Etiology/Risk Factors

EPIDEMIOLOGY

Type 1 Diabetes Atlas (International Diabetes Federation, 2011).

• Around the world, the incidence of DM1 is highest in Sardinia, Finland, Sweden, Portugal, the U.K., Canada and New Zealand at over 20 cases/100,000/year. The lowest incidence was in China and South America at less than 1/100,000/year (Karvonen, Kajander, Moltchanova, Libman, LaPorte et al., 2000).
• Approximately 7-9% of the U.S. and 5-10% of the Canadian population has DM1. This translates to approximately 25.8 million Americans and 300,000 Canadians.
• Canada has the sixth highest incidence rate of DM1 in children, 14 years and younger, in the world (Jeuvenile Diabetes Research Foundation, Canada).
• DM1 is one of the most common childhood diseases in children while at the same time approximately 50% of incidence of DM1 occurs in adults.

Increased Incidence:

• In a 10 year epidemiology project completed in 2009 in Europe, called EURODIAB, similar results were found across 17 countries and approximately 17.1 million children with an overall 3.2% annual incidence rate occurring in children but a 4.8% increase for 0 - 4 years olds specifically. They predict in 2020, that this age of children acquiring the disease will nearly double (McKenna, 2012).
• The incidence rate of type 1 diabetes is rising by 3 to 5 % in Canada and 3% annually worldwide. The greatest rise occurs in five to nine year olds (JDRF). This was determined by examining incidence over 10 years in 57 different countries by WHO in 2006.
• The incidence is growing amongst children,teens and adults (Huether et al., 2012, p. 459). The incidence has increased over the past 40 years significantly in parts of Scandinavian and European countries and has tripled in the U.S. (Simon, 2009).

Age of Onset:

• Age of onset of DM1 occurs in 2 age groups in children: between the age of 4-6 and 10-14 years.
• African and Asian populations have lower risk of acquiring DM1 and the age of onset is higher in these 2 populations

Range of Incidence:

• Scandinavia and Sardinia (Mediterranean island off east coast of Italy), have the highest incidence in the world.
• A child in Finland has a 400 times greater chance of acquiring DM1 than a child in parts of Asia.
• Asia and other equatorial countries have the lowest rates in the world.
• There is a strong North-South gradient that maps incidence of DM1

Ethnic rates:

• In the U.S. a study in California showed that non-Hispanic whites had an incidence of 32.9 % (which is comparable to Scandinavian populations), Hispanics 17.6 %, African Americans 19.2 % and Asians 8.3 %.
• In Montreal Canada, people of British origin had a 50% greater incidence of DM1 than those of French origin.

Gender:

• There is generally no difference in incidence of DM1 with either sex. Females do tend to acquire it 1-2 years earlier than males

ETIOLOGY: GENETIC & ENVIRONMENTAL:

The beta cells of the pancreas produce insulin. In diabetes type 1 (DM1), the beta cells are gradually progressively destroyed. When there is complete destruction of the beta cells, no insulin is produced. The causes of diabetes 1 are considered to have both genetic and environmental factors. There are two types of DM1. Diabetes type 1A refers to diabetes as a result of the beta cells being attacked and destroyed by an auto-immune reaction. The other much less common type of type 1 diabetes is referred to as non-immune. The non-immune type of diabetes is found either secondary to another disease such as pancreatitis or, occurs following an unknown event where it is called idiopathic or type IB diabetes. Diabetes type 1B is most common in those of Asian and African descent (Huether et al., 2012, p.461).

1) GENETIC FACTORS:

• The genetic component alone is low at approximately 10%. This means that a sibling or another family member who are a 1^st degree relative has a 10% chance of also acquiring DM1. A twin has a 33% chance of acquiring DM1 if their identical twin has acquired the disease (University of Maryland Medical Centre). Although identical twins have a 3 fold chance of acquiring DM1 if their sibling has it, the likelihood still remains low and dependant on other factors despite having the same genome.
• They have also found that children are more likely to inherit T1D from a father than a mother.
• There have been 18 different genetic links identified for type 1 diabetes, called or labelled IDDM 1-IDDM 18. The region of the IDDM1 contains the area of genes that affect the immune response of a person and is encoded for HLA (histocompatibility leukocyte antigen).
• Research has identified that HLA class II alleles have the strongest immune association with diabetes type IA auto-immune reaction. The 2 alleles are HLA-DQ and HLA-DR.
• The other genes and chromosomes continue to be identified in genetic research.

1) ENVIRONMENTAL FACTORS:

In the January 2012 edition of Scientific America magazine, in an article by Maryn McKenna, titled "Diabetes Type 1: Why are cases surging?", McKenna states that if the incidence of DM1 is rising, then the cause(s) must also be rising. In the article, a physician responsible for a epidemiology research team at the CDC, Giueseppina Imperatore, states that the 3-5% per year increase is too fast to be due to genetic alterations alone and therefore the disease must also be due to environmental factors, many of which are mentioned below. Environmental factors need to be present to influence the expression of DM1. With the genetic component of the disease at the low rate of 10% for non-identical twins, the search for causal factors appear to fall in the area of environmental factors or triggers. There are other epidemiological factors that point to environmental factors. These other factors include (1) the fact that the incidence rates for caucasions varies widely across different countries within Europe and around the world and (2) the fact that immigrants who had low rates of DM1 in their home country tend to take on the incidence of DM1 in their new country of residence (Wild et al., 2004). The theories of various environmental factors that influence gene expression and the acquisition of DM1 tend to fall into the areas of toxins (medications and chemicals), diet, foods and vitamins and micro-organisms (bacteria, virus and other microbes).

TOXINS / CHEMICALS: One known industrial chemical that selectively destroys beta cells in the pancreas, resulting in DM1 is Pyrinuron (Vacor, N-3-pyridylkmethyl-N'-p-nitrophenyl urea), a urea rodenticide (rodent or rat killer). In Agro-pages.com, this toxin is shown to be available only in China out of 6 continents listed. A Journal of Forestry Research from 2010 indicates the killing rates of forest rodents by Chinese authors (Li et al., 2000). This drug was introduced in the U.S. in 1976 and withdrawn in 1979. Pentamidine is an antiprotozoal drug used to treat infection associated with the AIDS virus (Pneumocystis carinii pneumonia (PCP)), but it also causes destruction of beta cells in the pancreas (ADA).  Zanosar, (trade name for streptozotocin), is an antibiotic and antineoplastic drug that is used as chemotherapy for pancreatic cancer and therefore targets and kills pancreatic beta cells specifically. Beta cells are triggered to release another hormone, amylin, in pancreatic cancer but of course the drug is not selective to one particular hormone in the beta cell and the entire cell is targeted. The pharmaceutical drug classes of glucocorticosteroids (impair insulin action), beta blockers and phenytoin are all able to cause "temporary diabetes" (University of Maryland) and the ADA stated that beta blockers can cause DM1 as a side effect to treating another condition(ADA). Dilantins, thiazides, beta-adrenergic agonists, thyroid hormone, nicotinic acid, gamma interferon, diazoxides are listed on the American Diabetics Association of etiology of DM1. These medications are all listed as possible agents but not solely responsible for DM1.

VIRUS: Research indicates that there may be a viral trigger to the auto-immune response of DM1 in genetically prone individuals. Some of the associations and research came about following significant increases in DM1 following epidemics or mass immunization programs in certain countries. The coxsackie virus is a family of enteric viruses (an important and diverse group of viruses found in the intestinal tract of humans and animals). There is some current ongoing research that is investigating how these viruses attack the intestinal lining and what the association might be (University of Maryland). These are the most studied viruses for an association with DM1. The mumps virus and congenital rubella virus(Huether et al., 2012, p.461) are also implicated (MMR vaccine). In 1982 in Finland, the MMR vaccine was added to the schedule for children. Following this the HiB vaccine (haemophilus influenza type B), was administered to 114,00 children. The introduction of these new vaccines were followed by a 62 % increase in DM1 in the 0-4 year olds and 19% increase in DM1 in the 5-9 year olds at years 1980-1982 and 1987-1989 (Coulter, 2007). The cytomegalovirus (S. Huether, p. 459) (a viral genus of the herpesvirus), Epstein-Barr virus and varicella-zoster virus are also considered to have a link with DM1 (Hjelmesaeth, Muller, Jenssen, Rollag, Sagedal et al., 2005). Hepatitis B vaccinations also have a connection. In New Zealand, a hep B vaccination program was initiated in 1988 which led to a 60% increase in DM1 in children under 20 years. Prior to the program, the incidence in this age group was 18.2/100,000/year cases (from 1982-1991). According to Dr. J Barthelow Classen M.D., the vaccines may trigger DM1 auto-immunity through the release of interferons (which have been found to trigger DM1 and other auto-immune diseases). Another theory behind these associations are that viral proteins are very similar in structure to the proteins in beta-cells. Once the virus is in the system, T cells and antibodies are triggered and end up attacking both the virus and the beta cells (ADAM, 2010).

FOODS: There are many interesting associations with certain foods, or food ingredients and vitamins. Some associations are stronger than others as well as the research focus and money invested in each area. In cow's milk, there are 2 proteins, one of which is called A1 beta-casein protein. If a child is given cow's milk in the first 3 months of life, antibodies that are produced against the A1 beta protein also attack the beta cells in the pancreas through an auto-immune reaction (Buckley, 2011).  Another food item, soy formulas for babies, has been implicated in triggering DM1 in children. A research team of the Cornell University Medical College and the Long Island Community Hosptial medical experts found that children who developed DM1 were twice as likely to have been fed soy formula over other food (McCarthy, 2007), (American Journal of clinical nutrition, May 2010).
Alloxan, a derivative of uric acid and a glucose analogue is a component that is used to cause bleaching in white bread. It is well known within the research community that Alloxan triggers DM1 through beta cell destruction. Alloxan is used widely in lab animals to create the diabetic condition for research purposes, which is called "Alloxin diabetes". The theory behind this mechanism is that Alloxan, paraquat and other chemicals put a high free radical burden on the pancreatic beta cells and create ROS (reactive oxygen species). They seem to be taken up preferentially by the beta cells by GLUT2 glucose transporters, where the damage occurs. Although there is mixed research on this substance, Europe has banned this chemical from use in bread and allows the wheat flour to change colour naturally (EU banned substances),(Schwarcz, 2003).

VITAMIN D / EQUATOR RELATIONSHIP: On a more controllable and positive note, there is research to suggest that the closer populations live to the equator, the less DM1 there is and vice versa. Possibly in relation to this are the studies linking vitamin D levels and DM1 prevention or reduction in incidence. One study in Northern Finland demonstrated that the risk to acquiring DM1 later in life was decreased by 80% with a group of infants who were given 2000mg vitamin D per day in the 1st year of life. The results of a systematic review and meta-analysis "showed promise" for a positive association between vitamin D and DM1 occurrence (Zipitis et al.,2008). Animal studies have demonstrated this connection. Also, it has been shown that vitamin D deficiency can lead to beta cell destruction (Bailey et al. 2007). The National reported on a Manitoban M.D. who was interested in pursuing this line of research:

The human genome project describes the connection between vitamin D deficiency, our genes and DM1. Over 200 genes are affected by vitamin D. With a vitamin D deficiency, people are left vulnerable to many diseases including DM1. :

http://www.folderol.org/tag/diabetes-mellitus-type-1

Additional factors that can influence the pancreas and beta cell function include physical trauma and conditions that damage or destroy the pancreas, such as; pancreatitis, pancreatic cancer, cystic fibrosis (which affects the islet cells of the pancreas) and pancreatic surgery. These factors are primarily the cause of DM1B.