HONORING THE DISCOVERY OF INSULIN: 100 YEARS OF DECODING METABOLISM

2021 marks the 100 year anniversary of the discovery of one of the world’s most vital substances: insulin!

For many decades, scientists have been investigating the many properties of this crucial compound. The below discussion intends to summarize much of what is currently known about insulin. This includes a brief history, its primary functions, risk factors for insulin resistance, diseases in which faulty insulin signaling predominates and what one can do to reduce the risk for contracting insulin resistance.

What is Insulin?

Insulin is one of the most important hormones in the body. Without insulin, our cells would fail to absorb and utilize glucose in order to produce energy. The hormone also plays a prime role in both lipid and carbohydrate metabolism. It’s secreted by the islets of Langerhans in the pancreas in response to blood glucose, ensuring that glucose levels remain stable.

At the molecular level, insulin is a very complex protein that consists of two amino acid chains joined by two disulfide bonds. One of the amino acid chains contains 21 amino acid residues, while the other contains 30. Amino acids required to produce insulin include: phenylalanine, valine, glutamine, cysteine, histidine, leucine, arginine, glycine, proline, threonine, tyrosine, lysine, serine, and asparagine.

The chemical formula of insulin reads as: C257H383N65O77S6.[1]

Defective insulin signaling is known to cause insulin resistance over time, a state in which cells lose the ability to respond to insulin and make proper use of glucose[2]. Insulin resistance often results in diabetes, for which insulin medications are administered. Medical insulin is manufactured by inserting human insulin genes into E. Coli bacteria. These genetically engineered organisms produce a chemically-identical synthetic alternative to human insulin that is used to treat type I and II diabetes.

How Was Insulin Discovered?

Insulin was officially discovered in 1921, for which the Nobel Prize in Physiology or Medicine was awarded to Frederick Grant Banting and John James MacLeod in 1923.[3]

This ground-breaking discovery completely changed the future of medicine, setting the tone for much of what we know pertaining to metabolism today. Its importance is perhaps highlighted by the fact that it was (and still is) the quickest Nobel Prize nomination in history; a process that can often take decades to achieve.

The History of Insulin and Diabetes

Prior to its modern discovery, the history of insulin goes back all the way to 1550 BCE in ancient Egypt. The first descriptions of symptoms akin to insulin resistance and diabetes were recorded onto papyrus. The author, Hesy-Ra, noted that those with the condition tended to have larger volumes of urine than healthy individuals.

Honey Urine

In 280 BCE, Indian physician Charaka named the condition Madhumeha or Honey Urine, noting that ants and flies were more attracted to the sweeter urine of diabetics. The term diabetes became known shortly after (200-130 BCE), coined by Aretaeus of Cappadocia from the Greek word diabainein. The word means ‘passing through’ and refers to excessive urinary voiding.

Through the ages, these observations became expanded upon, with mellitus (meaning sweet or honey) being added to diabetes by physician Thomas Willis in the 17^th century. Eventually, the symptom of sweet urine was connected to blood glucose levels by Matthew Dobson in the 18^th century.

The Islets of Langerhans

Paul Langerhans discovered the pancreatic islets of Langerhans in 1869, which were soon proven to be dysfunctional in diabetic patients by Etienne Lancereaux.

Their work was furthered in 1890 by Oskar Minkowski and Josef von Mering, when it was realized that removing the pancreas of dogs caused them to die from diabetes. Once this connection was established, it was noted in 1893 by Gustave-Eduoard Laguesse that the islets in the pancreases of deceased diabetic patients conveyed an abnormal structure.

Exploring Pancreatic Extracts

Near this time, future laureate John MacLeod wrote a book cataloguing what was known about diabetes back then, which caused the surgeon Frederick Banting to contact him with an idea. Banting theorized that a substance produced by the islets of Langerhans may be involved in regulating blood sugar and may be able to prevent diabetes. The meeting of these two scientists in MacLeod’s laboratory led to the discovery of insulin in 1921.

Initially, the first insulin extracts were toxic for diabetic dogs, in spite of showing immense promise. The two scientists then got the help of James B Collip, a qualified biochemist. Collip took the extracts and managed to purify them.

Successful Treatment of Diabetes

In 1922, 14-year-old Leonard Thompson was the first diabetic to be successfully treated with purified dog insulin, exhibiting full remission. After this success, many more were to follow. By 1923, MacLeod and Banting were awarded the Nobel Prize for their efforts and shared the prize money with Collip and Best (MacLeod’s lab assistant).

Hidden Contributions of Paulescu

It is speculated that Banting and MacLeod were inspired by the original ideas of Nicolai Paulescu, who had already managed to treat diabetic dogs with a pancreatic extract in 1916. His work was referenced by Banting. However, due to World War I, Paulescu’s experiments were put on hold until 1921 – by which time it was too late.

Historical experts argue that the nomination was done in too much of a hurry without due investigation, as Paulescu was not even considered for the prize. Nevertheless, his extract was the first to be commercialized; patented by the Romanian Ministry of Industry and Trade in 1922.

Sequencing of Insulin

Later on, the chemical structure of insulin was discovered by Frederick Sanger, who was awarded a Nobel Prize in 1958. Rosalyn Yellow developed the radioimmunoassay for insulin and shared the Nobel Prize in 1977 with Roger Guillemin and Andrew Schally for developing radioimmunoassays for multiple peptide proteins.

While insulin has been extracted for medical use since 1925, the above advances have allowed for its synthetic production to become widespread. Today, hundreds of thousands of lives are saved thanks to the work of all the above medical pioneers.

Primary Roles of Insulin

When insulin binds to cell receptors, it invokes different responses in the cell depending on the concentration. Within the healthy spectrum of insulin signaling, low concentrations of the hormone promote metabolic activities in the cell which make use of glucose in order to generate ATP (or energy). At higher levels, the metabolic activity of the cell increases and shifts the mode of the cell into one of cellular growth and division (mitosis).

Insulin has been most closely studied in skeletal muscle, the liver and white fat cells[4]. In all three of these tissues, insulin stimulates the production of glycogen and fat (only glycogen in muscle tissue), while decreasing the utilization of stored glucose. Glycogen is a stored form of glucose which can be used when glucose levels are low. [5]

The liver is the first to use up stores of fat and glycogen when blood sugar levels drop; an action brought about by glucagon[6]. Glucagon exerts the opposite effects to that of insulin, working together with insulin in the right ratios to maintain constant blood glucose levels[7]. In contrast to insulin, perpetually high glucagon levels promote muscle wasting, as once glycogen has been used, proteins and lipids are the next to be converted into glucose for cellular use.

Insulin Outside the Pancreas

While the discovery of insulin was no doubt a major breakthrough, the classic paradigm of pancreatic insulin has recently been challenged. It would seem that many cells outside of the mouse pancreas have the ability to make and store insulin in order to make use of glucose. Some cell types with the ability to produce insulin include liver, spleen, thymus, bone marrow, embryonic stem cells[8] and fat cells.[9]

Therefore if the pancreas is under-functioning, it does not necessarily mean that one is with depleted insulin levels. Nonetheless, it does mean that insulin in the digestive tract is greatly decreased, which over time, will disrupt bodily glucose metabolism. In this respect, the pancreas is deemed the major regulator of insulin, glucagon and glucose[10]. Those with diabetes tend to rely heavily on the insulin-producing capacity of all other bodily cells.

Other Roles of Insulin

Since its discovery in 1921, many more roles of insulin were discovered over and above that of metabolism and growth.

Insulin is also known to play a role in regulating the following:

• Immune Function

Those with diabetes have a reduced inflammatory and immune response.[11] Insulin regulates the process of immune cell expansion when fighting an infection, allowing for quick and efficient growth of immune cells. It also appears to regulate the innate immune response by ensuring that energy requirements of the cell can be adequately met.

On the other hand, insulin appears to have anti-inflammatory properties in the absence of insulin resistance. Those with low insulin levels and high glucagon (plus blood glucose) levels, are more inclined to have exaggerated immune reactions and suffer from heightened effects of inflammation.[12]

• Cognition

A large percentage of bodily insulin is sent to the brain, where some of the highest numbers of insulin receptors can be found across neurons and astrocytes (neuron-supportive glial cells). Insulin appears to play a role in regulating ordinary cognitive functions, such as memory and learning. During the process of learning, more insulin receptors express in these cells in parts of the brain associated with learning, facilitating an increased energy demand.

Healthy insulin concentrations in the brain not only ensure that neurons are able to meet energy requirements, but promote their growth and survival[13]. This has further implications for neuroplasticity and neurogenesis, which both enhance cognition and flexibility of thought.

Alzheimer’s is occasionally referred to as diabetes type 3 as brain insulin resistance is believed to play a role in the progression of the disease, giving rise to many aspects of related cognitive decline.[14] Insulin was also shown to reduce amyloid plaque formation and regulate the disposal of amyloid.

Is Insulin a Neurotransmitter?

Insulin is classified as a hormone. However, it has a very close relationship with many neurotransmitters, including serotonin and dopamine. Like all neurotransmitters, insulin is released through a process known as exocytosis. This refers to a release mechanism where insulin is made and stored in advance, so that it may be immediately available when it’s required by the cell. Neurotransmitters are stored and released in precisely the same fashion.

• Bone Turnover

Insulin and osteoblasts (bone cells) have been proven to have an intricate biological relationship[15]. Osteoblasts secrete a number of substances that regulate hormones throughout the body, one of the most important being osteocalcin. Osteocalcin has been shown to play a role in cognition, fat metabolism, muscle turnover, male fertility and insulin signaling[16].

The production of osteocalcin depends upon effective insulin signaling in osteoblasts[17]. Likewise, animal studies have shown how osteocalcin stimulates pancreatic secretion of insulin, as well as the expression of insulin receptors in both fat and muscle tissue[18]. Osteoblasts and other bone cells rely on osteocalcin in order to grow and turnover. Diabetes is associated with low bone mineral density and an increased risk of bone fractures.[19]

More research is required to confirm osteocalcin’s full role in glucose metabolism, as those with insulin resistance on display mildly perturbed osteocalcin levels. Nonetheless, rats with hyperglycemia in the absence of insulin resistance were shown to produce substantially less osteocalcin[20]. This may explain one possible cause for the formation of insulin resistance.

• Steroidal Hormones

Insulin appears to be involved in regulating the production of steroidal hormones in both sexes. This is especially pronounced for sex steroid hormones, yet also extends to the production of adrenal corticosteroids[21]. This is related to the metabolic requirements of hormone-producing cells, including neurons, adrenal cells, leydig cells and ovarian egg cells.

Diabetic subjects exhibit lower levels of sex-specific hormones and increases in hormones traditionally appropriate for the opposite sex[22] [23](i.e. estradiol increases in men; testosterone increases in women). Administering insulin to diabetic rats reversed all the hormonal changes seen, increasing balanced ratios of sex hormones in both sexes.

Risk Factors for Insulin Resistance

Erratic insulin levels do not necessarily mean that one has diabetes or another chronic lifestyle illness. Insulin is known to fluctuate in an individual’s lifetime, naturally reaching ranges indicative of disease. The difference pertains to whether one’s insulin levels can normalize or not over time.

The below factors all serve to increase the risk of insulin resistance:

• Stress. Chronic severe stress is destined to result in a state of insulin resistance. During the stress response, the body goes into a different metabolic mode that lowers appetite and increases the production of glucose in the liver.[24] Under normal circumstances, this provides more than enough energy for one to either “fight or flight”; after which, the energy is expended and the body returns to normal. Under pathological circumstances, this results in prolonged elevation of blood glucose, erratic fluctuations in insulin levels and eventual insulin resistance.
• Physical inactivity. Sedentary living reduces ones energy requirements and has long been associated with promoting vascular dysfunction and insulin resistance.[25]
• Smoking. Smoking tobacco products has been associated with developing both insulin resistance and cardiovascular disease.[26]
• Hypercholesterolemia and hyperlipidemia. Excessive production of cholesterol and fats can exacerbate the formation of insulin resistance. These compounds serve as additional substrates for producing glucose in the liver when both glucose and insulin levels drop.
• Diseases affecting the blood. Excessive blood clotting factors and reduced blood flow both can contribute towards increasing the risk of high blood glucose and insulin resistance or sensitivity. Heparin, one of the body’s natural blood thinning substances, has been shown to promote stable insulin levels.
• Hypertension. Insulin and hypertension may have a bi-directional relationship. Those with hypertension have more difficulty absorbing insulin due to chronic vasoconstriction and impaired blood flow. Increased levels of blood insulin can also promote hypertension through increasing sodium reabsorption in the kidneys.[27] As a result, those with one of these conditions tend to land up having the other by default.[28]
• Autoimmunity. When the immune system loses tolerance for self proteins, it can result in the destruction of multiple cellular components that hamper the utilization of glucose and/or fats. In the case of diabetes; the islets of Langerhans, insulin and its receptors typically become targets for the immune system. Atherosclerosis[29] and multiple sclerosis are examples of autoimmune diseases associated with insulin resistance.
• Chronic Low-Grade Inflammation. While inflammation does not cause insulin resistance, per se, it is associated with promoting other diseases that do, such as obesity[30], autoimmunity and several other diseases. In most cases, inflammation results in (necessary) tissue damage, which may transiently affect aspects of cellular metabolism depending on the area of the body that is inflamed. Furthermore, inflammation mimics or is part of catabolism, which is a state of cellular breakdown[31]. Insulin is required for anabolism[32], which is the process of cellular building (especially in muscle). During inflammation and catabolism, insulin is suppressed, resulting in increased blood glucose levels[33].
• Digestive Disorders. Fluctuating insulin and glucagon levels in the pancreas negatively affects cholecystokinin. Cholecystokinin is a hormone that stimulates the pancreas to secrete vital digestive enzymes[34]. If the level of these enzymes is unbalanced, digestion is affected, which can in turn perpetuate abhorrent insulin signaling and result in insulin resistance. Diabetes itself tends to be accompanied by digestive symptoms, while other digestive disorders increase the risk of insulin resistance.
• Chronic infection. Chronic infection is associated with insulin resistance, hypertension and increased blood glucose levels. Naturally, chronic infections increase inflammation for a prolonged time, which eventually acts to deregulate insulin signaling.
• Obesity. Excessive fat may be a product of insulin resistance or a cause for it. Elevated blood insulin levels can promote fat deposition as well as prevent the breakdown of fat. Subsequently, when insulin levels drop, there is more than enough fat for the body to maintain chronically high blood glucose levels. Prolonged elevations of blood glucose may result in insulin resistance.
• Circadian disruption. Insulin is regulated by major neurotransmitters and hormones, including serotonin, glucagon and somatostatin. These hormones are in turn regulated by the intricate hormonal signaling dependent on circadian cues. When we get insufficient sleep of a poor quality, it disrupts the circadian rhythm, which typically induces erratic release of hormones and other major signaling molecules – particularly those that govern alertness, appetite and metabolism. One is typically more tired after sleep deprivation, as well as with elevated blood glucose levels.
• Liver disease. During the course of liver ailments, the production of many substances that regulate insulin in the bloodstream can become hampered. Furthermore, liver disease can complicate the prognosis of diabetes by inadequately producing enough glucose to sustain energy requirements in the fasting state, potentially leading to dangerous dips in blood sugar levels.

While this list is extensive, it is not exhaustive!

Diseases Characterized by Insulin Resistance

After many years of painstaking research, scientists in the last couple of decades have begun to realize that insulin resistance contributes towards more than just the pathology of diabetes.

• Diabetes is known to rest on a spectrum of metabolic diseases, each of which appear to be affected by fluctuations in insulin and eventual insulin resistance. Terms such as ‘cardio-diabesity’ have begun to surface in the literature to summarize how diabetes, cardiovascular disease, and obesity are closely related in this regard.

In Pre-Diabetes, both glucose and insulin levels are increased. Eventually, insulin receptors become blunted to the effects of insulin, resulting in the classic diabetic symptoms of insulin resistance and reduced cellular utilization of glucose. Glucagon levels become increased as cells lack insulin and blood glucose levels are increased. This is especially prevalent after consuming a meal, increasing the levels of glucose in the blood from both food and nutrient reserves in the liver.[35]

• Liver Disease. While insulin is not known to promote liver disease, high serum concentrations are known to increase biomarkers associated with liver damage: hepatic glycolysis and serum aminotransferase.[36] The rise in glucagon furthermore increases the risk for non-alcoholic fatty liver disease, as it disrupts amino acid and fat metabolism.

The rise in circulating amino acids can increase the risk for multiple other diseases as it promotes toxic ammonia build-up in the bloodstream (hyperammonemia), contributing towards chronic low-grade systemic inflammation.

• Obesity. For similar reasons, elevated glucagon may promote obesity, a common finding in those with diabetes and liver diseases.
• Metabolic syndrome. Metabolic syndrome refers to a collection of cardiometabolic risk factors. These include hypertension, dyslipidemia, obesity as well as insulin resistance. The former conditions are all well-studied risk factors for insulin resistance.[37]
• PCOS. Insulin resistance or sensitivity is seen in those with PCOS and is known to interfere with estrogen synthesis in the ovaries.

When to See a Healthcare Professional

If you suspect that you are suffering from irregular blood sugar levels, you ought to arrange an appointment with a healthcare practitioner.

Symptoms of insulin resistance and hyperglycemia include[38]:

• Increased thirst and appetite
• Blurry vision
• Headaches
• Frequent urination
• Fatigue
• Skin infections
• Weight loss
• Slow wound healing
• Nausea
• Heart arrhythmia

5 Tips for Maintaining Balanced Insulin Levels

The below 5 tips may help to lower the risk of developing insulin resistance, promote balance insulin levels, and encourage optimal metabolism.

1. Exercise

Exercise increases both cellular metabolism and insulin levels, however it is also known to promote increased insulin sensitivity, reduce blood glucose and lower glycogen stores.[39] These latter benefits balance the increase in insulin levels, burn fat, and help to promote muscle building.

In epidemiological studies, aging populations who engaged in regular physical activity throughout the course of their lives had a greatly reduced risk of age-related insulin resistance. This was proven through comparing the expression of glucose transporters, the number of which was higher in those that exercised regularly[40]. Those who lived a predominantly sedentary lifestyle were likely to develop insulin resistance as they aged.

2. Moderating Sugar, Fat and Salt Intake

Consuming high amounts of fat, salt or sugar will cause massive spikes in insulin, as well as increase the risk for metabolic syndrome. Sugar is faster-acting in this regard, however a diet high in salt or fat can eventually cause insulin resistance as well. Fruit sugars, when consumed as part of the whole fruit[41], are generally better tolerated than extracts as they are present alongside a host of nutrients that serve to regulate blood sugar levels. Nonetheless, too much fruit can be problematic. Fruit ought to be consumed in the context of a balanced diet plan.

In the case of fat, there are better and worse options for metabolic homeostasis. Fats likely to promote bodily inflammation, such as trans-fatty acids[42] (e.g. hydrogenated vegetable oils), are not a good option in this respect. Healthy fats such as omega-3 oils[43], medium and short-chain fats (e.g. MCT oil[44] and butter/butyrate[45]) and polyunsaturated fats (e.g. olive oil[46]) are complementary to well-being and optimal insulin signaling.

3. Optimizing Protein Digestion

Glucose transporters, insulin and its receptors are made up of many amino acids, which we get from the proteins in our diet. Consuming one protein-heavy meal per day, balanced with enough healthy wholefood carbohydrates, is associated with improving insulin signaling and glucose utilization.[47] Unfortunately, proteins are some of the most difficult nutrients to digest in the diet and consuming them in an excess tends to undermine their absorption and/or promote insulin resistance[48] [49].

In this respect, one needs to ensure to get a healthy variety of protein in moderation, particularly from plant-based sources such as legumes, wholegrains, nuts and seeds. The digestibility of these foods can be enhanced through consuming a well-balanced diet with foods that contain digestive enzymes, such as fruits, herbal teas, probiotic foods[50] and condiments like vinegar. Water-soluble fibers from leafy green vegetables also feed the healthy bacteria in the gut, which in return, produce numerous digestive enzymes that the body cannot produce itself.

4. Enhance Nutrient Intake

Adequate nutrition is vital for the health of the digestive tract, including the pancreas. Research on diet plans that are nutrient dense tend to show the best results in terms of disease prevention, including diseases associated with insulin resistance such as heart disease, diabetes, atherosclerosis, obesity and metabolic syndrome. Diets that are nutritionally balanced, with an emphasis on plant-based wholefoods, are known to help with blood sugar regulation and increase nutrient intake.[51]

While it is important to balance the ratios of proteins, carbohydrates and fats in the diet, vitamins and trace minerals are equally as important for promoting the balanced action of insulin. Epidemiological evidence supports the notion that deficiencies in iodine, zinc, selenium, magnesium, calcium, chromium, cobalt, iron and boron can contribute towards the formation of insulin resistance.[52] Likewise, a similar trend can be seen with deficiencies in essential vitamins. Those with diabetes are often deficient in Vitamin C, E, D, K, A and a few B Vitamins, which are all suspected to promote optimal metabolism, insulin signaling and glucose utilization.[53] [54] [55] [56]

A study highlights how more than 900 herbs and spices contain nutrients with anti-diabetic potential[57]. The effects are not comparable to pharmaceuticals designed to combat diabetes, however incorporating herbs and spices into one’s diet is known to improve overall health and well-being. Examples of potentially antidiabetic herbs and spices include cinnamon[58], rosemary, thyme, cumin, dill, black pepper, turmeric, lemongrass, saffron and garlic.

5. Improve Bone Health

Healthy bones are able to supply the body with a steady supply of insulin-regulating osteocalcin. Osteocalcin has been shown to lower inflammation and enhance the expression of insulin receptors and glucose transporters in muscle and fat mass.[59]

Bones require an adequate supply of minerals and vitamins, as well as regular weight-bearing, aerobic exercise[60] in order to keep healthy and functional. While the majority of these nutrients tend to be supportive, vitamin K2 and D3 deserve a special mention with regard to bone health. Both of these vitamins ensure that enough calcium and other minerals are absorbed by bone tissue, promoting optimal bone mineral density[61].

Additionally, vitamin K2 is required for the decarboxylation[62] and retention[63] of osteocalcin, which is specifically required for optimal insulin signaling in the rest of the body at large.

Conclusion

Our understanding of insulin has certainly traveled a long way since its discovery in 1921. Through the scientific exploration of the last 100 years, we have learned that insulin remains central to many intricate cellular networks that govern whole body metabolism and renewal.

The majority of chronic lifestyle diseases stand a chance of being accompanied by impaired insulin signaling, a state known as insulin resistance. Many of these conditions serve as risk factors for insulin resistance, alongside stress, physical inactivity and unbalanced dietary habits.  Consuming a nutrient-dense, plant-based diet consisting of balanced ratios of wholefoods goes a long way towards preventing the development of insulin resistance; as does regular exercise.

If you suspect you have problems with insulin signaling, then it’s best to see a doctor and get professional advice.

To search for the best Endocrinology Healthcare Providers in Germany, India, Malaysia, Spain, Thailand, Ukraine, the UAE, UK, the USA, please use the Mya Care search engine.

Source: