Is a hormone secreted by the pancreas in response to decreased blood glucose?

A Liver and skeletal muscle

Pancreatic hormone-mediated effects of the incretins on glucose homeostasis have been well established. However, based on a number of metabolic studies in humans, it has been suggested that GLP-1R activation suppresses hepatic glucose production and enhances tissue glucose utilization via noninsulin-dependent mechanisms (D'Alessio et al., 1994, 2004; Egan et al., 2002; Meneilly et al., 2001; Prigeon et al., 2003). This proposal has proven controversial for a number of reasons (Abu-Hamdah et al., 2009; D'Alessio et al., 2004; Holst, 2007; Toft-Nielson et al., 1996). Much of the evidence is based on studies using glucose clamps with SS infused to reduce endogenous insulin and glucagon secretion, and the ability to finely control these parameters has been questioned (Holst, 2007). A direct effect of GLP-1R-mediated suppression of hepatic glucose output has also been considered unlikely, due to the extremely low levels, or complete lack of, detectable GLP-1R mRNA in extracts from mouse, rat, dog, or human liver (Blackmore et al., 1991; Bullock et al., 1996; Sandhu et al., 1999; Wei and Mojsov, 1996; Wheeler et al., 1993; Yamato et al., 1997). In vitro studies have also provided conflicting results. Although there are reports of GLP-1-induced inhibition of glucagon-stimulated cAMP production and stimulation of glycogen synthase activity (Redondo et al., 2003; Valverde et al., 1994), others have reported a complete lack of effect of GLP-1 on hepatic cyclic AMP production (Ghiglione et al., 1985) or glycogenolysis in the perfused liver (Murayama et al., 1990). GLP-1 stimulated glucose transport (O'Harte et al., 1997; Villanueva-Penacarrillo et al., 1994) and glycogenesis (Acitores et al., 2004; Morales et al., 1997; O'Harte et al., 1997) in skeletal muscle has also been observed. However, the physiological significance of such effects (Fürnsinn et al., 1995; Hansen et al., 1998; Holst, 2007) as well as the identity of the receptor involved (Yang et al., 1998) have been questioned. Similarly, although GIP-R mRNA transcripts were not found in muscle or liver (Usdin et al., 1993), GIP was also reported to increase muscle glucose uptake and glycogen production in vitro (O'Harte et al., 1998) and to suppress glucagon-dependent hepatic glycogenolysis in vivo (Hartmann et al., 1986).

The in vitro studies have not provided a consensus viewpoint on direct actions of the incretins on liver and muscle. However, in vivo glucose and hormone clamp studies on dogs and rodents have demonstrated noninsulin-dependent effects of GLP-1 on glucose uptake, although they introduce the possibility of neurally mediated pathways. In dog clamp studies, intraportal administration of GLP-1 increased whole body glucose disposal, similar to humans (Dardevet et al., 2004, 2005), but responses were small and only observed in the presence of high intraportal glucose levels (Johnson et al., 2008). Evidence both for (Ionut et al., 2008) and against (Dardevet et al., 2005) the involvement of GLP-1Rs in the dog portal vein for noninsulin-dependent lowering of glycemia has been presented. Recently, insulin clamps and exercise were used to compare insulin-independent GLP-1 effects in GLP-1-R−/− mice and controls (Ayala et al., 2009). GLP-1R activation was concluded to regulate both hepatic glucose production and muscle glucose uptake under conditions of increased glucose flux (Ayala et al., 2009) via activation of receptors in the arcuate nucleus (Ayala et al., 2009; Sandoval et al., 2008). Outflow from hypothalamic neurons to skeletal muscle (Knauf et al., 2005, 2008) was speculated to involve endothelium-mediated effects on glycogen storage (Knauf et al., 2005). In conclusion, although there is a significant literature on the noninsulin-dependent effects of GLP-1 on glucose metabolism, it is currently unclear as to whether such effects are mediated indirectly, through autonomic neural activation, or via direct actions on peripheral tissues and, if the latter, whether they are mediated via conventional GLP-1 receptors. Similar uncertainty pertains to the actions of GIP.

Abstract

The pancreatic hormone insulin plays a well-described role in the periphery, based principally on its ability to lower circulating glucose levels via activation of glucose transporters. However, insulin also acts within the central nervous system (CNS) to alter a number of physiological outcomes ranging from energy balance and glucose homeostasis to cognitive performance. Insulin is transported into the CNS by a saturable receptor-mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is dependent on numerous factors including diet, glycemia, a diabetic state and notably, obesity. Obesity leads to a marked decrease in insulin transport from the periphery into the CNS and the biological basis of this reduction of transport remains unresolved. Despite decades of research into the effects of central insulin on a wide range of physiological functions and its transport from the periphery to the CNS, numerous questions remain unanswered including which receptor is responsible for transport and the precise mechanisms of action of insulin within the brain.

X Exocrine pancreatic disease

Exocrine pancreatic hormones that are present in the duodenum of birds include amylase, lipase, trypsin, and chymotrypsin. They facilitate degradation of carbohydrates, fats, and proteins, respectively. The inactive precursors of trypsin and chymotrypsin, trypsinogen, and chymotrypsinogen enter the duodenum, where they are activated by intestinal enterokinase. This mechanism prevents autodigestion of pancreatic tissue (Duke, 1986).

There are two basic manifestations of exocrine pancreatic hormone disorders: (1) acute pancreatitis or acute pancreatic necrosis, and (2) chronic pancreatitis resulting in pancreatic fibrosis and pancreatic exocrine insufficiency.

The pathogenesis of acute pancreatitis involves the activation of pancreatic enzymes in and around the pancreas and bloodstream, resulting in coagulation necrosis of the pancreas and necrosis and hemorrhage of peripancreatic and peritoneal adipose tissue. Increased amylase and lipase activities in plasma have been reported from birds with active pancreatitis.

Reference values for plasma lipase and amylase have been established in a population of 87 African grey parrots (Van der Horst and Lumeij, unpublished observations).α-Amylase activity in plasma was determined with a kinetic p-nitrophenylmaltoheptaoside method (Sopachem α-Amylase kit # 003-0311-00 Sopar-biochem, 1080 Brussels) at 30°C. Values ranged from 571 to 1987 U/L (inner limits of P2.5 to P97.5 with a probability of 90%).

Lipase activity was measured at 30°C using a test based on the conversion of triolein by lipase to monoglyceride and oleic acid. The associated decreased turbidity was measured in the UV range (Boehringer Mannheim kit # MPR 3-1442651). Reference values ranged from 268 to 1161 U/L.

Hochleithner (1989b) reported reference values for plasma amylase in four different psittacine species using a dry chemistry system (Kodak Ektachem, Amylopectin, 25°C; Kodak Company, 1986). The values were considerably lower as compared to the ones just discussed: budgerigar (n=50) 187 to 585 U/L, African grey parrot (n=68) 211 to 519 U/L, Amazon parrot (n=30) 106 to 524 U/L, and macaw 276 to 594 U/L.

In racing pigeons (n=24), plasma amylase and lipase activities were determined with a Synchron CX chemistry analyzer (Beckman Coulter, Mijdrecht, The Netherlands) with reagents provided by the manufacturer. Lipase was measured by a time enzymatic rate method. Briefly, 1–2 diglyceride substrate is hydrolyzed by pancreatic lipase to 2-monoglyceride and fatty acid. The change of absorbance at 560 nm because of formation of the red quinone dimine dye after four consecutive chemical reactions is directly proportional to lipase activity. Amylase was measured by the rate of formation of maltose from maltotetraose through three coupled reactions. The change of absorbance at 340 nm is directly proportional to amylase activity. Reference values (inner limits of P2.5 and P97.5 with a probability of 90%) for plasma amylase and lipase activities in pigeons were 382 to 556 IU/L and 0 to 5 IU/L, respectively (Amann et al., 2006).

Chronic pancreatitis may results in fibrosis and decreased production of pancreatic hormones. When insufficient pancreatic enzymes are available in the duodenum, maldigestion and passing of feces with excessive amylum and fat will occur. Affected animals have voluminous, pale, or tan greasy feces. Fat can be demonstrated by Sudan staining.

Fecal amylase and proteolytic activity were determined in African grey parrots (n=87) by Van der Horst and Lumeij (unpublished observations), using radial enzyme diffusion as reported by Westermarck and Sandholm (1980). Reference values (inner limits of P2.5 to P97.5 with a probability of 90%) for fecal amylase were 6 to 18 mm and for fecal trypsin 14 to 19 mm.In racing pigeons (n=24), these values were 13 to 16 mm and 11 to 14 mm, respectively (Amann et al., 2006). In a clinical case of exocrine pancreatic insufficiency in a racing pigeon, which was histologically confirmed at postmortem examination, values for fecal amylase and proteolytic activity were 0 and 2 mm, respectively, whereas plasma amylase and lipase activities were within the reference limits (Amann et al., 2006).

Insulin

Insulin is a pancreatic hormone that regulates blood glucose levels by stimulating the conversion of glucose to glycogen. In addition to this role in carbohydrate metabolism, insulin suppresses the appetite, as shown by the effect of direct insulin injections into the brain. Insulin receptors are distributed in the hypothalamus and NTS and are particularly concentrated on NPY and POMC neurons in the arcuate nucleus, where their distribution is similar to that of the leptin receptor. This additional role for insulin may be related to its function in lipid homeostasis since, as well as promoting the storage of carbohydrates, insulin promotes the storage of fats. Overall levels of insulin correlate with the degree of adiposity in a manner similar to the correlation shown by leptin.

Pancreatic polypeptide (PP)

PP is a pancreatic hormone that is secreted from endocrine cells located not only in the islets of Langerhans but also scattered diffusely in the exocrine pancreas. The early phase of meal-stimulated PP secretion, but not the late phase, may be under the influence of cholinergic nerves. In healthy subjects, the acute administration of oral ethanol may suppress cholinergic neural pathways to the pancreas. In heavy drinkers, the early phase PP response to the meal is enhanced and no suppression is caused by ethanol. In patients with chronic pancreatitis, the early phase PP response to the meal is reduced but ethanol enhances this response. Therefore, persistent drinking may cause postprandial hypersensitivity of parasympathetic neural pathways to the pancreas and may cause a resistance to the inhibitory effect of acute oral ethanol on postprandial cholinergic activation (Hirano et al., 1996).

Regulation of Pancreatic Secretion

The secretion of pancreatic hormones and enzymes is controlled by neural innervation and by hormones and metabolites. Many of the regulating hormones come from neighboring pancreatic or GEP cells. Notably, many of the hormones produced in the pancreas are also produced by the gut (e.g., GIP, glucagon, GLP, NPY, PYY, and somatostatin; see also INTEGRATED FUNCTION AND CONTROL OF THE GUT | Endocrine Systems of the Gut) and help in coordination of digestion and metabolism. The control of islet hormone release is discussed in INTEGRATED FUNCTION AND CONTROL OF THE GUT | Gut Secretion and Digestion and INTEGRATED FUNCTION AND CONTROL OF THE GUT | Nervous System of the Gut the focus of this section is on the exocrine portion of the pancreas.

Nutrients in the lumen of the gastrointestinal tract stimulate the secretion of pancreatic enzymes. Breakdown products from macronutrient lysis are more potent activators of enzyme secretion than whole feed itself. Most importantly, single amino acid mixtures increase enzyme secretion, whereas intact protein with a similar amino acid composition release little to no enzymes. Studies with rainbow trout indicate that fish regulate their pancreatic enzyme stores according to specific diet composition. Proteolytic activity of pancreatic tissue, measured 24 h after the last meal, increases with increasing levels of dietary protein.

The luminal environment (e.g., nutrients, low pH, and ionic composition) also stimulates the secretion of several GEP hormones that in turn affect the exocrine pancreas and other digestive processes. For example, secretin from the intestine stimulates the release of bicarbonate from the exocrine pancreas that is used to buffer gastric acid emptying from the stomach. In addition, CCK and secretin are released from the gastrointestinal tract to stimulate the release of exocrine pancreatic enzymes (e.g., pancreatic phospholipase) that aid in the digestion of food.

Numerous interactions between and among GEP hormones also exist. Insulin stimulates the release of GLP-1 that acts synergistically on the gastrointestinal tract and other tissues, recruiting the uptake of nutrients (see also INTEGRATED FUNCTION AND CONTROL OF THE GUT | Intestinal Absorption). Inhibitory regulators from endocrine pancreatic cells, such as somatostatin, PP, and PYY, inhibit the release of secretin and CCK. GLP-1 and PYY also inhibit gastric secretion and motility, while GLP-2 stimulates growth and digestion. Somatostatin also modulates the intestinal active transport of Na+ and Cl− ion uptake, aiding in maintaining osmoregulatory homeostasis. Overall, the GEP exhibits a dynamic relationship regulating various physiological processes throughout food intake, digestion, nutrient absorption, and intermediary metabolism (Table 1).

Mechanisms of Action

Insulin and the other pancreatic hormones are secreted into the interstitial fluid; they cross the endothelial barrier and enter the circulation. Effects at the target cells are initiated by the action and binding of the hormone to specific cell surface receptors (Figure 5). The binding of the hormone to these receptors initiates a sequence of postreceptor events ultimately culminating in the various biological actions of the hormone. Rapid events on the secretion of other hormones are mediated by changes of [Ca2+]i and the activities of adenylate cyclase and phospholipase C (see above). Stimulation of glucose uptake by muscle and adipose tissue results from insulin-induced translocation of glucose transporter proteins (GLUT4) from cytoplasmic vesicles to the plasma membrane. Classical metabolic effects of insulin and glucagon at target cells are achieved by activation and suppression of enzyme activity (so redirecting cell metabolism) or by altering the rate of synthesis of enzymes at the level of transcription and translation.

Insulin binding to the external α-subunit of the glycoprotein insulin receptor leads to a conformational change in the receptor that stimulates tyrosine kinase activity. The activated the β-subunit autophosphorylates at tyrosine sites in addition to phosphorylating intracellular proteins (Figure 5). Indeed it is the tyrosine kinase activity that is essential for insulin signaling. The best characterized postreceptor signal transduction pathway centers around insulin-receptor substrate 1 (IRS-1). Rapid tyrosine phosphorylation following insulin stimulation results in noncovalent binding between phosphorylated sites and specific domains on intracellular protein targets. This ultimately results in the various important biological effects of insulin on target tissues (Figure 5). Following initiation of postreceptor events, the insulin–receptor complex is internalized by the target cell, and whereas receptors are recycled to the cell surface, insulin is degraded intracellularly. Elevated insulin levels, for example in obesity or type 2 diabetes, results in insulin receptor ‘downregulation’ through decreasing numbers on the cell surface and also by reducing tyrosine kinase activity of the receptor.

I Enteroglucagon and oxyntomodulin

The topics of enteroglucagon and oxyntomodulin are covered in Chapter 6, Pancreatic Hormones: Insulin and Glucagon. The same proglucagon (160 amino acids) in the pancreas secretes the classical 29-amino-acid pancreatic glucagon. However, in the intestine it secretes the 69-amino-acid glicentin that includes the 29-amino-acid sequence of pancreatic glucagon; see Fig. 6.8. Enteroglucagon is biosynthesized in the intestinal mucosal L cells of the ileum and colon. It has been postulated to be a trophic factor for the intestinal mucosa.

Oxyntomodulin is a 37-amino-acid peptide that is produced by the stomach’s fundic cells (also known as oxyntic cells) that, like parietal cells, secrete gastric acid. The oxyntomodulin 37-amino-acid peptide includes the exact amino acid sequence of pancreatic glucagon. The oxyntomodulin is also found in intestinal and colon cells. Oxyntomodulin and peptide tyrosine–tyrosine (PYY) are secreted from intestinal enteroendocrine cells in response to a meal. These circulating hormones are considered to be satiety signals, as they have been found to decrease food intake, body weight, and adiposity in rodents. It has been proposed that the effects on energy homeostasis are mediated by the brainstem and hypothalamus.