pancreas

pancreas The pancreas (from the Greek meaning ‘all flesh’) is a pale, rubbery gland in the upper part of the abdomen, responsible for the production of digestive juices and hormones. The juices pass into the cavity of the duodenum (an example of exocrine secretion) while the hormones pass into the circulating blood (endocrine secretion). By means of these products the pancreas is essential to the proper processing of food, through digestion to absorption, storage, and utilization of nutrients.

Early authors found great difficulty in ascribing a function to the organ, as its rather evasive name implies. The rubbery texture suggested to some that the gland might be a shock absorber preventing the stomach from damaging itself on the vertebral column. It was not until the nineteenth century that any firm ideas of its function evolved. It was known that a small tube (the ‘duct of Wirsung’, described by him in 1642) connected the gland with the duodenum; in 1664, de Graaf inserted a wild duck's quill into the duct of a dog and collected a clear fluid, which he examined and decided was acidic. He had no idea of the fluid's function — and we now know that pancreatic juice is unambiguously alkaline, because the cells lining the duct system secrete bicarbonate ions.

Exocrine function

The function of the digestive juices became known long before hormones were recognized. The advances in chemistry in the nineteenth century led the way to understanding the process of digestion. It became clear that pancreatic juice contained agents — ‘ferments’ (subsequently renamed enzymes) that were capable of breaking down the three major components of food: carbohydrates, fats, and proteins. Many of the molecules in our diet are large, having been synthesized by the plant or animal being eaten. These large molecules are then reduced in size by the enzymes from the pancreas — continuing the digestive process already begun in the stomach; only small molecules can be absorbed from the intestines. Carbohydrates are broken down to simple sugars (mono- and di-saccharides) by pancreatic amylase, fats to glycerol and fatty acids by pancreatic lipase, and proteins to amino-acids and small peptides by a variety of proteolytic enzymes. The French physiologist Claude Bernard showed in the 1840s that both pancreatic juice and bile (from the liver) were necessary for the absorption of fat. These two fluids enter the duodenum together where their main ducts converge. We know now that bile, by a detergent action, converts fats into tiny particles (micelles), and it is only when the surface area of the fat has been increased in this way that the lipase in pancreatic juice can break the fats down to fatty acids and glycerol. Probably to prevent the pancreas from digesting itself, proteolytic enzymes are secreted by the gland as ‘pro-enzymes’. These molecules are inactive at digesting protein until they reach the cavity of the duodenum, where they are rendered active by another enzyme (enterokinase). Chronic disease of the exocrine component of the pancreas often results in a deficiency of pancreatic enzymes, giving rise to poor absorption of foodstuffs: the excretion of fat in faeces (steatorrhoea) provides the most conspicuous feature of this malabsorption. Microscopically, the gland is divided up into units known as acini (acinus: Latin for ‘berry’). Each acinus is spherical, with the enzyme-secreting cells surrounding a central space (remarkably, every enzyme-secreting cell synthesizes all the pancreatic enzymes). The enzymes pass into the centre of the acini, whence they enter the narrowest ducts of the branching secretory system, and then pass by larger and larger ducts to the single pancreatic duct itself. The cells lining the duct system secrete water and bicarbonate ions and add them to the enzymes; the final juice is consequently alkaline.

The volume of juice secreted precisely neutralizes the acid contents of the stomach as they both enter the duodenum. This remarkable feat of homeostasis is brought about by acid in the duodenum causing release of the hormone secretin from cells in its wall; this secretin passes into the bloodstream and stimulates the production of water and bicarbonate ions from the duct system of the pancreas. Hence the greater the volume of acid gastric juice passing into the duodenum, the greater the volume of bicarbonate-rich juice produced by the pancreas. This tends to keep the contents of the duodenum neutral — the pH at which the pancreatic enzymes are most effective. Secretin, a protein hormone, was first demonstrated by Bayliss and Starling in London in 1902 — the earliest recognition that such ‘chemical messengers’ existed.

A similar mechanism exists for the enzyme component of pancreatic juice. Another hormone, cholecystokinin (literally ‘gall-bladder mover’) is synthesized in the wall of the duodenum and jejunum, and is released in response to the presence of amino acids and fatty acids as partly-digested food starts to arrive from the stomach. Cholecystokinin passes round the circulation and causes enzyme secretion by the pancreatic acinar cells, thereby increasing the ability of the juice to break down more fats and proteins. Cholecystokinin also causes contraction of the gall bladder, providing bile that promotes the absorption of fatty acids and glycerol. About a litre of pancreatic juice is secreted each day in a person with typical eating habits.

Endocrine function

The main ‘internal’ secretions of the pancreas are the hormones insulin and glucagon. These are necessary for the regulation of storage, release, and utilization of fuels for metabolism. Insulin has a well-known association with sugar (glucose) in the body, because of its role in diabetes. Insulin lowers the blood sugar, and glucagon raises it; but these hormones are also important in the body's handling of nutrients derived from fat and protein, as well as carbohydrate.

Among the acini and ducts which secrete enzymes and bicarbonate there are small clumps of cells which do not connect with a duct system. These account for a small fraction of the bulk of the pancreas, but their function is vital. They were first described by Langerhans, in his MD thesis in 1869. A clue to their function came twenty years later, when Mering and Minkowski, in Strasbourg, removed the pancreas from dogs under surgical anaesthesia, and found that they developed the features of human diabetes. At the turn of the century, Opie, at Johns Hopkins University, reported degeneration of the ‘islands of Langerhans’ in the pancreas of people who had died from diabetes. In 1916, the English physiologist Sharpey-Schafer linked these observations and proposed that diabetes was due to the lack of an internal secretion — a hormone — from the ‘islets’. All this provided the background and the impetus for the accelerating and better known part of the story: the preparation in 1921 by Banting and Best, in Macleod's laboratory in Toronto, of an extract of pancreatic tissue, which reversed the rise in blood sugar in dogs whose pancreas had been removed. Next, the biochemist Collip prepared a refined extract, which was first used to treat human diabetes mellitus in 1922. Thus it was proved that the pancreas had an internal secretion — and it was named insulin from Latin insula; an island. The ‘islets’ were later shown to have two main types of endocrine cell, one producing insulin (beta cells) and the other producing glucagon (alpha cells). In the liver, the two hormones influence in opposite directions the balance between the storage of glucose (as glycogen) and its release into the blood; and they have contrary effects on new formation of glucose from amino acids. In fatty tissue they likewise have opposing effects on storage versus release of fuels. Insulin facilitates the uptake and usage of glucose by body tissues, notably muscle. In these ways the two hormones have opposite effects on the level of glucose in the blood.

The insulin: glucagon (I:G) ratio is therefore important and variable. By this balance, blood glucose level in particular is maintained for supplying the brain, nutrient supply in general is matched to the immediate needs of the body's tissues, and surplus is stored. When nutrients flood into the blood after digestion of a meal, insulin takes precedence, facilitating uptake and storage: the I:G ratio is high. When use of fuels for energy is at a peak during muscular work, glucagon promotes release of glucose and of fatty acids into the circulating blood, from liver and adipose stores: the I:G ratio is relatively low. In fasting, and its extension to starvation, glucagon is of major importance, along with others of the body's hormones.

The regulation of these counterbalancing secretions is mainly by direct response of the secretory cells to the levels of glucose and amino acids in the blood supplying the pancreas: for example, a rise in blood glucose affects cell membrane receptors on beta cells, resulting in enhancement of synthesis and extrusion of insulin.

In recent years it has become clear that the islets secrete several more hormones (apart from insulin and glucagon). These include gastrin and pancreatic polypeptide. How these interact with insulin and glucagon is the subject of much current research.

Autonomic effects

As well as the hormonal and chemical mechanisms for regulating the exocrine and endocrine functions of the pancreas, the autonomic nervous system plays a faster, and even anticipatory role — preparing the pancreas to deal with food which is on its way. Parasympathetic fibres from the vagus nerves stimulate enzyme secretion in response to eating, before ever the meal reaches the duodenum, and branches from the network of autonomic nerves in the nearby gut send signals related to events in the stomach and duodenum. The hormone-secreting cells also are supplied by nerves from both the sympathetic and the parasympathetic systems, which respectively inhibit and promote insulin release, and have the reverse action on glucagon. These actions accord with nutrient mobilization from body stores during exercise and stress, and on the other hand, the need for storage after digestion of a meal.

The pancreas is thus vital for the proper ‘feeding’ of the body tissues. Without its exocrine function, the digestion and absorption of foodstuffs is deranged. Without its endocrine function, untreated, we cannot long survive the inability to organize the use or storage of nutrients after their intake to the bloodstream.

John Henderson, and Sheila Jennett

See also alimentary system; blood sugar; insulin.