Insulin

October 30, 2021


Types of Insulins

Insulin is a polypeptide hormone made up of 51 amino acids. It is a key player in the intermediary metabolism of carbohydrates, proteins, and fats. Insulin is called a hormone of abundance. It is secreted after a meal when there is an abundance of nutrients, especially carbohydrates. It organizes the use of fuels for either storage or oxidation. It promotes the storage of glucose, amino acid, and fatty acids and facilitates glucose utilization by tissues for energy. It also inhibits glucose production by the liver. if insulin is deficient or there is tissue resistance to insulin, all its actions get reversed and glucose, fatty acids, and amino acid levels increase in the blood. Amino acids are used to make glucose. Glucose production by the liver also increases but the body can not use it and use fatty acids for energy and glucose is secreted in the urine.

Insulin was discovered in 1921 and it transformed the management of patients with T1D which was a fatal disorder till then. Insulin was made by extraction and purification from the pancreas of animals. In 1980 human insulin was produced by recombinant DNA technology. Human Insulin (regular or soluble insulin) aggregates in subcutaneous tissue which must dissociate before absorption resulting in delayed onset and longer duration of action. Several analogs were created in 1990 by modifying the regular insulin molecule with novel pharmacokinetics. By altering the amino acid sequence or protein structure of human insulin, its behavior following injection is either accelerated or prolonged.

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There are three main groups of insulin

Action can be prolonged for example in insulin glargine by addition and substitution of amino acids, action is prolonged to 24 hours. Duration of action can also be extended by adding chemicals to regular insulin, For example, protamine and zinc at neutral PH ( isophane or NPH insulin) or by adding excess zinc ( Lente insulin). In insulin detemir and degludec, the duration is extended by adding fatty acids. Following injection, these bind to albumin in the blood and then slowly dissociate.

There is wide variability in the kinetics of insulin action among different people and even with repeated doses in the same person. The time to peak hypoglycemic effect and insulin levels can vary by 50% due in part to large variation in the rate of absorption from the injection site.

The standard insulin concentration is 100U/ml.  New concentrated insulins  200U (Degludec and lispro insulin), 300U  (Toujeo -glargine insulin), or U500 (regular insulin) are also available. Which are respectively two, three, or five times more concentrated than regular insulin. Concentrated insulin is given to patients who are resistant to insulin and require a higher dose. Recently, oral insulin has also become available.

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Types of Insulin

The preparation of insulin is classified according to its duration of action.

Rapid Acting Analogs

Lispro, apart, and glulisine are rapid-acting Analogs of insulin. They are absorbed rapidly from the injection site. The onset of action is within 15 minutes so can be injected just before, during, or even after meals but have a shorter duration of action less than 4 hours. The time action profile of these analogs is similar. They instantaneously dissociate into monomers increasing the rate of absorption. These insulin are best used to control glucose spikes after a meal. They have lower rates of hypoglycemia and better A1c levels compared to regular insulin.

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Short Acting Insulin

Short-acting insulin, like regular insulin, needs to be injected 30-60 min before a meal. Regular insulin forms hexamers in subcutaneous tissue which break down slowly to monomers delaying their absorption from the injection site. They have a prolonged peak action of 2-5 hours and action can last up to 8 hours. Because of this, they cause a mismatch between the need and availability of insulin. Delayed onset of action cause hyperglycemia after food and a long duration of peak effect cause late hypoglycemia.

Intermediate Acting Insulin

NPH (Neutral Protamine Hagedorn) or isophane insulin is an intermediate-acting insulin. It is a suspension of regular insulin complexed with zinc and protamine. This produces a cloudy or whitish solution. NPH insulin dissolves more gradually thus its action is prolonged. It is given once or twice a day in combination with short-acting. Isophane and Lente insulin have to be resuspended before giving injection by mixing it well. The more modern long-acting Analogs insulins (Glargine, detemir, and degludec) are clear.

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Long Acting Analogs

Insulin glargine, detemir, and degludec are long acting insulins. Insulin glargine (Lantus) is a clear solution with a pH of 4.0. When injected into neutral PH of subcutaneous space aggregation occurs, resulting in prolonged absorption from the injection site. Owing to its acidic PH it can not be mixed with short-acting insulin which has neutral PH. Glargine, unlike NPH, has no discernible peak of action and provides a steady basal effect over 24 hours. It causes less hypoglycemia especially nocturnal hypoglycemia comparing NPH insulin.

Insulin detemir and glargine has similar action profile but detemir has a shorter duration of action so has to be administered twice daily. Insulin degludec has an even longer duration of action over 40 hours. It is dosed daily. Degludec causes less severe hypoglycemia than glargine. Basal insulin is required to suppress hepatic glucose production overnight and between meals.

Premixed formulations

Premixed formulations containing short-acting or rapid-acting insulin and Isophane Insulin in various proportions (30:70 or 50:50) are available. It provides convenience by reducing the number of daily injections and the need for directly mixing them. The drawback of premixed formulations is that the individual components can not be adjusted. These may be used in patients who are unable to inject more often or live a very fixed lifestyle and are more commonly used by type 2 diabetic patients.

Different insulin types can be drawn into the same syringe but should not be premixed in bottles except by a manufacturer.

Mixing insulins may affect rates of insulin absorption, producing variability of effect and making glycemic control less predictable, especially if mixed greater than 1 hour before use. Insulin glargine should never be mixed with any other insulin.

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Indications of Insulin in Type-2 Diabetes

Insulin is required for all patients with type-1 diabetes (T1D) and is also helpful for the management of many patients with type-2 diabetes (T2D). Many oral antihyperglycemics medicine are available for type-2 diabetes but sometimes insulin is needed to control high blood sugar. The following are indications for to use of insulin in type 2 diabetes:

  • Marked hyperglycemia such as fasting plasma glucose >250 mg/dl or random blood glucose >350mg/dl
  • Diabetic ketoacidosis or hyperosmolar state
  • Ketones in urine 2+ or greater
  • Newly diagnosed Diabetic with elevated Hb A1c 9 % or more
  • Significant weight loss
  • Pregnancy (preferably before pregnancy starts).
  • Acute illnesses requiring hospitalizations
  • Before surgical procedures or during intensive care when metabolic decompensation occurs.
  • Post myocardial infarctions
  • High-dose glucocorticoid therapy
  • Inability to tolerate or contraindication to using oral hypoglycemic medicines (hepatic or renal diseases)
  • The patient no longer achieves goals on other diabetic medications.
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Advantages of Insulin

  • Insulin is the oldest of the currently available medicines. It is a natural body hormone. Safe and effective. It decreases glucose toxicity and lipotoxicity. It causes no serious drug interactions. There are no contraindications to using insulin.
  • Most effective diabetes medications in lowering glucose. Can decrease any level of elevated glucose.
  • Easy to titrate. No maximum or minimum level beyond which therapeutic action can not occur.
  • Beneficial effects on blood lipids
  • Reduce the risk of developing long-term complications
  • Improve health and wellbeing

Side Effects of Insulin

  • The most common side effect is hypoglycemia
  • Local and generalized allergic reactions
  • Local fat atrophy or hypertrophy
  • Circulating anti-insulin antibodies.
  • Weight gain
  • Hypokalemia
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Hypoglycemia

Hypoglycemia is the major risk that must be compared against the benefits of efforts to normalize glucose control. It may result from a mismatch between insulin and carbohydrate intake, exercise, or alcohol consumption. Too high a bedtime insulin can cause nocturnal hypoglycemia and stimulate a counter-regulatory response, leading to morning hyperglycemia (Somogyi phenomenon).

A more common cause of unexplained morning hyperglycemia, however, is a rise in early morning growth hormone and cortisol (Dawn Phenomenon). In this case, the evening insulin dose should be increased, changed to a longer-acting preparation, or injected later. Exercise-induced hypoglycemia can occur because of improved blood flow at the injection site. Both insulin and muscle contractions increase glucose uptake causing a fall in blood glucose level. It occurs mostly with prolonged aerobic exercise.

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Weight gain

Weight gain is a common side effect of insulin therapy. It is because the anabolic action of insulin increases appetite, and decreases the loss of glucose in urine. This can be avoided by eating healthy food and increasing physical activity. Counting calories in food taken and being physically active helps to control weight. There are some diabetic medications if taken along with insulin help in weight loss and decrease insulin requirement also.

Hypokalemia

A decrease in blood potassium level may be caused by insulin but it is uncommon. Hypokalemia more commonly occurs when IV insulin is used.

Allergic Reactions

Local allergic reactions at the site of insulin injections are rare, especially with the use of human insulins. They can cause immediate pain or burning followed by redness, itching, and induration sometimes persisting for days. Most reactions spontaneously disappear after weeks of continued injection and require no specific treatment, although antihistamines may provide symptomatic relief.

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Generalized allergic reaction is extremely rare with human insulins but can occur when insulin is restarted after a lapse in treatment. Symptoms develop 30 minutes to 2 hours after injection and include urticaria, angioedema, pruritus, bronchospasm, and anaphylaxis. Antihistamines are given, but epinephrine and IV glucocorticoids may be needed. If insulin treatment is needed after a generalized allergic reaction, skin testing with purified insulin preparations and desensitization is carried out.

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Local Fat Hypertrophy or Hypotrophy

Local fat atrophy at injection sites is relatively rare and is thought to result from an immune reaction to a component of insulin preparation. lipohypertrophy (enlargement of the subcutaneous fat depot) is due to the lipogenic action of a high local concentration of insulin. It can be prevented by shifting injection sites.

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Insulin Resistance

Insulin obtained from animal sources is antigenic. Circulating anti-insulin antibodies are a very rare cause of insulin resistance. Some people still prefer to use animal insulin. This type of insulin resistance can sometimes be treated by changing insulin preparations from animal to human insulin and by administering corticosteroids if needed. Most patients use human insulin or insulin analogs as allergic reactions are less common with human insulin. Allergic reactions to recombinant human insulin may sometimes occur because of a small amount of aggregated or denatured insulin in preparations, minor contaminants, or because of sensitivity to added components (protamine or zinc, etc. )

One thought on “Insulin

  1. Insulin levels above the normal range lead to weight gain, water bloating, high blood pressure, magnesium deficiency, and more importantly an increase in the inflammatory compounds in blood, leading to blood clots and blood vessel damage. In order to measure the insulin level of a patient, a fasting insulin test must be conducted. Fasting of at least eight hours is required to take the blood sample for this test. Blood glucose test can be easily conducted at home using a compact glucometer https://bit.ly/3kme2vQ

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