Type 1 Diabetes Mellitus
This form of diabetes is immune-mediated in over 90% of cases and idiopathic in less than 10%. The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others. Type 1 diabetes is usually associated with ketosis in its untreated state. It occurs at any age but most commonly arises in children and young adults with a peak incidence before school age and again at around puberty. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all insulinogenic stimuli. Exogenous insulin is therefore required to reverse the catabolic state, prevent ketosis, reduce the hyperglucagonemia, and reduce blood glucose.
Immune-mediated type 1 diabetes mellitus
The highest incidence of immune-mediated type 1 diabetes mellitus is in Scandinavia and northern Europe, where the annual incidence is as high as 37 per 100,000 children aged 14 years or younger in Finland, 27 per 100,000 in Sweden, 22 per 100,000 in Norway, and 19 per 100,000 in the United Kingdom. The annual incidence of type 1 diabetes decreases across the rest of Europe to 10 per 100,000 in Greece and 8 per 100,000 in France. Surprisingly, the island of Sardinia has as high an annual incidence as Finland (37 per 100,000) even though in the rest of Italy, including the island of Sicily, it is only 10 per 100,000 per year. In the United States, the annual incidence of type 1 diabetes averages 15 per 100,000, with higher rates in states more densely populated with persons of Scandinavian descent such as Minnesota. Worldwide, the lowest incidence of type 1 diabetes (< 1 case per 100,000 per year) is in China and parts of South America. The global incidence of type 1 diabetes is increasing (approximately 3% each year).
Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors. Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–50% of white controls. HLA-DQ genes are even more specific markers of type 1 susceptibility, since a particular variety (HLA-DQB1*0302) is found in the DR4 patients with type 1, while a "protective" gene (HLA-DQB1*0602) is often present in the DR4 controls. The other important gene that contributes to about 10% of the genetic risk is found at the 5' polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. In linkage studies, 16 other genetic regions of the human genome have been identified as being important to pathogenesis but less is known about them.
Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GAD65), and tyrosine phosphatases (IA-2 and IA2-) at the time the diagnosis is made. These antibodies facilitate screening for an autoimmune cause of diabetes, particularly screening siblings of affected children, as well as adults with atypical features of type 2 diabetes (Table 27–3). Antibody levels decline with increasing duration of disease. Also, low levels of anti-insulin antibodies develop in almost all patients once they are treated with insulin.
Family members of diabetic probands are at increased lifetime risk for developing type 1 diabetes. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child's father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic proband. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.
Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Islet cell antibody surveys among northern Europeans indicate that up to 15% of "type 2" diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA). Evidence for environmental factors playing a role in the development of type 1 diabetes include the observation that the disease is more common in Scandinavian countries and becomes progressively less frequent in countries nearer and nearer to the equator. Also, the risk for type 1 diabetes increases when individuals who normally have a low risk emigrate to the Northern Hemisphere. For example, it was recently shown that Pakistani children born and raised in Bradford, England have a higher risk for developing type 1 diabetes compared with children who lived in Pakistan all their lives.
Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (rubella, Coxsackie B4) and consumption of cow's milk. Also, in developed countries, childhood infections have become less frequent and so perhaps the immune system becomes dysregulated with development of autoimmunity and conditions such as asthma and diabetes. This theory is referred to as the hygiene hypothesis. None of these factors has so far been confirmed as the culprit. Part of the difficulty is that autoimmune injury undoubtedly starts many years before clinical diabetes mellitus develops.
Idiopathic type 1 diabetes mellitus
Less than 10% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as "idiopathic type 1 diabetes" and designated as "type 1B." Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin. It was recently reported that about 4% of the West Africans with ketosis-prone diabetes are homozygous for a mutation in PAX-4 (Arg133Trp)—a gene that is essential for the development of pancreatic islets.
Immune-mediated type 1 diabetes mellitus
The highest incidence of immune-mediated type 1 diabetes mellitus is in Scandinavia and northern Europe, where the annual incidence is as high as 37 per 100,000 children aged 14 years or younger in Finland, 27 per 100,000 in Sweden, 22 per 100,000 in Norway, and 19 per 100,000 in the United Kingdom. The annual incidence of type 1 diabetes decreases across the rest of Europe to 10 per 100,000 in Greece and 8 per 100,000 in France. Surprisingly, the island of Sardinia has as high an annual incidence as Finland (37 per 100,000) even though in the rest of Italy, including the island of Sicily, it is only 10 per 100,000 per year. In the United States, the annual incidence of type 1 diabetes averages 15 per 100,000, with higher rates in states more densely populated with persons of Scandinavian descent such as Minnesota. Worldwide, the lowest incidence of type 1 diabetes (< 1 case per 100,000 per year) is in China and parts of South America. The global incidence of type 1 diabetes is increasing (approximately 3% each year).
Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors. Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–50% of white controls. HLA-DQ genes are even more specific markers of type 1 susceptibility, since a particular variety (HLA-DQB1*0302) is found in the DR4 patients with type 1, while a "protective" gene (HLA-DQB1*0602) is often present in the DR4 controls. The other important gene that contributes to about 10% of the genetic risk is found at the 5' polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. In linkage studies, 16 other genetic regions of the human genome have been identified as being important to pathogenesis but less is known about them.
Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GAD65), and tyrosine phosphatases (IA-2 and IA2-) at the time the diagnosis is made. These antibodies facilitate screening for an autoimmune cause of diabetes, particularly screening siblings of affected children, as well as adults with atypical features of type 2 diabetes (Table 27–3). Antibody levels decline with increasing duration of disease. Also, low levels of anti-insulin antibodies develop in almost all patients once they are treated with insulin.
Family members of diabetic probands are at increased lifetime risk for developing type 1 diabetes. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child's father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic proband. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.
Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Islet cell antibody surveys among northern Europeans indicate that up to 15% of "type 2" diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA). Evidence for environmental factors playing a role in the development of type 1 diabetes include the observation that the disease is more common in Scandinavian countries and becomes progressively less frequent in countries nearer and nearer to the equator. Also, the risk for type 1 diabetes increases when individuals who normally have a low risk emigrate to the Northern Hemisphere. For example, it was recently shown that Pakistani children born and raised in Bradford, England have a higher risk for developing type 1 diabetes compared with children who lived in Pakistan all their lives.
Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (rubella, Coxsackie B4) and consumption of cow's milk. Also, in developed countries, childhood infections have become less frequent and so perhaps the immune system becomes dysregulated with development of autoimmunity and conditions such as asthma and diabetes. This theory is referred to as the hygiene hypothesis. None of these factors has so far been confirmed as the culprit. Part of the difficulty is that autoimmune injury undoubtedly starts many years before clinical diabetes mellitus develops.
Idiopathic type 1 diabetes mellitus
Less than 10% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as "idiopathic type 1 diabetes" and designated as "type 1B." Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin. It was recently reported that about 4% of the West Africans with ketosis-prone diabetes are homozygous for a mutation in PAX-4 (Arg133Trp)—a gene that is essential for the development of pancreatic islets.
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