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The causes of type 1 diabetes

Author: Dr Sorin Ioacara | Last update: November 9th, 2020

A woman with arms raised suggesting the question why?

Discover here: Causes during pregnancy | Causes after birth | Acceleration factors | Genetic causes of type 1 diabetes | Mechanisms of development

Environmental factors play a significantly higher role among the causes of type 1 diabetes compared to genetic factors. This is also the reason why the incidence of type 1 diabetes has increased, primarily based on cases at low genetic risk. In other words, more and more people with low genetic risk end up with type 1 diabetes.

Environmental factors are initially involved in the development of type 1 diabetes-specific autoimmunity. They can act either in the intrauterine period or after birth. Some of them may also be risk factors, while others work as protective factors.

Causes of type 1 diabetes during pregnancy

A pregnant woman with a big belly, dressed in a red robe holds her belly with a hand.

During pregnancy, a lot of environmental factors act. They may increase or decrease the risk of type 1 diabetes in the future child. Ecological factors change the risk for type 1 diabetes-specific autoimmunity. Most of them are related to the diet of the pregnant mother. The main risk factors for the development of autoimmunity specific to type 1 diabetes in children (after birth), which act during pregnancy are the following:

  1. Enterovirus infection
  2. Maternal obesity before becoming pregnant (pre-conception)
  3. Pre-conception father’s obesity
  4. Maternal obesity during pregnancy
  5. A higher baby weight at birth
  6. Cesarean birth
  7. The amount of gluten in the mother’s diet
  8. The mother’s older age

However, during pregnancy, there are also protective factors for the appearance of autoimmunity, among which the most important would be:

  1. Higher vitamin D levels in the mother
  2. Mild respiratory infections of the mother

Weight in utero

Pre-conception maternal obesity increases the risk of developing type 1 diabetes-specific autoimmunity by about 40%. This risk increases further with the persistence of excess weight during pregnancy.

Surprisingly, it appears that the father’s obesity at the time of conception increases the risk of autoimmunity by 50%. Excess baby weight in utero is a risk factor for autoimmunity if birth weight is higher than 3.5 kg.

Gluten-rich diet in pregnancy

A higher amount of gluten in the mother’s diet may be responsible for a significantly increased risk of developing autoimmunity specific to type 1 diabetes in the child. The risk is double for an intake of 20g of gluten per day compared to 7g per day. Among the gluten-rich foods we mention here:

  • bread
  • pasta
  • pastry
  • bagels
  • biscuits

Vitamin D in pregnancy

A diet rich in vitamin D during pregnancy is associated with a higher level of vitamin D in pregnant women. This higher level of vitamin D obtained through diet reduces by half the risk of developing autoimmunity specific for type 1 diabetes in the future child.

Trying to increase the level of vitamin D in the mother using vitamin D supplements to reduce the risk of type 1 diabetes, unfortunately, does not work. Studies have shown that although there was a significant increase in vitamin D levels in the mother, the subsequent risk of type 1 diabetes in the child did not change.

Respiratory infections in pregnancy

Respiratory infections of viral origin during pregnancy do not increase the risk of developing autoimmunity specific for type 1 diabetes. On the contrary, in the presence of unique genetic variants, this risk may even decrease. In reality, these infections double the risk of developing type 1 diabetes, but the appearance of autoimmunity less often precedes it.

Stimulating the immune system naturally, by contacting some infections by the mother, can prevent the development of autoimmune diseases in children. In addition to the formation of antibodies, viruses induce essential changes in the immune system.

Viruses release some particular molecules in the body, called cytokines. Their effects are multiple and not completely known in terms of preventing the occurrence of autoimmunity specific to type 1 diabetes.

Another hypothesis described is “antigenic competition”. The immune system is trying to fight the virus. The response of the immune system to other antigens, such as those in the pancreas, is thus diminished. In other words, the immune system is “busy” eradicating the virus and forgetting about pancreatic beta cells.

However, congenital rubella or cytomegalovirus infection leads to diseases that include several organs and systems of the newborn and infant. Diabetes is present in about 10% of these cases.

Environmental factors involved after birth in the emergence of autoimmunity

An infant with a toy in his mouth.

After birth, there is an extremely important period for shaping the immune system. The baby has to adapt to new environmental conditions, including the presence of pathogens. During this period, the immune system learns to better distinguish the body’s own structures from foreign ones, which can harm it (pathogens). The main risk factors for the onset of autoimmunity specific to type 1 diabetes that act after birth are:

  1. Enterovirus infection
  2. Rotavirus infection
  3. Other viral infections
  4. Respiratory infections
  5. A higher rate of weight gain in the infant
  6. Premature exposure to cereals and root vegetables
  7. Cow’s milk
  8. Major mental stress

The protective factors for the appearance of autoimmunity that act after birth are the following:

  1. Breastfeeding
  2. Early exposure to gluten or egg
  3. Omega 3 fatty acids
  4. Probiotics
  5. The rotavirus vaccine

Enterovirus infection

Enterovirus infection in children can increase the risk of later-onset autoimmunity specific to type 1 diabetes by more than ten times. Enteroviruses are transmitted by the faecal-oral route. They can even colonize the digestive tract asymptomatically. The large group of enteroviruses includes:

  • poliovirus
  • coxsackieviruses
  • echovirus
  • other enteroviruses

The poliovirus can be considered eradicated and is not discussed here. Among coxsackieviruses, variant B1 is associated with a significantly increased risk for type 1 diabetes-specific autoimmunity. Infection with other coxsackievirus subtypes (e.g. B3 or B6) does not increase the risk of subsequent autoimmunity.

The reduction in this way of the risk of subsequent B1 infection decreases the risk of type 1 diabetes-specific autoimmunity.

Rotavirus infection

Rotavirus is an orally transmitted virus that infects cells inside the small intestine. It can cause diarrhoea in infants and young children. By the age of 5, almost any child has already been infected with this virus at least once.

It seems that infection with this virus can trigger the autoimmune process in the pancreas. Recent studies have shown that rotavirus vaccination is associated with a significant reduction in the risk of developing type 1 diabetes-specific autoimmunity.

Other viral infections

In addition to enterovirus and rotavirus, there are other types of viruses involved in the development of autoimmunity specific to type 1 diabetes. Their contribution is still incompletely elucidated. Of these viruses, some more consistent evidence exists for:

  • herpes viruses, including cytomegalovirus and Epstein-Barr virus
  • rubivirus (rubella)
  • rubulavirus (mumps)
  • parechovirus
  • picobirnavirus
  • tobamovirus
  • bacteriophage viruses

Bacteriophage viruses represent most of the viruses normally present in the intestine. Their role is to infect and destroy bacteria. They thus contribute to the regulation of the composition of the intestinal bacterial flora. There are species of bacteriophage viruses that significantly increase the risk of autoimmunity in type 1 diabetes. At the same time, there are species of bacteriophages that decrease this risk.

The rubella virus has an interhuman transmission through the air. It produces an eruptive disease in young children and adolescents. Infection during pregnancy can lead to congenital rubella syndrome. About 10-20% of children born with this syndrome also have an atypical form of diabetes. The rubella vaccine is included in the national compulsory vaccination program. The protection offered by this vaccine is effective for the rest of your life. Therefore, the introduction of rubella vaccines into practice currently excludes this virus from the list of risk factors for type 1 diabetes.

Mumps virus causes epidemic mumps. The infection is common in children, where it evolves with an inflammation of the salivary glands. The parotids are most commonly affected. There is also sore throat or earache, fever, headache and lack of appetite. Most of the time, mumps does not pose special problems. Immunization by widespread vaccination of children with attenuated mumps virus, currently excludes this candidate from the list of risk factors for type 1 diabetes.

Respiratory infections

Respiratory infections significantly increase the risk of developing autoimmunity specific for type 1 diabetes. Their onset in the first month of life doubles this risk. Infections can increase the risk of autoimmunity through the following possible mechanisms:

  • antibiotics used to treat them alter the intestinal flora. This has negative effects on the immune system, especially in infants.
  • activation of the interferon pathway in the immune response leads to local inflammation of pancreatic beta cells. This mechanism activates some special lymphocytes (CD8 +), which can destroy the pancreatic beta cells.
  • the immune system has a genetically coded defect, which makes it respond aberrantly to a certain type of infection. The aberrant response is to confuse pancreatic beta cells with a real infection.

Weight in infants

Excess weight during infancy may double the risk of later-onset autoimmunity specific to type 1 diabetes. In addition, rapid weight gain carries an additional risk for autoimmunity. The mechanism by which overweight leads to autoimmunity appears to involve increased resistance to insulin.

Cow’s milk

Cow’s milk may be responsible for the increased risk of autoimmunity specific to type 1 diabetes in children. However, this only happens in children with a low genetic risk for type 1 diabetes. In the presence of a high genetic risk for type 1 diabetes, exposure to cow’s milk does not change the risk of developing autoimmunity.

However, the use of a hydrolyzed formula, in which the cow’s milk-specific protein has been removed, does not alter the risk of type 1 diabetes compared to “whole” cow’s milk.

Regardless of the genetic risk, exposure to cow’s milk in the first three months of life may increase the risk of developing autoimmunity in the event of an enterovirus infection. This increase in the risk of autoimmunity is in addition to the increase brought about by the enterovirus infection itself.

Breastfeeding and gluten exposure

Breastfeeding is associated with multiple benefits for the infant. They are present both in the short and long term. One of the long-term benefits is the reduction by about 25% of the risk of developing autoimmunity specific to type 1 diabetes.

Celiac disease is an autoimmune condition commonly associated with type 1 diabetes. Responsible for the onset of autoimmunity in celiac disease is gliadin, a protein in gluten. Consequently, doctors suspected gluten exposure to be involved in type 1 diabetes development.

Studies that have tried to delay the baby’s gluten exposure until after the age of 9 months have not been able to show any benefit from this intervention. Attempting to delay gluten exposure beyond 12 months showed the same result. There was no influence on the risk of developing autoimmunity specific to type 1 diabetes.

Studies that have looked at whether premature gluten exposure before the age of 4 months influences the risk of developing type 1 diabetes have had a surprising result. This early exposure to gluten has reduced the risk of developing autoimmunity in type 1 diabetes by 30%.

Exposure to eggs

Studies have shown that the introduction of eggs in the infant’s diet before the age of 9 months is associated with a reduction in the risk of subsequent onset of autoimmunity specific to type 1 diabetes. The decrease in risk is about 20%. Except for gluten exposure before the age of 4 months, no other dietary option in infants significantly influences the risk of autoimmunity.

Some smaller studies have suggested a significantly increased risk associated with exposure to root legumes or fruits before the age of 4 months. An ample confirmatory research has shown that this is not true. However, some populations may have particular risk factors for type 1 diabetes. Therefore, their risk factors might not be among those found in other communities in different geographical areas.

Environmental factors accelerating the progression of autoimmunity

Many arrows flying.

Stage 1 of type 1 diabetes diagnosis means that you have persistent autoimmunity against pancreatic beta cells. What follows is a period in which the progressive destruction of pancreatic beta cells takes place. This period can last for several months, several years or even several decades. Environmental factors may accelerate the transition from autoimmunity to full-blown disease. This symptomatic onset of high blood sugar is the stage 3 in the development of type 1 diabetes.

The main environmental factors that can accelerate the transition to stage 3 of type 1 diabetes are:

  1. Enterovirus infection
  2. Insulin resistance (e.g. puberty, overweight)
  3. Hyperglycemic diet
  4. Changes in the intestinal bacterial flora
  5. Major psychological stress

The intestinal bacterial flora modifies the risk of type 1 diabetes

The intestinal bacterial flora interacts continuously with the host’s immune system. Following these interactions, the immune system has a lot of benefits. The intestinal bacterial flora plays a vital role in regulating the immune response to various substances foreign to the body.

The two main bacterial classes present in the intestine are:

  • bifidobacteria
  • firmicutes

Bifidobacteria have a positive influence on the immune system. Firmicutes generally hurt the immune system, including the risk of type 1 diabetes.

The risk of progression to type 1 diabetes also increases in conditions of low biodiversity of the intestinal flora. This decrease in biodiversity may occur as a result of antibiotic treatment, which is not followed by exposure to probiotics. Restoration of the intestinal flora after an infectious or diarrheal episode is essential. The administration of probiotics should support it.

Breastfeeding ensures a massive presence of bifidobacteria in the digestive tract. These good bacteria will metabolize milk to short-chain fatty acids. Switching to infant formula significantly increases the presence of firmicutes. As a result, there is a notable decrease in the production capacity of short-chain fatty acids through local milk processing.

Decreased bioavailability of short-chain fatty acids is a risk factor for the onset of type 1 diabetes. These short-chain fatty acids are also crucial for maintaining the protective function of the intestinal epithelium.

Genetic causes of type 1 diabetes

Blood tubes on a stand and some cotton.

Some genetic tests can help you find out the inherited risk of diabetes. These tests will show you whether there are genes that predispose or protect the body from type 1 diabetes. There is no gene or combination of genes that are distinct to this disease. The best known “diabetic genes” are on chromosome 6. They are called HLA (Human Leukocyte Antigen). This class includes genes that designate susceptibility to type 1 diabetes, but also genes that indicate protection against this disease.

HLA genes and the risk for type 1 diabetes

Every human has two HLA genes. One inherited from the mother and one from the father. The two HLA genes can be denoted as HLA from the mother / HLA from the father. For example, the genetic “constellation” that increases the most the risk of developing type 1 diabetes is HLA DR3/DR4. This notation means that we have a DR3 type HLA gene and a DR4 type HLA gene. The HLA variant DR3 was received from one parent, and the other transmitted the DR4 variant. Two other risk combinations for type 1 diabetes are HLA DR3/DR3 and DR4/DR4.

Approximately 95% of patients with type 1 diabetes have one of the following combinations of HLA:

  • DR3/DR4
  • DR3/DR3
  • DR4/DR4

According to research, 10% of people with HLA susceptible to type 1 diabetes develop the disease. Therefore, identifying a predisposing HLA variant in a person confers an increased risk, not a certainty of developing diabetes.

These types of diabetic HLA are common in many people who will never get the disease. Besides, many people who are not genetically susceptible will develop type 1 diabetes in the future. Hence the paramount importance of environmental factors in the appearance of type 1 diabetes.

Some genes protect against the onset of type 1 diabetes, such as HLA DR2, DQ6, DQ7, DQ9. The risk remains low in their presence even when combined with risk variants (DR3 or DR4).

Other genes associated with an increased risk for type 1 diabetes

Other genes besides HLA that carry a significantly increased risk for type 1 diabetes are the following:

  • a special area (VNTR) next to the insulin gene
  • PTPN22
  • CTLA4
  • IL2R
  • UBASH3A
  • SH2B3
  • ErbB3
  • CLEC16A
  • IL18RAP
  • PTPN2
  • CCR5

Genetic analysis is available to those interested. Your doctor might recommend it in the presence of a grade 1 relative affected by type 1 diabetes. However, there is limited value for the genetic analysis beyond the evaluation of the HLA gene.

The cause of the onset differs from the primary cause of type 1 diabetes

books on a shelf in a library

Type 1 diabetes can evolve for many years without symptoms or high blood sugar. The destruction of pancreatic beta cells can be slow, over several years, sometimes even decades. The clinical onset of high blood sugar and specific symptoms characterises stage 3 of the evolution of type 1 diabetes. Gradually, the secretory capacity of pancreatic beta cells becomes so small that it can only provide the needs of the perfectly healthy and “unstressed” body. Any minor infection or mental stress will increase the body’s need for insulin far beyond what the remaining beta cells can secrete.

The difference between the increased insulin demand of the body and the reduced insulin supply from the beta cells results in a sudden increase in blood sugar. This sudden rise in blood glucose causes the insulin secretion of the beta cells to stop abruptly and completely. Thus appears the symptomatic onset of type 1 diabetes (stage 3), with high blood glucose.

Some patients remember that a black cat cut them off 2-3 days before the clinical onset of type 1 diabetes. It is evident that the current infection, scare, or superstition is not the root of type 1 diabetes. The real cause of diabetes is that which triggered autoimmunity a long time ago.

If it weren’t for the current infection or psychological stress, type 1 diabetes would have started with high blood sugar anyway, but a few months later. The reason for which the onset is now and not in a few months is not the real cause of type 1 diabetes.

Mechanisms of type 1 diabetes development

A complex mechanism of mechanical hand watch

The primary mechanism of type 1 diabetes is the destruction of pancreatic beta cells by the immune system. When we manage to demonstrate this, we say about type 1 diabetes that it is autoimmune. When we fail to find evidence of immune system involvement, we assume that type 1 diabetes is idiopathic. However, the term “idiopathic” only means unknown. In our case, it is a type 1 diabetes caused by unknown mechanisms. Please note that the presence of antibodies specific for type 1 diabetes in the blood does not harm pancreatic beta cells. These are destroyed by other mechanisms, as we will see below.

The fact that we fail to highlight the involvement of the immune system does not mean that it does not exist. As modern medicine progresses, we will be able to prove this evidence better and better. In this way, the idiopathic mechanism of type 1 diabetes will decrease until it disappears.

The immune system uses antibodies and specialised cells

The immune system has the role of defending the body against various microorganisms, like viruses, parasites or bacteria. It also deals with the destruction of some cells from the body. These cells have undergone changes that endanger the surrounding cells and therefore needs removal. An easy-to-understand example would be the destruction of tumour-transformed cells, which could otherwise multiply indefinitely, leading to cancer. Tumour-transformed cells appear daily, and the immune system invariably destroy them.

Substances that trigger the immune system’s reaction are called antigens. These substances reside both in the body’s cells and various pathogens. The response of the immune system to antigens is of two kinds:

  • humoral reaction, by antibodies
  • cellular reaction, through white blood cells

Antibodies specific for type 1 diabetes

A particular class of white blood cells called B lymphocytes produces antibodies. Other lymphocytes, such as T or NK lymphocytes do not produce antibodies. Instead, they are involved in the cellular immune response. Antibodies specific for type 1 diabetes do not harm the pancreatic beta cells. They are just a way to highlight the reaction of the immune system against them. The cellular component of the immune system damages the pancreatic beta cells.

The main antibodies specific to type 1 diabetes are the following:

  • GAD65 antibodies (GADA)
  • Insulin antibodies (IAA)
  • IA-2 or IA-2beta antibodies (IA-2A)
  • Zinc transporter 8 antibodies (ZnT8A)

Pancreas islet cell antibodies, sometimes called anti-pancreatic beta cells, are no longer used in high-quality diabetes centres. The reason is related to the too-high variability of the results coming from the laboratory (even for the same sample). Besides, the correlation with the subsequent onset of type 1 diabetes is much weaker compared to other antibodies. For this reason, most highly qualified doctors no longer recommend their measurement.

The importance of determining type 1 diabetes-specific antibodies

The presence of three or four specific antibodies makes the risk of type 1 diabetes 100% for the next 2-3 decades of life. In other words, no one escapes. You can easily measure these blood antibodies in a (private) laboratory. These antibodies do not appear suddenly, all at once. You don’t have any of these antibodies at birth. Later on, a single antibody appears initially in the blood. It is most often GADA or anti-insulin. Then comes the appearance of the second, third and sometimes fourth antibody.

All grade 1 relatives of a patient with type 1 diabetes should measure their antibodies specific for type 1 diabetes titre. In this way, you can find out the answer to the question “What is the risk of type 1 diabetes in the other child, still unaffected now?”.

A higher titer (concentration) of these antibodies gives an increased predictability for the onset of type 1 diabetes. The same is true for the persistence over time of the presence of these antibodies in the blood. After the clinical onset of type 1 diabetes, the determination of these antibodies would have a purely theoretical, academic value. Their presence or absence will not influence treatment and prognosis.

The only exception to this rule is diabetes with onset until the age of six months. In this case, we are dealing with a neonatal diabetes, in which the antibodies specific to type 1 diabetes are negative.

Who destroys pancreatic beta cells?

The cellular component of the immune system contains the following cells:

  • cytotoxic lymphocytes (also called CD8 +)
  • natural killer cells
  • macrophages
  • mast cells

Upon activation, they agglomerate massively in the Langerhans islets of the pancreas. These islets hold the insulin-secreting beta cells. On a genetic background of susceptibility, an environmental factor usually activates these immune system cells. The effect of this activation is the appearance of a significant local inflammation called insulitis.

The main mechanisms of activation against beta cells of the cellular immune system are the following:

  • Direct injuries
  • Indirect injuries

First, an unknown environmental factor can destroy several beta cells through direct damage. Dead beta cells “irritate” the immune system, which triggers a response against them. In the second variant, an infection occurs with a virus or bacterium that has portions that resemble some sections of the beta-cell. The immune system activates against that part of the virus or bacterium that looks like something on the beta cell and removes the pathogen. But then, the immune system will continue to attack the part of the beta cell that looks like the original virus or bacterium.

Once they accumulate in huge numbers around beta cells, the cells of the immune system will begin to discharge a series of substances. These substances are incredibly toxic to the pancreatic beta-cell. The main substances released by the immune system that destroy the pancreatic beta-cell are:

  • pro-inflammatory cytokines
  • prostaglandin E2

The immune system also secretes some antibodies directed against the pancreatic beta cells, but they are harmless.

References

  1. American Diabetes Association Guideline 2020
  2. ISPAD Clinical Practice Consensus Guidelines 2018
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