Insulin therapy, conventional

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 called "conventional insulin therapy."

NPH- insulin (neutral protamine Hagedorn) was introduced by Hagedorn in 1946 (Berger 2013).

It was not until the 1980s that the so-called "intensified insulin therapy" was developed. This was initially reserved exclusively for type 1 diabetics (Hollenrieder 2021).

Conventional insulin therapy (CT) is understood to be a rigid regimen of at least 2 insulin doses / d administered at precise intervals and a correspondingly rigid range of meals precisely timed and sized (Herold 2021).

Pharmacodynamics

The mode of action of insulin consists of a membrane effect and metabolic effects.

• Membrane effect:
  • Promotion of the transport of glucose, potassium and amino acids into muscle and fat cells.
• metabolic effects:
  • Promotion of anaerobic metabolic processes such as lipid synthesis, protein synthesis glycogen synthesis
  • Throttling of catabolic processes such as lipolysis, proteolysis, glycogenolysis (Herold 2021).

Other effects include:

• anti-inflammatory effect
• antioxidant
• antilipolytic
• anti-apoptotic
• cardioprotective
• neuroprotective (Kalra 2020)

Indication

• Diabetes mellitus type 2
  • so-called secondary failures (patients who cannot be satisfactorily controlled with oral antidiabetics)
  • Patients with contraindications to oral antidiabetics
  • Patients with diabetes after pancreatic diseases (Mehnert 2003)
  • special forms of diabetes (Greten 2005)
  • temporarily during an illness or surgery
  • temporarily during treatment with, e.g., steroids, parenteral nutrition, etc. (Mehnert 2003)
• Diabetes mellitus type 1

Nowadays, type 1 diabetics are treated with CT only in exceptional cases. The DCCT- study published in 1993 showed a significant risk reduction of sequelae when using ICT and a significant improvement in quality of life for the patient in comparison between CT and intensified insulin therapy (ICT) (Schmeisl 2019).

Dosage and mode of administration

Insulin requirement:

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 insulin requirement is usually higher at approximately 2.0 I. E. / kg KW / d (Greten 2005).

Lowering blood glucose:

To achieve a reduction in blood glucose of 30 - 40 mg / dl (1.6 - 2.2 mmol / l), 1.0 I. E. normal insulin or rapid-acting analog insulin is required (Haak 2018).

Raising blood glucose:

To achieve an elevation of blood glucose by 30 - 40 mg / dl (1.6 - 2.2 mmol / l), 10 g of carbohydrate = 1 KE is required (Haak 2018).

The size of the meal is measured in carbohydrate units = KE, the outdated term is bread unit = BE [Dellas 2018]) (Herold 2021).

A mixed insulin is usually used in CT, often consisting of 70-75% intermediate insulin(NPH) and 25-30% normal insulin. However, a mixture of short-acting insulin analogues and a longer-acting protamine analogue suspension can also be used (Greten 2005).

Onset and duration of action with s. c. Injection at:

• Mixed insulin e.g. 70 NPH and 30 normal insulin: onset after 30 - 60 min, duration 14 h
• Normal ins ulin: onset after 30 - 60 min, duration 8 h (Haak 2018).

If injections are given twice / d, 2/3 to ¾ of the required amount of insulin is injected before breakfast and the remaining 1/3 or 1/4 is injected before dinner (Herold 2021).

The interval between injections and meals, the so-called SEA, is about 30 min for normal insulin. An SEA is not required for insulin analogues (Herold 2021).

Sometimes three injections / d have been shown to be more beneficial, using mixed insulin in the morning, normal insulin at noon, and mixed insulin in the evening (Herold 2021).

The amount of insulin dose depends on:

• Nutritional habits/diet
• Body weight (the heavier a patient is, the higher the proportion of normal ins ulin should be in the morning injection)
• resistance level
• physical exercise
• still existing endogenous insulin production (Mehnert 2003)

Since the insulin level between meals is quite high, the patient should eat between 5 - 7 meals / d with exact KE- indication (Greten 2005 / Waldhäusl 2004). The insulin dose should be given gradually at the beginning of the treatment, i.e. initially only 40% of the expected dose is injected and this is gradually increased by 2 - 4 IU every 2 days (Waldhäusl 2004).

Variations: Provided the patient is able to perform blood glucose checks independently, the insulin doses of normal and intermediate insulin can be modified according to BG and meal content. (Mehnert 2003)

Another variation is the change of the injection-meal distance, the food quality and the food quantity. This is especially important for patients with gastroparesis, for example, because in them the peak of the glycemic response occurs later after the start of the meal.

Changing the spraying- eating interval is also important for patients who can no longer eat food on their own. In this case, for example, the meal is sometimes started immediately after the injection or the required amount of insulin is injected only after the meal, since it is then clear how many carbohydrates the patient has eaten (Mehnert 2003).

Advantages

• less need for training of the patient
• easier handling for the patient or the diabetes team (German Medical Association 2021)

Disadvantages

• between meals, the insulin level is sometimes too high and requires (additional) intermediate meals
• Intermediate insulins (now predominantly referred to as "delay insulins", are usually not sufficient to intercept the postprandial rise in blood glucose (Herold 2021)
• Little flexibility in therapy for acute illness, additional exercise, etc.
• Hypoglycemias:
  • more than with basal insulin
  • less than with preprandial or intensive insulin therapy (Bundesärztekammer 2021)
• Patient has to eat food because he injected (Herold 2021)
• Phases of hyperinsulinemia, hypoinsulinemia, hyperglycemia, hypoglycemia with corresponding metabolic consequences are preprogrammed (Mehnert 2003)
• HbA1c < 6.5% can be achieved in many type 2 diabetics, but only in 20% of type 1 diabetics (Waldhäusl 2004)

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])

Preparations

• Normal insulin such as::
  • Actrapid
  • Berlinsulin H Normal
  • Huminsulin Normal
  • Insuman Rapid (Alawi 2019)
• NPH insulins such as:
  • Berlinsulin H Basal
  • Protaphane
  • Insuman Basal
  • Huminsulin Basal (Alawi 2019)

In a recent 2020 study by Gupta et al, intensified insulin therapy (BG between 80-110 mg %) was compared to conventional (BG between 180-200 mg %) in surgical and medical ICU patients. Both mortality and morbidity were reduced by tight control of BG levels (not by insulin administration).

• Mortality was lower with:
  • conventional insulin therapy in 58
  • intensified insulin therapy in 6

The rate of complications was also lower with intensified insulin therapy:

• Infections were reduced by 46% with intensified insulin therapy.
• need for blood transfusion occurred in 20% versus 40% with conventional therapy
• Inotropic support was required in 26% versus 48% on conventional therapy (Gupta 2020)

1. Alawi H et al (2019) Insulin types and insulin action. Ascensia DiabetesCollege Advisory Board 2019
2. Berger M et al (2013) Practice of insulin therapy. Springer Verlag Berlin / Heidelberg 42
3. German Medical Association (2021) National health care guideline type 2 diabetes. AWMF- Register No.: nvl-001
4. Dellas C (2018) Short textbook pharmacology. Elsevier Urban and Fischer Publishers Munich 155, 506 - 510, 512.
5. 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.
6. Freissmuth M et al. (2016) Pharmacology and toxicology: from molecular basis to pharmacotherapy. Springer Verlag Berlin / Heidelberg 665
7. Greten H et al (2005) Internal medicine. Georg Thieme Verlag Stuttgart 624
8. Gupta R et al. (2020) The efficacy of intensive versus conventional insulin therapy in reducing mortality and morbidity in medical and surgical critically ill patients: A randomized controlled study. Anesth essays Res. 14 (2) 295 - 299
9. Haak T et al. (2018) S3 guideline therapy of type 1 diabetes. AWMF register number: 057-013
10. Herold G et al (2020) Internal medicine. Herold Publishers 736 - 739
11. Hollenrieder V (2021) Diabetes mellitus: insulin therapy yesterday and today - a journey through time. Info Diabetologie 15 (6) 6 - 9https://doi.org/10.1007/s15034-021-3773-2.
12. Kalra S et al (2020) Insulin Therapy - Made Easy. Jaypee Brothers Medical Publishers (P) Ltd 1, 4,
13. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education
14. Mehnert H et al (2003) Diabetology in clinic and practice. Georg Thieme Verlag Stuttgart 252 - 254
15. Schmeisl G W (2019) Diabetes training manual. Elsevier Urban and Fischer Publishers 81
16. Waldhäusl W K et al (2004) Diabetes in practice. Springer Verlag Berlin / Heidelberg 196 - 197