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Endocrine

The term endocrine refers to all endocrine glands, i.e. all glands that release their secretions (called hormones) into the blood, whereby the site of action can be different from the site of production or, more precisely, the site of secretion. This distinguishes endocrine glands from exocrine glands. In contrast to exocrine secretions, hormones can therefore produce a long-distance effect, even throughout the entire body at the same time. Recent research shows that in addition to the classic remote effects, paracrine (acting in the neighbourhood of the site of production) or autocrine (acting in the cell of origin) glandular tissues also exist.
Due to the complexity of the human endocrine system, only some of the most important endocrine glands and hormones will be mentioned here without attempting to explain all glands, regulatory circuits and interrelationships.

autocrine

Autocrine refers to the secretion mode of glandular cells, which release their secretions into the interstitium, but also possess a receptor for this messenger substance and respond to it. Autocrine secretion is therefore a special case of paracrine secretion.

paracrine

Parakrine refers to the secretion mode of glandular cells, which release their secretions to neighbouring cells via the interstitium (the extracellular space between cells). Parakrine control is an important mechanism of self-regulation in organs. The paracrine secretions diffuse in the interstitium and dock onto suitable receptors on cells, which they activate, triggering a signal for a response such as a metabolic process.

endocrine

Endocrine refers to the secretion mode of glandular cells, which release their secretions into the bloodstream. These secretions are also known as hormones. They bind to a receptor with which they have an affinity and activate it, triggering a signal for a reaction such as a metabolic process. The complex entirety of the hormone system is referred to as the endocrine system. Since endocrine secretions are released into the interior of the body, namely the blood, endocrine secretion is an internal secretion, just like internal autocrine and paracrine secretion.

Hypothalamus

The hypothalamus (Greek: „under the thalamus“) is the part of the brain located above the pituitary gland and connected to it by the infundibulum, which together with the pituitary gland represents one of the body’s most important endocrine control centres. The hypophyseal posterior lobe (HHL) is usually considered part of the hypothalamus. The hypothalamus produces many important releasing hormones (liberins) and inhibiting hormones (statins) as well as dopamine and some neuropeptides. As the most important vegetative control centre, it is significantly involved in the vegetative control of the body, which is implemented in various homoeostatic control circuits. Temperature (via thyrotropin (TSH) and thyroglobulin (TRH)), blood pressure, osmolarity (via ADH) of the blood, water intake and food intake (via the inhibitory effect of leptin on neuropeptide Y) are controlled here, as are the circadian rhythm and sleep (via histamine, orexin and the stimulation of melatoin release in the pineal gland). Sexuality is also influenced here.
Liberins and statins of the hypothalamus control the release of the hormones of the anterior pituitary (adenohypophysis); the hormones released by the posterior pituitary (neurohypophysis) are produced by the pituitary gland itself.

Hormones of the hypothalamus

Releasing-Hormone (Liberine):

• TRH (thyrotropin-releasing hormone), also known as thyreoliberin, causes the release of thyrotropin (TSH), which releases thyroxine and triiodothyronine at the thyroid gland, and prolactin.
• CRH (corticotropin-releasing hormone), also known as corticoliberin, causes the release of adrenocorticotropin (ACTH), which releases aldosterone, cortisol and sex hormones in the adrenal cortex.
• GnRH (gonadotropin-releasing hormone), also known as gonadoliberin, causes the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH) in the gonads
• GHRH (growth hormone releasing hormone), also known as somatoliberin, causes the release of somatotropin (growth hormone, GH).
• MSH-RH (melanolibre, liberin to MSH)
• PRL-RH (prolactin-RH, prolactoliberin. Suspected, not proven!)

Statine (Inhibiting-Hormone):

• MSH-IH (Melanostatin, MSH-Statin)
• Dopamine (is both a neurotransmitter and a hormone), suppresses the release of prolactin
• Somatostatin (is a statin to GH), inhibits the secretion of pancreatic enzymes, gastrin and pepsin and reduces blood flow in the splanchnic area; is involved in the initiation of programmed cell death (apoptosis)

Hypophyse (pituitary gland)

1. HVL (anterior pituitary gland, adenohypophysis)

glandotrop:

• FSH (follicle-stimulating hormone), stimulates the gonads.
• TSH (thyroid stimulating hormone, thyrotropin, stimulates the thyroid gland)
• LH (luteinising hormone), stimulates the gonads.
• ACTH (adrenocorticotropic hormone), stimulates the adrenal cortex

not glandotropic:

• MSH (melanocyte-stimulating hormone) or melanotropin from the middle lobe of the pituitary gland
• Prolactin (dopamine is a statin for this),
• STH (somatotropic hormone) or somatotropin (GH or HGH).

2nd HHL (neurohypophysis, posterior lobe of the pituitary gland)

• Oxytocin (is also stored),
• ADH (antidiuretic hormone, vasopressin)

3rd HZL (intermediate pituitary lobe)

• – MSH (melanocyte-stimulating hormone)

Epiphysis (pineal gland)

produces melatonin, which regulates the sleep-wake rhythm and other time-dependent rhythms of the body. In fish, reptiles and amphibians, the epiphysis is still sensitive to light itself. In mammals, the transmission of light information is far more complex. It has been known since 1973 that of all organs apart from the heart, only the kidney is supplied with more blood than the epiphysis.
It is assumed that the epiphysis has a puberty-inhibiting effect.

Thyroid gland (thyroid gland):

The largest endocrine gland in humans, it produces the iodine-containing thyroid hormones triiodothyronine and thyroxine as well as the peptide hormone calcitonin. It can store the required iodine itself. It is important in the regulation of energy balance and cell growth. Calcitocin inhibits osteoclasts and stimulates the incorporation of calcium and phosphate into the bones. In the negative feedback thyrotropic control loop, an increased level of T3, T4 inhibits the release of TSH (which promotes the release of T3, T4) in the HVL and of TRH in the hypothalamus.
The thyroid hormones have an effect on the heart and the circulation. They can lead to an increase in heart rate and blood pressure as well as to vasodilation. They affect the metabolism of sugar, fat and connective tissue by increasing their metabolism. They increase the activity of sweat and sebaceous glands in the skin and the activity of the intestinal motor system. In the nervous system, they lead to increased excitability of the cells. Overall, the effect of thyroid hormones increases the body’s energy consumption and basal metabolic rate. This results in a rise in body temperature.

Parathyroid gland (glandulae parathyroideae)

PTH (antagonist of calcitocin), increases the calcium concentration of the blood through indirect activation of osteoclasts.

Thymus gland

The thymus gland is not an endocrine gland. However, the effect of the peptides produced there has not yet been conclusively clarified: it degenerates after puberty, which is the cause of immunosenescence (deterioration of the immune system with ageing). As a primary or central lymphatic organ, it trains thymocytes from the bone marrow into T lymphocytes, which then migrate to the secondary lymphatic organs (lymphatic follicles, Peyer’s plaques, tonsils, spleen, lymph nodes, vermiform appendix)

liver

• Somatomedin (insulin-like growth factor)
• Prohormon Angiotensinogen
• Thrombopoietin

In addition, the liver reacts to insulin and glucagon and tries to keep the blood sugar level constant (storage of glucose from portal vein blood, controlled release into the blood. Storage of currently superfluous glucose as glycogen, which is released into the blood as glucose by glycolysis when required). Insulin stimulates the liver to store glucose, glucagon to release it. The liver also inactivates steroid hormones. Thrombopoietin stimulates the formation and differentiation of platelet-forming cells, the megakaryocytes. The thrombocytes have a receptor for thrombopoietin that binds it from the bloodstream, which represents the regulatory cycle.

Duodenum

• Secretary, Cholecystokinin (Pankreozymin, ist im Gehirn auch Neurotransmitter). Cholezystokinin löst in der medulla oblongata das Sättigungsgefühl aus, regt die Pankreassekretion an und bewirkt gleichzeitig eine Contraction der glatten Muskulatur der Gallenblasenwand sowie die Erschlaffung des Musculus sphincter oddi und ermöglicht dadurch den Gallenfluss, stimuliert die Peristaltik von Dünndarm und Dickdarm, vermindert die Wirkung von Gastrin und die Sezernierung von HCl. Spielt eine Rolle bei der Angststörung bzw. Auslösung von Panikattacken.
• Secretin is secreted at a pH of the chyme in the duodenum of < 4.5, inhibits gastrin production and thus reduces gastric acid production. It causes the pancreas to release secretions rich in sodium hydrocarbonate and stimulates the release of insulin and somatostatin.

Magen

• Gastrin from the antrum of the stomach and the duodenum promotes the production of Hcl in the stomach. Stretching of the stomach through food, certain proteins in the food, irritation of the vagus nerve, alcohol and caffeine stimulate the release; it is inhibited by somatostatin, secretin, GIP (gastrin inhibiting peptide) and the gastric acid-inhibiting and peristaltic-promoting neurotensin, among others.
• Ghrelin (Growth Hormone Release Inducing), appetite-stimulating hormone; stimulates the release of neuropeptide Y in the hypothalamus, which promotes food intake
• Neuropeptide Y, controls hunger, anxiety, blood vessel contraction, insulin release, gastric motility; acts as a tissue hormone (i.e. paracrine) on the immune system
• Somatostatin (s.o.)
• Histamine (tissue hormone and neurotransmitter, also found in plants and bacteria), messenger substance for tissue swelling in inflammation. Also involved in the regulation of gastric acid production and motility as well as in the central nervous system in the control of the sleep-wake rhythm and appetite control
• Endothelin, strongest known vasoconstrictor, 100 times stronger than noradrenaline; is elevated in CHD, heart failure and arteriosclerosis, also impairs the contractility of the heart, the heart rhythm and blood flow to the kidneys

kidneys

• Renin, from the JGA (juxtaglomerular apparatus), is released at low blood pressure in the afferent arteriole or at low sodium concentrations in the distal tubule. Catecholamines such as dopamine also lead to release. RAAS see below.
• Erythropoietin, stimulates the formation of erythrocytes (as a reminder: around 200 billion erythrocytes are formed per day), apoptosis inhibitor, slight stimulation of megakaryocytes (thrombopoiesis)
• Calcitriol, physiologically active form of the prohormone vitamin D3, acts against osteoporosis, modulates the immune system (improves defence against infections, reduces autoimmune processes), protects against cancer, acts against psoriasis and alopecia areata, promotes sperm motility
• Thrombopoietin (s.o.)

Adrenal glands

• Aldosterone, inhibits sodium excretion and thus increases blood volume, promotes potassium excretion. The increase in potassium in the serum can increase aldosterone synthesis. Very important in the short term when coping with life-threatening stress, chronic increase has multiple pathological effects
• Cortisol (cortisol), the most important stress hormone alongside (nor-)adrenaline, but more sluggish than the latter; activates catabolic metabolic processes and thus provides energy; immunosuppressive, anti-inflammatory, glycolytic, promotes the lipolytic effect of adrenaline and noradrenaline as well as catabolic protein metabolism. Is oxidised in the kidneys and intestines to cortisone, which does not have an antidiuretic effect. CRH and ACTH control the release. Cortisone is released in 7-10 spurts per day, the maximum in the serum is in the morning
• Androgens (andosterone, testosterone, etc.; also from testicles and in small amounts from the ovaries), virilising, make beard growth, deeper voice, stronger muscles)
• (nor-)adrenaline (adrenaline is also called epinephrine; noradrenaline lacks the methyl group of adrenaline). Adrenaline is a vasoconstrictor, particularly in the skin and kidneys, but a vasodilator in the central vessels supplying the muscles. In the heart it is chronotropic (accelerates the pulse), inotropic (increases contraction force) and dromotropic (accelerates conduction). Together with peripheral vasoconstriction, this significantly increases blood pressure. It increases respiration and inactivates vital functions such as digestion in the short term by paralysing peristalsis by relaxing the smooth muscles. The urinary bladder sphincter contracts under adrenaline. It promotes lipolysis, glycolysis and gluconeogenesis and thus increases the blood sugar level. At the same time, it inhibits the effect of insulin and releases glucagon. As a neurotransmitter, adrenaline activates the sympathetic nervous system, which in turn releases more adrenaline and noradrenaline. Increased sweat production, goose bumps, dry mouth and mydriasis (dilated pupils) are also caused by adrenaline. Intravenously, and very rarely intracardially, adrenaline is an important emergency medication. It is also administered intramuscularly in cases of shock or anaphylaxis.
• Noradrenaline acts mainly as a vasoconstrictor of the arterioles and is also a neurotransmitter with the same effect as adrenaline.

Pancreas (islet organ)

• Insulin, promotes the uptake of glucose into the cells and thus (as the only hormone) lowers the blood glucose level. Many hormones raise blood sugar levels, including the direct antagonist glucagon, but also adrenaline, cortisol and thyroid hormones. With insulin as the key, the liver and muscles in particular can absorb large amounts of glucose in a short time and store it as glycogen. Nerve cells and erythrocytes absorb glucose independently of insulin. Insulin inhibits lipolysis, so insulin deficiency leads to increased lipolysis and the formation of ketone bodies (acetone, 3-ketobutyric acid and ß-hydroxybutyric acid). By providing the appropriate enzymes, the brain and muscles can also obtain energy from ketone bodies. For example, with prolonged fasting, it is possible for the brain to manage with 40 mg/dl instead of 120 mg/dl glucose after the change in diet.
  In the liver, fatty tissue and muscles, insulin promotes triglyceride synthesis from food lipids, as well as protein synthesis. Insulin promotes glycogen synthesis and storage in the liver, triglyceride synthesis in the liver and adipose tissue and the storage of amino acids in the muscle; it inhibits hepatic gluconeogenesis and is therefore one of the most important regulators of glucose metabolism. The half-life of insulin in serum is around 5 minutes. It is taken up by cells, but is also broken down in the liver and kidneys. This suggests that blood glucose regulation is faster than it is possible to intervene therapeutically in the long term.
• Glucagon, promotes glycolysis in the liver and is an antagonist of insulin in its effect on glucose, protein and fatty acid metabolism
• Somatostatin,
• PP (pancreatic polypeptide), inhibits pancreatic enzyme and hydrogen carbonate production, intestinal motility and bile flow
• Ghrelin (s.o.)

Ovarien

• Oestrogens, also from the adrenal cortex and testicles; testosterone is also partially converted into oestrogen in fatty tissue
• Gestagens (progesterone and others)

Hoden

• Testosterone

Some important control mechanisms

RAAS (renin-angiotensin-aldosterone system)

As a protease, renin converts the previously inactive angiotensinogen from the liver into angiotensin I. This in turn is converted into angiotensin II by angiotensin converting enzyme (ACE), which is mainly produced in the lungs and has a negative feedback effect on renin formation, thus preventing renin overproduction. Angiotensin II has a very strong vasoconstrictive effect and also promotes the release of aldosterone and antidiuretic hormone (ADH), which is also known as adiuretin or vasopressin. Release stimuli for renin include Reduced blood flow in the Malpighi corpuscle of the kidney, reduced blood pressure in the vas afferens (the arterial vessel leading to the glomerulum, the renal corpuscle), reduced glomerular filtration rate, activation of the sympathetic NS, reduction of Cl ions at the macula densa on the straight part of the distal tubule.

Thyrotropic control loop

The pituitary gland releases the control hormone thyrotropin (TSH), which stimulates the secretion of thyroxine (T4) and triiodothyronine (T3) in the thyroid gland. These thyroid hormones in turn inhibit the production and release of TSH and T4, including TRH, in the sense of a negative feedback loop, so that an equilibrium level of the amount of thyroid hormones in the blood is normally established.

insulin resistance

Under conditions of chronically elevated blood glucose and chronic binding of insulin to receptors due to hyperinsulinaemia associated with the increase in glucose, cells produce fewer new receptors (activated receptors are partially internalised and recycled). The reduced number of receptors („downregulation“) leads to fewer triggered signalling pathways (PI3K → Akt → GLUT4) and less glucose uptake. This „receptor degradation“ is referred to as insulin resistance. However, this causes the regulation of both glucose and insulin to spiral completely out of control, because hyperinsulinaemia and hyperglycaemia persist. What’s more, the overall effect of the insulin present in the blood on the cells is reduced. This leads to a glucose-insulin vicious cycle: the initial receptor degradation causes the pancreas to detect hyperglycaemia, leading to an increased release of insulin that no longer corresponds to the glucose concentration. However, the glucose level remains high, which is why more insulin is released, causing receptor degradation to progress, which in turn causes glucose and, consequently, insulin to rise, leading to further receptor degradation, and so on.

In addition, increased insulin secretion causes increased fat storage in the cells, which impairs cell function. Hyperinsulinemia also causes increased inflammatory reactions in adipose tissue, which disrupt the response to insulin and exacerbate insulin resistance. Hyperglycaemia also triggers inflammatory processes in which various inflammatory cytokines are released.

Hyperinsulinemia also directly leads to increased feelings of hunger, which are countered by increased carbohydrate intake, leading to a further increase in glucose levels.

Two further pathomechanisms lead to a lower and later to a low uptake of glucose into the cell:
Post-receptor signalling dysfunction (serine phosphorylation of IR or IRS-1, inhibition of the Akt/PI3K signalling pathway) and glucotoxicity (ROS, PKC activation leads to inhibition of insulin signal transduction). As a result, despite an excess supply of glucose and insulin, the cell can slip into glucose deficiency and dysfunctionality.

The kidneys are no longer able to excrete the accumulated amount of glucose (glucosuria) at a very early stage and are therefore unable to prevent the escalation.

In addition to the sheer oversupply of food, its quality (simple carbohydrates, sugary drinks and foods, starchy foods, etc., carbohydrates without fibre or other energy sources such as fats or protein) and the timing of consumption are also responsible for this situation. If small or large amounts of food or glucose-equivalent liquids are consumed repeatedly (e.g. snacks between meals, sweet drinks), insulin and glucose levels remain elevated throughout the day and, at best, drop slightly at night after a significant delay.

This situation has serious consequences as a chronic condition, especially in the long term, as both hyperglycaemia (too much glucose in the blood) and hyperinsulinaemia (too much insulin in the blood) persist. This means that the harmful effects of excess levels of both substances occur throughout the body, including the brain and the vascular system. The damage, risks and diseases caused include:

1. Prediabetes, LADA (late onset autoimmune diabetes in adults, „diabetes 1.5“), type 2 diabetes, type 1 diabetes, relative pancreatic insufficiency („exhaustion diabetes“). This can later lead to, among other things:
   • diabetic nephropathy (kidney damage) due to impaired vascular regulation, renal hypertension
   • diabetic neuropathy (polyneuropathy)
   • diabetic retinopathy, ranging from visual impairment to blindness
2. Obesity, metabolic syndrome: Lipid metabolism disorders with hyperlipidaemia, blocked lipolysis due to hyperinsulinaemia, hypertriglyceridaemia, arterial hypertension, also due to reduced NO production in the vascular endothelium, hypercholesterolaemia, decrease in HDL, increase in LDL, clearly risky for plaques in connection with lumen reduction
3. Polycystic ovary syndrome (PCOS), menstrual disorders, infertility in some cases
4. Increased risk of CHD, arteriosclerosis (thickening and inflammation of the vessel walls, loss of vascular compliance) with increased blood pressure increased risk of heart attack and stroke, also due to increased tendency to clot
5. Fatty liver disease, fatty liver
6. Chronic inflammation, silent inflammations
7. increased tendency to clot, therefore increased tendency to thrombosis
8. erectile dysfunction caused by vascular damage
9. Impaired brain function, disturbances in memory, cognition, mood, development of dementia, Alzheimer’s disease
10. Increase in visceral fat and the disorders it causes: exhaustion, fatigue, brain fog, food cravings, weight gain/obesity, reduced quality of life
11. Increased risk of depression and other mental illnesses
12. Impaired function of various cell changes due to insufficient supply: receptor degradation (insulin resistance) usually exceeds the level required, as insulin levels rise inadequately in relation to glucose levels. This insufficient supply occurs independently of the additional restriction of supply caused by damaged blood vessels. Oxidative stress (increased levels of molecules with reactive oxygen compounds) damages organs, increasing the need for antioxidants. Impaired mitochondrial energy production (reduced ability to metabolise ketone bodies and fats, reduced mitochondrial quality control and disposal of dysfunctional mitochondria, increased cell stress and further reduced mitochondrial function due to metabolic products such as lactate)
13. increased risk of cancer, as hyperinsulinemia promotes cell growth and division
14. Since stress hormones inhibit insulin action and are themselves diabetogenic (releasing glucose into the blood), they promote hyperglycaemia, hyperinsulinaemia and insulin resistance. These in turn disrupt nervous (chronically elevated sympathetic tone) and endocrinological (activation of the hypothalamic-pituitary-adrenal axis) homeostasis. In addition, insulin resistance increases the tendency towards chronic inflammation, to which the brain also responds by activating the hypothalamic-pituitary-adrenal axis. Increased CRH is released, which in turn leads to ACTH release, causing cortisol levels to rise. This creates a vicious circle.

Insulin resistance is fundamentally reversible if the conditions for this are created. Under favourable conditions, reversal takes around 3–4 months. The following are particularly important:

1. An adapted diet that is relatively low-glycaemic and avoids glucose spikes in particular by consuming easily metabolised carbohydrates without proteins and fibre, as well as sweetened drinks.
2. Endurance training and strength training are important factors in improving insulin resistance by restoring the insulin sensitivity of cells through increased demand. Endurance training does this primarily during exercise, while strength training does so through increased muscle mass, even at rest. In addition, strength training in particular causes the release of a whole range of helpful myokines, which have a wide range of positive effects in the body, such as anti-inflammatory, metabolic or regulatory effects.
3. Stress reduction and sufficient sleep (reduces the cofactor stress hormones)
4. Weight reduction is an important factor, especially in cases of obesity.

After two to four weeks, the first results become measurable, and after six to eight weeks, there is a noticeable decrease in fasting blood sugar and HbA1c. If insulin resistance has not been present for very long, it should be reversed after three to six months, depending on its severity and duration.

Glucose and insulin metrics

In connection with the body’s response to foods metabolised into glucose (postprandial glucose excursion, PPG), several parameters have been defined that have been in widespread use for some time:

1. Glycaemic index (GI): The GI is the quotient of the total glucose release into the blood after consuming a food containing 50 g of carbohydrates and the corresponding response to 50 g of pure glucose (dextrose). By definition, glucose itself has a GI of 100. As an integral of the increase (measured within 2, 3 or 4 hours), the GI is therefore only a scalar value and says nothing about the temporal course of the release, in particular nothing about peaks or drops after peaks, which is why this value is sometimes less useful. The second difficulty with the GI is that the carbohydrate density in a food can vary greatly. Although the GI of cooked carrots is 70, with a carbohydrate content of 7.1%, 700 g of carrots would have to be consumed to achieve this. Baguette also has the same GI of 70, but due to its high carbohydrate content (48 g / 100 g), only 104 g need to be consumed. In terms of quantity, 104 g of baguette and 700 g of cooked carrots have the same effect in terms of GI, but the absorption time of the starch in the baguette is significantly shorter and the glycaemic load (see below) is significantly higher than in the cooked carrots. This also results in a much more pronounced insulin response (insulinemic index, see below) to the baguette. Another factor is that carrots contain significantly more fibre in relation to carbohydrates, which delays absorption and makes the glucose and insulin curve much flatter.
2. Glycaemic load (GL): GL is the product of GI and the carbohydrate density in the food. This means that GL is also a scalar value that does not provide any information about the time course. Nevertheless, it can be more helpful than GI, as it is easier to relate to realistic food quantities. In the example above, 100 g of cooked carrots have a GL of 5.0 and 100 g of baguette have a GL of 33.6. For both foods, it is also important to consider how they are prepared, especially if water is lost through heating or added through cooking in water, as well as their composition, since fibre, protein and fat in food can significantly influence absorption behaviour by delaying absorption.
3. Insulin index (II): The insulin response is also a scalar value, but it indicates the body’s actual insulin response to a food. The fact that some protein-rich foods (such as meat and cheese) can trigger a high insulin response makes the II an important and realistic value. The II and GI diverge particularly in the case of high protein content or highly refined carbohydrates. Similar to the GI, white bread is used as a reference and defined as 100. Starchy potatoes have a value of 121, white beans 120 and gummy bears (glucose) 160, while white pasta has a value of only 40 and rice 79. Protein-rich foods (i.e. carbohydrate-free) such as meat have a value of 51 and cheese 45.

In addition to the above scalar variables, which measure the integral of the glucose increase but do not provide any information about the temporal distribution or the height of the peaks, further variables have been defined.

Modern metrics

1. Glucose Excursion (ΔGlucose): measures the height of the peak above the baseline and shows a strong association with oxidative stress.
2. Rate of Appearance (Ra) / Rate of Increase: measures how steeply blood sugar rises (gradient in mg/dL per minute).
3. Time to Peak (TTP): measures the time to maximum blood sugar level; a short TTP indicates rapid absorption and high metabolic stress.
4. Time Above Range (TAR): Measures the proportion of time above a defined threshold value. This is an important parameter in diabetes research.
5. MAGE (Mean Amplitude of Glycaemic Excursions, average height of relevant peaks and troughs): measures not only increases but also excessive decreases and is one of the best predictors of vascular stress.
6. Coefficient of Variation (CV): measures the relative range of variation. Values above 36% are considered critical.
7. Early-phase insulin response: measures insulin secretion in the first 30 minutes. Strong, early peaks represent significant β-cell stress in the long term.
8. Disposition index: a value that takes insulin secretion and insulin sensitivity into account and thus indicates the extent to which peaks can be compensated for or how resilient the regulation is.
9. Glycaemic Variability Index (GVI): a value that combines the magnitude, duration and frequency of the increase.
10. Glycaemic Risk Index (GRI): a peak-sensitive value that assesses the risk of hyperglycaemia and hypoglycaemia.

These more modern metrics can provide far better information about the risk of peaks and excessive drops leading to hypoglycaemia, the risk to blood vessels, for example, and the body’s ability to regulate blood sugar than the classic metrics GI, GL and II.

Second-Meal Effect

Decades ago, it was discovered that the glucose response varies greatly not only between individuals but also within individuals, and that it depends in particular on the previous meal, a phenomenon known as the second-meal effect. The physiological background to this effect has not yet been sufficiently clarified, but the effect itself has been confirmed by several studies. One hypothesis to explain the effect postulates an altered insulin response or changes in signalling pathways, while another attributes it more to reactions of the intestinal flora. It is known that:

1. A diet rich in fibre has a more pronounced second-meal effect than a diet low in fibre.
2. Meals that are richer in protein and fat have a greater second-meal effect than those that are lower in these nutrients.

This knowledge provides another opportunity to positively influence insulin resistance and type 2 diabetes.

diagnosis

Last but not least, we must answer the question of how to measure insulin resistance in a practical manner. The three most important metrics are:

1. HOMA index (Homeostasis Model Assessment): After fasting for at least 12 hours, the HOMA-IR = insulin (µU/ml) × glucose (mmol/l) / 22.5) is calculated. Values of 2.0 or higher indicate a risk that increases with rising values. Insulin resistance is assumed from 4.65, as well as from 3.6 with a BMI greater than 27.5 kg/m². Insulin resistance is also highly likely with a BMI of 28.7 kg/m² or 27.0 kg/m² if diabetes occurs among first-degree relatives (parents, siblings). Insulin resistance is also very likely with triglycerides above 2.44 mmol/l (215 mg/dl).
   The ratio of triglycerides to HDL is also often used as a very good indicator of insulin resistance. Optimal values for this ratio are below 1; up to 2 is considered a good value, above 2 is a warning of possible incipient insulin resistance, and above 3 is assumed to be insulin resistance.
2. Oral glucose tolerance test (oGTT): after fasting overnight, blood sugar levels are measured at various intervals following the administration of a glucose solution.
3. Proinsulin: Proinsulin is the precursor to insulin in the blood. In cases of insulin resistance, it is incompletely converted and can be detected in elevated levels in the blood.
4. Clamp test: this complex test is used more in a research environment.