Endocrinology-Diabetes Questions Type 1 Diabetes

What causes type 1 diabetes?

My daughter was diagnosed with type 1 diabetes recently, but we're really unclear on how it developed in the first place. As far as we know, neither me or my husband have diabetes in our family. What can cause type 1 diabetes to develop?

3 Answers

Diabetes is the most common metabolic disorder affecting over 30 million (10%) Americans. Type 2 diabetes is over 90% of diabetes. There are also about 80 million Americans with prediabetes.
Currently in America the rate of type 2 diabetes by race is as follows.
8% non-Hispanic whites
9%% Asian Americans
12.% of Hispanics
13% blacks
15% of Natives Americans
Type 1 diabetes is about 5% of the diabetic population (1.3 million) and 0.4% of the general population. About 16% of the total population with type 1 diabetes are children.
There are other forms of diabetes such as gestational diabetes (affects 3% of pregnancies), MODY (maturity onset diabetes of the Young and others.

Most adults have type 2 diabetes and most children have type 1 diabetes. However most of the Type 1 diabetics are adults not children. There are about 200,000 (0.24%) of children and adolescents with type 1 diabetes out of 84 million of them. There are one million adults with type 1 diabetes.
The incidence of type 1 diabetes may be more in adults than in children though most of childhood diabetes is type 1 diabetes. About 10% of adults are usually misdiagnosed as type 2 though they may have type 1 diabetes.
The incidence rate of type 1 diabetes is about 40,000 new cases per year in America. Out of these about 20,000 are children and adolescent.
In 90% of cases of new onset type 1 diabetes in children, there is no family history of diabetes at all. Only about 10% have history of affected family members.
Type 1 diabetes affected 0.4% of children in the general population and about 6% of children with siblings of childhood onset diabetes which is about 20 fold increase from the general population. Early-onset diabetes affected fathers will transmit 8% risk to their off springs (20 fold increase) while mothers with childhood onset type 1 diabetes will transmitted to their offsprings about 3% risk (10 fold) of developing type 1 diabetes. Dizygotic twins will transmit similar to the rest of the siblings about 7% risk (20 fold) of transmitting to other siblings.
Monozygotic twins will have 30-40% risk (100 fold) to the other twin but about 8% to the rest of none twins.

About 1.5 million Americans are diagnosed with type 2 diabetes each year. About 6,000 children are diagnosed with type 2 diabetes each. year. There are an estimated 50,000children and adolescents with type 2 diabetes.
Childhood diabetes is on the rise. Every year type 1 diabetes is increasing by about 3%. Type 2 diabetes in children is also increase in parallel to the rise of childhood obesity.
By the year 2050 childhood diabetes both type 1 and type 2 will triple. Type 1 diabetes in children will be about 600,00 in the next 30 years. A 3 fold increase from the current 200,000 children with type 1 diabetes. During the same period the total type 1 diabetes population (adults + children) will increase by 4-5 fold to about 5 million from 1.3 million.
All autoimmune diseases including type 1 diabetes are on the rise especially in the northern hemisphere. The more these societies residing in the northern hemisphere (especially Europeans and European descents) become cleaner and wealthier the incidence of all autoimmune diseases are increasing. In less developed countries the incidence of type 1 diabetes is low. In these countries children are more exposed to microbes and viruses and are less likely to have hypersensitivity reactions or autoimmune diseases. As the body gets exposed to constant stream of microbes it somehow learns to distinguish serious invaders from, from some environmental and dietary factors. When the immune systems does not get that kind of exposure, it gets bored and starts to overreact to its own antigens, causing hypersensitivity reactions and different autoimmune diseases.
Genetic factors are important for type 1 diabetes. However the concordance rate of identical twins is about 40%. This demonstrates that environmental factors also influence the immune system. The incidence of type 1 diabetes is more common in Fall and Winter demonstrating the importance of viral infections as a trigger for type 1 diabetes. During these seasons vitamin D level is low. It is possible that, low Vitamin D level may be related to the increased incidence of type 1 diabetes via modulating the immune system.
Type 1 diabetes is most common in children during puberty. However there are three peaks were children 0-4 years 7-10 years and 11-15 years. But the highest incidence is during adolescence.

Type 1 diabetes is insulin dependent diabetes or also known as juvenile diabetes. It is classified in to two groups. About 90% of type 1 diabetes (type A) is due to autoimmune disease process while the 10% type 1 diabetes (type B) is not related to autoimmune process. But both require insulin not only to control diabetes but also for survival.
Type 1 diabetes is therefore an autoimmune destruction of the insulin producing cells called Islet cell, located mainly at the head of the pancreas. About 90% of type 1 diabetes is therefore due to a destructive inflammatory process of the islet cell called insulitis. This inflammatory process destroys about 85% of islet cells before full blown diabetes will emerge. The remaining 15-20 % of islet cells can not make enough insulin to support the metabolic demand of the body.
The purpose of insulin is to transport glucose from the blood to the tissues (cells) to be utilized for energy and for other purposes. In the absence of insulin the blood sugar increase and spills through the kidneys to the urine. Eventually dehydration and acidosis will prevail making survival impossible. Type 1 diabetes is therefore insulin dependent and needs insulin not only to control blood sugars but also for survival.
Type 1 diabetes is a destruction of insulin producing cell. Three things are required for type 1 diabetes to happen.
1) Genetic susceptibly
2) Environmental trigger
3)An Autoimmune cascade.
For an individual to develop type 1 diabetes he has to have genetic susceptibity (susceptible alleles) interacting with environmental factors leading to chronic autoimmune inflammation of the islet cell leading to the destruction of at list 80% of the cells that make insulin.
Genetic susceptibilities are conferred by specific genes or alleles involved in cell surface recognition. Environmental factors (triggers) could be viruses, food products and other environmental or cellular agents that interact with the susceptible host. An autoimmune process is a dysregulation of the immune system that fails to tolerate self antigens. It takes place when auto reactive cell fail to tolerate self antigens and initiate chronic inflammation of specific tissue targeted for destruction (islet cells).
The immune system is a hosts defense mechanism to defend from invader such as viruses, bacteria, fungus and other organisms. It also have to have a recognition process to identify self (its own cells) so that it does not make a mistake in misidentifying its own cells as invaders. The immune system therefore needs to identify internal tissues and foreign invaders. The immune system is arranged similar to the United states Army with different army missions.
The immune system have to recognize itself and foreign invaders using a special molecule called Major histocompatibity molecule/complex (MHC).
There are three Major histocopatibity complex ( in humans they are called human leukocyte antigen (HLA)).
1) Class 1 MHC: is found in all nucleated cells except red blood cells.
2) Class 2 MHC: is found only on antigen presenting cells (macrophage, dendritic cells, B cells(plasma cells)
3) Class 3 MHC: found in complement cells.
The MHC 1 is made in all nucleated cells and the HLA the human leukocyte antigen which is made inside the cell and is brought up to the surface of the cell and binds to the MHC receptor on the cell surface acts as a recognition antigen (showcase) and tells the immune system (mainly CD8 T lymphocytes) that it should not be attacked. Once the lymphocytes see the self antigen mounted on the cell surface MHC 1 of normal cell, the immune cell do not bother the cell. However if the cell is sick (lets say thyroid or islet cell) it will showcase on her surface receptor MHC1 a different antigen for the T lymphocytes to recognize. When the T lymphocytes identify the bad or non self antigen they will destroy the sick cell or the cell that is showcasing a bad non self antigen.
When a cell is invaded by bacteria or virus it will showcase part of the invader on it surface MHC receptor/clip. The showcase antigen will be recognized and will be designated for destruction so that the infection does not spread to other cells.
Also when the cell showcases a none recognizable protein or antigen on it surface receptor (MHC 1 ) the T lymphocytes (CD8 killer cells) will designate the cell for destruction. This is also similar to tissue graft or transplant rejection. When the transplant cells present none compatible antigens on their MHC 1 receptor, the immune system will destroy the graft promptly.
All nucleated cells have to present an identifiable antigen MHC1 on their cell surface all the time other wise they will be flagged for destruction.. But if they either alter the MHC receptor or the self antigen is not recognized by the immune surveillance unit, the tissue demonstrating those unrecognized antigens will be killed by the surveillance of the immune system promptly. Or if the cell/tissue are infected they will present part of the invading antigen on their surface MHC1 surface receptor and be marked for destruction.

MHC 2 on the other hand is present on Antigen presenting cells. These are specialized surveillance cell such as macrophage, dendritic cells and B cells. These cell have MHC 2 surface receptor on their cell surfaces. When they encounter invaders (bacteria or viruses) before they enter cells, they engulf them and process them or tear them into small pieces and present them on their surface receptor MHC 2. Once the antigens are present on their surface MHC receptor/clip the T helper lymphocyte (CD4 cells) come promptly and unleash a deadly assault on the invading organism. They recruited more helper cells and deadly antibody producing plasma cells also participate to completely annihilate the invading organism that has not infected the cells yet. The cells that are already infected have to present/showcase the invaders antigen on their MHC1 surface receptor for CD8 T killer lymphocytes to kill the infected cell to prevent the spread of the invaders into other cells.

MHC /HLA is also involved in autoimmune disease besides killing invaders and infected cells. The ( MHC 2 ) Major histocompatibility complex gene is located on the 6p21. It may be responsible up to 50% of type 1 diabetes.
The rest of type 1 diabetes is due to other genes problems and there are over 40 of them located on different chromosomes, including on insulin receptor.

The MHC 2 genes have great polymorphism. Even though one gene comes from one parent and the other comes from the second parent, these genes have tremendous polymorphism, meaning that it can occur in different alternate forms or alleles. There are about 2000 alternative alleles (forms) for the same gene. These can lead to generating many different kinds of gene products/proteins.
The HLA gene have many classes, subclasses and sub sub classes.
There are 3 major and 3 minor MHC class I genes in HLA.
There are three Major MHC class I, as follows; HLA-A, B and C
There are also minor classes (HLA-E, HLA-F and HLA-G
.β2-microglobulin binds the MHC 1 receptor to stabilize the receptor.

Major MHC class II have three classes HLA-DP, DQ, DR; and many subclasses.
there are many possible combinations of these subclasses and sub sub classes. Some of these alleles confer suseptibity to autoimmune diseases. And some of them confer protection from autoimmune disease.
Some examples that confer susceptibity are as follows.
B27 Ankylosing spondylitis, Reiter's syndrome syndrome, Arthritis
HLA-B47 21-hydroxylase deficiency.
HLA-DR2; Systemic lupus Erythematosis
HLA-DR3 Diabetes mellitus type type 1
HLA-DR4 Rheumatoid arthritis, Diabetes mellitus type 1 ( young age and sudden onset)
HLA-DQ2 and HLA-DQ8: Coeliac disease
The main T1D susceptibility alleles are located on class II loci HLA-DRB1 and HLA-DQB1. The DR/DQ haplotypes specifically DR3-DQA1*0501-DQB1*0201 (DR3) and DR4-DQA1*0301-DQB1*0302 (DR4), and account for 50% of genetic T1D risk.
Over 40% of European Americans have HLA-DR3 or DR4 allele, at least 1 of these alleles is present in 95% of patients with T1D. The estimated risk of developing T1D for the general population in children who have the HLA-DR3/4 genotype is approximately 1 in 20 compared to the risk of 1 in 300 in the population.
Existence of DR3/DR4/DQ combinations may lead to a very high risk of type 1 diabetes. There are also protective alleles such as DP*0402 and DRB1*0403.
These susceptibly alleles can alter the immune tolerance, cause antigenic mimicry or other means and lead to autoimmune destruction of the target tissue, in this case islet cell that make insulin..
Since Type 1 diabetes is an autoimmune process it takes 2-5 years to evolve into full blown diabetes. Though it is mainly a cell mediated immune destruction of the islet cells, antibodies against various components of islet cell and insulin can be identified years before diagnosis of diabetes. The commonest antibodies are: Islet cell (ICA) antibodies, Glutamic acid decarboxylase antibodies (GAD), (IAA) insulin autoantibodies, IA2 Protein Tyrosine phosphatase autoantibodies and ZnT8 zinc transporter 8 antibodies.
ICA is the first one to appear followed by GAD. Some of these antibodies will fade away with time. These antibodies can be used as markers of diabetes in siblings or families with type one diabetes.
Going back to your daughter: Your daughter have type 1 diabetes. It is likely that she has Type 1 A diabetes, meaning it is autoimmune mediated diabetes in concert with environmental triggers. There are many trigger factors such as viruses, food products and other auto antigens. She could have genetic susceptibility mostly due to MHC 2 DR3/DR4/DQ conferring suseptiblity that leads to chronic inflammation and destruction of the islet cells. She could also have mutations in the other over 40 genes involved in type 1 diabetes (autoimmune). Over 90% of new onset type 1 diabetes have no family history. Family history only contributes up to 10% in type 1 diabetes with the exception of identical twins (about 40%).
Type 1 diabetes will take about 2-5 years to evolve in most cases. In young children it can be drastic. There are about three peaks in the incidence of type 1 diabetes 0-5 years old. 7- 10 years and adolescent 12-15 years. Type 1 diabetes needs insulin therapy for survival and rarely goes a way. Understanding diabetes, monitoring blood sugars adequately and better insulin treatment will bring near normal glycemic control.
Good Luck
Type 1 diabetes mellitus is an autoimmune disease. That means that her own immune system produced antibodies that attacked her pancreas and consequently decreased her insulin production.
You have ask the "million $ ?" We don't know the answer but we do have some clues. First of all Type 1 DM is a genetic disease. It is inherited by a recessive gene so you have to get a gene from each parent. You & your husband do not have diabetes but both are carrying the diabetes gene & transmitted it to your child. But that is not the whole story. Not every one, even identical twins, who carry the diabetes gene will develop diabetes or will get it at the same time as in twins. So there must be an environmental trigger. We understand the genetics better than we do the trigger. Various triggers have been investigated but no one has been identified as "the Trigger". Probably the best bet is a virus or perhaps several different viruses. The gastrointestinal viruses have gotten the most play. This group of viruses include rotovirus, coxsackie viruses & several more that usually cause vomiting & diarrhea. They are vary common. Other triggers have or are being investigated such as cows milk, charred meat, food additives, etc. How these & other substances work is to cause defects in the intestinal lining that cause small proteins to be absorbed intact into the circulation. The immune system the sees them as foreign bodies & produces antibodies to get rid of them. Since there are similar proteins on the surface of the beta cells (the cells in the pancreas that produce insulin) the immune system attacks them as well destroying the beta cells as well & diabetes is the result. Research is in progress & we hope to have an answer soon. Please contact your senators & congressmen & ask the to support more research funding for this research. Also contact the American Diabetes Association Advocacy Committee for help in doing this. And don't forget to keep your childs diabetes under control to prevent complications latter. Thanks for the ? it is good one & an area I Have researched for many years. Good luck & all the best.