Type 1 diabetes
Type 1 diabetes (T1D), also known as juvenile diabetes, is a form of diabetes in which very little or no insulin is produced by the pancreas.[4] Insulin is a hormone required for the body to use blood sugar.[2] Before treatment this results in high blood sugar levels in the body.[1] The classic symptoms are frequent urination, increased thirst, increased hunger, and weight loss.[4] Additional symptoms may include blurry vision, tiredness, and poor wound healing.[2] Symptoms typically develop over a short period of time.[1]
The cause of type 1 diabetes is unknown.[4] However, it is believed to involve a combination of genetic and environmental factors.[1] Risk factors include having a family member with the condition.[5] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas.[2] Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood.[5][7] Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.[5]
There is no known way to prevent type 1 diabetes.[4] Treatment with insulin is required for survival.[1] Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump.[9] A diabetic diet and exercise are important parts of management.[2] If left untreated, diabetes can cause many complications.[4] Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma.[5] Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.[4] Furthermore, complications may arise from low blood sugar caused by excessive dosing of insulin.[5]
Type 1 diabetes makes up an estimated 5–10% of all diabetes cases.[8] The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year.[5] Within the United States the number of people affected is estimated at one to three million.[5][10] Rates of disease vary widely with approximately 1 new case per 100,000 per year in East Asia and Latin America and around 30 new cases per 100,000 per year in Scandinavia and Kuwait.[11][12] It typically begins in children and young adults
The cause of type 1 diabetes is unknown.[4] However, it is believed to involve a combination of genetic and environmental factors.[1] Risk factors include having a family member with the condition.[5] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas.[2] Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood.[5][7] Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.[5]
There is no known way to prevent type 1 diabetes.[4] Treatment with insulin is required for survival.[1] Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump.[9] A diabetic diet and exercise are important parts of management.[2] If left untreated, diabetes can cause many complications.[4] Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma.[5] Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.[4] Furthermore, complications may arise from low blood sugar caused by excessive dosing of insulin.[5]
Type 1 diabetes makes up an estimated 5–10% of all diabetes cases.[8] The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year.[5] Within the United States the number of people affected is estimated at one to three million.[5][10] Rates of disease vary widely with approximately 1 new case per 100,000 per year in East Asia and Latin America and around 30 new cases per 100,000 per year in Scandinavia and Kuwait.[11][12] It typically begins in children and young adults
Signs and symptoms
The classical symptoms of type 1 diabetes include: polyuria (increased urination), polydipsia (increased thirst), dry mouth, polyphagia (increased hunger), fatigue, and weight loss.[4]
Type 1 diabetes is often diagnosed when diabetic ketoacidosis occurs. The signs and symptoms of diabetic ketoacidosis include dry skin, rapid deep breathing, drowsiness, increased thirst, frequent urination, abdominal pain, and vomiting.[14]
About 12 percent of people with type 1 diabetes have clinical depression.[15]
About 6 percent of people with type 1 diabetes also have celiac disease, but in most cases there are no digestive symptoms[6][16] or are mistakenly attributed to poor control of diabetes, gastroparesis or diabetic neuropathy.[16] In most cases, celiac disease is diagnosed after onset of type 1 diabetes. The association of celiac disease with type 1 diabetes increases the risk of complications, such as retinopathy and mortality. This association can be explained by shared genetic factors, and inflammation or nutritional deficiencies caused by untreated celiac disease, even if type 1 diabetes is diagnosed first.[6]
Some people with type 1 diabetes experience dramatic and recurrent swings in glucose levels, often occurring for no apparent reason; this is called "unstable diabetes", "labile diabetes" or "brittle diabetes".[17] The results of such swings can be irregular and unpredictable hyperglycemias, sometimes involving ketoacidosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics.
The classical symptoms of type 1 diabetes include: polyuria (increased urination), polydipsia (increased thirst), dry mouth, polyphagia (increased hunger), fatigue, and weight loss.[4]
Type 1 diabetes is often diagnosed when diabetic ketoacidosis occurs. The signs and symptoms of diabetic ketoacidosis include dry skin, rapid deep breathing, drowsiness, increased thirst, frequent urination, abdominal pain, and vomiting.[14]
About 12 percent of people with type 1 diabetes have clinical depression.[15]
About 6 percent of people with type 1 diabetes also have celiac disease, but in most cases there are no digestive symptoms[6][16] or are mistakenly attributed to poor control of diabetes, gastroparesis or diabetic neuropathy.[16] In most cases, celiac disease is diagnosed after onset of type 1 diabetes. The association of celiac disease with type 1 diabetes increases the risk of complications, such as retinopathy and mortality. This association can be explained by shared genetic factors, and inflammation or nutritional deficiencies caused by untreated celiac disease, even if type 1 diabetes is diagnosed first.[6]
Some people with type 1 diabetes experience dramatic and recurrent swings in glucose levels, often occurring for no apparent reason; this is called "unstable diabetes", "labile diabetes" or "brittle diabetes".[17] The results of such swings can be irregular and unpredictable hyperglycemias, sometimes involving ketoacidosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics.
Cause
The cause of type 1 diabetes is unknown.[4] A number of explanatory theories have been put forward, and the cause may be one or more of the following: genetic susceptibility, a diabetogenic trigger, and exposure to an antigen.[19]
Genetics
Main article: Genetic causes of type 1 diabetes
Type 1 diabetes is a disease that involves many genes. The risk of a child developing type 1 diabetes is about 5% if the father has it, about 8% if a sibling has it, and about 3% if the mother has it.[20] If one identical twin is affected there is about a 40% chance the other will be too.[21][22] Some studies of heritability have estimated it at 80 to 86%.[23][24]
More than 50 genes are associated with type 1 diabetes. Depending on locus or combination of loci, they can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II region on chromosome 6, at staining region 6p21. Certain variants of this gene increase the risk for decreased histocompatibility characteristic of type 1. Such variants include DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are common in North Americans of European ancestry and in Europeans.[25] Some variants also appear to be protective.[25]
Environmental
There is on the order of a 10-fold difference in occurrence among Caucasians living in different areas of Europe.[19] Environmental triggers and protective factors under research include dietary agents such as proteins in gluten,[26] time of weaning, gut microbiota,[27] viral infections,[28] and bacterial infections like paratuberculosis.[29]
Chemicals and drugs
Some chemicals and drugs selectively destroy pancreatic cells. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental poisoning.[30] Pyrinuron was withdrawn from the U.S. market in 1979 and it is not approved by the Environmental Protection Agency for use in the U.S.[31] Streptozotocin (Zanosar), an antineoplastic agent, is selectively toxic to the beta cells of the pancreatic islets. It is used in research for inducing type 1 diabetes on rodents[32] and for treating metastatic cancer of the pancreatic islet cells in patients whose cancer cannot be removed by surgery.[33] Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or benign) can also lead to loss of insulin production.
Monoclonal antibodies used for the treatment of cancer (checkpoint inhibitors inhibiting PD-1 and PD-L1), especially nivolumab and pembrolizumab have been reported to occasionally induce autoimmune diabetes.[34]
Pathophysiology
The pathophysiology in diabetes type 1 is a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present.
Individual risk factors can have separate pathophysiological processes to, in turn, cause this beta cell destruction. Still, a process that appears to be common to most risk factors is a type IV hypersensitivity autoimmune response towards beta cells, involving an expansion of autoreactive CD4+ T helper cells and CD8+ T cells, autoantibody-producing B cells and activation of the innate immune system.[25][35]
After starting treatment with insulin a person's own insulin levels may temporarily improve.[36] This is believed to be due to altered immunity and is known as the "honeymoon phase".[36]
Alpha cell dysfunction
Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon,[37] which acts in antagonism with insulin to regulate blood sugar and metabolism. While the causes and mechanisms are still being studied and hypotheses abound, what is clear and agreed upon is that progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon incipient hypoglycemia prevents a glucagon-mediated rescue of glucose levels.[38]
Hyperglucagonemia
Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%.[39] Insulin production will continue to fall as the immune system follows its course of progressive beta cell destruction, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early overt stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia.[38] Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia.[40] Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.[41][42] Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.[43]
Hypoglycemic glucagon impairment
Hypoglycemia in type 1 diabetics is often a result of over-administered insulin therapy, though being in a fasting state, exercising without proper adjustment of insulin, sleep, and alcohol can also contribute.[44] The normal counter regulatory responses to hypoglycemia are impaired in type 1 diabetics. Glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted when measured in type 1 diabetics and compared to healthy individuals experiencing an equal insulin-induced hypoglycemic trigger.[45][46] Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.
The cause of type 1 diabetes is unknown.[4] A number of explanatory theories have been put forward, and the cause may be one or more of the following: genetic susceptibility, a diabetogenic trigger, and exposure to an antigen.[19]
Genetics
Main article: Genetic causes of type 1 diabetes
Type 1 diabetes is a disease that involves many genes. The risk of a child developing type 1 diabetes is about 5% if the father has it, about 8% if a sibling has it, and about 3% if the mother has it.[20] If one identical twin is affected there is about a 40% chance the other will be too.[21][22] Some studies of heritability have estimated it at 80 to 86%.[23][24]
More than 50 genes are associated with type 1 diabetes. Depending on locus or combination of loci, they can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II region on chromosome 6, at staining region 6p21. Certain variants of this gene increase the risk for decreased histocompatibility characteristic of type 1. Such variants include DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are common in North Americans of European ancestry and in Europeans.[25] Some variants also appear to be protective.[25]
Environmental
There is on the order of a 10-fold difference in occurrence among Caucasians living in different areas of Europe.[19] Environmental triggers and protective factors under research include dietary agents such as proteins in gluten,[26] time of weaning, gut microbiota,[27] viral infections,[28] and bacterial infections like paratuberculosis.[29]
Chemicals and drugs
Some chemicals and drugs selectively destroy pancreatic cells. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental poisoning.[30] Pyrinuron was withdrawn from the U.S. market in 1979 and it is not approved by the Environmental Protection Agency for use in the U.S.[31] Streptozotocin (Zanosar), an antineoplastic agent, is selectively toxic to the beta cells of the pancreatic islets. It is used in research for inducing type 1 diabetes on rodents[32] and for treating metastatic cancer of the pancreatic islet cells in patients whose cancer cannot be removed by surgery.[33] Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or benign) can also lead to loss of insulin production.
Monoclonal antibodies used for the treatment of cancer (checkpoint inhibitors inhibiting PD-1 and PD-L1), especially nivolumab and pembrolizumab have been reported to occasionally induce autoimmune diabetes.[34]
Pathophysiology
The pathophysiology in diabetes type 1 is a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present.
Individual risk factors can have separate pathophysiological processes to, in turn, cause this beta cell destruction. Still, a process that appears to be common to most risk factors is a type IV hypersensitivity autoimmune response towards beta cells, involving an expansion of autoreactive CD4+ T helper cells and CD8+ T cells, autoantibody-producing B cells and activation of the innate immune system.[25][35]
After starting treatment with insulin a person's own insulin levels may temporarily improve.[36] This is believed to be due to altered immunity and is known as the "honeymoon phase".[36]
Alpha cell dysfunction
Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon,[37] which acts in antagonism with insulin to regulate blood sugar and metabolism. While the causes and mechanisms are still being studied and hypotheses abound, what is clear and agreed upon is that progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon incipient hypoglycemia prevents a glucagon-mediated rescue of glucose levels.[38]
Hyperglucagonemia
Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%.[39] Insulin production will continue to fall as the immune system follows its course of progressive beta cell destruction, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early overt stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia.[38] Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia.[40] Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.[41][42] Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.[43]
Hypoglycemic glucagon impairment
Hypoglycemia in type 1 diabetics is often a result of over-administered insulin therapy, though being in a fasting state, exercising without proper adjustment of insulin, sleep, and alcohol can also contribute.[44] The normal counter regulatory responses to hypoglycemia are impaired in type 1 diabetics. Glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted when measured in type 1 diabetics and compared to healthy individuals experiencing an equal insulin-induced hypoglycemic trigger.[45][46] Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.
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