When the body fails to secrete sufficient quantities of insulin, this invariably results in diabetes mellitus – itself caused by excessive blood glucose levels. When fasting plasma concentrations exceed 7 mmol/L-1, the condition is diagnosed as diabetes. Diabetes may take the form of type 1 or type 2, depending on the cause. Type 1 diabetes usually presents in younger people, resulting from a deficiency of insulin production. These patients are also at risk of diabetic ketoacidosis. Type 2 diabetes usually presents later in life, accounting for more than 90 percent of all diabetic cases. First, though, let’s take a closer look at the pharmacology of insulin analogues – how and why they work.
What are insulin analogues?
Insulin is, at its most fundamental, a string of amino acids. These amino acids may be altered in order to enhance the ADME characteristics of the insulin. Such modifications have resulted in two main types of insulin analogue: fast-acting and long-acting insulin analogues – such as those tabulated below.
Fast-acting analogues include insulin lispro, insulin aspart and insulin glulisine. Long-acting analogues include insulin detemir, insulin glargine and insulin degludec. Each group has a different function. Fast-acting analogues supply insulin needed for meals, whereas long-acting analogues supply insulin throughout the day and night.
Pharmacology of Insulin Analogues
In order to understand the amino acid modifications that form insulin analogues, we must first understand the structure of natural insulin itself. Insulin is a 51 amino acid protein which is split into two chains: A (21 amino acids) and B (30 amino acids). These chains are linked by two disulphide bonds, with a third cysteine bridge extending out from the A chain. The primary structure of insulin was itself determined by Frederick Sanger, who was awarded the Nobel Prize in Chemistry for this work in 1958.
Insulin lispro – marketed under the name Humalog – was the first such analogue to enter the market. The name lispro comes from the two amino acids lysine and proline – both of whose positions are reversed at B28 and B29 (respectively) on the insulin molecule. This amino acid reversal does not alter insulins binding affinity to receptors, but it does prevent formation of dimers and hexamers – meaning modified insulin is more readily absorbed from injection sites.
Insulin glulisine is similar. Glutamic acid is exchanged for lysine at position B29, and lysine for asparagine at position B3. Insulin aspart, similarly, exchanges aspartic acid for proline at position B28. Long-acting insulin analogues also undergo amino acid modifications. Insulin detemir omits threonine from position B30 while, at the same time, adding a fatty acid chain to position B29. These changes have two effects: to increase formation of insulin complexes and to increase albumin binding.
As a result, absorption of insulin detemir is markedly slowed down. This is what constitutes its long-acting mechanism. The other long-acting insulin analogue – insulin glargine – has two amino acid changes: glycine is substituted for asparagine at A21 and two arginines are added to the C-terminus of the B chain. These two simple amino acid modifications render the molecule more soluble at low pH and at physiological pH. As a result, insulin glargine precipitates after injection, before being slowly reabsorbed.
The pharmacology of insulin analogues can, therefore, be boiled down to molecular transformations to the insulin molecule – simple, effective amino acid transfers.
Short-acting insulin analogues are more rapidly absorbed compared to natural insulin. Their duration of action is approximately 3 hours, and are usually administered before a meal – but may be administered after a meal, too. In addition, short-acting insulins may be combined with long-acting analogues – and are available as biphasic formulations: for example, insulin aspart with insulin aspart protamine in a 30:70 ratio. Long-acting insulin analogues are uniformly absorbed after subcutaneous injection, thereby avoiding plasma insulin peaks. This contrasts with short-acting analogues which achieve an early and high peak plasma concentration.
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