The pancreas, situated in the cranial abdomen, is a glandular organ that has both endocrine and exocrine functions. The endocrine function—production of insulin and other hormones—is performed by small groups of cells, the islets of Langerhans, that make up only 2% of the pancreatic parenchyma. The islets are completely surrounded by acinar (exocrine) cells that secrete digestive enzymes into networks of ductal cells.
The endocrine and exocrine portions of the pancreas are closely related during development, and islet, acinar, and ductal cells all arise from multipotent stem cells called pancreatic progenitor cells.
Pancreatic islets contain alpha, beta, delta, and epsilon cells, each type synthesizing a unique polypeptide hormone. In dogs, beta cells account for approximately 50% of the islet cell population and secrete insulin, alpha cells secrete glucagon, delta cells secrete somatostatin, and epsilon cells secrete ghrelin.
The pancreatic islets function as discrete microendocrine organs. They are distributed throughout the pancreas with a characteristic pattern of cellular interrelationships to ensure an appropriate balance of hormones:
Afferent vessels and nerves enter the islet in the peripheral tricellular region. The close anatomical relationships of alpha, beta, delta, and epsilon cells in this heterogeneous cortical region enable it to function as a local glucose sensor, permitting a coordinated output of insulin and glucagon in response to fluctuations in blood glucose.
Specialized tight junctions between membranes of adjacent endocrine cells tend to partition the intercellular space and may permit somatostatin to exert a direct local (paracrine) inhibitory effect on glucagon and insulin release.
Insulin is formed initially as a single polypeptide chain of 81–86 amino acid residues. This prohormone (proinsulin) contains the A and B chains of the insulin molecule, plus a connecting peptide. Proinsulin is converted enzymatically to insulin before being stored in membrane-limited secretory granules.
Insulin secretion is tightly regulated by blood glucose concentration. Unlike most other cells, beta cells depend on insulin for the entry of glucose via facilitative glucose transporters:
With increasing blood glucose concentrations, insulin secretion gradually increases, eventually reaching a plateau.
With decreasing blood glucose concentrations, insulin secretion is inhibited.
An appropriate concentration of extracellular calcium is required for insulin secretion. Sugars other than glucose (fructose, mannose, ribose), amino acids (leucine, arginine), hormones (glucagon, secretin), drugs (sulfonylurea, theophylline), short-chain fatty acids, and ketone bodies may also stimulate insulin secretion under certain conditions.
Pancreatic beta cells are able to respond to a specific physiological stimulus by releasing stored hormone in a modulated fashion, rather than releasing all of the stored hormone at once.
Either directly or indirectly, insulin affects the function of every organ in the body. The liver, adipose cells, and muscle are three principal target sites for insulin. The main function of insulin is to decrease blood glucose concentrations by inhibiting gluconeogenesis, glycogenolysis, fatty acid breakdown, and ketogenesis, and stimulating glycogenesis and protein synthesis.
The actions of insulin are opposed by glucagon, which is secreted by alpha cells. Ghrelin, secreted by epsilon cells, also influences glucose metabolism, by inhibiting the beta-cell response to glucose, leading to a decrease in insulin release.
Glucagon is secreted in response to a decrease in blood glucose concentration. It promotes the mobilization of stores of energy-yielding nutrients by increasing glycogenolysis, gluconeogenesis, and lipolysis. At physiological concentrations, glucagon increases both hepatic glycogenolysis and gluconeogenesis, thereby increasing blood glucose.
Insulin and glucagon act in concert to maintain the concentration of glucose in extracellular fluids within relatively narrow limits. A glucose sensor in the pancreatic islets controls the relative amounts of insulin and glucagon secreted. Glucagon controls glucose release from the liver into the extracellular space, and insulin controls glucose transport from the extracellular space into insulin-sensitive tissues such as fat, muscle, and liver.
Somatostatin—originally described as growth hormone–inhibiting hormone—affects several areas of the body by hindering the secretion of other hormones:
In the hypothalamus, it inhibits the secretion of hormones coming from the pituitary gland, including growth hormone and thyroid-stimulating hormone.
In the pancreas, it inhibits the secretion of pancreatic hormones, including glucagon and insulin.
In the GI tract, it decreases gastric secretion and the emission of GI hormones, such as secretin and gastrin.
