1. INTRODUCTION:

Peptides are naturally occurring short chains of amino acid monomers connected by amide bonds. Proteins are the most abundant organic molecules in animals, playing important roles in all aspects of cell structure and function. Proteins are biopolymers of acids, so named because the amino group is bonded to the carbon atom, next to the carbonyl group. The physical and chemical properties of a protein are determined by its constituent amino acids. The individual amino acid subunits are joined by amide linkages called peptide bonds.

Pancreatic polypeptide (PP) is a hormone predominantly secreted by the ventral pancreas .Its release is stimulated by fasting, administration of cholecystokinin, insulin-induced hypoglycemia, and ingestion of a mixed meal The increase in PP levels in response to protein and fat ingestion (i.e. a mixed meal) has an initial peak at 30 min, and persists for up to 3 h after a meal. In other words, any substance of which molecules is structurally like those smaller proteins. Peptides include many antibiotics, hormones and other substances that involve in the biological functions of living beings.

Peptides separated from proteins on the basis of size. These are comprised of multiple polypeptides that are placed in a biologically functional way [1-3].

There are many types of peptides; Di- peptide is the shortest peptides which consist of only two amino acids connected by one peptide bond. A polypeptide is a continuous long and single peptide chain. Therefore, it can be stated that peptides belong to a broad category of biological polymers and oligomers.

2. THE DISCOVERY OF A PEPTIDE:

Kimmel (1968) discovered PP whilst purifying insulin from chicken pancreas. Subsequent to extraction of avian pancreatic polypeptide (aPP), mammalian homologues bovine (bPP), porcine (pPP), ovine (oPP) and human (hPP), were isolated by Lin and Chance (Kimmel, Hayden and Pollock, 1975) [4].

Classification of Peptides:

Peptides are divided into several classes depending their production, which are described below as:

(a) Milk peptides:

Two naturally occurring milk peptides are formed from the milk protein casein when digestive enzymes break this down; they can also arise from the proteinases formed by lactobacilli during the fermentation of milk [5].

(b) Ribosomal peptides:

Ribosomal peptides are synthesized by translation m RNA. They are often subjected to proteolysis to generate the mature form. These function, typically in higher organisms, as hormones and signaling molecules. Some organisms produce peptides as antibiotics, such as microns [6]. Since they are translated, the amino acid residues involved are restricted to those utilized by the ribosome.

However, these peptides frequently have post translational modifications such as phosphorylation, hydroxylation, sulfonation, palmitoylation, glycosylation and disulfide formation. In general, they are linear, although lariat structures have been observed. [7] More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom [8].

(c) Non ribosomal peptides:

Non ribosomal peptides are assembled by enzymes that are specific to each peptide, rather than by the ribosome. The most common non-ribosomal peptide is glutathione, which is a component of the antioxidant defenses of most aerobic organisms. [9] Other non-ribosomal peptides are most common in unicellular organisms, plant, and fungi and are synthesized by modular enzyme complexes called non-ribosomal peptide synthetases [10].

These complexes are often laid out in a similar fashion, and they can contain many different modules to perform a diverse set of chemical manipulations on the developing product [11]. These peptides are often cyclic and can have highly complex cyclic structures, although linear non-ribosomal peptides are also common. Since the system is closely related to the machinery for building fatty acids and polyketides, hybrid compounds are often found. The presence of oxazoles or thiazoles often indicates that the compound was synthesized in this fashion [12].

(d) Peptones:

Peptones are derived from animal milk or meat digested by proteolysis. [13] In addition to containing small peptides, the resulting spray -dried material includes fats, metals, salts, vitamins and many other biological compounds. Peptones are used in nutrient media for growing bacteria and fungi [14].

(e) Peptide fragments:

Peptide fragments refer to fragments of proteins that are used to identify or quantify the source protein [15]. Often these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can also be forensic or paleontological samples that have been degraded by natural effects [16, 17].

3. PANCREATIC POLYPEPTIDE:

Pancreatic polypeptide (PP) is a polypeptide secreted by PP cells in the endocrine pancreas predominantly in the head of the pancreas. It consists of 36 amino acids and has molecular weight about 4200 Da [18]. The function of PP is to self-regulate pancreatic secretion activities (endocrine and exocrine); it also has effects on hepatic glycogen levels and gastrointestinal secretions. Its secretion in humans is increased after a protein meal, fasting, exercise, and acute hypoglycemia and is decreased bysomatostatin and intravenous glucose. Plasma PP has been shown to be reduced in conditions associated with increased food intake and elevated in anorexia nervosa.

In addition, peripheral administration of PP has been shown to decrease food intake in rodents [19]. PP is secreted by PP pancreatic cells of Langerhans islets. It stimulates the gastric juice secretion, but inhibits the gastric secretion induced by pentagastrine. It is the antagonist of cholecystokinin and inhibits the pancreatic secretion which is stimulated by cholecystokinin. On fasting, PP seric concentration is 80 pg/ml; after the meal, it rises up from 8 to 10 times more; glucose and fats also induce PP's level increase, but on parenteral introduction of those substances, the level of hormones doesn't change.

The administration of atropine, the vagotomy, blocks the PP's after-meal secretion. The excitation of the vagus nerve, the administration of gastrin, secretin or cholecystokinin induce PP secretion. The augmentation of PP secretion has been observed in hormonal-active pancreatic tumors (insulin, glucagon), in Verner-Morrison syndrome, and in gastrinomas. The PPY gene encodes an unusually short protein precursor that is cleaved to produce PP, as well as pancreatic icosapeptide and a 5- to 7- amino-acid oligopeptide [20].

3.1 Molecular Structure:

PP is a member of the NPY family including neuropeptide Y (NPY) and peptide YY .These biologically active peptides are characterized by a single chain of 36-amino acids and exhibit the same ‘PP-fold’ structure; a hair-pin U-shaped molecule PP has a molecular weight of 4,240 Da (Figure 1) and an isoelectric point between pH6 and 7 thus carries no electrical charge at neutral pH [21].

3.2 Synthesis of polypeptides:

Like many peptide hormones, PP is derived from a larger precursor of 10,432 Da. Isolation of a cDNA construct, synthesized from hPP mRNA, proposed that this precursor, pre-propancreatic polypeptide, comprised 95 residues and is processed to produce three products PP, an icosapeptide containing 20-amino acids and a signal peptide. PP is derived from the amino-terminus and the icosapeptide from the carboxy-terminus [22].

3.3 Secretion of polypeptides:

PP is predominantly secreted by the PP cells, also known as ‘F cells’ dominating the duodenal pancreas. Minor amounts are also secreted by colonic and rectal cells of the distal gut. Most PP cells are located at the periphery of the endocrine islets of Langerhans with fewer present within the exocrine acinar cells [23].

Figure 1. A schematic diagram illustrating the primary structure of pancreatic polypeptide (PP) and the icosapeptide synthesized within the common precursor hormone, prepropancreatic polypeptide.

3.4 Stimulatory mechanisms:

The principal stimulus for PP secretion is parasympathetic vagal cholinergic innervations. Vagotomy reaffirms this as ablation of the vagal nerves attenuates PP secretion. Administration of atropine, a competitive muscarinic acetylcholine antagonist, also eliminates PP response, demonstrating that release is governed by cholinergic mechanisms. Consequently, basal PP levels correspond to parasympathetic activity. Concentrations fluctuate diurnally measuring lowest in the morning and peaking during the evening. Also, secretion increases with age, quadrupling between 30 and 70 years old, reflecting heightened vagal tone [24].

PP is mainly released in response to food intake proportional to caloric consumption. Secretion is biphasic with a cephalic and gastrointestinal phase. The initial cephalic phase is represented by a rapid postprandial rise in plasma PP shortly after eating, the rate of which surely depends on neural mechanisms. Sham-feeding, a process whereby food ingested does not reach the stomach, triggers this cephalic phase. Gustatory and olfactory sensations are responsible for transmission of neural afferent signals to the CNS with vagal efferent neurones subsequently stimulating PP release [25].

The secondary gastrointestinal phase is stimulated by various enteric stimuli, primarily protein and lipid consumption and is prolonged with plasma PP concentrations remaining elevated for up to 6 hours post-satiation. Food entering the stomach causes gastric distension which mediates food intake. Activation of gut epithelial mechanoreceptors induces vagal afferent stimulation of PP cells thus PP release [26].

Duodenal entry of pancreaticobiliary juice also stimulates secretion other secretagogues include bioactive peptides; gastrin, gastrin releasing peptide (GRP), secretin, ghrelin, motilin vasoactive intestinal polypeptide (VIP) and cholecystokinin. Hypoglycaemia, which can be induced by insulin infusion, is another powerful stimulus. The extent of secretion is proportional to the decrement in blood glucose. During exercise, endogenous sympathetic adrenergic mechanisms provoke mild PP secretion. This is markedly lower than observed following meal consumption. Conversely, hyperglycaemia; which can be induced by glucose infusion, inhibits PP secretion. Peptide hormones; somatostatin and bombesin, glucocorticoids, elevated plasma fatty acids and morphine are examples of PP inhibitors [27-28].

3.5 Receptor Interactions:

PP-fold peptides elicit their effects through interaction with G-protein-coupled receptors; Y1 to Y6. These seven-transmembrane-domain receptors are distributed within central tissues; the hypothalamus and brainstem. PP, unable to diffuse across the blood-brain barrier, interacts with Y4 and Y5 receptors but is the most potent agonist for Y4 receptors located within the hypothalamic arcuate nucleus (ARC) or dorsal vagal complex (DVC) of the brainstem. The brainstem, a principal region for PP activity, comprises neuronal populations crucial for appetite regulation the dorsal motor nucleus of vagus (DVN), area postrema (AP) and nucleus of the tractussolitarius. Circulating PP can access the DVN and bind its respective receptor to modulate energy balance [29-31].

4. PANCREATIC CELLS AND ITS ROLE IN DIABETES OF PANCREATIC PEPTIDES:

4.1 Normal functions of the pancreas:

The pancreas has both exocrine and endocrine function. This chapter is devoted to the exocrine functions of the pancreas. The exocrine function is devoted to secretion of digestive enzymes, ions and water into the intestine of the gastrointestinal (GI) tract. The digestive enzymes are necessary for converting a meal into molecules that can be absorbed across the surface lining of the GI tract into the body. Of note, there are digestive enzymes secreted by our salivary glands, stomach and surface epithelium of the GI tract that also contribute to digestion of a meal.

However, the exocrine pancreas is necessary for most of the digestion of a meal and without it there is a substantial loss of digestion that results in malnutrition. The ions and water secreted are also critical for pancreas function as the resultant fluid is necessary to carry the digestive enzymes through the pancreatic ductal system into the intestine. In addition, the pH of the pancreatic secretions is alkaline due to a very high concentration of NaHCO3 in the fluid. A major function of the NaHCO3 is to neutralize the acidic pH of the gastric contents delivered to the intestine from the stomach. A neutral pH in the intestinal lumen is necessary for normal digestion and absorption [32].

4.2 Pancreatic cells:

The pancreas is a glandular organ that belongs to both the digestive and the endocrine systems of vertebrates. It is an endocrine gland that produces several important hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide. It is also a digestive, exocrine organ, that secretes pancreatic juice that contains digestive enzymes to assist with digestion and the absorption of nutrients in the small intestine. These enzymes help to further break down the carbohydrates, proteins, and lipids in the chime.

4.2.1. Islets of Langerhans:

The pancreatic islets are small islands of cells that produce hormones that regulate blood glucose levels. Hormones produced in the pancreatic islets are secreted directly into the blood flow by five different types of cells. The endocrine cell subsets are:

(a) Alpha cells:

that produce glucagon, and make up 15-20% of total islet cells. Glucagon is a hormone that raises blood glucose levels by stimulating the liver to convert its glycogen into glucose.

(b) Beta cells:

That produce insulin and amylin, and make up 65- 80% of the total islet cells. Insulin lowers blood glucose levels by stimulating cells to take up glucose out of the blood stream. Amylin slows gastric emptying, preventing spikes in blood glucose levels.

(c) Gamma cells:

That produce pancreatic polypeptide, and make up 3-5% of the total islet cells. Pancreatic polypeptide regulates both the endocrine and exocrine pancreatic secretions.

(d) Epsilon cells:

That produce ghrelin, and make up less than 1% of the total islet cells. Ghrelin is a protein that stimulates hunger.

The islets of Langerhans can influence each other through paracrine and autocrine communication. The paracrine feedback system is based on the following correlations:

· The insulin hormone activates beta cells and inhibits alpha cells.

· The hormones glucagon activates alpha cells which then activate beta cells and delta cells.

· Somatostatin hormone inhibits alpha cells and beta cells [33].

4.3. Glucagon like Peptide-1:

The actions of Glucagon like peptide-1 (GLP-1) have been greatly examined over the last twenty years, due to the hormones effectiveness at lowering blood glucose levels and increasing insulin secretion in type 2 diabetic patients [34,35]. GLP-1 exerts its actions through them GLP-1 Receptor (GLP-1R), a family B G-Protein Coupled Receptor (GPCR) which mediates its effects through the Gαs subunit, which in turn activates Adenylyl Cyclase(AC). The involvement of Gαs and subsequent accumulation of cyclic Adenosine Monophosphate (cAMP) in glucose-induced insulin secretion is well established [36].

4.4. Type 2 Diabetes Background:

The World Health Organization describes diabetes mellitus as a “metabolic disorder of multiple actiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both” [37,38]. It was estimated that 366 million people (8.4% of the world’s adult population) lived with diabetes in 2011 [39]. This number will continue to rise and has been estimated to reach 439 million by 2030 [40]. Diabetes remains the leading cause of blindness, end stage renal disease, lower limb amputation, and cardiovascular disease [41,42].

4.5 GLP-1 Treatment for Type 2 Diabetes:

Incretins are gastrointestinal hormones that contribute to postprandial insulin release [43,44]. GLP-1 and Glucose-dependent Insulinotropic Polypeptide (GIP) are two major incretins and are thought to be responsible for up to 70% of insulin secreted from the β-cells of the pancreas following food intake. This increase in insulin is called the ‘incretin effect’ and maintains glucose concentrations at low levels irrespective of the amount of glucose ingested. This is achieved by increasing the sensitivity of β-cells to glucose [45]. The ‘incretin effect’ has been shown to be either reduced or absent in type 2 diabetics due to the loss of insulinotropic activity of GLP-1 and GIP. However, more recently it’s been suggested that the secretion of GIP and GLP-1 is normal in type 2 diabetic patients [46]. This strongly suggests a role for incretin hormones or their actions in the treatment of type 2 diabetes [39,52-55].

Cells of the proximal small intestine. GIP secretion is stimulated by enteral glucose, lipids and products of meal digestion in a concentration dependent manner [47]. In patients with type 2 diabetes, GIP concentrations after food intake are either normal or slightly elevated. GIP infusion does not reduce plasma glucose concentrations in patients with type 2 diabetes. As a result GIP has not been thought of as a suitable candidate for therapeutic development [48,49]. In contrast, patients with type 2 diabetes have decreased GLP-1 activity [50-52]. It is currently unknown whether reduced GLP-1 activity is a cause or consequence of diabetes. First degree relatives of patients with type 2 diabetes have normal GLP-1 activity in response to glucose, this suggests that a reduction in GLP-1 activity seen in type 2 diabetic patients is more likely acquired [53,54]. Additionally, GLP-1 is able to stimulate glucose-dependent insulin secretion in type 2 diabetic patients under hyperglycaemic conditions [55-57]. Furthermore, administration of exogenous GLP-1 to type 2 diabetic patients leads to normalisation of hyperglycaemic conditions [58-60]. As a result, GLP-1 based strategies appear an interesting and more suitable target for the treatment of type 2 diabetes [61].

4.6 GLP-1R signal transduction in pancreatic β-cells:

In β-cells, the main action of GLP-1 through the GLP-1R is the formation of cAMP and its insulinotropic activity [62]. Upon agonist binding, the Gαs subunit dissociates from the receptor, couples to AC and generates cAMP [63,64]. When blood glucose levels rise, it enters the β-cell through GLUT1 and GLUT2 transporters. Glucose is phosphorylated by glucokinase to glucose-6-phosphate, and results in the ATP/ ADP ratio in the cytosol increasing and the plasma membrane depolarising by closing KATP channels. The closure of KATP channels, in turn opens calcium channels, releasing intracellular stores of calcium. The increase of cytosolic calcium causes secretory granules containing insulin to fuse to the plasma membrane and m insulin is exocytosed [65,66]. It is also likely that human glucokinase activity is more important in glucose-induce insulin secretion than the rate at which glucose enters the β-cell [67]. GLP-1 has been shown to increase the quantity of insulin secreted per cell and cause morβ-cells to become more sensitive to increased glucose levels by GLP-1 modulated KATP channels [68,69].

Activation of GLP-1 can also increase calcium concentration by partial activation of L-type voltage dependent calcium channel and/ or increase calcium-induced calcium release from intracellular stores and is mediated by PKA phosphorylation in an ADP-dependent manner [70]. The release of intracellular stores of calcium is achieved by one of two ways: either due to PKA activation or EPAC activation [71,72]. It has been suggested that PKA activation is achieved through the IP3 receptor (PKA dependent) and EPAC activation is achieved through ryanodine receptors (PKA independent) [73,74]. The increase in calcium levels causes an exocytotic response and is potentiated by elevated cAMP levels due to an increase in the amount of vesicles available for release. In pancreatic β-cells, there are three different pools of insulin secretory vesicles. A reserve pool is situated in the cytoplasm; a readily release pool and immediately release pool are situated close to the membrane. GLP-1 increases the amount of insulin secretory vesicles in the readily release pool. GLP-1 depolarises the cell membrane closing KATP channels and therefore the current is inactivated before the cell can begin repolarising. Consequently, the cell does not reach its resting membrane potential and starts to depolarize before it has recovered from inactivation [75].

Additionally, a sustained increase in cAMP induced nuclear translocation leads to the activation of cAMP Response Element Binding-protein (CREB) and cell proliferation. The phosphorylation of PKA is said to activate CREB, interact with Transducer of Regulated CREB activity (TORC2), increase insulin receptor substrate-1 expression and cause activation of a serine-threonine protein kinase, Akt [76]. Akt has been described to link GLP-1 signalling to β-cell growth and survival [77]. Furthermore, the activation of Ribosomal protein S6 (rbS6) in animal models has been reported as a key regulator of glucose homeostasis and β-cell mass [78]. Two mutations within the GLP-1R have been shown to alter insulin secretion. In a Japanese study, one patient diagnosed with type 2 diabetes had a missense mutation that resulted in the substitution of Thr149 with methionine [79]. The patient exhibited impaired glucose tolerance, insulin secretion and sensitivity. The mutated receptor had reduced affinity in vitro for GLP-1 and exendin-4 [80]. Further, GLP-1R mutants lacking Lys334-Leu335-Lys336 of ICL3 in the HIT-T15 insulinoma cell line showed an absence of GLP-1 induced cAMP production, calcium channel activation and insulin secretion [81].

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Received on 12.06.2017 Modified on 19.07.2017

Res. J. Pharmacology & Pharmacodynamics.2016; 8(3): 211-218.

DOI: 10.5958/2321-5836.2017.00038.6