The World Health Organization, estimates that diabetes was the seventh (7th) leading cause of death in the world in 2016. It is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time, and is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that lowers blood sugar.
THE ENDOCRINE PANCREAS
The pancreas is an organ of the digestive system, but has also a major role in the endocrine system. The majority of the pancreas’ tissue serves an exocrine function, in which it secretes pancreatic juices that contain digestive enzymes into the pancreatic duct towards the duodenum – the first section of the small intestine – to aid in digestion. A very small (yet very important) portion of pancreatic tissue serves a different – endocrine function. This group of endocrine cells, called islets of Langerhans – named after the German pathologist who discovered it – houses the alpha cells which produces glucagon and the beta cells which produces insulin.
The distribution of cells in the endocrine portion of the pancreas is as follows:
- Alpha cells producing glucagon – composed of 20%
- Beta cells producing insulin and amylin – 70%
- Delta cells producing somatostatin – less than 10%
- Epsilon cells producing ghrelin – less than 1%
- Gamma cells or F cells, also known as PP cells producing pancreatic polypeptide – less than <5%
However, while the pancreas itself is a beautiful organ that hosts important physiology and pathology, this article will mostly focus on its Insulin production (and its antagonist pair, glucagon) to elaborate on their contribution to the development of the disease entity that is Diabetes Mellitus.
INSULIN vs GLUCAGON
Insulin and glucagon are types of hormones – which are signaling molecules responsible for affecting the physiology and behavior in the body, mostly to rebalance it especially when there are physiological changes or insults.
Basically Insulin’s role is to facilitate the transport of blood glucose into the cells of the body, while glucagon’s role is to facilitate the transport of glucose from the cells to the blood (they are functionally opposites). While a lot of molecular processes happen in the islets of Langerhans before any of these hormones get released, generally they are released by triggers such as hyperglycemia (high blood glucose) and hypoglycemia (low blood glucose).
When there are large doses of glucose circulating in the blood, perhaps after a meal, insulin gets formed from the beta cells and gets released. When there are large doses of glucose in the cells and not enough in the blood, perhaps the body is in a fasting state, glucagon is formed from the alpha cells and gets released.
INSULIN and GLUCAGON in the LIVER
The liver contains Glucose Transporter type 2 (GLUT-2) receptors in which glucose enters freely. For glucose to be utilized, Insulin binds to another receptor in the liver called a Tyrosine Kinase Receptor (specifically the Insulin receptor type) in which the overall result is the activation of the enzyme called PI3K/AKT. This enzyme converts the glucose absorbed by the liver into either of the two: Glycogen – in the process of glycogenesis or into pyruvate which will eventually be converted into energy, in the process of glycolysis.
Now in a fasting state (hypoglycemia) in which the blood lacks glucose, Glucagon binds to its receptor in the liver and activates another receptor called the “g-protein coupled receptor” and eventually along the way this process lead to the activation of protein kinase A (PKA). The liver at this state has a storage of glycogen due to the previous glycogenesis processes helped by insulin. Protein kinase A activates an enzyme called glycogen phosphorylase to break down this glycogen into glucose in a process called glycogenolysis. This glucose goes to the blood and effectively increases blood glucose levels.
Another unique process helped by glucagon (especially the protein kinase A enzyme that glucagon’s responsible for activating) is gluconeogenesis – which also happens in the liver. In contrast to glycolysis that creates glucose from stored glycogen, gluconeogenesis creates glucose through the help of protein kinase A from non-carbohydrate products, such as glycerol, glucogenic amino acids and even lactate.
INSULIN in the SKELETAL MUSCLES
In contrast to the Liver, the glucose transporter in the muscles is type 4 (GLUT 4) in which the difference from GLUT 2 is that it needs insulin in order to be activated. As such without insulin, glucose has a hard time entering the muscle cell and consequently no glycolysis takes place. Skeletal muscles also have amino acid channels in which the enzyme PI3K /ATK (which remember gets activated upon the binding of insulin) activates. Food generally contain a lot of compounds that can be used by the body, and amino acids are one. Amino acids are basically the building blocks of protein and essential in building and maintaining muscle cells. Once the amino acid channel becomes activated, insulin aids amino acid uptake into the muscle cell and these amino acids combine into protein polymers in the process of protein synthesis.
To be continued