With the festive season soon to be in full swing and the calorific intake about of soar, we are taking the month of December to look into diabetes mellitus, a condition that prevents patients from over indulging like most of us.
Sugar comes in many forms; the most basic form is that of glucose. When measuring blood sugar levels, glucose is the level that is measured. Having high levels of blood glucose can be very dangerous to your health. High blood sugar levels are most commonly due to diabetes mellitus. This condition comes in various types and with 10% of the world’s population having this disorder it is of great importance that it is understood. Therefore, over the next few weeks we will be looking at the different forms, complications and treatment options for diabetes mellitus. Today we are focusing on the normal physiology of regulating blood glucose levels within our bodies.
Within our body there is an organ known as the pancreas. This is both an endocrine and an exocrine organ, meaning it has both hormonal and digestive functions respectively. We are going to focus on the endocrine function specifically the insulin and glucagon hormones, as these are affected in diabetes. The pancreas is a gland and contains a variety of cells. There are clusters of cells known as the islets of Langerhans. These are responsible for the hormonal function of the pancreas. There are many different types of cells within the islets of Langerhans, most importantly in terms of diabetes are the alpha and beta cells. The alpha cells produce the hormone glucagon and the beta cells produce insulin.
Insulin is produced in the beta cells of the islet of Langerhans. A preform to insulin is first produced, preproinsulin, this contains 3 chains that are spiralled around each other and a signalling sequence at the N-terminal end of the chain. The molecule is first converted from preproinsulin to proinsulin through the removal of this signalling sequence. When in the endoplasmic reticulum the chain is broken down even further and one of the 3 chains is removed, the c-chain. This leaves the A and B chain connected by sulphide bridges to form insulin molecule.
Glucose is the trigger for insulin release, this is an increased level of glucose in the extracellular fluid (ECF). There is a GLUT2 transporter which allows the passage of glucose into the Beta cells within the pancreas. This rise in glucose within the beta cell leads to an increased production of ATP (a molecule involved in energy currency). This then inhibits the efflux of potassium, which causes voltage gated calcium channels to open allowing the influx of calcium into the beta cells. This increase in calcium levels within the cell cause activation of the insulin gene expression, via the CREB (calcium responsive element binding protein). This insulin is then exocytosed out of the beta cell.
So how does insulin work to allow the uptake of glucose into cells? Insulin binds to a highly specific receptor on the surface of cells, this receptor contains two identical subunits that span the cell membrane, each subunit contains; one alpha and one beta chain. The alpha chain is on the exterior of the cell membrane, outside the cell. Whereas the beta chain spans the membrane in a single segment. There is a single disulphide bridge that connects the two. In the present of insulin the alpha chains move together and fold around the insulin; resulting in the beta chains moving together, causes them to activate into whats known as a tyrosine kinase enzyme. This activation of the enzyme formed by the beta chains results in a cascade eventually causing the cell to increase it’s production of GLUT4 receptors which migrate to the cell membrane. This GLUT4 is a protein channel that allows the entrance of glucose into the cells.
This is the hormone that causes the opposite function to insulin, so acts in order to raise your blood glucose level. Glucagon is secreted by alpha cells within the islets of Langerhans and is stimulated by low levels of glucose within the blood, which is detected by the alpha cells which then release the glucagon via exocytosis.
When glucagon binds to a glucagon receptor, it binds to whats known as a G coupled receptor this activates the enzyme adenylate cyclase which causes an increased production of cAMP. This cAMP molecules activates an enzyme called protein kinase A which activates a number of enzymes that are involved in not allowing glucose out of the cell in order to be used by that cell. This causes a decrease in blood glucose levels. Other metabolic effects glucagon has on the liver are, increase in glycogenolysis (breakdown of glycogen, stored version of glucose therefore increasing the amount of glucose in the blood), decrease in glycogenesis (decrease in the creation of glycogen), increase in ketogenesis (breakdown of fatty acids to be used as energy instead of glucose) and increase in gluconeogenesis (formation of glucose from non-carbohydrate sources). It also works on adipose tissue in order to increase lipolysis. All these functions act to increase the amount of glucose in your blood and reduce the amount that is being used by the cells for energy.
Join us for our blog next time where we will be discussing type 1 diabetes mellitus