Insulin resistance

Towards the end of the 1930s, insulin resistance was documented by Himsworth and Kerr in patients with NIDDM (non insulin dependent diabetes mellitus) (Hanefeld 2020).

The term "insulin resistance" was coined by Gerald Reaven in 1988 (Fritsche 2015).

The oral glucose tolerance test (oGTT) was first described by Ivar Bang in 1917. The test is still used today (Jagannathan 2020).

Insulin resistance (IR) is defined as a disturbance in the interaction between insulin and its receptor on the cell surface and / or a disturbance in the utilization of glucose within the cell (Herold 2021).

The impaired glucose transport leads to a compensatory increase in the release of insulin from the beta cells and thus to reactive hyperinsulinemia (Leidenberger 2009).

Insulin resistance is composed of a hepatic and a peripheral component. However, the two cannot be seen in isolation.

• Hepatic insulin resistance: This refers to insufficient suppression of hepatic gluconeogenesis by insulin.
• Peripheral insulin resistance: In peripheral insulin resistance, the response of peripheral tissues to the release of insulin is inadequately low, i.e. there is too little increase in glucose influx into adipocytes and muscle cells (Nawroth 2001). Peripheral insulin resistance forms the basis for the development of metabolic syndrome and type 2 diabetes (Stalla 2007).

Type A insulin resistance syndrome is a genetic defect in insulin secretion (Schatz 2006).

Type B insulin resistance syndrome occurs in connection with immunological disorders and is very rare overall (Stalla 2007).

The extent of insulin resistance varies with age. IR occurs more frequently in the peripubertal phase and in postmenopause. Women with android fat distribution patterns are also more frequently affected (Leidenberger 2009).

Kasper (2015) emphasizes the generally greater insulin resistance in Latinos.

Genetic IR is found in about 25% of Europeans, half of whom develop metabolic syndrome (Hanefeld 2020).

Insulin resistance can be acquired or genetically determined. In the case of genetically determined IR, this is reinforced by corresponding environmental factors such as obesity, lack of exercise, etc. (Stalla 2007).

At the pre-receptor level, a role is played by (Siegenthaler 2006):

• Proliferation of contrainsulinic hormones such as:
  • Somatotropic hormone (STH)
  • Glucagon
  • Corticosteroids
  • Thyroxine
  • Adrenalin
  • ACTH (Herold 2021)
• Formation of antibodies:
  • against insulin receptors (mostly occur in connection with autoimmune diseases such as lupus erythematosus disseminatus and is often associated with acanthosis nigricans (Siegenthaler 2005)
  • Insulin antibodies (these inhibit the biological activity of insulin)
• In pre-existing insulin-dependent diabetes mellitus, increased local insulin degradation through subcutaneous injections (Siegenthaler 2006).

At the target cell level, a role is played by:

• intra-abdominal adipose tissue (most frequent cause)
• Stress
• Trauma
• Infections
• Fever
• Hypertriglyceridemia
• Ketoacidosis
• (Pre-) Coma diabeticum (Herold 2021)
• Chronic liver disease:

These can lead to insulin resistance due to receptor and postreceptor defects (Gerok 2007).

• malignant diseases
• Leprechaunism (Siegenthaler 2006)

IR frequently occurs in the context of the following diseases:

• Metabolic syndrome:

According to WHO, IR is one of the symptoms of a metabolic syndrome (Fritsche 2015).

• Type 2 diabetes mellitus:

In early stages of the disease, glucose tolerance remains almost normal - despite pre-existing insulin resistance - because the islet cells can compensate by increasing the secretion of insulin. The exact molecular mechanism that leads to insulin resistance has not yet been clarified (Kasper 2015).

• Mutations in the insulin receptor
• Gestational diabetes (associated with metabolic changes).
• Sleep apnea syndrome (Kasper 2015).
• Polycystic ovary syndrome:

This is associated with insulin resistance in 50-80% of cases. The pathophysiological mechanism is not yet clear.

• Acanthosis nigricans (Siegenthaler 2006)

Insulin resistance is caused by a defect in insulin action that has not yet been fully explained (Kasper 2015).

Visceral fat is - compared to subcutaneous fat - metabolically more active. Through visceral fat, many free fatty acids first reach the liver via the circulation of the portal vein and cause a poorer response to insulin, first in the liver and then in the muscles (Leidenberger 2009).

At the onset of insulin resistance, there is an increased release of insulin into the bloodstream, which causes beta cells to hypertrophy. Under fasting conditions, this compensation is initially sufficient to keep BG within the normal range. However, when glucose is rapidly absorbed from the gut after a meal, a relative insulin deficiency occurs (Roberts 2013).

The inability to adequately absorb and dispose of glucose after a meal is called glucose intolerance (Roberts 2013).

As IR progresses, postprandial hyperinsulinemia occurs, followed by fasting hyperinsulinemia and finally hyperglycemia (Kasper 2015).

V. a. Insulin resistance should arise in patients with:

• Type 2 diabetes in 1st degree relatives
• Patients with:
  • abdominal obesity
  • polycystic ovary syndrome
  • gestational diabetes
  • impaired glucose tolerance (Rao 2001)

Often these patients also have arterial hypertension, dyslipidaemia and cardiovascular diseases (Rao 2001).

Diagnosis is primarily based on laboratory chemical changes (see "Laboratory") and the test procedures listed below (Leidenberger 2009).

Oral glucose tolerance test (oGTT)

• Pre-test preparations:
• Starvation state: When performing the oGTT, make sure that the patient is not in a starvation state. He should consume ≥ 150 g of carbohydrates / d at least 3 days before.
• no presence of febrile temperatures
• in women, not at the time of menstruation (from 3 d before to 3 d after, as otherwise false positive values may occur (Schäffler 2009)
• from 22.00 h of the previous day, the patient should remain fasting (Herold 2020)
• a previous substitution is required in the case of:
  • Hypokalemia
  • Hypomagnesemia (Schäffler 2009)
• Test administration:

The test is performed according to the criteria of the WHO (Reinhardt 1994).

First, the fasting BG is determined by an i.v. blood sample. The patient then drinks 75 g of glucose or, in the case of gestational diabetes, 50 g of glucose (Schäffler 2009). In children, the dosage is based on weight: 1.75 g / kg KG, maximum dose 75 g (Eyth 2021). The drinking time should not exceed 5 min (Eyth 2021).

The patient must then continue to fast, excessive fluid intake should be avoided (Eyth 2021), and physical rest should also be observed (Herrmann 2007).

BG measurements in whole blood (Herrmann 2007) are performed at precisely defined intervals after 30 min, 60 min, 90 min, 2 h, 3 h and 5 h. In addition to glucose, the blood glucose is also measured. In addition to glucose, insulin and C-peptide are also determined.

This form of glucose tolerance testis used to clarify postprandial hypoglycaemia, insulin resistance or beta cell failure (Schäffler 2009).

• Test evaluation:

In the case of insulin resistance, elevated basal values and / or an excessive increase in both insulin and C-peptide after 2 h are found.

Normal values for C-peptide:

-- fasting approx. 0.81 - 3.85 ng / ml

-- after 1 h and after 2 h approx. 2,7 - 5,7 ng / ml (Schäffler 2009)

HOMA- Index: The HOMA- Index (Homeostatic Model Assessment) offers the possibility of a clinical estimation of insulin resistance. Fasting insulin and fasting glucose values are required:

Fasting insulin value multiplied by fasting glucose value divided by 405.

• Analysis:

Normal range: < 2

Borderline range: 2 - 2.5

Pathological range: > 2.5 (Leidenberger 2009)

Other testing options include:

• ISSI- 2 Index (Insulin Secretion- Sensitivity Index- 2)
• Matsuda Index
• QUICKY (Quantitative Insulin Sensitivity Check Index)

In these tests, the values for the indices vary according to age, sex, population group, ethnic group. Therefore, these tests are less important in practice (Placzkowska 2019).

Patients with insulin resistance often experience

• increased postprandial BG values (Gerok 2007)
• elevated triglycerides
• low HDL (Fletcher 2004)

• lipometabolic disorders (Gerok 2007)
• Cardiovascular diseases such as:
  • arterial hypertension
  • myocardial infarction
  • apoplexy
  • atherosclerosis (Leidenberger 2009)
• Type 2 diabetes mellitus

Manifest type 2 diabetes can only occur if, in addition to insulin resistance, there is also a disturbance of the B cells (Gerok 2007).

• Mamma carcinoma
• Acanthosis nigricans (Leidenberger 2009)
• metabolic syndrome (insulin resistance is probably the primary pathological mechanism of MetS [Kasper 2015])

Lifestyle modification with weight loss and increased physical activity leads to an improvement in insulin resistance (Kasper 2015).

• Carbohydrate days: In a study by Lammert (2005) has shown that carbohydrate days with 15 BE gruel lead to an improvement in insulin resistance. The amount of insulin required fell from an average of 1.43 IU/kg before the oatmeal days to 0.76 IU/kg afterwards, i.e. the amount of insulin fell by 47.6%. The positive effect was still detectable for 4 weeks.
• Sleep apnoea: In patients with sleep apnoea syndrome, treatment with continuous airway pressure alone shows an improvement in insulin sensitivity (Kasper 2015).

There are drugs that increase insulin sensitivity:

• Biguanides such as metformin: Biguanides suppress endogenous glucose production and increase insulin action in the liver.
• Glitazones (thiazolidinediones [TZD]) such as rosiglitazone: They suppress endogenous glucose production, enhance insulin action in the liver, and furthermore, they improve insulin-mediated glucose uptake in adipose and muscle tissue (Kasper 2015). Patients with an insulin requirement of > 1 IU / kg / d should be adjusted to combination therapy with additional metformin or TZD (Kasper 2015). Werner (2021) was able to show in an acute study that a sufficiently high intake of magnesium or Mg supplementation can prevent further progression of IR.

Insulin resistance plays an important role in the development of metabolic syndrome and diabetes mellitus. It is therefore important to detect IR at an early stage in order to be able to intervene therapeutically (Placzkowska 2019).

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