Type 1 diabetes

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Type_1_diabetes 

 

Type 1 diabetes
Other names	Diabetes mellitus type 1, insulin-dependent diabetes, juvenile diabetes
A blue circle, the symbol for diabetes.
Pronunciation	/daɪəbiːtəs/
Specialty	Endocrinology
Symptoms	Frequent urination, increased thirst, increased hunger, weight loss
Complications	Diabetic ketoacidosis, nonketotic hyperosmolar coma, poor healing, cardiovascular disease, damage to the eyes
Usual onset	Relatively short period of time
Duration	Long term
Causes	Body does not produce enough insulin
Risk factors	Family history, celiac disease
Diagnostic method	Blood sugar, A1C
Prevention	Unknown
Treatment	Insulin, diabetic diet, exercise
Frequency	~7.5% of diabetes cases

Type 1 diabetes (T1D), previously known as juvenile diabetes, is an autoimmune disease that is a form of diabetes in which very little or no insulin is produced by the islets of Langerhans (containing beta cells) in the pancreas. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate normal glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms are frequent urination, increased thirst, increased hunger, and weight loss. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks.

The cause of type 1 diabetes is unknown, but it is believed to involve a combination of genetic and environmental factors. Risk factors include having a family member with the condition. The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood.Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.

There is no known way to prevent type 1 diabetes. Treatment with insulin is required for survival. Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump. A diabetic diet and exercise are important parts of management. If left untreated, diabetes can cause many complications. Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma. Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes. Furthermore, since insulin lowers blood sugar levels, complications may arise from low blood sugar if excessive amount of insulin is taken than necessary.

Type 1 diabetes makes up an estimated 5–10% of all diabetes cases. The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year. Within the United States the number of people affected is estimated at one to three million. Rates of disease vary widely, with approximately one 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. It typically begins in children and young adults.

Signs and symptoms

Overview of the most significant symptoms of diabetes

 

A posterior subcapsular cataract is a rare symptom in those with type 1 DM

The classic symptoms of type 1 diabetes include: polyuria (increased urination), polydipsia (increased thirst), dry mouth, polyphagia (increased hunger), fatigue, and weight loss.

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.

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". 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.

Type 1 diabetes is associated with alopecia areata (AA). Type 1 diabetes is also more common in the family members of people with AA.

Cause

The cause of type 1 diabetes is not yet known. 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.

Genetics

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. If one identical twin is affected there is about a 40% to 50% chance the other will be too. Some studies of heritability have estimated it at 80 to 86%.

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. Some variants also appear to be protective.

Environmental

There is on the order of a 10-fold difference in occurrence among Caucasians living in different areas of Europe. Environmental triggers and protective factors under research include dietary agents such as proteins in gluten, time of weaning, gut microbiota, viral infections, and bacterial infections like paratuberculosis.

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. 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. 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 and for treating metastatic cancer of the pancreatic islet cells in patients whose cancer cannot be removed by surgery. 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.

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.

After starting treatment with insulin a person's own insulin levels may temporarily improve. This is believed to be due to altered immunity and is known as the "honeymoon phase".

Alpha cell dysfunction

Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon, 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.

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%. 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. Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia. 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. Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.

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. 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. Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.

Autonomic inputs to alpha cells are much more important for glucagon stimulation in the moderate to severe ranges of hypoglycemia, yet the autonomic response is blunted in a number of ways. Recurrent hypoglycemia leads to metabolic adjustments in the glucose sensing areas of the brain, shifting the threshold for counter regulatory activation of the sympathetic nervous system to lower glucose concentration. This is known as hypoglycemic unawareness. Subsequent hypoglycemia is met with impairment in sending of counter regulatory signals to the islets and adrenal cortex. This accounts for the lack of glucagon stimulation and epinephrine release that would normally stimulate and enhance glucose release and production from the liver, rescuing the diabetic from severe hypoglycemia, coma, and death. Numerous hypotheses have been produced in the search for a cellular mechanism of hypoglycemic unawareness, and a consensus has yet to be reached. The major hypotheses are summarized in the following table: 

Mechanisms of hypoglycemic unawareness
Glycogen supercompensation	Increased glycogen stores in astrocytes might contribute supplementary glycosyl units for metabolism, counteracting the central nervous system perception of hypoglycemia.
Enhanced glucose metabolism	Altered glucose transport and enhanced metabolic efficiency upon recurring hypoglycemia relieves oxidative stress that would activate sympathetic response.
Alternative fuel hypothesis	Decreased reliance on glucose, supplementation of lactate from astrocytes, or ketones meet metabolic demands and reduce stress to brain.
Brain neuronal communication	Hypothalamic inhibitory GABA normally decreases during hypoglycemia, disinhibiting signals for sympathetic tone. Recurrent episodes of hypoglycemia result in increased basal GABA which fails to decrease normally during subsequent hypoglycemia. Inhibitory tone remains and sympathetic tone is not increased.

In addition, autoimmune diabetes is characterized by a loss of islet specific sympathetic innervation. This loss constitutes an 80-90% reduction of islet sympathetic nerve endings, happens early in the progression of the disease, and is persistent though the life of the patient. It is linked to the autoimmune aspect of type 1 diabetics and fails to occur in type 2 diabetics. Early in the autoimmune event, the axon pruning is activated in islet sympathetic nerves. Increased BDNF and ROS that result from insulitis and beta cell death stimulate the p75 neurotrophin receptor (p75^NTR), which acts to prune off axons. Axons are normally protected from pruning by activation of tropomyosin receptor kinase A (Trk A) receptors by NGF, which in islets is primarily produced by beta cells. Progressive autoimmune beta cell destruction, therefore, causes both the activation of pruning factors and the loss of protective factors to the islet sympathetic nerves. This unique form of neuropathy is a hallmark of type 1 diabetes, and plays a part in the loss of glucagon rescue of severe hypoglycemia.

Diagnosis

WHO diabetes diagnostic criteria

Condition	2-hour glucose		Fasting glucose		HbA1c
Unit	mmol/L	mg/dL	mmol/L	mg/dL	mmol/mol	DCCT %
Normal	< 7.8	< 140	< 6.1	< 110	< 42	< 6.0
Impaired fasting glycaemia	< 7.8	< 140	6.1–7.0	110–125	42–46	6.0–6.4
Impaired glucose tolerance	≥ 7.8	≥ 140	< 7.0	< 126	42–46	6.0–6.4
Diabetes mellitus	≥ 11.1	≥ 200	≥ 7.0	≥ 126	≥ 48	≥ 6.5

Diabetes is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:

• Fasting plasma glucose level at or above 7.0 mmol/L (126 mg/dL).
• Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test.
• Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol/L (200 mg/dL).
• Glycated hemoglobin (hemoglobin A1C) at or above 48 mmol/mol (≥ 6.5 DCCT %). (This criterion was recommended by the American Diabetes Association in 2010, although it has yet to be adopted by the WHO.)

About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids) by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening, detection of hyperglycemia during other medical investigations, and secondary symptoms such as vision changes or unexplained fatigue. Diabetes is often detected when a person suffers a problem that may be caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia (low blood sugar).

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes.

In type 1, pancreatic beta cells in the islets of Langerhans are destroyed, decreasing endogenous insulin production. This distinguishes type 1's origin from type 2. Type 2 diabetes is characterized by insulin resistance, while type 1 diabetes is characterized by insulin deficiency, generally without insulin resistance. Another hallmark of type 1 diabetes is islet autoreactivity, which is generally measured by the presence of autoantibodies directed towards the beta cells.

Autoantibodies

The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any hyperglycemia arises, the main ones being islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65-kDa isoform of glutamic acid decarboxylase (GAD), autoantibodies targeting the phosphatase-related IA-2 molecule, and zinc transporter autoantibodies (ZnT8). By definition, the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs, but the emergence of autoantibodies may itself be termed "latent autoimmune diabetes". Not everyone with autoantibodies progresses to diabetes type 1, but the risk increases with the number of antibody types, with three to four antibody types giving a risk of progressing to diabetes type 1 of 60–100%. The time interval from emergence of autoantibodies to clinically diagnosable diabetes can be a few months in infants and young children, but in some people, it may take years – in some cases more than 10 years. Islet cell autoantibodies are detected by conventional immunofluorescence, while the rest are measured with specific radiobinding assays.

Prevention

Type 1 diabetes is not currently preventable. Some researchers believe it might be prevented at the latent autoimmune stage, before it starts destroying beta cells.

Immunosuppressive drugs

Cyclosporine A, an immunosuppressive agent, has apparently halted destruction of beta cells (on the basis of reduced insulin usage), but its kidney toxicity and other side effects make it highly inappropriate for long-term use.

Anti-CD3 antibodies, including teplizumab and otelixizumab, had suggested evidence of preserving insulin production (as evidenced by sustained C-peptide production) in newly diagnosed type 1 diabetes patients. A probable mechanism of this effect was believed to be preservation of regulatory T cells that suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. The duration of the effect is still unknown, however. In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy, potentially due to an insufficient dosing schedule.

An anti-CD20 antibody, rituximab, inhibits B cells and has been shown to provoke C-peptide responses three months after diagnosis of type 1 diabetes, but long-term effects of this have not been reported.

Diet

Some research has suggested breastfeeding decreases the risk in later life and early introduction of gluten-containing cereals in the diet increases the risk of developing islet cell autoantibodies; various other nutritional risk factors are being studied, but no firm evidence has been found. Giving children 2000 IU of vitamin D daily during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.

Children with antibodies to beta cell proteins (i.e. at early stages of an immune reaction to them) but no overt diabetes, and treated with niacinamide (vitamin B₃), had less than half the diabetes onset incidence in a seven-year time span than did the general population, and an even lower incidence relative to those with antibodies as above, but who received no niacinamide.

People with type 1 diabetes and undiagnosed celiac disease have worse glycaemic control and a higher prevalence of nephropathy and retinopathy. Gluten-free diet, when performed strictly, improves diabetes symptoms and appears to have a protective effect against developing long-term complications. Nevertheless, dietary management of both these diseases is challenging and these patients have poor compliance of the diet.

Management

Diabetes is often managed by a number of health care providers including a dietitian, nurse educator, eye doctor, endocrinologist, and podiatrist.

Lifestyle

There is limited evidence for the usefulness of routine use of low-carbohydrate dieting for people with type 1 diabetes. Although for certain individuals it may be feasible to follow a low-carbohydrate regime combined with carefully managed insulin dosing, this is hard to maintain and there are concerns about possible adverse health effects caused by the diet. In general, people with type 1 diabetes are advised to follow an individualized eating plan rather than a pre-decided one.

There are camps for children to teach them how and when to use or monitor their insulin without parental help. As psychological stress may have a negative effect on diabetes, a number of measures have been recommended including: exercising, taking up a new hobby, or joining a charity, among others.

Insulin

Injections of insulin – via subcutaneous injection using either a syringe or using an insulin pump – are necessary for those living with type 1 diabetes because it cannot be treated by diet and exercise alone. Insulin dosage is adjusted taking into account food intake, blood glucose levels and physical activity.

Untreated type 1 diabetes can commonly lead to diabetic ketoacidosis which can result in death. Diabetic ketoacidosis can cause cerebral edema (accumulation of liquid in the brain). This is a life-threatening issue and children are at a higher risk for cerebral edema than adults, causing ketoacidosis to be the most common cause of death in pediatric diabetes.

Treatment of diabetes focuses on lowering blood sugar or glucose (BG) to the near normal range, approximately 80–140 mg/dL (4.4–7.8 mmol/L). The ultimate goal of normalizing BG is to avoid long-term complications that affect the nervous system (e.g. peripheral neuropathy leading to pain and/or loss of feeling in the extremities), and the cardiovascular system (e.g. heart attacks, vision loss). This level of control over a prolonged period of time can be varied by a target HbA_1c level of less than 7.5%.

There are four main types of insulin: rapid acting insulin, short-acting insulin, intermediate-acting insulin, and long-acting insulin. The rapid acting insulin is used as a bolus dosage. The action onsets in 15 minutes with peak actions in 30 to 90 minutes. Short acting insulin action onsets within 30 minutes with the peak action around 2 to 4 hours. Intermediate acting insulin action onsets within one to two hours with peak action of four to 10 hours. Long-acting insulin is usually given at the same time once per day. The action onset is roughly 1 to 2 hours with a sustained action of up to 24 hours. Some insulins are biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from fish.

People with type 1 diabetes always need to use insulin, but treatment can lead to low BG (hypoglycemia), i.e. BG less than 70 mg/dL (3.9 mmol/L). Hypoglycemia is a very common occurrence in people with diabetes, usually the result of a mismatch in the balance among insulin, food and physical activity. Symptoms include excess sweating, excessive hunger, fainting, fatigue, lightheadedness and shakiness. Mild cases are self-treated by eating or drinking something high in sugar. Severe cases can lead to unconsciousness and are treated with intravenous glucose or injections with glucagon. Continuous glucose monitors can alert patients to the presence of dangerously high or low blood sugar levels, but continuous glucose monitors still have a margin of error.

As of 2016 an artificial pancreas continues to look promising with safety issues still being studied. In 2018 they were deemed to be relatively safe.

Pancreas transplantation

In some cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required may be more dangerous than continued insulin replacement therapy, so is generally only used with or some time after a kidney transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine, which allows the introduction of a new pancreas to a person with diabetes without any additional immunosuppressive therapy. However, pancreas transplants alone may be beneficial in people with extremely labile type 1 diabetes.

Islet cell transplantation

Islet cell transplantation may be an option for some people with type 1 diabetes that is not well controlled with insulin. Difficulties include finding donors that are compatible, getting the new islets to survive, and the side effects from the medications used to prevent rejection. Success rates, defined as not needing insulin at 3 years following the procedure, occurred in 44% of people on registry from 2010. In the United States, as of 2016, it is considered an experimental treatment.

Complications

Complications of poorly managed type 1 diabetes may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease as well as neuropathy may have an autoimmune basis, as well. Women with type 1 DM have a 40% higher risk of death as compared to men with type 1 DM. The life expectancy of an individual with type 1 diabetes is 11 years less for men and 13 years less for women. People with type 1 diabetes are higher risk for other autoimmune diseases, such as autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and lupus.

About 12 percent of people with type 1 diabetes have clinical depression. About 6 percent of people with type 1 diabetes also have celiac disease, but in most cases there are no digestive symptoms or are mistakenly attributed to poor control of diabetes, gastroparesis or diabetic neuropathy. 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.

Urinary tract infection

People with diabetes show an increased rate of urinary tract infection. The reason is bladder dysfunction is more common in people with diabetes than people without diabetes due to diabetes nephropathy. When present, nephropathy can cause a decrease in bladder sensation, which in turn, can cause increased residual urine, a risk factor for urinary tract infections.

Sexual dysfunction

Sexual dysfunction in people with diabetes is often a result of physical factors such as nerve damage and poor circulation, and psychological factors such as stress and/or depression caused by the demands of the disease.

Males

The most common sexual issues in males with diabetes are problems with erections and ejaculation: "With diabetes, blood vessels supplying the penis’s erectile tissue can get hard and narrow, preventing the adequate blood supply needed for a firm erection. The nerve damage caused by poor blood glucose control can also cause ejaculate to go into the bladder instead of through the penis during ejaculation, called retrograde ejaculation. When this happens, semen leaves the body in the urine." Another cause of erectile dysfunction is reactive oxygen species created as a result of the disease. Antioxidants can be used to help combat this.

Females

Sexual problems are common in women who have diabetes, including reduced sensation in the genitals, dryness, difficulty/inability to orgasm, pain during sex, and decreased libido. Diabetes sometimes decreases estrogen levels in females, which can affect vaginal lubrication. Less is known about the correlation between diabetes and sexual dysfunction in females than in males.

Oral contraceptive pills can cause blood sugar imbalances in women who have diabetes. Dosage changes can help address that, at the risk of side effects and complications.

Women with type 1 diabetes show a higher than normal rate of polycystic ovarian syndrome (PCOS). The reason may be that the ovaries are exposed to high insulin concentrations since women with type 1 diabetes can have frequent hyperglycemia.

Epidemiology

Type 1 diabetes makes up an estimated 5–10% of all diabetes cases or 11–22 million worldwide. In 2006 it affected 440,000 children under 14 years of age and was the primary cause of diabetes in those less than 10 years of age. The incidence of type 1 diabetes has been increasing by about 3% per year.

Rates vary widely by country. In Finland, the incidence is a high of 57 per 100,000 per year, in Japan and China a low of 1 to 3 per 100,000 per year, and in Northern Europe and the U.S., an intermediate of 8 to 17 per 100,000 per year.

In the United States, type 1 and 2 diabetes affected about 208,000 youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type 1 diabetes every year. Every year about 234,051 Americans die due to diabetes (type I or II) or diabetes-related complications, with 69,071 having it as the primary cause of death.

In Australia, about one million people have been diagnosed with diabetes and of this figure 130,000 people have been diagnosed with type 1 diabetes. Australia ranks 6th-highest in the world with children under 14 years of age. Between 2000 and 2013, 31,895 new cases were established, with 2,323 in 2013, a rate of 10–13 cases per 100,00 people each year. Aboriginals and Torres Strait Islander people are less affected.

History

Type 1 diabetes was described as an autoimmune disease in the 1970s, based on observations that autoantibodies against islets were discovered in diabetics with other autoimmune deficiencies. It was also shown in the 1980s that immunosuppressive therapies could slow disease progression, further supporting the idea that type 1 diabetes is an autoimmune disorder. The name juvenile diabetes was used earlier as it often first is diagnosed in childhood.

Society and culture

Type 1 and 2 diabetes was estimated to cause $10.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4.4 billion in indirect costs ($366 per month per person with diabetes) in the U.S. In the United States $245 billion every year is attributed to diabetes. Individuals diagnosed with diabetes have 2.3 times the health care costs as individuals who do not have diabetes. One in ten health care dollars are spent on individuals with type 1 and 2 diabetes.

Research

Funding for research into type 1 diabetes originates from government, industry (e.g., pharmaceutical companies), and charitable organizations. Government funding in the United States is distributed via the National Institutes of Health, and in the UK via the National Institute for Health Research or the Medical Research Council. The Juvenile Diabetes Research Foundation (JDRF), founded by parents of children with type 1 diabetes, is the world's largest provider of charity-based funding for type 1 diabetes research. Other charities include the American Diabetes Association, Diabetes UK, Diabetes Research and Wellness Foundation, Diabetes Australia, the Canadian Diabetes Association.

A number of approaches have been explored to understand causes and provide treatments for type 1.

Diet

Data suggest that gliadin (a protein present in gluten) might play a role in the development of type 1 diabetes, but the mechanism is not fully understood. Increased intestinal permeability caused by gluten and the subsequent loss of intestinal barrier function, which allows the passage of pro-inflammatory substances into the blood, may induce the autoimmune response in genetically predisposed individuals to type 1 diabetes. There is evidence from experiments conducted in animal models that removal of gluten from the diet may prevent the onset of type 1 diabetes but there has been conflicting research in humans.

Virus

One theory proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas. Several viruses have been implicated, including enteroviruses (especially coxsackievirus B), cytomegalovirus, Epstein–Barr virus, mumps virus, rubella virus and rotavirus, but to date there is no stringent evidence to support this hypothesis in humans. A 2011 systematic review and meta-analysis showed an association between enterovirus infections and type 1 diabetes, but other studies have shown that, rather than triggering an autoimmune process, enterovirus infections, as coxsackievirus B, could protect against onset and development of type 1 diabetes. Some studies have found a decreased risk with oral rotavirus vaccine while others found no effect.

Gene therapy

Gene therapy has also been proposed as a possible cure for type 1 diabetes.

Stem cells

Pluripotent stem cells can be used to generate beta cells but previously these cells did not function as well as normal beta cells. In 2014 more mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice. Before these techniques can be used in humans more evidence of safety and effectiveness is needed.

Vaccine

Vaccines are being looked at to treat or prevent type 1 diabetes by inducing immune tolerance to insulin or pancreatic beta cells. While Phase II clinical trials of a vaccine containing alum and recombinant GAD65, an autoantigen involved in type 1 diabetes, were promising, as of 2014 Phase III had failed. As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical development. The rotavirus vaccine and BCG vaccine are associated with a lower risk of type 1 diabetes. Research continues to look at the BCG vaccine in type 1 diabetes as of 2019.

Nitric oxide

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Nitric_oxide

 

Nitric oxide

Names
IUPAC name Nitric oxide
Systematic IUPAC name Oxidonitrogen(•) (additive)
Other names Nitrogen oxide Nitrogen monoxide Nitrogen(II) oxide
Identifiers
CAS Number	10102-43-9
3D model (JSmol)	Interactive image
3DMet	B00122
ChEBI	CHEBI:16480
ChEMBL	ChEMBL1200689
ChemSpider	127983
DrugBank	DB00435
ECHA InfoCard	100.030.233
EC Number	233-271-0
Gmelin Reference	451
IUPHAR/BPS	2509
KEGG	D00074
PubChem CID	145068
RTECS number	QX0525000
UNII	31C4KY9ESH
UN number	1660
CompTox Dashboard (EPA)	DTXSID1020938

Properties
Chemical formula	NO
Molar mass	30.006 g·mol−1
Appearance	Colourless gas
Density	1.3402 g/L
Melting point	−164 °C (−263 °F; 109 K)
Boiling point	−152 °C (−242 °F; 121 K)
Solubility in water	0.0098 g / 100 ml (0 °C) 0.0056 g / 100 ml (20 °C)
Refractive index (nD)	1.0002697
Structure
Molecular shape	linear (point group C∞v)
Thermochemistry
Std molar entropy (So298)	210.76 J/(K·mol)
Std enthalpy of formation (ΔfH⦵298)	91.29 kJ/mol
Pharmacology
ATC code	R07AX01 (WHO)
License data	EU EMA: by INN
Routes of administration	Inhalation
Pharmacokinetics:
Bioavailability	good
Metabolism	via pulmonary capillary bed
Biological half-life	2–6 seconds
Hazards
Main hazards	Fatal if inhaled Causes severe burns Causes eye damage Corrosive to the respiratory tract
Safety data sheet	External SDS
GHS pictograms
GHS Signal word	Danger
GHS hazard statements	H270, H280, H330, H314
GHS precautionary statements	P244, P260, P220, P280, P304+340+315, P303+361+353+315, P305+351+338+315, P370+376, P403, P405
NFPA 704 (fire diamond)	3 0 3 OX
Lethal dose or concentration (LD, LC):
LC50 (median concentration)	315 ppm (rabbit, 15 min) 854 ppm (rat, 4 h) 2500 ppm (mouse, 12 min)
LCLo (lowest published)	320 ppm (mouse)
Related compounds
Related nitrogen oxides	Dinitrogen pentoxide Dinitrogen tetroxide Dinitrogen trioxide Nitrogen dioxide Nitrous oxide Nitroxyl (reduced form) Hydroxylamine (hydrogenated form)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. Nitric oxide is a free radical, i.e., it has an unpaired electron, which is sometimes denoted by a dot in its chemical formula (·N=O or ·NO). Nitric oxide is also a heteronuclear diatomic molecule, a historic class that drew researches which spawned early modern theories of chemical bonding.

An important intermediate in industrial chemistry, nitric oxide forms in combustion systems and can be generated by lightning in thunderstorms. In mammals, including humans, nitric oxide is a signaling molecule in many physiological and pathological processes. It was proclaimed the "Molecule of the Year" in 1992. The 1998 Nobel Prize in Physiology or Medicine was awarded for discovering nitric oxide's role as a cardiovascular signalling molecule.

Nitric oxide should not be confused with nitrogen dioxide (NO₂), a brown gas and major air pollutant, nor with nitrous oxide (N₂O), an anesthetic.

Reactions

With di- and triatomic molecules

Upon condensing to a liquid, nitric oxide dimerizes to dinitrogen dioxide, but the association is weak and reversible. The N–N distance in crystalline NO is 218 pm, nearly twice the N–O distance.

Since the heat of formation of ·NO is endothermic, NO can be decomposed to the elements. Catalytic converters in cars exploit this reaction:

2 NO → O₂ + N₂.

When exposed to oxygen, nitric oxide converts into nitrogen dioxide:

2 NO + O₂ → 2 NO₂.

This conversion has been speculated as occurring via the ONOONO intermediate.

In water, nitric oxide reacts with oxygen to form nitrous acid (HNO₂). The reaction is thought to proceed via the following stoichiometry:

4 NO + O₂ + 2 H₂O → 4 HNO₂.

Nitric oxide reacts with fluorine, chlorine, and bromine to form the nitrosyl halides, such as nitrosyl chloride:

2 NO + Cl₂ → 2 NOCl.

With NO₂, also a radical, NO combines to form the intensely blue dinitrogen trioxide:

NO + NO₂ ⇌ ON−NO₂.

Organic chemistry

The addition of a nitric oxide moiety to another molecule is often referred to as nitrosylation. The Traube reaction is the addition of a two equivalents of nitric oxide onto an enolate, giving a diazeniumdiolate (also called a nitrosohydroxylamine). The product can undergo a subsequent retro-aldol reaction, giving an overall process similar to the haloform reaction. For example, nitric oxide reacts with acetone and an alkoxide to form a diazeniumdiolate on each α position, with subsequent loss of methyl acetate as by-product:

This reaction, which was discovered around 1898, remains of interest in nitric oxide prodrug research. Nitric oxide can also react directly with sodium methoxide, ultimately forming forming sodium formate and nitrous oxide by way of an N-methoxydiazeniumdiolate.

Coordination complexes

Nitric oxide reacts with transition metals to give complexes called metal nitrosyls. The most common bonding mode of nitric oxide is the terminal linear type (M−NO). Alternatively, nitric oxide can serve as a one-electron pseudohalide. In such complexes, the M−N−O group is characterized by an angle between 120° and 140°. The NO group can also bridge between metal centers through the nitrogen atom in a variety of geometries.

Production and preparation

In commercial settings, nitric oxide is produced by the oxidation of ammonia at 750–900 °C (normally at 850 °C) with platinum as catalyst in the Ostwald process:

4 NH₃ + 5 O₂ → 4 NO + 6 H₂O

The uncatalyzed endothermic reaction of oxygen (O₂) and nitrogen (N₂), which is effected at high temperature (>2000 °C) by lightning has not been developed into a practical commercial synthesis:

N₂ + O₂ → 2 NO

Laboratory methods

In the laboratory, nitric oxide is conveniently generated by reduction of dilute nitric acid with copper:

8 HNO₃ + 3 Cu → 3 Cu(NO₃)₂ + 4 H₂O + 2 NO

An alternative route involves the reduction of nitrous acid in the form of sodium nitrite or potassium nitrite:

2 NaNO₂ + 2 NaI + 2 H₂SO₄ → I₂ + 2 Na₂SO₄ + 2 H₂O + 2 NO

2 NaNO₂ + 2 FeSO₄ + 3 H₂SO₄ → Fe₂(SO₄)₃ + 2 NaHSO₄ + 2 H₂O + 2 NO

3 KNO₂ + KNO₃ + Cr₂O₃ → 2 K₂CrO₄ + 4 NO

The iron(II) sulfate route is simple and has been used in undergraduate laboratory experiments. So-called NONOate compounds are also used for nitric oxide generation.

Detection and assay

Nitric oxide (white) in conifer cells, visualized using DAF-2 DA (diaminofluorescein diacetate)

Nitric oxide concentration can be determined using a chemiluminescent reaction involving ozone. A sample containing nitric oxide is mixed with a large quantity of ozone. The nitric oxide reacts with the ozone to produce oxygen and nitrogen dioxide, accompanied with emission of light (chemiluminescence):

NO + O₃ → NO₂ + O₂ + hν

which can be measured with a photodetector. The amount of light produced is proportional to the amount of nitric oxide in the sample.

Other methods of testing include electroanalysis (amperometric approach), where ·NO reacts with an electrode to induce a current or voltage change. The detection of NO radicals in biological tissues is particularly difficult due to the short lifetime and concentration of these radicals in tissues. One of the few practical methods is spin trapping of nitric oxide with iron-dithiocarbamate complexes and subsequent detection of the mono-nitrosyl-iron complex with electron paramagnetic resonance (EPR).

A group of fluorescent dye indicators that are also available in acetylated form for intracellular measurements exist. The most common compound is 4,5-diaminofluorescein (DAF-2).

Environmental effects

Acid rain deposition

Nitric oxide reacts with the hydroperoxy radical (HO₂^•) to form nitrogen dioxide (NO₂), which then can react with a hydroxyl radical (^•OH) to produce nitric acid (HNO₃):

·NO + HO₂^•→ ^•NO₂ + ^•OH

·NO₂ + ^•OH → HNO₃

Nitric acid, along with sulfuric acid, contributes to acid rain deposition.

Ozone depletion

·NO participates in ozone layer depletion. Nitric oxide reacts with stratospheric ozone to form O₂ and nitrogen dioxide:

·NO + O₃ → NO₂ + O₂

This reaction is also utilized to measure concentrations of ·NO in control volumes.

Precursor to NO₂

As seen in the Acid deposition section, nitric oxide can transform into nitrogen dioxide (this can happen with the hydroperoxy radical, HO₂^•, or diatomic oxygen, O₂). Symptoms of short-term nitrogen dioxide exposure include nausea, dyspnea and headache. Long-term effects could include impaired immune and respiratory function.

Biological functions

NO is a gaseous signaling molecule. It is a key vertebrate biological messenger, playing a role in a variety of biological processes. It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.

Nitric oxide, known as an endothelium-derived relaxing factor (EDRF), is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. One of the main enzymatic targets of nitric oxide is guanylyl cyclase. The binding of nitric oxide to the haem region of the enzyme leads to activation, in the presence of iron. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule. Once nitric oxide is converted to nitrates and nitrites by oxygen and water, cell signaling is deactivated.

The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Sildenafil (Viagra) is a common example of a drug that uses the nitric oxide pathway. Sildenafil does not produce nitric oxide, but enhances the signals that are the downstream of the nitric oxide pathway by protecting cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, allowing for the signal to be enhanced, and thus vasodilation. Another endogenous gaseous transmitter, hydrogen sulfide (H₂S) works with NO to induce vasodilation and angiogenesis in a cooperative manner.

Occupational safety and health

In the U.S., the Occupational Safety and Health Administration (OSHA) has set the legal limit (permissible exposure limit) for nitric oxide exposure in the workplace as 25 ppm (30 mg/m³) over an 8-hour workday. The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 25 ppm (30 mg/m³) over an 8-hour workday. At levels of 100 ppm, nitric oxide is immediately dangerous to life and health

 

Acid–base homeostasis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Acid%E2%80%93base_homeostasis 

 

Acids and bases
Acid Acid–base reaction Acid–base homeostasis Acid strength Acidity function Amphoterism Base Buffer solutions Dissociation constant Equilibrium chemistry Extraction Hammett acidity function pH Proton affinity Self-ionization of water Titration Lewis acid catalysis Frustrated Lewis pair Chiral Lewis acid
Acid types
Brønsted–Lowry Lewis Acceptor Mineral Organic Oxide Strong Superacids Weak Solid
Base types
Brønsted–Lowry Lewis Donor Organic Oxide Strong Superbases Non-nucleophilic Weak

Acid–base homeostasis is the homeostatic regulation of the pH of the body's extracellular fluid (ECF). The proper balance between the acids and bases (i.e. the pH) in the ECF is crucial for the normal physiology of the body, and cellular metabolism. The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.

Many extracellular proteins such as the plasma proteins and membrane proteins of the body's cells are very sensitive for their three dimensional structures to the extracellular pH. Stringent mechanisms therefore exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3-D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.

In humans and many other animals, acid–base homeostasis is maintained by multiple mechanisms involved in three lines of defense:

1. Chemical: The first lines of defense are immediate – the various chemical buffers which minimize pH changes that would otherwise occur in their absence. These buffers include the bicarbonate buffer system, the phosphate buffer system, and the protein buffer system.

2. Respiratory Component: The second line of defense of the extracellular fluid pH is rapid, measured by PCO₂, and consists of controlling the carbonic acid concentration in the ECF by changing the rate and depth of breathing (i.e. by hyperventilation or hypoventilation). This blows off or retains carbon dioxide (and thus carbonic acid) in the blood plasma as required.

3. Metabolic Component: The third line of defense is slow, best measured by the Base Excess, and mostly depends on the renal system which can add or remove bicarbonate ions to or from the ECF. The bicarbonate is derived from metabolic carbon dioxide which is enzymatically converted to carbonic acid in the renal tubular cells. The carbonic acid spontaneously dissociates into hydrogen ions and bicarbonate ions. When the pH in the ECF tends to fall (i.e. become more acidic) the hydrogen ions are excreted into the urine, while the bicarbonate ions are secreted into the blood plasma, causing the plasma pH to rise (correcting the initial fall). The converse happens if the pH in the ECF tends to rise: the bicarbonate ions are then excreted into the urine and the hydrogen ions into the blood plasma.

The second and third lines of defense operate by making changes to the buffers, each of which consists of two components: a weak acid and its conjugate base. It is the ratio concentration of the weak acid to its conjugate base that determines the pH of the solution. Thus, by manipulating firstly the concentration of the weak acid, and secondly that of its conjugate base, the pH of the extracellular fluid (ECF) can be adjusted very accurately to the correct value. The bicarbonate buffer, consisting of a mixture of carbonic acid (H₂CO₃) and a bicarbonate (HCO⁻
₃) salt in solution, is the most abundant buffer in the extracellular fluid, and it is also the buffer whose acid to base ratio can be changed very easily and rapidly.

An acid–base imbalance is known as Acidemia when the pH is Acid, or Alkalemia when the pH is Alkaline.

Acid–base balance

The pH of the extracellular fluid, including the blood plasma, is normally tightly regulated between 7.32 and 7.42, by the chemical buffers, the respiratory system, and the renal system.

Aqueous buffer solutions will react with strong acids or strong bases by absorbing excess hydrogen H⁺
ions, or hydroxide OH⁻
ions, replacing the strong acids and bases with weak acids and weak bases. This has the effect of damping the effect of pH changes, or reducing the pH change that would otherwise have occurred. But buffers cannot correct abnormal pH levels in a solution, be that solution in a test tube or in the extracellular fluid. Buffers typically consist of a pair of compounds in solution, one of which is a weak acid and the other a weak base. The most abundant buffer in the ECF consists of a solution of carbonic acid (H₂CO₃), and the bicarbonate (HCO⁻
₃) salt of, usually, sodium (Na⁺). Thus, when there is an excess of OH⁻
ions in the solution carbonic acid partially neutralizes them by forming H₂O and bicarbonate (HCO⁻
₃) ions. Similarly an excess of H⁺ ions is partially neutralized by the bicarbonate component of the buffer solution to form carbonic acid (H₂CO₃), which, because it is a weak acid, remains largely in the undissociated form, releasing far fewer H⁺ ions into the solution than the original strong acid would have done.

The pH of a buffer solution depends solely on the ratio of the molar concentrations of the weak acid to the weak base. The higher the concentration of the weak acid in the solution (compared to the weak base) the lower the resulting pH of the solution. Similarly, if the weak base predominates the higher the resulting pH.

This principle is exploited to regulate the pH of the extracellular fluids (rather than just buffering the pH). For the carbonic acid-bicarbonate buffer, a molar ratio of weak acid to weak base of 1:20 produces a pH of 7.4; and vice versa - when the pH of the extracellular fluids is 7.4 then the ratio of carbonic acid to bicarbonate ions in that fluid is 1:20.

This relationship is accurately defined by the simple Henderson Equation:

[H⁺] x [HCO₃^-] = K x [CO₂] x [H₂O]

which relates the concentrations of the four variables with K being the dissociation constant of carbonic acid

However this can be further simplified because:

[H₂O] is constant and the partial pressure of CO₂ is more familiar which leaves us:

[H⁺] x [HCO₃^-] = K x PCO₂

Recognition of an acute change now becomes simple:

With a constant PCO₂, an increase in [H⁺] must lower the [HCO₃^-]

And an increase in the PCO₂ initially at least increases both [H⁺] and [HCO₃^-]

For more chronic changes there is time for compensation – see below.

Unfortunately, Hasselbalch entered:

This is not the equation most commonly taught.

With no benefit and a huge penalty in complexity the Henderson–Hasselbalch is used.

The Logarithmic notation makes recognition much harder.

It is described here because it is customary, not because it is useful.

The Henderson–Hasselbalch equation when applied to the carbonic acid-bicarbonate buffer system in the extracellular fluids, states that:

${\displaystyle \mathrm {pH} =\mathrm {p} K_{\mathrm {a} ~\mathrm {H} _{2}\mathrm {CO} _{3}}+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{[\mathrm {H} _{2}\mathrm {CO} _{3}]}}\right),}$

where:

• pH is the negative logarithm (or cologarithm) of molar concentration of hydrogen ions in the ECF. It indicates the acidity in the ECF in an inverse manner: the lower the pH the greater the acidity of the solution.
• pK_{a H2CO3} is the cologarithm of the acid dissociation constant of carbonic acid. It is equal to 6.1.
• [HCO⁻
  ₃] is the molar concentration of bicarbonate in the blood plasma
• [H₂CO₃] is the molar concentration of carbonic acid in the ECF.

However, since the carbonic acid concentration is directly proportional to the partial pressure of carbon dioxide (${\displaystyle P_{{\mathrm {CO} }_{2}}}$) in the extracellular fluid, the equation can be rewritten as follows:

${\displaystyle \mathrm {pH} =6.1+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{0.0307\times P_{\mathrm {CO} _{2}}}}\right),}$

where:

• pH is the negative logarithm of molar concentration of hydrogen ions in the ECF, as before.
• [HCO⁻
  ₃] is the molar concentration of bicarbonate in the plasma
• P_CO2 is the partial pressure of carbon dioxide in the blood plasma.

The pH of the extracellular fluids can thus be controlled by the regulation of the Respiratory Acid (PCO₂), and the Metabolic Acids (Every other acid).

Compensation:

In general, metabolism produces more waste acids than bases. Respiratory Acidosis tends to cause an acid pH. When Acute, e.g., from poisoning or trauma, there is no time for compensation. There is a Pure Respiratory Acidosis and the change in pH is Typical. However, lung disease usually causes Chronic Respiratory Acidosis and Metabolic Compensation returns the pH roughly Half Way Back to Normal. Metabolic Acidosis also tends to cause an acid pH but normal lungs usually compensate promptly to maintain the pH roughly Half Way Back to Normal.

Homeostatic Mechanisms:

The homeostatic control can change the PCO₂ and hence the pH of the arterial plasma within a few seconds. The partial pressure of carbon dioxide in the arterial blood is monitored by the central chemoreceptors of the medulla oblongata, and so are part of the central nervous system. These chemoreceptors are sensitive to the pH and levels of carbon dioxide in the cerebrospinal fluid.

The central chemoreceptors send their information to the respiratory centres in the medulla oblongata and pons of the brainstem. The respiratory centres then determine the average rate of ventilation of the alveoli of the lungs, to keep the partial pressure carbon dioxide in the arterial blood constant. The respiratory center does so via motor neurons which activate the muscles of respiration (in particular the diaphragm). A rise in the partial pressure of carbon dioxide in the arterial blood plasma above 5.3 kPa (40 mmHg) reflexly causes an increase in the rate and depth of breathing. Normal breathing is resumed when the partial pressure of carbon dioxide has returned to 5.3 kPa. The converse happens if the partial pressure of carbon dioxide falls below the normal range. Breathing may be temporally halted, or slowed down to allow carbon dioxide to accumulate once more in the lungs and arterial blood.

The sensor for the plasma HCO⁻
₃ concentration is not known for certain. It is very probable that the renal tubular cells of the distal convoluted tubules are themselves sensitive to the pH of the plasma. The metabolism of these cells produces CO₂, which is rapidly converted to H⁺ and HCO⁻
₃ through the action of carbonic anhydrase. When the extracellular fluids tend towards acidity, the renal tubular cells secrete the H⁺ ions into the tubular fluid from where they exit the body via the urine. The HCO⁻
₃ ions are simultaneously secreted into the blood plasma, thus raising the bicarbonate ion concentration in the plasma, lowering the carbonic acid/bicarbonate ion ratio, and consequently raising the pH of the plasma. The converse happens when the plasma pH rises above normal: bicarbonate ions are excreted into the urine, and hydrogen ions into the plasma. These combine with the bicarbonate ions in the plasma to form carbonic acid (H⁺ + HCO⁻
₃ = H₂CO₃), thus raising the carbonic acid:bicarbonate ratio in the extracellular fluids, and returning its pH to normal.

Urine is generally acid which, to a certain extent, is usually neutralized by the ammonia (NH₃) which is excreted into the urine when glutamate and glutamine (carriers of excess, no longer needed, amino groups) are deaminated by the distal renal tubular epithelial cells. Thus some of the "acid content" of the urine resides in the resulting ammonium ion (NH₄⁺) content of the urine, though this has no effect on pH homeostasis of the extracellular fluids.

Imbalance

An Acid Base Diagram for human plasma, showing the effects on the plasma pH when PCO₂ in mmHg or Standard Base Excess (SBE) occur in excess or are deficient in the plasma

Acid–base imbalance occurs when a significant insult causes the blood pH to shift out of the normal range (7.32 to 7.42). An abnormally low pH in the ECF is called an acidemia and an abnormally high pH is called an Alkalemia.

"Acidemia" and "alkalemia", refer unambiguously to the actual change in the pH of the ECF. Two other similar sounding terms are "acidosis" and "alkalosis". They refer to the customary effect of a component, respiratory or metabolic. Acidosis would on its own (i.e. if left "uncompensated" by an alkalosis) cause an acidemia. Similarly an alkalosis would on its own cause an alkalemia. The terms acidosis and alkalosis should always be qualified by an adjective to indicate the cause of the disturbance: "respiratory" (indicating a change in the partial pressure of carbon dioxide), or "metabolic" (indicating a change in the Base Excess of the ECF). There are therefore four different acid-base problems: metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. One or a combination these conditions may occur simultaneously. For instance, a metabolic acidosis (as in uncontrolled diabetes mellitus) is almost always partially compensated by a respiratory alkalosis (hyperventilation), or a respiratory acidosis can be completely or partially corrected by a metabolic alkalosis.