When we consume food, we absorb the sugar in food in order to feed our cells. However, even though we successfully absorb the sugar in the intestine and it manages to reach the blood stream, some cells still do not receive sugar. In order for the cells to receive the sugar, insulin attaches to the cells to signal it to absorb sugar. Insulin is the key to using the sugar we consume.
What exactly is insulin?
Insulin is a peptide hormone that is made in the pancreas by beta cells. It regulates the metabolism of proteins, fats and carbohydrates by promoting the absorption of sugar into liver, fat and other cells. In the cells the glucose is either converted into glycogen via glycogenesis or to fats via lipogenesis where it can be saved for later use. Insulin helps balancing the blood sugar levels when it is high by promoting its storage in the liver and releases it when your body has low blood sugar levels.
The problem arises when your body cannot produce sufficient insulin (type1 diabetes) or when your cells are unresponsive to insulin (type2 diabetes). These complications might lead to hyperglycemia, which is increased blood sugar lever. If left untreated it might cause other complications such as hypertension, or chronic kidney disease. Fortunately, modern medicine have helped people who suffer from such problems from developing other fatal/dangerous complications.
The goal of treatment for type 1 diabetes is to keep blood sugar level in the normal range, which is accomplished by taking insulin injections daily and checking blood sugar regularly. The treatment of type 2 diabetes however is to increase the sensitivity of the cells to insulin, which is made possible by Metformin. However for both type of diabetes, lifestyle adjustments must be made in order to maintain a balanced blood sugar lever.

Insulin binds to the insulin receptor on the surface of the cell called tyrosine kinase. This results in many protein activation cascades which ultimately triggers glut 4, an insulin regulated glucose transporter to dock onto the surface of the cell. Then the cell utilize the sugar by glycolysis.

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As mentioned earlier, insulin is synthetized in beta cells of the pancreas as proinsulin. It is made of 2 peptide chains, chain A and chain B. chain A is made of 21 amino acids meanwhile chain B is made of 30 amino acids. Both chains are connected by three disulfide bonds which helps keep the 2 chains together.

The chain in black is “Chain A” and the chain in green is “Chain B” connected together by 3 disulphide bonds shown in yellow

Not until the 1960’s did scientists find out about the precursor of insulin, Proinsulin. This protein held both chain A and chain B in a single continuous chain joined together by a segment known as the C segment, which is made of 30 – 35 residues ending with Arg-Arg and Lys-Arg on each respective end. The protein is cleaved at those endings in the Golgi apparatus by 2 enzyme endoproteases, resulting in the formation of insulin, which unlike proinsulin has 2 disulfide bonds only.

Insulin naturaly is a monomer at low concentrations and forms dimers at higher concentrations in neutral pH. However at higher concentrations especially where zinc is present it forms hexameric complexes. Although having many forms, it is only the monomer that binds to the receptor of the cell. With the help of modern technology scientists have been able to view the 3d structe of insulin which helped greatly in determining the residues which are important for binding. The structe-activity relationship of insulin has been determined by preparation of different insulin analouges which have different, additional or missing amino acids. After much work have done testing with these analouges scientists came with the conclusion that there is 3 reigons that are relevant for insulin binding to the receptor; 1) the NH2 Terminal located at the alpha chain, 2) the COOH terminal located at the beta chain, and 3) COOH terminal located at the alpha chain.

NH2 terminal at a chain contents which are important for activity:
(GlyA1-IleA2-ValA3-GluA4) or (AspA4)

COOH terminal at a chain contents which are important for activity:

COOH terminal at b chain contents which are important for binding:

Red star: Imp for activity Yellow star: Imp for binding
After much research, much have been known about the relevance of these regions.
Firstly the NH2 terminal at the a-chain. N-acetylation of the NH2 terminal showed significant decrease in activity, approximately by 30%. This indicates that this region is indeed important for activity and the importance of that area having a positive charge, which means that there is possibly an ionic interaction between this region and the receptor. Furthermore, deletion of the glyA-1, an amino acid located in the NH2 terminal area, have also shown decrease in activity. This suggests that GlyA1 is relevant in insulin binding possibly due to the correct positioning of the positively charged NH2-terminus which forms a salt bridge with the carboxy terminus of the B-chain. Substitution however has another story. When glutA1 was substituted with L-amino acids such as Ala, Leu, and Val it showed decrease in binding by 20% not in activity. However when substituted with D-amino acids such as D-Phe, D-Leu and D-Ala it showed full biological activity. This shows that conformation of the insulin is important and gluta1 helps achieving D-conformations.

Secondly the COOH terminal at a-chain. Mono-iodization of the amino acid TyrA19 results in decrease in activity by approximately 40%. To make sure that iodization was only specific to the TyrA19, researchers testing iodizing another Tyr group located in the a-chain. The result was that it was specific to the COOH terminal only and so we can conclude iodization the TyrA19 located at the COOH terminal does exclusively cause decrease in activity. Tests with the amino acid AsnA21 has been conducted and has shown that after the removal of the AsnA21 amino acid, it has shown no relevance whatsoever in receptor binding.

Finally the COOH terminal at b-chain. Tests show that deletion of TyrB26, ThrB27, ProB28, LysB29, and AlaB30 resulted in dispentapeptide insulin which has 20% of the binding potency of insulin. Removal of GlyB23-PheB24-PheB25-TyrB26 however resulted in an analogue that was incapable of dimerization which decreased binding substantially. Specifically PheB24 and PheB25 are crucial in binding.