Insulin

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, the London surgeon Frederick Banting came up with the idea of obtaining pancreatic secretions by ligating the pancreatic ducts . He began in the University of Toronto with Prof. J. J. R. Macleod, together with Charles Best, the first experiments with dogs, which were successful.

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

In 1923, Banting and Macleod received the Nobel Prize for the discovery of insulin. In (American) history, however, Banting and Best are considered the discoverers of insulin (Bliss 1982).

In 1923, two years after the discovery of insulin, insulin production began in Europe (Egidi 2019). Insulin was laboriously extracted in small quantities from the pancreases of cattle (Haas 2013).

The first biphasic insulin was developed in 1964. Frederick Sanger published the complete sequence determination of insulin in 1959, for which he received the Nobel Prize 4 years later (Kalra 2020).

After the BSE scandal, human insulin could be synthesized from porcine insulin for the first time in 1976, and genetic analysis of human insulin has been possible since 1979 (Egidi 2019).

Fast-acting insulin analogues came on the market in 1996, and long-acting analogues in 2000 (Egidi 2019).

Insulin is an anabolic hormone. It is the most important regulator of glucose homeostasis, i.e. the balance between hepatic glucose production and peripheral glucose utilization or uptake (Kasper 2015).

Insulin is formed in the pancreas in the beta cells of the islets of Langerhans from the precursors of preproinsulin and proinsulin.

The formation of proinsulin to insulin takes place by cleavage of a C-peptide. Insulin and C-peptide are secreted simultaneously into the blood.

By determining the C- peptide, an approximate statement can be made about the function of the beta cells, since C- peptide has a longer biological half-life of 25 min than plasma insulin and is not influenced by exogenous insulin (Herold 2021).

Insulin is stored in the granules of beta- cells and is released in healthy individuals in proportion to the blood glucose level. The plasma half-life is short at 5 min. Insulin is inactivated by enzymes collectively known as "insulysin" (formerly also known as "insulinase" {Leal 2013}) (Herold 2021).

Receptors that bind insulin are located in large numbers in skeletal muscle, hepatocytes, adipocytes of adipose tissue, and in small numbers in almost all cells (Kalra 2020).

Insulin stimulates:

• Glycogen synthesis
• Protein synthesis
• Fatty acid synthesis
• Triglyceride synthesis (Stalla 2007)
• mannose
• intestinal hormones such as GIP, GLP- 1, gastrin, CCK, secretin
• Amino acids such as arginine, leucine
• Glucagon
• Acetylcholine
• Theophylline
• Beta-keto acids
• Sulfonic acid
• Beta adrenergic stimulants (Kalra 2020)

Insulin inhibits:

• Gluconeogenesis
• Lipolysis
• proteolysis (Stalla 2007)
• Somatostatin
• alpha-adrenergic stimulators such as norephedrine, ephedrine
• 2- deoxyglucose
• beta- adrenergic blockers such as propranolol
• Mannoheptulose
• Galanin
• Phenytoin
• Diazoxide
• Alloxan
• thiazide diuretics
• microtubular inhibitors
• K depletion (Kalra 2020)

Contrainsulin hormones are:

• Somatotropic hormone (STH)
• Glucagon
• Corticosteroids
• Thyroxine
• Epinephrine
• ACTH (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)

Indications

The indication for insulin therapy is primarily in patients with diabetes mellitus, in whom glucose uptake is impaired by insulin deficiency or insulin resistance:

• 1. diabetes mellitus type 1

Insulin is obligatory in all phases of type 1 (Mehnert 2003)

• 2. type 2 DM in
  • Insulin mandatory (after failure of oral therapy [Mehnert 2003]).
  • Infections
  • Gravidity
  • Complications of DM
  • in the context of surgery (Herold 2021)
  • younger, lean patients with tendency to ketosis and / or autoimmune antibodies
  • patients with severe polyneuropathy
  • Postinfarction phase
• 3. secondary forms of diabetes in e.g.:
  • Hemochromatosis
  • Pancreatic diseases such as:
    • Pancreatic cancer
    • chronic pancreatitis
    • cystic fibrosis
    • Z. n. pancreatectomy
  • advanced liver cirrhosis
  • diabetes with abnormalities of the insulin receptor
  • Diabetes secondary to endocrine disorders such as:
    • M. Cushing's disease
    • Acromegaly
  • Diabetes in the context of certain genetic syndromes (Mehnert 2003)

Insulin is also not infrequently used as a doping agent in bodybuilding and sports because of its anabolic effect(Ramspeck 2019)

Dosage and method of use

The daily insulin requirement of a healthy person is 0.67 I. E. / kg / d = approx. 40 I. E. Of this, about 40% is for basal secretion and about 60% for postprandial (Dellas 2018 / Seifert 2018).

However, the values of healthy individuals cannot be transferred to diabetics. In a 2021 study by Quast, insulin requirements after total pancreatectomy were compared with insulin requirements in type 1 diabetics. This was significantly lower (p < 0.0001) in pancreatectomized patients: basal insulin by 48.6%, meal insulin by 38.1%.

Individual insulin requirements in type 1 depend on various factors such as:

• individual insulin sensitivity
• extent of insulin deficit
• BMI
• physical activity
• food intake
• possible presence of other diseases
• Medication intake (see below "Drug interactions")
• Pharmacodynamics and kinetics of the insulin preparations used (Haak 2018).

Lowering of blood glucose:

To achieve a decrease in blood glucose of 30 - 40 mg / dl (1.6 - 2.2 mmol / l), 1.0 I.U. 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 higher dose of insulin may be required, for example, for:

• Blood glucose > 270 mg / dl
• Dehydration
• Infections
• Fever
• Detection of ketone bodies

A lower dose of insulin may be needed in cases such as:

• insufficiency of the adrenal cortex
• severe renalinsufficiency
• hepatic insufficiency
• physical stress

(Haak 2018)

Onset and duration of action with s. c. Injection

• Aspart: onset after 20 - 25 min, duration 4 - 5 h
• Lispro: onset after 20 - 25 min, duration 4 - 5 h
• Normal ins ulin: onset after 30 - 60 min, duration 8 h
• Mixed insulin e.g. 70 NPH and 30 normal insulin: onset after 30 - 60 min, duration 14 h
• Glargin U 100 (Lantus): onset after 1 h, duration > 20 - 27 h
• Degludec (Tresiba): onset after 1 h, duration 19 - 26 h
• NPH- Insulin: onset after 1 - 2 h, duration 14 h
• Detemir (Levemir): onset after 1 - 2 h, duration > 42 h (Haak 2018).

Adverse effects

• Hypoglycemia (most common complication [Paumgartner 1999]).
• in the context of hypoglycemia may occur:
  • Tachycardias due to release of adrenaline
  • Arrhythmias
  • increased risk of angina pectoris complications
  • premature ventricular contractions
• weight gain (Liebl 2005)
• infection at the infusion site (Herold 2021)
• iatrogenic hyperinsulinism
• Lipohypertrophy:

In this case, there is hypertrophy of adipose tissue around the injection sites. This occurs preferentially if the injection sites are not changed regularly (Paumgartner 1999).

• Lipoatrophies:

The constant injections cause the subcutaneous tissue to become atrophic (Paumgartner 1999).

• Transitory refractive anomalies:

These are found with significant changes in metabolic status and are reversible (Paumgartner 1999).

• Edema due to insulin:

Edema occurs at the beginning of insulin treatment or during recompensation and is usually passive (Paumgartner 1999).

• Insulin sensitivity:

Insulin sensitivity is said to occur when the insulin requirement is more than 80 - 100 IU per day (Paumgartner 1999).

• Insulin resistance:

In insulin resistance, the insulin requirement is more than 200 IU per day (Paumgartner 1999).

• insulin allergy:
  • Allergic reactions to exogenous insulin or its carrier and accompanying substances. These occur only rarely nowadays (Paumgartner 1999). They are type I allergic reactions with formation of IgE class antibodies (Oberdisse 1999). They appear as subcutaneous infiltrates or urticarial reactions at the injection sites.
  • The hypersensitivity late reaction, so-called Arthus type, manifests itself after 3 - 48 h in the area of the injection site (Paumgartner 1999).
  • Another form of allergy is circulating antibodies that bind insulin and thus lead to insulin resistance (Oberdisse 1999).

Contraindication

Relative contraindications:

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

Absolute contraindications:

- Hypoglycemia

- Insulinoma (Flake 2021)

Drug interactions

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

• Enhancement of effect by:
  • ASA
  • Cyclophosphamide
  • Methyldopa
  • Tetracyclines
  • Fenfluramine
  • Clofibrate and its derivatives
  • Alpha- blockers (Flake 2021)

• Beta-blocker therapy:

Decreased perception of hypoglycemia and prolongation of hypoglycemia are possible with beta blocker treatment (Flake 2021).

Preparations

• The human insulins ("normal insulin" or outdated designation "old insulin") include e.g.:
  • Actrapid
  • Berlinsulin H Normal
  • Huminsulin Normal
  • Insuman Rapid
  • Protaphane (Alawi 2019)

• Insulin analogues include e.g.:
  • InsulinAspart (e.g. NovoRapid)
  • InsulinGlulisin (e.g. Apidra)
  • InsulinLispro (e.g. Humalog, Liprolog)
  • Insulinglargine (e.g. Lantus)
  • Insulindetemir (e.g. Levemir)

(Alawi 2019)

• Depending on the duration of efficacy, a distinction is made between:
  • very short-acting insulins such as:
    • Insulinaspart (e.g. NovoRapid)
    • Insulinglulisine (e.g. Apidra)
    • Insulinlispro (e.g. Humalog, Liprolog)
  • short-acting insulins such as:
    • Normal insulin such as::
      • Actrapid
      • Berlinsulin H Normal
      • Huminsulin Normal
      • Insuman Rapid
  • long-acting insulins such as:
    • Berlinsulin H Basal
    • Protaphane
    • Insuman Basal
    • Huminsulin Basal
    • Insulindetemir (e.g. Levemir)
    • Insulinglargine (e.g. Abasaglar)
    • Insulin degludec (e.g., Tresiba)

(Alawi 2019)

When insulin is administered, there is always a shift of potassium ions into the intracellular space (Flake 2021).

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