What Is Ultralente Insulin?

In the 1990s, people used genetic engineering technology to locally modify the amino acid sequence and structure of human insulin to synthesize human insulin analogs.

Insulin analogs generally refer to substances that can mimic the secretion of normal insulin while also being structurally similar to insulin.

Chinese name: Insulin analog
Foreign name: insulin analogue

Definition: Simulate normal insulin secretion
colour: Colorless clear liquid
Treatment object: diabetes

History of insulin analog development

Insulin is an important method for the treatment of diabetes. Since it was discovered and used to treat diabetes in 1921, it has played an irreplaceable role. The discovery of insulin has opened a new page in the treatment of diabetes. Life is saved. It can be said that the discovery of insulin is a landmark and a milestone in the treatment of diabetes. However, insulin is not a panacea, and it has its limitations and some unsatisfactory places.For example, ordinary insulin needs to be injected 30 minutes before a meal.Some patients will have increased body mass, insulin allergy, and large blood sugar fluctuations. Increasing the dose is prone to hypoglycemia. , Reduced dose will lead to increased fasting blood glucose, conventional insulin can not really simulate the human physiological insulin secretion and so on. Therefore, in response to the above situation, scientists have developed a new type of insulin, an insulin analog, which has provided more new options for the treatment of diabetes.

In the late 1990s, in the in-depth study of insulin structure and composition, humans discovered that modification of the peptide chain may change the physicochemical properties and biological characteristics of insulin, so that it can develop more suitable human physiological needs than traditional human insulin. Insulin analogs. In 1996, Eli Lilly and Company launched the world's first insulin analogue, insulin lispro (Umilot). In 2000, Sanofi of France listed the first long-acting insulin analogue, insulin glargine (at the time). Today, a variety of insulin analogs produced by different companies continue to emerge.

Types of insulin analogs

Insulin analogues can be divided into: fast-acting insulin analogues, long-acting, premixed insulin analogues, and ultra-long-acting insulin analogues according to their duration of action.

() Fast -acting (ultra-short-acting) insulin analogs

The characteristics of these drugs are that they have a good effect on reducing postprandial blood glucose, and basically ensure the stability of blood glucose after eating. After subcutaneous injection, the onset time was 10 minutes, the peak time was 40 minutes, and the duration of effect was 3 to 5 hours.

Lispro (Insulin lispro) was developed by Lilly company in 1996. It is to exchange the 28th position of proline and the 29th position of lysine on the human insulin B chain, other amino acid sequences and structures No change, this constitutes a new protein, insulin lispro. As a result of the reversal of the order of the two amino acids, the function of insulin has not changed, but the insulin that was prone to form dimers and hexamers is no longer easy to aggregate into dimers and hexamers, but exists as monomers. In this way, it can be easily absorbed after subcutaneous injection, so that it can work quickly and take effect quickly.
Aspart (Insulin Aspart, Insulin Aspart) is a fast-acting insulin analog developed by Novo Nordisk.It was first listed in Europe in 1999 and in China in 2002.It is used for type 1 and type 2 diabetes. treatment. It replaces proline at position B28 of human insulin with aspartic acid, which makes it difficult for the insulin analog to form a hexamer, which makes it easy to absorb under the skin and quickly functions.
Glulisine is a new fast-acting insulin analog that Aventis is developing. It replaces asparagine at position B3 with lysine and replaces lysine at position B29 with glutamic acid. It is preliminarily believed to have a protective effect on islet B cells.

() Insulin analog long acting (basic) insulin analog

The long-acting insulin analogue has a slower action time, and the onset time is delayed by 4 to 5 hours. There is no significant peak. The duration of action lasts 30 hours. It is very suitable for basic insulin treatment. The combination with fast-acting insulin analogues can control blood sugar well. Lipidated insulin binds to albumin in the blood, slowing down the time for insulin to work.

Glargine (insulin glargine, insulin glargine, Lantus) is a long-acting insulin analog developed by Aventis. It was listed in the United States and Europe in 2000 and China in 2003.It differs from human insulin in that: the aspartic acid at the 21st position of the A chain is replaced by glycine; the C-terminus of the B chain is added with 2 arginines Residues. The result of this change can be as follows: the result of the substitution of A21 with glycine makes the binding of hexamers more stable. Under the neutral environment of subcutaneous tissue, the solubility decreases and the precipitate is formed, so that it is slowly absorbed, similar to the peak-free secretion of basal insulin. , Suitable for long-acting treatment, if a small amount of zinc is added, its action time will be further extended; the result of adding 2 arginine residues at the C-terminus of the B chain changes the isoelectric point of insulin, rising from the original pH 4.5 to At pH 6.7, microprecipitation is formed in the neutral environment of the subcutaneous tissue, which prolongs the decomposition, absorption and action time of insulin.
Detemir (Insulin detemir, Levermir) is developed and produced by Novo Nordisk.It removes the amino acid at the B30 position and attaches an N-16-alkanoic acid group to the lysine position at the B29 position. 14 carbon free fatty acid chain. In the medicinal solution with zinc ions, the insulin molecule still exists as a hexamer, and the modification of the fatty acid chain makes it slowly absorbed under the skin. In addition, Detemir in plasma, because it contains fatty acids, binds to albumin in plasma, so the Detemir that binds to the target tissue will be slowed down, and only free Detemir can play a hypoglycemic effect, Detemir cannot interact with albumin and The insulin receptor binds at the same time, and the Detemir complex bound to albumin in plasma cannot be excreted through glomerular filtration; its time of entering the liver is also later than that of human insulin, and the comprehensive result of several aspects has prolonged the action time of insulin. Detemir solution does not form a precipitate under the skin, so the absorption rate is constant.

Insulin analog premix

Premixed insulin analogs Premixed insulin analogs are insulin preparations that mix fast-acting insulin analogs (insulin lispro or insulin aspart) and protamine zinc fast-acting insulin analogs in a certain ratio, including low-premixed insulin analogs. And pre-mixed insulin analogs. Domestic low premixed insulin analogues are mainly 75/25 dosage forms, such as insulin lispro 25 (25% lispro insulin + 75% protamine zinc lispro insulin) and 70/30 dosage forms, such as insulin aspart 30 (30% gate Insulin winter + 70% protamine zinc aspart). Medium premixed insulin analogs are mainly 50/50 dosage forms, such as insulin lispro 50 (50% insulin lispro + 50% protamine zinc lispro) and insulin aspart 50 (50% insulin aspart + 50% protamine) Insulin Zinc).

Aspart30 is a mixed solution of 30% soluble Aspart (aspartic acid insulin) and 70% protamine crystal aspartic acid insulin, which is a fast-acting insulin analog and an intermediate-acting insulin analog. In combination, it has the advantages of fast-acting analogs and premixed dosage forms.Aspart has fast effects, short action time, protamine crystal aspartic insulin, slow action, long action time, and the combination of the two can play a physiological insulin-like effect. It can be injected immediately before meals, instead of 30min before meals. Aspart30 can be injected once a day before breakfast and before dinner to maintain a stable blood glucose level of 24h. It is more ideal for controlling postprandial blood glucose and for HbA1c. The reduction effect is comparable to, or even better than, NPH insulin.
Lispro premix is made from Lispro and Lispro Protamine Suspension (NPL) in a 25:75 ratio. The biggest benefits of Lispro premix are postprandial glycemic control and ease of use. Research on the effect of this premixed preparation and human insulin mixed preparation (20:80) found that there was no significant difference in the reduction in postprandial blood glucose and HbA1c between the two groups, but the incidence of nighttime hypoglycemia in the Lispro premixed preparation was significantly reduced, which may be It is related to the small proportion of intermediate-acting insulin it contains.

Use of insulin analogs

Fast-acting insulin analogs
Aspart, Lispro, Glulisine and other fast-acting insulin analogs are similar to ordinary insulin, but do not require injection 30 minutes before a meal, and can be injected immediately at meals, which is convenient for diabetic patients, and can also be used for the rescue of severe diabetes complications and insulin pumps. Treatments work faster, such as the rescue of ketoacidosis and hypertonic coma. The effect of injection site on its absorption is the same as that of ordinary insulin. Some studies have shown that the absorption rate of abdominal injection is faster than that of deltoid muscle and the inner thigh. Lispro at the same site is faster than ordinary insulin. Can be injected intravenously or added to the fluid.
Long acting insulin analogs
Glargine, Detemir, and ww99-S32 are mainly used in the basic treatment of insulin, 1 d injection, no time period limitation, the effect lasts 24 hours, and there is no peak-to-valley concentration change, similar to basic insulin secretion. Patients with short-acting or fast-acting insulin therapy can be used as basal insulin, as an alternative to insulin pumps, and can be used in combination with hypoglycemic drugs.
Premixed insulin analogs
Aspart30 and Lispro premix, 2 subcutaneous injections, injections immediately before and after dinner, 30 minutes before meals are not needed, the injection site does not affect the efficacy, the results of the two injections can maintain blood sugar stability, especially the stability of blood sugar after meals, It is not suitable for application to insulin pumps. Injecting once a day cannot meet the physiological needs of patients. Premixed insulin analogs sometimes have poor glycemic control after lunch. Pre-lunch drugs, such as alpha-glucosidase inhibitors, biguanides, short-acting sulfonylureas (Novolon), can be added.

Safety of Insulin Analogs

1 Hypoglycemic response Injected insulin therapy cannot simulate the accuracy and flexibility of normal people's own insulin secretion to regulate blood glucose, and blood glucose fluctuations will inevitably occur. If the body's insulin secretion pattern can be approached, the incidence of hypoglycemia will be relatively low. Patients who used insulin lispro and insulin aspart had a reduced risk of severe hypoglycemia events by about 20% compared to regular insulin. Suspension insulin (such as NPH) has unstable absorption and is prone to fluctuations in blood glucose levels; while the absorption variation of glargine and detemir is small, and hypoglycemic events occur, especially the risk of hypoglycemia at night is lower than NPH.

2 Allergic reactions Insulin preparations can cause allergic reactions. With the improvement of the preparation level and the application of recombinant human insulin, only a few patients are allergic to the human insulin preparation. Insulin analogs mainly modify the amino acid positions 26 to 30 of the insulin B chain, and the modification of this region can retain the low immunogenicity of insulin. Those who are allergic to human insulin in the clinic can try insulin analogs.

3 Injection site reactions Insulin analogs can cause injection site reactions. Compared with NPH, insulin glargine has a higher incidence of injection site reactions, which is related to the lower pH value and stronger irritation of the preparation; but the general response is lighter and can be tolerated by patients. Other insulin analogs did not increase the incidence of injection site reactions.

4. The potential mitogenic effect is similar to the safety of insulin and insulin-like growth factor (IGF-1) during pregnancy. The amino acid sequences of the two are approximately 50% homologous. IGF-1 receptor activation can regulate cell growth and differentiation, and insulin does not promote mitosis under physiological conditions. Insulin analogs change the structure of insulin molecules, and may change their affinity for insulin receptors and IGF-1 receptors. Whether they have potential mitogenic effects has attracted attention. At present, only insulin prosthesis is classified as Class B for safety during pregnancy. Other insulin analogs are classified as Class C.