Insulin mixtures

In 1869, Paul Langerhans discovered a distinct accumulation of cells in the pancreas. In 1889, Mering and Minkowski demonstrated that total pancreatectomy induced diabetes mellitus in dogs (Kalra 2020).

In the fall of 1920, Frederick Banting, a London surgeon, had the idea of obtaining pancreatic secretions by ligating the pancreatic ducts. He began initial experiments with dogs at the University of Toronto under Prof. J. J. R. Macleod, together with Charles Best, which were successful.

In the winter of 1921 - 22, the first human to receive animal insulin was Leonard Thompson, a young diabetic, who survived (Bliss 1982).

In 1923, two years after the discovery of insulin, factory production of insulin began in Europe (Egidi 2019). Insulin was administered according to a rigid regimen known as "conventional insulin therapy" (Herold 2021).

NPH insulin (Neutral Protamine Hagedorn) was introduced by Hagedorn in 1946 (Berger 2013).

An insulin mixture is understood to be mixtures of certain insulins, which are usually administered 2 x / d and - as far as possible - adapted to the patient's eating behavior (Scherbaum 2000).

A distinction is made between:

• free insulin mixtures

In this case, the patient mixes an NPH insulin with a human normal insulin immediately before the injection.

• fixed insulin mixtures

Fixed insulin mixtures are preformulated ready-to-use preparations (Scherbaum 2000).

Short-acting normal ins ulin includes, for example:

- Actrapid

- Berlinsulin H Normal

- Huminsulin Normal

- Insuman Rapid (Herold 2022)

The onset of action occurs after 30 - 60 min and the duration of action is 8 h (Haak 2018).

NPH insulins include, for example:

- Berlinsulin H Basal

- protaphane

- Insuman Basal

- Huminsulin Basal (Alawi 2019).

NPH insulin contains protamine and insulin in isophanic amounts (Berger 2001). Onset of action is 1 - 2 h (Haak 2018), duration of action is approximately 12 - 14 h (Berger 2001).

NPH insulins can be mixed with short-acting regular insulin, the only exception being zinc insulins (Herold 2022).

When mixing, please note:

• mixing should take place immediately before injection of the syringe; injection should be carried out within a maximum period of 2 min thereafter
• Never store insulin as a mixture
• Insulin glargine or insulin detemir cannot be mixed with other insulins (Kasper 2015)

Pharmacodynamics

In an insulin mixture, some of the normal insulin binds to the NPH insulin. Once the mixture is injected, this binding reverses (Hirsch 2020).

Mixing the insulins can result in a change in the insulin absorption profile: absorption is shortened, for example, by mixing Lispro with NPH (Kasper 2015).

The short-acting normal insulins mimic physiological insulin secretion during meals (Kasper 2015).

Insulin mixtures with a low proportion of normal insulin have a longer effect than mixtures with a high proportion of normal insulin (Mehnert 2003).

Indication

Insulin mixtures are used in conventional insulin therapy (Herold 2022), especially in type 2 diabetics with constant food intake at precisely defined times (Hirsch 2020).

Only a fixed insulin mixture should be used in the following patients:

• Patients with reduced vision that cannot be corrected.
• Patients with impaired fine motor skills of the fingers (Mehnert 2003).

Type 1 diabetics are treated with insulin mixtures in the context of conventional insulin therapy only in exceptional cases. These are patients:

• who, due to cognitive impairments, illness or age, are unable to undergo another form of treatment, the so-called "intensified insulin therapy".
• who decide against intensified insulin therapy after having been informed in detail about the benefits and risks of the treatment
• Who show significant adherence problems in long-term care (Bahrmann 2018).

Dosage and mode of administration

Insulin requirements:

The daily insulin requirement of a healthy person is 0.67 I. E. / kg KW / d = approximately 40 I. E. (Dellas 2018). S. a. Insulin

In obese patients, the requirement is usually higher. These patients require approximately 2.0 I. E. / kg KW / d (Greten 2005).

Adverse effects

• Hyperinsulinemia between meals
• Hypoglycemia (Waldhäusl 2004)
• Dawn phenomenon (predominantly initiated by an insulin dose that is too low in the evening [Mehnert 2003])

Contraindication

Relative contraindications for insulin mixtures:

• severe insulin allergies (although these are a rarity)
• unreliable insulin injections e.g. drug abuse
• dietary treatable type 2 diabetes
• more difficult practical implementation, e.g., in blind, elderly patients living alone (Paumgartner 2013)

Absolute contraindications to treatment with insulins:

- Hypoglycemia

- Insulinoma (Flake 2021)

Drug interactions

• Weakening of the effect of insulin by:
  • Isonicotinic hydrazide
  • Sympathomimetics
  • Corticosteroids
  • Phenothiazines
  • oral contraceptives
  • Heparin
  • nicotinic acid and its derivatives
  • phenytoin
  • tricyclic antidepressants
  • saluretics (Flake 2021)

• Effect enhancement of insulin by:
  • ASA
  • Cyclophosphamide
  • Methyldopa
  • Tetracyclines
  • Fenfluramine
  • Clofibrate and its derivatives
  • Alpha blockers (Flake 2021)

Preparations

The ready-to-use preparations include:

• Actraphane 30 (consists of 30 % normal ins ulin and 70 % NPH insulin)
• Humalog Mix 25 (consists of 25 % insulin lispro and 75 % NPH insulin)
• Huminsulin Profile III (also consists of 30 % normal insulin and 70 % NPH insulin)
• Insuman Comb. 25 (consists of 25 % normal insulin and 75 % NPH insulin)
• Novo Mix 30 (consists of 30 % insulin aspart and 70 % NPH insulin)

(Herold 2022)

The NPH insulins must be panned at least 20 times to achieve uniform mixing (Herold 2022).

1. Alawi H et al (2019) Insulin types and insulin action. Ascensia DiabetesCollege Advisory Board 2019.
2. Bahrmann A et al. (2018) S2k- Guideline Diagnosis, therapy and follow-up of diabetes mellitus in old age. 2nd edition AWMF Register Number: 057-017.
3. Berger M et al (2013) Practice of insulin therapy. Springer Verlag Berlin / Heidelberg 42
4. Bliss M (1982) The discovery of insulin. University of Totonto Press. Introduction
5. German Medical Association (2021) National health care guidelines: type 2 diabetes. AWMF- Register- No. nvl-001
6. Dellas C (2018) Short textbook pharmacology. Elsevier Urban and Fischer Publishers Munich 155, 506 - 510, 512.
7. Egidi G (2019) What is the place of insulin analogues In the treatment of diabetes? ZFA (95) 360 - 365. doi10.3238/zfa.2019.0360-0365.
8. Flake F et al (2021) Emergency medications. Elsevier Urban and Fischer Publishers 157 - 158.
9. Greten H et al (2005) Internal medicine. Georg Thieme Verlag Stuttgart 624
10. Haak T et al. (2018) S3 guideline therapy of type 1 diabetes. AWMF Register Number: 057-013.
11. Herold G et al (2022) Internal medicine. Herold Publishers 737
12. Herold G et al (2021) Internal medicine. Herold Publishers 737
13. Hirsch I B et al (2020) The Evolution of Insulin and How it Informs Therapy and Treatment Choices. Endocr Rev 41 (5) 733 - 755
14. Kalra S et al (2020) Insulin Therapy - Made Easy. Jaypee Brothers Medical Publishers (P) Ltd 1, 4,
15. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 2411
16. Mehnert H et al (2003) Diabetology in clinic and practice. Georg Thieme Verlag Stuttgart 242 - 245
17. Paumgartner G et al (2013) Therapy of internal diseases. Springer Verlag Berlin / Heidelberg / New York 743
18. Scherbaum W A et al. (2000) Evidence-based diabetes guidelines DDG: diagnosis, therapy and follow-up of diabetic retinopathy and maculopathy. Evidence-based diabetes guidelines DDG: diagnosis, therapy and follow-up of diabetic nephropathy.
19. Waldhäusl W K et al (2004) Diabetes in practice. Springer Verlag Berlin / Heidelberg 196 - 197