp1r_–/– mice. Elimination of GLP1 activity with GLP1-immunoneutralizing antisera or the GLP1R antagonist exendin9–39, which is a truncated form of the lizard GLP1-related peptide exendin-4, results in impaired glucose tolerance, and diminished glucose-stimulated insulin levels in both animals and humans (17, 42–44). Furthermore, basal GLP1 signaling in the fasting state is essential for regulation of glucose homeostasis, because infusion of exendin9-39 increases levels of fasting glucose and glucagon in human subjects, demonstrating that even low basal levels of GLP1 exert a tonic inhibitory effect on glucagon-secreting α cells (45). Similarly,_Glp1r_–/– mice are glucose intolerant and have defective glucose-stimulated insulin secretion and fasting hyperglycemia (46).

The insulinotropic and glucagonostatic effects of GLP1 depend on elevated levels of plasma glucose, thereby reducing the likelihood that treatment of diabetic subjects with GLP1R agonists would lead to hypoglycemia. In in vitro islet studies, GLP1 confers glucose sensitivity to β cells and improves the number of β cells able to respond to glucose. However, GLP1R signaling is not essential for β cells to sense glucose in mouse islets (47). The demonstration that GLP1 upregulates molecular components of the glucose-sensing system in β cells (that is, glucose transporters, ATP-sensitive K+ channels, and glucokinase) might provide a partial mechanism for understanding the effects of GLP1 on the glucose responsiveness of β cells (48, 49). Furthermore, short-term exposure to GLP1R agonists markedly improves glucose-stimulated insulin secretion in patients with T2DM (50–52).

GLP1 also promotes the proliferation and neogenesis of β cells, reduces β cell apoptosis, and increases differentiation of exocrine-like cells toward a more differentiated β cell phenotype (2, 53–57). Conversely, elimination of mouse GLP1R signaling is associated with reduced numbers of large β cell clusters and alterations in α cell topography (58). Furthermore, following partial pancreatectomy,_Glp1r_–/– mice exhibit a reduced adaptive islet-regenerative response and greater hyperglycemia than littermate controls (59)._Glp1r_–/– mice are also more sensitive to the cytotoxic and diabetogenic actions of streptozotocin (60). The signal transduction pathways whereby GLP1 mediates its proliferative effects have not been completely defined but involve PI3K, EGFR transactivation, and p38 MAPK and PKCζ (61, 62). Furthermore, GLP1 also activates a transcriptional program critical for cell survival; and pancreatic and duodenal homeobox gene 1 (PDX1), FOXO1, and insulin receptor substrate 2 (IRS2) have been identified as essential downstream targets for GLP1R-dependent cytoprotection in β cells (60, 63, 64). GLP1 also reduces the expression of proapoptotic genes, enhances glucose-stimulated insulin secretion, and prevents apoptosis induced by high levels of glucose and/or palmitate in human β cells through mechanisms involving AKT (65, 66).

Biological actions of glicentin, oxyntomodulin, and GLP2. Glicentin is a 69–amino acid PGDP that contains the 29–amino acid sequence of glucagon flanked by peptide extensions at both the amino and the carboxyl terminus. Although secreted together with GLP1 and GLP2 from enteroendocrine L cells, glicentin has not been shown to regulate glucose homeostasis. Oxyntomodulin also contains the 29–amino acid sequence of glucagon with an additional 8–amino acid carboxy-terminal extension. Oxyntomodulin stimulates intestinal glucose uptake (67) and insulin secretion (68) and inhibits gastric emptying, food intake, and meal-stimulated gastric acid secretion. Oxyntomodulin also induces satiety, inhibits food intake, and increases energy expenditure in humans (69, 70). Although oxyntomodulin is a weak agonist of both GLP1R and the glucagon receptor, the anorectic actions of oxyntomodulin are blocked by the GLP1R antagonist exendin9-39 (71) and are eliminated in the absence of a functional GLP1R (72). Therefore, it seems that many of the pharmacological actions of oxyntomodulin represent heterologous activation of related PGDP receptors.

GLP2 is a 33–amino acid peptide secreted with GLP1 from enteroendocrine cells in a nutrient-dependent manner. GLP2 rapidly induces hexose transport in jejunal basolateral membrane vesicles (73). The main biological consequence of exogenous GLP2 administration is expansion of the mucosal epithelium in the small bowel. The intestinotrophic actions of GLP2 have been demonstrated in rodents with intestinal injury (74, 75) and in humans with short bowel syndrome (76–78). Although acute GLP2 administration increased levels of plasma glucagon, triglycerides, and FFAs in the postprandial state (79), there is no evidence that acute or chronic GLP2 administration directly regulates insulin secretion or glucose homeostasis in humans (76).