Insulin

Diabetes

Introduction to Diabetes

The Story of Insulin
Insulin Synthesis
The insulin-making cells of the body are called beta cells, and they are found in the pancreas gland. These cells clump together to form the "islets of Langerhans", named for the German medical student who described them. The synthesis of insulin begins at the translation of the insulin gene, which resides onchromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane. Once the preproinsulin reaches the endoplasmic reticulum, a proteasecleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulinand free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the beta cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.

Insulin Structure
In 1958, Frederick Sanger was awarded his first Nobel Prize [http://www.nobel.se/chemistry/ laureates /1958/] fordetermining the sequence of the amino acids that make up insulin. This marked the first time that a protein had had the order of its amino acids (the primary sequence) determined. Insulin is composed of two chains of amino acids named chain A (21 amino acids) and chain B (30 amino acids) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6thand 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can be used to replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin bybacteria (recombinant insulin). Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in away that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations of insulin is made, varying from short acting to long acting.

Insulin secretion
Rising levels of glucose inside the pancreatic beta cells trigger the release of insulin:

1. Glucose is transported into the betacell by type 2 glucose transporters (GLUT2). Once inside, the first step in glucose metabolism is the phosphorylation of glucose to produce glucose-6-phosphate. This step is catalyzed by glucokinase—it is the rate-limiting step in glycolysis, and it effectively traps glucose inside the cell. 2. As glucose metabolism proceeds, ATP is produced in the mitochondria. 3. The increase in the ATP:ADP ratiocloses ATP-gated potassium channels in the beta cell membrane. Positively charged potassium ions (K+) are now prevented from leaving the beta cell. 4. The rise in positive charge inside the beta cell causes depolarization. 5. Voltage-gated calcium channels open, allowing calcium ions (Ca2+) to flood into the cell. 6. The increase in intracellular calcium concentration triggers the secretion of...