Alimentary tract and pancreas

Alimentarni trakt i pankreas

ARCH GASTROENTEROHEPATOL 2001; 20 ( No 3 – 4 ):

Review

The entroinsular axis

Enteroinsularna osovina

( accepted July 10th, 2001 )

¹Tatjana Radosavljevic, ²Vera Todorovic, ³Anna JudithNikolic, ¹Branka Sikic

¹Institute of Pathophysiology, School of Medicine, University of Belgrade,

²Institute for Medical Research, Department of Experimental Pathology and Cytology, University of Belgrade,

³INEP – Institute for the Application of Nuclear Energy, Zemun-Belgrade, ⁴Institute of Pathology, School of Medicine, University ogf Belgrade, Belgrade, Serbia, Yugoslavia.

Address correspondence to:

Docent Dr Tatjana Radosavljevi}

Institute of Pathophysiology,

School of Medicine, University of Belgrade,

Dr Subotica 1/II St.

YU-11000 Belgrade, Serrbia

Yugoslavia

FAX + 381 11 685 340

E-mail: [email protected]

……………………….. ………………………………

Enteroinsular axis Gastroenteroloska sekcija SLD-

O1711, 2001.

ABSTRACT

The entero-insular is a network of neural and endocrine communications between the alimentary tract and the pancreatic islets, which promotes insulin release in response to feeding. This review article describe of the major hormones of the enteroinsular axis, and mechanism of actions of this hormones.

Key words: enteroinsular axis, gut hormones, pancreatic islet of Langerhans

Sa`etak

Enteroinsularna osovina je mre`a endokrine i neuralne komunikacije izme|u gastrointestinalnog trakta i ostrvaca pankreasa koja omogu}ava osloba|anje insulina u zavisnosti od unosa hrane. U ovom revijskom ~lanku opisani su glavni hormoni enteroinsularne osovine i mehanisam dejstva.

Kljucne reci: enteroinsularna osovina, crevni hormoni, Langerhansova ostrvca.

The importance of gut-endocrine pancreas interaction on glucose metabolism was first reported by Claude Bernard about a century ago and outlined by Zunz and La Barre who used the term incretin as a hypoglycemic factor in the extract of duodenum (1). With increasing knowledge of the influence of the gut on the function of the pancreatic islet, Unger and Eisentraut 1969 unify these relations in the single concept: "enteroinsular axis" (2). The entero-insular axis is a network of neural and endocrine communications between the alimentary tract and the pancreatic islets, which promotes insulin release in response to feeding. This axis comprises variety of different interactions of the small intestine with the function of the islets of Langerhans. Figure 1. The different interactions can be of endocrine or neural origin, or caused directly by nutrients absorbed from the gut. Incretin concept encompasses GI hormonal interaction with glucose-induced insulin release from the pancreas. The components of the enteroinsular system, which are basic for the incretin effect, are the endocrine transmission in combination with substrate stimulation of the pancreatic islet by glucose (3, 4). Glucose-induced insulin release from pancreatic b-cells is modulated by a number of hormones and neurotransmitters, which may act as inhibitors and potentiators on b-cells function. In Table 1 is demonstrated localization, response to glucose and effect on insulin release of the gut hormones. Although the majority of hormones belonging to the secretin/glucagon family potentate glucose-stimulated insulin release, only two of all GI hormones are potent incretin: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (5,6). Both GIP and GLP-1 stimulate the secretion of insulin in the pancreatic b-cells and are therefore, likely to play important roles in the regulation of postprandial glucose homeostasis in man. GLP-1 represents one of the most potent endogenous peptides, which stimulates glucose-dependent insulin secretion (6, 7, and 8).

Glucagon-like peptide-1 (GLP-1)

If one consider GLP-1 as an incretin, this would imply that physiological increments of GLP-1 plasma concentrations are accompanied by evidence of stimulated insulin secretion during the postprandial phase of physiological hyperglycemia (9,10). Insulin release after plasma glucose concentration rise is greater when GLP-1 secretion is stimulated by the ingestion of various nutrients such as carbohydrates, glucose, fat and mixed meal and by the administration of various gut peptides and neurotransmitters including bombesin, enkephalin, galanin and GIP (11,12, 13, 14, 15).

If hypersecretion of insulin stimulated by incretin hormones is continuos, this may cause hypoglycemia. W.Creutzfeldt proposed a negative feed back control as a fail-safe system, of incretin hormones secretion by insulin (3). GLP-1 could be regulated by the negative feed back inhibition by hyperglycemia and hyperinsulinemia. Therefore, GLP-1 secretion could be regulated by blood glucose level and insulin (16). The interdependence between glucose and incretin actions involves a cross talk between glycolysis and cAMP signaling pathways of the activated GLP-1 receptor (17). Glucose competence concept has been used to describe the mutual interdependence between glucose metabolism and GLP-1 actions on b-cells (glucose is required for GLP-1 action and GLP-1 is required to render b-cells competent to respond to glucose) (9). Mechanism of action of GLP-1 is presented in Figure 2.

Glucagon-like peptid-1 (GLP-1) is gut hormone from the incretin family, which stimulates insulin secretion, and plays an important role as primary hormonal regulator of the entero-insular axis (3, 18,19,20). GLP-1 stimulates insulin secretion during hyperglycemia and suppresses glucagon secretion (20, 21). However, it is uncertain whether GLP-1 inhibits glucagon secretion by direct actions on a-cells or indirectly by its paracrine-inhibitory effects of insulin and somatostatin on a-cells (22). This perfectly fits with concept of intraislet hormonal interaction (7). GLP-1 stimulates transcription of proinsulin gene and biosynthesis of insulin. Recent evidence indicates that GLP-1 may stimulate proliferation and neogenesis of b-cells (9). Moreover, GLP-1 decreases gastric emptying rate and acid secretion, and has pro-satiety effect (23, 24). On fat, muscle and liver, GLP-1 induce lipogenesis and glycogenesis ("insulinomimetic" actions of GLP-1). GLP-1 is an excellent candidate for the treatment of patients with type 2 diabetes mellitus (9, 10, 19, 25, 26).

GLP-1 is released into the portal circulation in response to a meal. This hormone exhibits insulinotropic action when combined with tGLP-1 pancreatic islet receptors. The hepatic vagal nerve branches, which possess specific neural tGLP-1 receptors, may fix tGLP-1 from the portal blood through a mechanism mediated by specific receptor for this hormone. When this occur, hepatic vagal afferent neural activity is facilitated/augmented what leads to further facilitation/augmentation of efferent vagal neural activity in its pancreatic vagal branches, revealing a novel vagal hepatopancreatic reflex pathway. The neural reception of tGLP-1 involves a receptor mechanism distinct from that in the well-known humoral insulinotropic action. tGLP-1 plays a role as neuroincretin in the enteroinsular axis, which is in concordance with concert of its role as humoral incretin (27, 28, 29).

Leptin, the obesity hormone produced by cells from the adipose tissue, has opposite actions to GLP-1 on pancreatic b-cells. Leptin suppresses insulin secretion and gene expression. The feedback loop between leptin and insulin constitutes an adipoinsular axis that operates physiologically in parallel with the enteroinsular axis, which involves GLP-1 and insulin (9). Disruption of either axis lead to glucose intolerance. Leptin inhibits glucose- and GLP-1-stimulated insulin secretion by activation of phosphodiesterase 3B on b-cells (30).

Glucose-dependent insulinotropic polypeptide (GIP)

GIP is a peptide produced by K-cells of the mammalian proximal small intestine, which stimulates insulin release in the presence of hyperglycemia. Using GIP (7-30)-N which is specific receptor antagonist of naturally occurring GIP, inhibition of insulin release occur thus indicating that GIP may have a dominant role in mediating postprandial insulin secretion (5). GIP together with other gut hormones or meal stimulated neurotransmission, might contribute to enchanted insulin secretion. Under conditions of pathologic hyperglycemia, GIP may act a "fail-safe" mechanism (31). GIP has been found to be a very weak stimulator of somatostatin secretion. D-cells seem to be less sensitive to GIP than the b-cells, and the D-cells are much less sensitive to GIP, than to GLP-1. This phenomenon might explain the contrasting effects of GIP and GLP-1 on glucagon release (7).

Cholecystokinin (CCK)

The gut hormone, CCK is released from the intestinal I-cells after meal and in pancreatic islets. In pancreatic islets, CCK activates specific CCK-receptors and stimulates insulin secretion (32). CCK stimulate insulin secretion through an effect which involves mediation by phospholipase C (PLC) and protein kinase C (PKC), and partially mediated by a pathway involving phospholipase A2 (PLA2) with subsequent formation of arachidonic acid (AA) (33).

Insulinotropic action of the gastrointestinal neuropeptides: vasoactive intestinal polypeptide (VIP), and gastric releasing peptide (GRP)

VIP is localized in ganglia and nerve fibers of many organs, including gut and pancreas, but not in epithelial cells, and therefore acts only as neurotransmitter. VIP causes a prompt increase of insulin secretion, which is followed by a prolonged continuation of increased release (34).

GRP is confined to intrapancreatic nerves of the islets and the ganglia. This peptide acts as an intrapancreatic neurotransmitter, stimulating insulin release both directly through an action on the b-cells and indirectly through activation postganglionic cholinergic nerves by an action at the ganglionic level (35).

Somatostatin

Somatostatin (SS) is the brain-gut hormones, distributed in CNS and peripheral nervous systems as well as in the pancreas and gastrointestinal tract (36, 37). SS-28, secreted into the circulation from enterocytes after food, and SS-14, released from gastric and pancreatic D cells, and enteric neurons inhibit the release of a variety of peptides and neurotransmitters (38). SS-28 is potent inhibitor of insulin release, with a high affinity for b-cells (39). SS-28 participates in the enteroinsular axis as a decretin to regulate postprandial insulin secretion that controls enchanced insulin release in response to absorbed nutrients and secreted incretins during to early phases of alimentation. This leads to proper regulation of waning of insulin to avoid unwanted hypoglycemia (38).

Splanchnic organs are known to be the major source of circulating SS. It suggests that peptide hormones secreted from the splanchnic organs acts on its own specific receptor on the afferent vagal nerve in the hepatoportal area. This neural monitoring system which important parts are SS and GLP-1, convert humoral information to neural information through the unique receptor mechanism in the hepatoportal area (40).

Secretin

The secretin-producing cells are localized in the proximal part of the small intestine. Intraluminal secretion concentrations go up in the interdigestive period following a mixed meal. Secretin stimulates glucose-induced insulin release. Moreover, this hormone exhibited a glucose-dependent stimulation of glucagon and somatostatin secretion (4). Secretin-induced glucagon release could implicate glucagon as an intermediate paracrine or endocrine hormone in the potentiation of insulin release.

Glucose-induced insulin release from the pancreatic b-cell is controlled by three regulatory pathways involving changes in cytosolic Ca²⁺ concentration, intracellular concentration of cAMP, diacylglicerol and inositol phosphates depending on the activation of protein kinase A, B and C. Secretin stimulated glucose-dependent insulin release by interacting with the intracellular cAMP-dependent pathway (4).

Figure 2. Mechanism of action of GLP-1

Figure 1. Entero-insular axis

(Creutzfeldt and Ebert, 1986; Kofod, 1992)

Table 1. Familyes of gastrointestinal hormones


Family	Localization	insulin release	released by glucose

Secretin / glucagon
Secretin	intestine	yes	yes
Glucagon	Pankreas	yes	no
GLP-1 (7-36) amid	intestine	yes	yes
GLP-2	intestine	no	yes
GIP	intestine	yes	yes
VIP	intestine	yes
PHI	intestine	yes
Cholecystokinin / gastrin
Cholecystokinin	intestine	yes	no
Gastrin	intestine	yes	Very litle
PP group
PP	pancreas
PYY	intestine	no
NPY	brain	no
Tachikinins
Substance P	intestine	inhibits	yes
Opioids	intestine	yes
Bombesin – GRP	intestine	yes
Somatostatin	intestine	inhibits	yes
	pancreas

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