In 1889 Von Mering and Minkowski(1890) performed the crucial experiment that inspired the later discovery of the hypoglycaemic effect of insulin: By surgically removing the pancreas (pancreatectomy) of a dog they found that the animal showed clear signs of diabetic polyuria after the operation. By that they clearly demonstrated that the pancreas is involved in the endocrine regulation of carbohydrate homeostasis.
The pancreas is a retroperitoneal organ located posterior to the stomach on the posterior abdominal wall. The adult human organ presents itself as a well defined and
compact structure with an elongated, tapering gross morphology. In mice and rats, however, the pancreas is more diffusely organized and consists of a body and two lobes:
The pancreatic body is located along the cranial part of the duodenum and the right lobe extends into the duodenal ligament, whereas the left lobe extends toward the spleen (Miyaki et al.,1994). Because of its soft structure it is difficult to distinguish rodent pancreas from the mesenteric adipose tissue to which it is tightly associated.
The pancreas is a mixed exocrine and endocrine gland of endodermal origin (Slack, 1995). Its primary exocrine function is to secrete digestive enzymes and enzyme precursors like trypsinogen, chymotrypsinogen, pancreatic lipase and amylase. These proteins are secreted from pancreatic acinar cells which are the most abundant cell type of the organ. The cells that constitute the widely ramified ductal system of the pancreas produce and secrete bicarbonate ions to neutralize the acidic gastric juice at the entrance of the duodenum.
In 1893, endocrine secretion was first suggested to originate from the discrete cell-clusters scattered throughout the exocrine tissue of the pancreas, called the islets of Langerhans. Today it is known that insulin indeed is secreted together with other hormones (glucagon, somatostatin, pancreatic polypeptide) from these complex mi-croorgans. In spite of the fact that the endocrine pancreas makes up only 2–3% of the total mass of the gland, it receives ∼20% of the pancreatic blood flow (Lifson et al., 1985). Furthermore, the islet blood circulation can be prominently enhanced during hyperglycaemic conditions by a mechanism which is under control of the autonomic nervous system (Jansson and Hellerstrom,1983,1986;Jansson,1994).
The adult human pancreas contains about 1 million islets that generally consist of at least four cell types. The insulin-secreting β-cells comprise 65–80% of the total islet cell population in humans. The rest is comprised of the glucagon-releasingα-cells (15–20%), the somatostatin-producingδ-cells (3–10%) and the smallest group, the pancreatic polypeptide-containing PP-cells (∼1%) (Rahier et al.,1981). The size of the pancreatic islets is highly variable but the morphology of single islets is relatively uniform. A central core ofβ-cells is surrounded by a cortex composed of all four cell types.
The different cell types of the islets of Langerhans are regulated by complex para-and autocrine interactions that are yet not fully understood in their characteristics
1 Introduction
and function. Insulin or other secretory products ofβ-cells likeγ-aminobutyric-acid (GABA) or zinc inhibitα- (Rorsman et al.,1989;Ishihara et al.,2003;Ravier and Rutter, 2005;Franklin et al.,2005) andδ-cells (Rouiller et al.,1981), whereas glucagon release fromα-cells stimulates both insulin (Samols et al.,1966) and somatostatin (Patton et al., 1977) secretion. The latter, in turn, prominently inhibits bothβ- andα-cells (Strowski et al.,2000). However, since the microvasculature of the islets directs the blood flow from the afferent arterioles in theβ-cell rich islet medulla to the collecting venules in the mantle region of α-,δ-, and PP-cells, the secretory products of the latter have to pass the systemic circulation to act on the precedingβ-cells (Stagner et al.,1992). Still, it is possible that interstitial paracrine regulation bypasses the microvascularβ→α→δ perfusion direction (Samols and Stagner,1988). Accordingly, it is not known to which extent many of the reported putative paracrine effects studied by exogenous application of the respective islet cell secretions are able to significantly regulate cellular functionsin vivo. For instance, the role of glucagon in the paracrine regulation of insulin release has recently been questioned (Moens et al.,2002). A further local effect of secreted islet cell products is the autocrine inhibition ofβ-cells by islet amyloid precursor peptide (IAPP) which is cosecreted with insulin (Tokuyama et al.,1997). In a similar wayα-cells are positively regulated by endogenously released glucagon acting back onα-cell glucagon receptors (Ma et al.,2005).
In addition to the complex chemical cell interactions, theβ-cells of an islet are also able to electrically communicate with each other (Meissner,1976). Human as well as rodent β-cells express connexin36 (Cx36) proteins (Serre-Beinier et al.,2000;Theis et al.,2004) that form low conducting, weak voltage dependent gap junctions between neighboring cells (Srinivas et al.,1999). The resulting electrical coupling is believed to synchronize the secretory activity ofβ-cells, decrease cell-to-cell heterogeneity and by that generate a “secretory syncytium” (Santos et al.,1991).
The cells of the pancreatic islets are not only regulated by local para- and autocrine mechanisms but are also subjected to intense innervation by the autonomic nervous system (for review see: Ahren,2000). Postganglionic parasympathetic release of acetyl-choline (ACH) ontoβ-cells is believed to underly the phenomenon of the pre-absorptive release of insulin: In rodent model animals as well as in humans the sensory stimulus of food ingestion alone leads to a rapid onset of insulin secretion even before any increase
in the blood sugar concentration can be measured (cephalic phaseof insulin release) and this response is abolished by vagotomy (Strubbe and Steffens,1975;Berthoud et al., 1980).