The complex mechanisms that have evolved to enable changes in extracellular nutrients to initiate an exocytotic secretory response are confined to islet β cells, and perhaps to a subset of hypothalamic neurons. However, the mechanisms that β cells use to recognize and respond to non- nutrient potentiators of secretion are ubiquitous in mammalian cells, and so are covered only briefly in this section, followed by a review of the physiologically relevant non- nutrient regulators of β- cell function.

Most, if not all, non- nutrient modulators of insulin secretion influence β cells by binding to and activating specific receptors on the extracellular surface. Because of their central role in coordinating whole- body fuel homeostasis, β cells express receptors for a wide range of biologically active peptides, glycoproteins, and neurotransmitters (Table 1), and quantitative reverse transcriptase polymerase chain reaction (RT- PCR) analysis has indicated that human islets express 293 different G- protein- coupled receptors. However, receptor occupancy generally results in the activation of a limited number of intracellular effector systems, which were introduced in the section ‘Nutrient- Induced Insulin Secretion’ (Figures 1 and 2).

Table1. Key non- nutrient regulators of insulin secretion.

Fig1. Adenylate cyclase and the regulation of insulin secretion. Some receptor agonists (e.g. glucagon, glucagon- like peptide- 1, pituitary adenylate cyclase- activating polypeptide) bind to cell- surface receptors that are coupled to adenylate cyclase (AC) via the heterotrimeric GTP- binding protein Gs. Adenylate cyclase hydrolyses adenosine triphosphate (ATP) to generate adenosine 5′ cyclic monophosphate (cAMP), which activates protein kinase A (PKA) and exchange proteins activated by cAMP (EPACs). Both of these pathways potentiate glucose- stimulated insulin secretion. Glucose also activates adenylate cyclase, but increases in intracellular cyclic AMP levels in response to glucose are generally smaller than those obtained with receptor agonists. Some inhibitory agonists (e.g. norepinephrine, somatostatin) bind to receptors that are coupled to adenylate cyclase via the inhibitory GTP- binding protein Gi, resulting in reduced adenylate cyclase activity and a decrease in intracellular cAMP.

Fig2. Phospholipase C and the regulation of insulin secretion. Some receptor agonists (e.g. acetylcholine, cholecystokinin) bind to cell- surface receptors that are coupled to phospholipase C (PLC) via the heterotrimeric GTP- binding protein Gq. Phospholipase C hydrolyses phosphatidylinositol bisphosphate (PIP2), an integral component of the membrane, to generate inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes calcium from the endoplasmic reticulum and DAG activates protein kinase C (PKC), both of which enhance insulin secretion. Nutrients also activate PLC in a calcium- dependent manner, but the importance of IP3 and DAG in nutrient- induced insulin secretion is uncertain.

Islet hormones

There is convincing evidence for complex intra- islet interactions via molecules released from islet endocrine cells. The physiological relevance of some of these interactions is still debated, but some of the intra- islet factors that influence insulin secretion are discussed briefly in this section.

It is clear that β cells express insulin receptors and the associated intracellular signalling elements, suggesting the existence of autocrine and/or paracrine feedback regulation of β- cell function. Earlier suggestions that secreted insulin regulates insulin secretion have not been confirmed, and the physiological rationale of a positive feedback loop for insulin to promote further insulin release is questionable. The main autocrine function of insulin on β cells is to regulate β- cell gene expression and β- cell mass through effects on proliferation and apoptosis.

Glucagon is a 29 amino acid peptide secreted by islet α cells. The precursor, proglucagon, undergoes differential post- translational processing in the gut to produce entirely different peptides with different receptors and biological activities. These include GLP- 1 (7–36) amide, an incretin hormone, and GLP- 2, which promotes growth of the intestinal mucosa. Although glucagon is the major proglucagon product in islet α cells, a subpopulation of human α cells also synthesizes and secretes GLP- 1, presumably to exert local effects within islets. Glucagon secretion is regulated by nutrients, islet and gastrointestinal hormones, and the autonomic nervous system, with hypoglycaemia and sympathetic nervous input being important stimulators of glucagon secretion. Glucagon enhances insulin secretion through the stimulatory G- protein (Gs)–coupled activation of adenylate cyclase and the consequent increase in intracellular cAMP (Figure 1).

Somatostatin (SST) is expressed by islet δ cells and in numerous other sites, including the central nervous system (CNS) and D cells of the gastrointestinal tract, where it acts predominantly as an inhibitor of endocrine and exocrine secretion. The precursor, pro- somatostatin, is processed by alternative pathways: in islets and the CNS SST- 14 is generated, while SST- 28, the major circulating form of somatostatin in humans, is produced in the gastrointestinal tract. Somatostatin secretion is regulated by numerous nutrients and endocrine and neural factors. Islets express five different somatostatin receptor (SSTR) subtypes, and SST- 14 released from islet δ cells has a tonic inhibitory effect on insulin and glucagon secretion, via activation of SSTR5 and SSTR2, respectively. Somatostatin receptors are coupled via an inhibitory G- protein (Gi) to the inhibition of adenylate cyclase and decreased formation of cAMP (Figure 1), and to ion channels that cause hyperpolarization of the β- cell membrane and reductions in intracellular calcium. Live cell imaging studies in rodent and human islets have shown that δ cells possess motile, neural- like processes that enable individual δ cells to reach, and potentially regulate, a large number of β cells within an islet.

Pancreatic polypeptide (PP) is a 36 amino acid peptide produced by PP cells that are found in the mantle of islets, predominantly those located in the head of the pancreas. PP secretion is mainly regulated via cholinergic parasympathetic stimulation, but the physiological function of PP as a circulating hormone, or as an intra- islet signal, is uncertain. Peptide YY (PYY), which is structurally related to PP, is also expressed in islets, mainly by sub populations of PP- and δ cells. PYY inhibits insulin secretion via the NPY family of receptors, the most abundant of which is Y1 in both mouse and human islets. Ablation of PYY- expressing cells in vivo causes β- cell destruction and induction of diabetes, suggesting a role for islet PYY in maintaining β- cell mass.

Ghrelin is a 23 amino acid peptide first identified in the gastro intestinal system, but now known to be expressed in islet ε cells that are localized to the islet mantle in rodents, and appear to be developmentally distinct from the classic islet endocrine cells. The physiological function of ε- cell–derived ghrelin has not been fully established, but most experimental evidence suggests an inhibitory role in the regulation of insulin secretion, analogous to that of δ- cell somatostatin. The inhibitory mode of action of ghrelin has been identified as being via GHSR1a receptors, leading to indirect opening of KATP channels and β- cell membrane hyperpolarization. The recent observations that the ghrelin receptor GHSR shows high co- expression with PP in islets and that its inhibition in vivo results in increased circulating PP add another layer of complexity to islet paracrine signalling.

Neural control of insulin secretion

The association of nerve fibres with islets was shown over 100 years ago by silver staining techniques. Since that time it has become well established that both mouse and human islets are innervated by cholinergic, adrenergic, and peptidergic autonomic nerves and that the central and autonomic nervous systems are important regulators of islet hormone secretion. Coordination between the brain and the islets is required for normal glucose homeostasis, such that defects in this cooperative system may be associated with the development of type 2 diabetes.

The neural pathways regulating autonomic outflow to the islets have been mapped in detail. Parasympathetic (cholinergic) fibres originate in the dorsal motor nucleus of the vagus, while sympathetic nervous system motor neurons (adrenergic) are located in the intermediolateral column of the spinal cord. The activity of both parasympathetic and sympathetic input to islets is regulated by neural input from multiple regions of the hindbrain, midbrain, and forebrain.

Neurotransmitters: acetylcholine and norepinephrine

Acetylcholine is the major post- ganglionic parasympathetic neuro transmitter, and it stimulates the release of insulin and glucagon in many mammalian species. Acetylcholine is also synthesized in and secreted from α cells in human islets, where it primes the β cells to respond optimally to increases in glucose. Acetylcholine acts predominantly via M3 receptors in β cells to activate PLC (Figure 2), generating IP3 and DAG, which act to amplify the effects of glucose by elevating cytosolic calcium and activating PKC. Activation of β- cell muscarinic receptors can also lead to PLA2 activation, with the subsequent generation of arachidonic acid and lysophosphatidylcholine, which can further enhance nutrient- induced insulin secretion. Acetylcholine also depolarizes the plasma membrane by affecting Na+ conductivity, and this additional depolarization induces sustained increases in cytosolic calcium.

The major sympathetic neurotransmitter norepinephrine (noradrenaline) can exert positive and negative influences on hormone secretion. Thus, norepinephrine can exert direct stimulatory effects on β cells via β2- adrenoreceptors, or inhibitory effects via α2- adrenoreceptors, and the net effect of norepinephrine may depend on the relative levels of expression of these receptor subtypes. Differences between species in the expression levels of adrenoreceptor subtypes probably account for the differential effects of β- adrenergic agonists on human islets, where they are stimulatory, and rodent islets, where they are ineffective. The stimulatory effects mediated by β2- receptors occur by activation of adenylate cyclase and an increase in intracellular cAMP (Figure 1), while the inhibitory effect of α2- receptor activation involves reductions in cAMP and of cytosolic calcium, and an unidentified inhibitory action at a more distal point in the stimulus–secretion coupling mechanism. Increased expression of α2A adrenoreceptors and decreased insulin secretion are a consequence of a SNP in the human α2A receptor gene [126], and an α2A receptor antagonist has been used to improve the insulin secretion deficiency in individuals with type 2 diabetes. In contrast to the inhibitory effects of norepinephrine on insulin release, it has direct stimulatory effects on glucagon secretion from α cells mediated by both β2- and α2- receptor subtypes. Circulating catecholamines secreted by the adrenal medulla (mainly epinephrine) also have the potential to influence islet hormone secretion through interactions with the adrenoreceptors expressed on the α and β cells.

Neuropeptides

Parasympathetic nerve fibres in islets contain biologically active neuropeptides, including VIP, PACAP, and gastrin- releasing poly peptide (GRP), all of which are released by vagal activation and stimulate the release of insulin and glucagon.

VIP (28 amino acids) and PACAP (27 or 38 amino acids) are abundantly expressed neuropeptides that are widely distributed in parasympathetic nerves that supply the islets and gastrointestinal tract. VIP and PACAP have similar structures, and VIP1 and VIP2 receptors also have an affinity for PACAP. The stimulatory effects of VIP and PACAP on insulin secretion in vitro and in vivo are through β- cell VIP2 and PAC1 receptors, respectively, and involve increases in intracellular cAMP (Figure 1) and cytosolic calcium. GRP is a 27 amino acid peptide that also stimulates the secretion of insulin, glucagon, somatostatin, and PP. These effects of GRP are mediated through specific receptors, and involve the activation of PLC and the generation of IP3 and DAG (Figure 2).

Sympathetic nerves contain different neuropeptides to parasympathetic nerves, including NPY and galanin, both of which have inhibitory actions within islets. NPY (36 amino acids) and galanin (29 amino acids) are expressed in fibres innervating both the endocrine and exocrine pancreas. Both neuropeptides inhibit basal and glucose- stimulated insulin secretion, although differences between species have been reported. Both NPY and galanin act through specific Gi- coupled receptors to inhibit adenylate cyclase, and galanin may have additional inhibitory effects at an undefined late stage of exocytosis.

Regulation of insulin secretion by gut- and adipose- derived factors

Incretins

It has been known for over 50 years that insulin secretion from islets is greater following oral rather than intravenous administration of glucose and it is now known that this enhanced insulin secretory output is a consequence of the release of gastrointestinal- derived incretin hormones. The main incretins that have been implicated in an elevated insulin response to absorbed nutrients after food intake are GLP- 1, glucose- dependent insulinotropic pep tide (GIP), and cholecystokinin (CCK), all of which are hormones secreted by specialized endocrine cells in the gastrointestinal tract in response to nutrient absorption. These hormones are carried to the islets in the blood and they interact with specific receptors on the β- cell surface to stimulate insulin secretion.

Glucagon- like peptide 1

After food intake, L cells of the distal gastrointestinal tract secrete GLP- 1 in response to elevated levels of nutrients derived from carbohydrates, lipids, and proteins in the intestinal lumen. GLP- 1 is generated by prohormone convertase 1–3 cleavage of pro glucagon in the L cells and it is highly conserved in mammals, with identical amino acid sequences in humans and mice. GLP- 1 is degraded by dipeptidyl protease 4 (DPP- 4), which cleaves two amino acids from its N- terminus. Full- length GLP- 1 (1–37) does not show biological activity, but the truncated peptides GLP- 1 (7–36) amide and GLP- 1 (7–37) are potent stimulators of insulin secretion in vitro and in vivo. Observations that infusion of the peptide into individuals with type 2 diabetes before food intake improved insulin output and reduced the post- prandial increase in circulating glucose led to studies to determine whether GLP- 1 or related peptides may be useful as therapies for type 2 diabetes. Reports of other beneficial effects of GLP- 1, including its capacity to inhibit glucagon secretion, delay gastric emptying, and decrease food intake, indicated its positive effects on normalizing post- prandial glycaemia, but its half- life of less than 2 minutes precludes its use as a diabetes therapy. Nonetheless, exenatide, which is present in the saliva of the Gila monster lizard and has ~50% amino acid homology with GLP- 1, has been developed for clinical use for type 2 diabetes. Exenatide exerts the same effects on islets as native GLP- 1, but its resistance to degradation by DPP- 4 increases its half- life to ~2 hours in vivo, which ensures effective regulation of blood glucose levels. Another GLP- 1 receptor agonist, liraglutide, has a greatly extended half- life ( > 12 12 hours) as a result of incorporation of the fatty acid palmitate into the GLP- 1 sequence, allowing it to bind to plasma albumin and reducing its exposure to DPP- 4. More recently, an oral GLP- 1 receptor agonist formulation (oral semaglutide) has been approved for clinical use and this provides a major advantage over other GLP- 1 receptor agonists, which are administered by subcutaneous injection. Selective DPP- 4 inhibitors, such as sitagliptin, are used clinically to treat type 2 diabetes by extending the half- life of endogenous GLP- 1. GLP- 1 and GLP- 1 receptor agonists act at islet GLP- 1 receptors that are linked, via Gs, to adenylate cyclase activation (Figure 1). Elevations in cAMP following GLP- 1 receptor activation potentiate glucose- induced insulin secretion via activation of both PKA and EPACs. Improved glucose homeostasis following bariatric gastric bypass surgery results, at least in part, from more rapid delivery of food to the L cells through a shorter gastrointestinal tract, which leads to enhanced post- prandial GLP- 1 secretion.

Glucose- dependent insulinotropic peptide

 GIP, a 42 amino acid peptide, is released from K cells in the duodenum and jejunum in response to the absorption of glucose, other actively transported sugars, amino acids, and long- chain fatty acids. It was originally called gastric inhibitory polypeptide because of its inhibitory effects on acid secretion in the stomach, but its main physiological effect is now known to be stimulation of insulin secretion in a glucose- dependent manner. GIP receptors, like those activated by GLP- 1, are coupled to Gs, with essentially the same downstream cascades leading to stimulation of insulin secretion (Figure 1). Although GLP- 1 and GIP both enhance insulin output following their release in response to food intake, development of GIP- related peptide monotherapies for type 2 diabetes is unlikely because GIP stimulates glucagon secretion and inhibits GLP- 1 release, and its infusion in individuals with type 2 diabetes worsens post- prandial hyperglycaemia. However, a GLP- 1/GIP receptor co- agonist is more effective in normalizing glycaemia and stimulating weight loss in people with type 2 diabetes than a GLP- 1 analogue, most likely as a consequence of stimulation of GIP receptor signalling pathways in the CNS.

Cholecystokinin

 CCK is another gastrointestinal hormone that is released from I cells in response to elevated fat and protein levels. It was originally isolated from porcine intestine as a 33 amino acid peptide and the truncated CCK- 8 form stimulates insulin secretion in vitro and in vivo. CCK- 8 acts at specific Gq- coupled receptors on β cells to activate PLC (Figure 2), and its potentiation of insulin secretion is completely dependent on PKC activation. However, the physiological role of CCK as an incretin has not been established because high concentrations are required for its effects on insulin secretion, and it is possible that its major function in humans is in digestion in the duodenum.

Bile acids

Bile acids act as endocrine factors to enable signalling between the gut and other tissues involved in metabolic homeostasis, including islet cells. They signal via the nuclear receptor farnesoid- X receptor (FXR) and the G- protein–coupled receptor TGR5, both of which are expressed in islets. TGR5 activation stimulates insulin secretion from mouse and human islets in vitro, but in vivo studies using transgenic mice suggest that FXR mediates most, if not all, of the effects of bile acids to enhance insulin secretion. The composition and plasma concentrations of bile acids are altered by gastric bypass surgery, perhaps as a consequence of changes in the gut microbiome, and these changes have been linked to improved β- cell function and metabolic regulation. However, a recent study in which an FXR- and TGR5- activating bile acid and a bile acid sequestrant were delivered to individuals after gastric bypass surgery reported only a limited role for bile acids in acute glucose regulation.

Decretins

 Starvation studies in humans and other mammals suggest the existence of gut- derived factors that are released post- prandially to suppress insulin secretion and thus prevent post- prandial hyperin sulinaemic hypoglycaemia, these factors being referred to as decretins or anti- incretins . Studies in baboons first identified gut- derived SST- 28 as a putative decretin by demonstrating that immunoneutralization of SST- 28 caused elevations in post- prandial plasma insulin concentrations. Foregut- derived dopamine has also been proposed as a physiological decretin that is released post- prandially to inhibit glucose- and GLP- 1- stimulated insulin secretion. In Drosophila the neuropeptide limostatin acts as a decretin by suppressing the activity of insulin- producing cells and reducing the secretion of Drosophila insulin- like pep tides. The mammalian homologue of limostatin is neuromedin U (NMU), a neuropeptide that is expressed in foregut enteroendocrine cells, and is proposed to act as a decretin by sup pressing glucose- induced insulin secretion from human islets through a specific β- cell receptor, NMUR1. However, intravenous delivery of neuromedin to rats does not affect insulin secretion or blood glucose levels. The same study reported that neuromedin receptors are not expressed by rat or human islets, raising doubts about the decretin status of neuromedin, but NMUR1 has been identified in human islets in another study. While decretins may be important in the pathophysiology of type 2 diabetes, most studies have been carried out in rodent models and it is clear that full understanding requires further research, including human clinical studies.

Adipokines

Obesity is a risk factor for diabetes, and hormones (adipokines) released from fat depots have been implicated in insulin resistance associated with obesity and type 2 diabetes. Some adipokines, such as leptin, resistin, and adiponectin, are also reported to influence islet function. Thus, β cells express Ob- Rb leptin receptors, which, when activated by leptin, lead to inhibition of insulin secretion, and specific deletion of β- cell Ob- Rb receptors is associated with enhanced insulin secretion. The inhibitory effects of leptin on glucose- stimulated insulin secretion have been attributed to activation of β- cell KATP channels or of c- Jun N- terminal kinases (JNKs). Leptin may also further impair β- cell function through reductions in β- cell mass. Resistin, another adipocyte poly peptide, also inhibits glucose- stimulated insulin release and stimulates apoptosis of rat β cells, suggesting that it has similar functions to leptin. However, resistin is not considered to be a true adipokine because, although it is secreted at high levels from mouse adipocytes, it is not produced by human adipocytes, and high plasma resistin levels do not correlate with reduced insulin sensitivity. Nevertheless, it is possible that resistin has paracrine effects on β- cell function in humans as it has been identified in human islets. Unlike leptin and resistin, adiponectin has protective effects by improving insulin sensitivity, and decreased plasma adiponectin levels may contribute to the development of type 2 diabetes . Human and rat β cells express AdipoR1 and AdipoR2 adiponectin receptors, and adiponectin is reported to stimulate insulin secretion, protect against β- cell apoptosis, and stimulate β- cell regeneration. The signalling cascades that couple adiponectin receptors to downstream effects in β cells have not been fully defined, but adiponectin is reported to activate the kinases Erk and Akt in islets, and it also stimulates expression of genes that regulate lipid transport and metabolism. Other less well- known adipokines, such as adipsin, apelin and chemerin, have also been implicated in improved insulin secretion, via activation of β- cell G- protein–coupled receptors.

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مواضيع ذات صلة

Glucagon actions in the liver: amino acid metabolism and the hepatic–α- cell axis

Glucagon actions in the liver: glucose and lipid metabolism

Regulation of α- cell secretion

Regulation of insulin secretion

Islet structure and function

الجلوكاجون Glucagon

هرمون الانسولين

المرض السكري (Diabetes Mellitus)

الغدة البنكرياسيةThe Pancreas