Crystalline Insulin: What is it? Types, Side Effects and Modifications

It results from recombinant DNA technology, where the amino acid B28, which is usually proline, is replaced by aspartate.

An insulin analog is an altered form of insulin, different from anything found in nature but still available to the human body to perform the same action as human insulin in terms of glycemic control.

By genetically engineering the underlying DNA, the amino acid sequence of insulin can be modified to alter its ADME characteristics (absorption, distribution, metabolism, and excretion).

Officially, the U.S. Food and Drug Administration (FDA) refers to these as “insulin receptor ligands,” although they are more commonly known as insulin analogs.

These modifications have been used to create two types of insulin analogs:

Those more easily absorbed from the injection site act faster than natural insulin injected subcutaneously, intended to deliver the bolus level of insulin needed at mealtime (prandial insulin).

And those released slowly over 8 and 24 hours are intended to supply the basal level of insulin during the day and particularly at night (basal insulin).


Eli Lilly and Company manufactured the first insulin analog approved for human therapy (Insulin Lispro rDNA).

What types of insulin are crystalline?

Fast-acting insulin

Rapid-acting insulins are usually taken just before or with a meal. They work very quickly to minimize the rise in blood sugar following food.

Rapid-acting insulins are commonly prescribed for people with type 1 diabetes. However, there may be times when they can also be prescribed for type 2 diabetes.

Because fast-acting insulins work very quickly, they can increase the chances of hypoglycemia. Therefore, care must be taken when dosing.

What type of insulin is rapid-acting insulin?

Rapid insulins, a type of insulin known as analog insulins, can be injected or given through an insulin pump.

Insulin Lispro

Eli Lilly and Company developed and commercialized the first rapid-acting insulin analog (insulin lispro rDNA) Humalog.

It was designed through recombinant DNA technology to reverse the penultimate lysine and proline residues at the C-terminus of the B chain.

This modification did not alter insulin receptor binding but did block the formation of insulin dimers and hexamers.

This allowed more significant amounts of active monomeric insulin for postprandial (after meal) injections.

Insulin lispro, sold under the brand name Humalog among others, is a fast-acting insulin analog. It was first approved for use in the United States in 1996, making it the first insulin analog to enter the market.

Engineered using recombinant DNA technology, the penultimate lysine and proline residues at the C-terminus of the B chain are reversed.

This modification does not alter receptor binding but blocks the formation of insulin dimers and hexamers. This allows large amounts of active monomeric insulin to be immediately available for postprandial injections.

Insulin lispro has a significant advantage over regular insulin for postprandial glucose control.

It has a shorter onset delay, allowing more flexibility than regular insulin, which requires a more extended waiting period before starting a meal after injection.

Both preparations should be coupled with longer-acting insulin (such as NPH insulin) for reasonable glycemic control.

Insulin Aspart

Novo Nordisk created ‘aspart’ and marketed it as NovoLog / NovoRapid (UK-CAN) as a fast-acting insulin analog.

The onset of action is approximately 15 minutes, the maximum effort is reached in 45-90 minutes, and the duration is 3-5 hours. However, as with all insulin, these figures are based on averages and vary between individuals due to blood flow, injection site, temperature, and exercise.

It was created through recombinant DNA technology so that the amino acid B28, which is usually proline, is replaced by an aspartic acid residue.

The sequence was inserted into the yeast genome, and the yeast expressed the insulin analog, which was then harvested from a bioreactor.

This analog has increased charge repulsion, preventing the formation of hexamers from creating faster-acting insulin. It is approved for use in continuous subcutaneous insulin infusion (CSII) and Flexpen and Novopen delivery devices for subcutaneous injection.

Insulin aspart is a rapid-acting insulin analog marketed by Novo Nordisk as NovoLog / NovoRapid. It is a manufactured form of human insulin, where a single amino acid has been exchanged.

This change helps the rapid-acting insulin analog absorb quickly into the bloodstream. As a result, it starts working in minutes, allowing one to take insulin and eat right away.

Rapid-acting insulin analogs are thought to act similarly to how insulin is released in people without diabetes mellitus.

The Novolog allows a flexible dosing schedule, allowing patients to adjust their insulin according to any change in their eating habits.

The safety and efficacy of insulin aspart (NovoLog / NovoRapid) in real-life clinical practice were evaluated in the A1chieve study.

According to JDRF (charity), the Food and Drug Administration approved the marketing of insulin aspart in the United States in June 2000.

There is a lack of convincing evidence to conclude the superiority of insulin aspart over human insulin concerning the efficacy, leading some to a reasonable question about patients switching from human insulin to this modern insulin.

Insulin Glulisina

Glulisine is a rapid-acting insulin analog, developed by Sanofi-Aventis and sold under the brand name Apidra, approved for use with a regular syringe in an insulin pump. Standard syringe delivery is also an option.

The Food and Drug Administration-approved label indicates that it differs from regular human insulin by its rapid onset and shorter duration of action.

Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine, and lysine at position B29 is replaced by glutamic acid.

When injected subcutaneously, it appears in the blood before human insulin. When used as a mealtime insulin, the dose should be given 15 minutes before or 20 minutes after starting a meal.

Intravenous injections can also be used for extreme hyperglycemia but should be done under the supervision of a medical professional.

Short-acting insulin

It includes regular insulin, which starts to work within 30 minutes and is active for about 5 to 8 hours.

Regular Insulin

Regular insulin, also known as neutral insulin and soluble insulin, is a short-acting type of insulin. It is used to treat type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states.

It is also used together with glucose to treat high potassium levels. It is usually given by injection under the skin, but it can also be used by injection into a vein or muscle. The onset of effect is usually 30 minutes and lasts for 8 hours.

The common side effect is low blood sugar. Other side effects can include pain or skin changes at injection sites, low potassium in the blood, and allergic reactions.

Use during pregnancy is relatively safe for the baby. Regular insulin can be made from the pancreas of pigs or cows. Human versions can be made by modifying the porcine arrangements or recombinant technology.

Insulin was first used as a medicine in Canada by Charles Best and Frederick Banting in 1922. On the World Health Organization’s Essential Medicines List, it is the safest and most effective medicines needed in a healthcare system.

The wholesale cost in the developing world is approximate $ 2.39-10.61 per 1,000 IU of regular insulin. In the U.K., 1000 costs the NHS £ 7.48, while in the U.S., this amount is approximately USD 134.00.

Versions are also available mixed with longer-acting versions of insulin, such as NPH insulin.

Long-acting insulin

It includes the analogs glargine and detemir, each of which starts working within 1 to 2 hours and continues to be active, without significant spikes or dips, for about 24 hours, although this varies for many people.

Insulin Detemir

Novo Nordisk created insulin detemir and marketed it under the brand name Levemir as a long-acting insulin analog to maintain basal insulin levels.

The basal insulin level can be maintained for up to 20 hours, but the time is affected by the size of the injected dose. This insulin has a high affinity for serum albumin, increasing its duration of action.

Insulin detemir is a long-acting human insulin analog for maintaining basal insulin levels. It is an insulin analog in which a fatty acid (myristic acid) is attached to the amino acid lysine at position B29.

It is rapidly absorbed, after which it binds to albumin in the blood through its fatty acid at position B29. Then it slowly dissociates from this complex.

In a clinical study that compared the efficacy and safety of the use of Levemir for the treatment of patients with type 2 diabetes who had suboptimal glycemic control while receiving maximum tolerated doses of metformin and sulfonylurea (standard tablet therapies for type 2 diabetes).

At 24 weeks, HbA1c (glycosylated hemoglobin) was found to have decreased by 1.8 and 1.9% (from 8.6 to 6.8 and 8.5 to 6.6%) for detemir and NPH, respectively (N.S.).

In both groups, 70% of the participants achieved an HbA1c of 7.0%, but the proportion that achieved this without hypoglycemia was higher with insulin detemir than with NPH insulin (26 vs. 16%, P = 0.008).

Compared with NPH insulin, the risk of total hypoglycemia with insulin detemir was reduced by 47% (P <0.001) and nocturnal hypoglycemia by 55% (P <0.001). The mean weight gain was 1.2 kg with insulin detemir and 2.8 kilograms with NPH insulin (P <0.001), and the difference in the final adjusted weight was: 1.58 (P <0.001).

In summary, insulin detemir reduced HbA1c to target levels of 7.0% for 70% of patients, similar to human basal insulin, NPH, but without the same risk of hypoglycemia and weight gain. Something minor.

On June 13, 2009, the U.S. Food and Drug Administration (FDA) issued a public health advisory for Levemir insulin after learning that 129,000 stolen vials reappeared and were sold in the U.S. market.

The Food and Drug Administration warned that the stolen vials “may not have been stored and handled properly and dangerous to patients.” The stolen vials were identified as lots XZF0036, XZF0037, and XZF0038.

Insulin Degludec

Insulin degludec (INN / USAN) is an ultra-fast acting basal insulin analog developed by Novo Nordisk, which markets it under the brand name Tresiba.

It is given by subcutaneous injection once a day to help control blood sugar in people with diabetes. It has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other insulin). Long-acting marketed as insulin glargine and insulin detemir).

It is modified insulin with a single amino acid removed compared to human insulin and is conjugated to hexadecanedioic acid through the gamma-L-glutamyl spacer at the amino acid lysine at position B29.

Insulin degludec is ultra-long-acting insulin that, unlike insulin glargine, is active at physiological pH. The addition of hexadecanedioic acid to lysine at position B29 allows the formation of multi-hexamers in subcutaneous tissues.

This allows the formation of a subcutaneous deposit that produces a slow release of insulin into the systemic circulation.

Insulin Glargine

Sanofi-Aventis developed glargine as a longer-lasting insulin analog and markets it under the Lantus brand name. It was created by modifying three amino acids.

It is given once a day to help control blood sugar in people with diabetes.

Two positively charged arginine molecules were added to the C-terminus of the B chain, and the isoelectric point was shifted from 5.4 to 6.7, making glargine more soluble at slightly acidic pH and less soluble at slightly acidic pH. Physiological pH.

The acid-sensitive asparagine at position 21 in the A chain needs to be replaced by glycine to avoid deamination and dimerization of the arginine residue.

These three structural changes and the zinc formulation result in a prolonged action compared to human biosynthetic insulin. When the pH 4.0 solution is injected, most material residues are not bioavailable.

A small amount is immediately available for use, and the rest is sequestered in subcutaneous tissue.

As glargine is used, small amounts of the precipitated material will move into the solution in the bloodstream, and the basal insulin level will be maintained for up to 24 hours.

The onset of action of subcutaneous insulin glargine is somewhat slower than human NPH insulin. It is a straightforward solution as there is no zinc in the formula.

It consists of microcrystals that release insulin slowly, providing a long-lasting action of 18 to 26 hours, with a “no-peak” profile (according to the insulin glargine package insert).

Pharmacokinetically, it resembles the basal insulin secretion of non-diabetic pancreatic beta cells. Sometimes in type 2 diabetes and in combination with a short-acting sulfonylurea (drugs that stimulate the pancreas to produce more insulin), it can reasonably control serum glucose levels.

In the absence of endogenous type 1 diabetes, impoverished type 2 diabetes (in some cases), or latent autoimmune of advanced-stage adults, insulin glargine needs the support of fast-acting insulin taken with food to reduce the effect of glucose derived from the prandial.

Unlike other long-acting insulins, glargine must not be diluted or mixed with another insulin or solution in the same syringe. However, this restriction has been questioned.

Side effects related to crystalline insulins

The side effects of insulin lispro

Common side effects include skin irritation at the injection site, hypoglycemia, hypokalemia, and lipodystrophy. Other serious side effects include anaphylaxis and hypersensitivity reactions.

The side effects of insulin aspart

The safety of Novolog in patients with diabetes has been evaluated in several clinical studies. Novolog was compared to regular human insulin, and there was no difference in the frequency of adverse effects between the two treatments.

Side effects commonly associated with insulin treatment include allergic reactions, injection site irritation, skin rashes, and hypoglycemia.

Long-term use of insulin, including Novolog, can cause lipodystrophy at repeated injections or infusions.

Weight gain can also occur with Novolog and has been attributed to the anabolic effects of insulin and decreased glycosuria. The use of Novolog has also been associated with sodium retention and edema.

The side effects of insulin degludec

A significant side effect of insulin therapy is hypoglycemia.

A meta-analysis of clinical trials published in July 2012 found 39 to 47.9 hypoglycemic events (defined as blood glucose <56 mg/dl) per patient year, with higher rates in the concentrated degludec formulation.

Nocturnal hypoglycemia rates ranged from 3.7 to 5.1 events per patient per year.


Before biosynthetic human recombinant analogs were available, porcine insulin was chemically converted to human insulin.

Chemical modifications of the amino acid side chains were made at the N-terminus and the C-terminus to alter the analog’s ADME (absorption, distribution, metabolism, and excretion) characteristics.

Semisynthetic insulins were used clinically based on chemical modification of animal insulins; for example, Novo Nordisk porcine insulin enzymatically converts ‘human’ insulin to semisynthetic insulin removing the amino acid that varies from the human variety and chemically adding the amino acid human.

Unmodified regular insulin is soluble at physiological pH. Analogs have been created that have a shifted isoelectric point. They exist in a solubility equilibrium in which most precipitate but slowly dissolve in the bloodstream and are eventually excreted by the kidneys.

These insulin analogs are used to replace basal insulin levels and can be effective for up to 24 hours.

However, some insulin analogs, such as insulin detemir, bind to albumin rather than fat like previous insulin varieties. Long-term use results (for example, more than ten years) are not currently available. Still, they are necessary to assess clinical benefits.

Unmodified human and porcine insulins tend to be complex with zinc in the blood, forming hexamers. Insulin in hexamer form will not bind to its receptors, so the hexamer has to equilibrate in its monomers to be biologically functional slowly.

Subcutaneously administered hexameric insulin is not readily available to the body when insulin is needed in larger doses, such as after a meal.

Although this is more a function of subcutaneous administration of insulin, as dosed intravenous insulin is rapidly distributed to cellular receptors, and therefore avoids this problem.

Insulin-zinc combinations are used for the slow release of basal insulin. Basal insulin support is required throughout the day, representing approximately 50% of the daily insulin requirement; the amount of insulin needed at mealtime makes up for the remaining 50%.

Non-hexameric insulins (monomeric insulins) were developed to be faster acting and to replace the injection of regular unmodified insulin before a meal. There are phylogenetic examples for such monomeric insulins in animals.