The Endocrine Pancreas

1. The Pancreas
2. Insulin
3. Glucagon
4. Quiz

• The endocrine function of the pancreas is to produce the hormones glucagon and insulin from α and β cells respectively. α and β cells are the main cell types in the pancreatic Islets of Langerhans (clusters of hormone-producing cells).
• Insulin is the hormone of energy storage, and is secreted from the pancreas in response to an increase in blood glucose concentration. It causes increased glucose uptake in target tissues and increased glycogenesis (making glycogen from glucose).
• Glucagon is the hormone that opposes insulin. It functions to increase plasma glucose concentrations during periods of fasting. It promotes gluconeogenesis (making new glucose) and glycogenolysis (breaking glycogen down into glucose).

The Pancreas

The pancreas is a large gland that develops embryologically as an outgrowth of the foregut (the upper part of the embryonic gut), and can be found posterior to the stomach. The pancreas lies across the upper abdomen. Its head sits in the curve (C loop) of the duodenum on the right, and its tail runs towards the spleen on the left, in the left upper quadrant (the upper left part of the abdomen).

At least 98% of pancreatic tissue is exocrine tissue, which acts to produce digestive enzymes that are then secreted directly into the duodenum. The exocrine function of the pancreas will be covered in greater detail in the gastrointestinal unit; this series focuses on the endocrine function of the pancreas.

Diagram: Shows the location and basic structure of the pancreas

Creative commons source by Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014" [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]

The endocrine function of the pancreas is to produce hormones from Islets of Langerhans. Islets of Langerhans are predominantly made up of α and β cells, which secrete glucagon and insulin respectively. The functions of insulin and glucagon are to regulate the metabolism of carbohydrates, proteins and fats. Insulin works to lower blood glucose levels, whilst glucagon works to raise them.

The brain relies on a steady supply of glucose from the blood, so blood glucose is kept within a narrow range. The plasma glucose reference range (the range of values seen in healthy people) when fasting is normally around 4.0 to 5.4 millimoles per litre (mmol/L). NICE treats a fasting value of 5.5 to 6.9 mmol/L as a sign of high risk of type 2 diabetes. After a meal, plasma glucose rises and then falls back towards fasting levels as insulin is released. The renal threshold for glucose (the blood glucose level above which the kidneys let glucose into the urine) is approximately 10 mmol/L, but this varies between individuals and is lower during pregnancy and higher in the elderly. Glycosuria is glucose in the urine, which occurs once blood glucose rises above the renal threshold. Insulin and glucagon have opposing effects on blood glucose and together help regulate its concentration.

Diagram: Table showing the differences between insulin and glucagon

SimpleMed original by Dr. Jenny Hubball

Insulin

Insulin is the hormone of energy storage. It is anti-gluconeogenic (stops new glucose being made), anti-lipolytic (stops fat breakdown) and anti-ketogenic (stops ketone production). Together these effects favour energy storage. It is a peptide hormone with an α-helix structure (a coiled protein shape), consisting of two unbranched (straight) peptide chains (the A and B chains) connected by two disulphide bridges (bonds between sulphur atoms). Insulin is synthesised in pancreatic β-cells via the following pathway:

1. The single polypeptide preproinsulin (the first, inactive precursor of insulin) is made on ribosomes (the cell’s protein-making machinery) in β-cells, using instructions copied from the INS gene in the nucleus.
2. A signal peptide (a short tag that tells the cell where to send the protein) on the preproinsulin directs the polypeptide chain to the rough endoplasmic reticulum.
3. Preproinsulin has its signal peptide cut off (cleaved), which leaves proinsulin.
4. The proinsulin is folded and the disulphide bridges are formed.
5. Proinsulin is transported to the Golgi apparatus, where it is packaged into secretory granules (small storage sacs). As the granule matures, the proinsulin is cut (cleaved) to produce insulin and C-peptide (the connecting fragment released with insulin). Both wait in the granule for a signal to be released.

Insulin is then released from the pancreatic β-cells via the following pathway:

1. Food intake results in an increase in blood glucose concentration.
2. Glucose diffuses into the pancreatic β cell via GLUT2 transporters (carrier proteins in the cell membrane; GLUT stands for glucose transporter).
3. The increase in intracellular glucose causes an increase in glycolysis and ATP production.
4. The increase in ATP production increases the intracellular ATP:ADP ratio.
5. The increased ATP:ADP ratio causes the ATP-dependent potassium (K⁺) channels on the cell membrane to close.
6. The closure of the K⁺ channels causes the membrane to depolarise.
7. Voltage-gated calcium (Ca²⁺) channels on the cell membrane open, and there is a calcium influx (inflow) into the cell.
8. The increase in intracellular calcium causes secretory granules to be released via exocytosis.

Diagram: Outlines the mechanism of release of insulin from pancreatic β-cells

SimpleMed original by Dr. Jenny Hubball

The release of insulin then increases the uptake of glucose into cells of target tissues (adipose tissue, which is body fat, and skeletal muscle). It does this by inserting GLUT4 transporters (glucose transporter 4) into the cell membrane, and it also increases glycogen synthesis. Insertion of GLUT4 transporters allows glucose to be carried across the target cell membrane. Insulin receptors are heterotetramers (proteins made of four parts of two kinds) composed of two α subunits (chains) and two β subunits (chains) linked by disulphide bonds. The α chain is on the exterior of the cell membrane, and the β chain spans the membrane in a single segment.

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