diabetes

Type 1 diabetes

Generality

Type 1 diabetes mellitus is a metabolic disease caused by the lack (or severe insufficiency) of insulin, a hormone produced by the pancreas.

The classic symptoms mainly concern the increase in urination, thirst and appetite, and weight loss.

The causes of severe or absolute deficiency of insulin in type 1 diabetes are related to an autoimmune reaction, which affects pancreatic cells responsible for hormone synthesis.

The underlying causes of this autoimmune reaction are poorly understood; it is assumed that they may be genetic or endogenous or exogenous.

The main test that allows to diagnose type 1 diabetes mellitus, and to distinguish it from type 2 diabetes, is based on the search for autoantibodies involved in the autoimmune reaction.

To live, the type 1 diabetic needs the administration of exogenous insulin, that is a synthetic form of the hormone, analogous to the natural one. This therapy must be followed indefinitely and generally does not compromise normal daily activities. All type 1 diabetics are instructed and trained in the self-management of insulin drug therapy.

If untreated, type 1 diabetes mellitus causes various serious complications, both acute and chronic. Other complications of type 1 diabetes mellitus are of a collateral nature and are based mainly on the IP-glycemia caused by the administration of an overdose of insulin.

Type 1 diabetes mellitus accounts for 5-10% of the total cases of diabetes in the world.

Pancreas and Diabetes Mellitus Type 1

Short Anatomo-Functional Recall

The pancreas is a glandular organ that intervenes supporting the digestive system and the endocrine system of vertebrates.

In humans, it is located in the abdominal cavity, behind the stomach.

It is an endocrine gland that produces several important hormones, including insulin, glucagon, somatostatin and pancreatic polypeptide.

It also plays an exocrine role, as it secretes a digestive juice containing enzymes specific for the digestion of carbohydrates, proteins and lipids in chyme.

In type 1 diabetes mellitus, only the endocrine function of insulin is compromised.

Pathophysiology

Type 1 (also known as T1D) is a form of diabetes mellitus caused by the autoimmune lesion of pancreatic beta cells. Once damaged, these cells no longer produce insulin, regardless of what the risk factors and causal entities may be.

In the past, type 1 diabetes mellitus was also called insulin-dependent or juvenile diabetes, but today these definitions are considered fundamentally incorrect or incomplete.

The individual causes of type 1 diabetes mellitus can relate to various pathophysiological processes that, in turn, destroy pancreatic beta cells. The process takes place through these steps:

  • Recruitment of autoreactive CD4 helper T cells and cytotoxic CD8 T lymphocytes
  • Recruitment of autoantibodies B
  • Activation of the innate immune system.

NB . Sometimes, after starting the exogenous insulin intake, the levels of residual endogenous secretion may temporarily improve. It is possible that this reaction, also known as the "honeymoon phase", is due to the alteration of the immune condition.

Causes

The causes of the onset of type 1 diabetes mellitus are unknown.

Several explanatory theories have been put forward and the causes can be one or more of those that we are going to list:

  • Genetic predisposition
  • Presence of a diabetogenic activator (immune factor)
  • Exposure to an antigen (such as a virus).

Genetics and Inheritance

Type 1 diabetes mellitus is a disease that involves more than 50 genes.

Depending on the locus or combination of loci, the disease may result: dominant, recessive or intermediate.

The strongest gene is IDDM1 and is found on chromosome 6, more precisely in the 6p21 staining region (MHC class II). Some variants of this gene increase the risk of reduction of the type 1 histocompatibility characteristic. These include: DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are more common in European and North American populations. Extraordinarily, some seem to play a protective role.

The risk of developing type 1 diabetes mellitus for a child is equal to:

  • 10% if the father is affected
  • 10% if the brother is affected
  • 4% if the mother is affected and, at the time of childbirth, she was 25 or younger
  • 1% if the mother is affected and, at the time of delivery, she was over 25 years old.

Environmental factors

Environmental factors influence the expression of type 1 diabetes mellitus.

For monozygotic twins (who have the same genetic heritage), when one of them is affected by the disease, the other has only 30-50% of the possibilities to manifest it. This means that in 50-70% of cases the disease only attacks one of two identical twins. The so-called concordance index is less than 50%, suggesting a VERY important environmental influence.

Other environmental factors refer to the home area. Certain European areas, in which Caucasian populations reside, have a risk of occurrence 10 times higher than many others. In the event of translocation, it appears that the danger increases or decreases based on the destination country.

Role of Viruses

A theory on the causes of the onset of type 1 diabetes mellitus is based on the interference of a virus. This would stimulate the triggering of the immune system which, for reasons that are still mysterious, ends up attacking even the beta cells of the pancreas.

The Coxsackie viral family, to which the rubella virus belongs, seems to be involved in this mechanism but the evidence is not yet sufficient to prove it. In fact, this susceptibility does not affect the entire population and only some individuals affected by rubella develop type 1 diabetes mellitus.

This suggested a certain genetic vulnerability and, not surprisingly, the hereditary tendency of particular HLA genotypes was identified. However, their correlation and autoimmune mechanism remain misunderstood.

Chemicals and Drugs

Certain chemicals and drugs selectively destroy pancreatic cells.

Pyrinurone, a rodenticide widespread in 1976, selectively destroys pancreatic beta cells causing type 1 diabetes mellitus. This product was withdrawn from most markets in the late 1970s, but not everywhere.

Streptozotocin, an antibiotic and anticancer agent used in chemotherapy for pancreatic cancer, kills the organ beta cells by depriving it of endocrine insulin capacity.

Symptoms

The classic symptoms of type 1 diabetes mellitus include:

  • Polyuria: excessive urination
  • Polydipsia: increased thirst
  • Xerostomia: dry mouth
  • Polyphagia: increased appetite
  • Chronic fatigue
  • Unjustified weight loss.

Acute Complications

Many type 1 diabetics are diagnosed at the onset of certain complications typical of the disease, such as:

  • Diabetic ketoacidosis
  • Non-ketosic hyperosmolar-hyperglycemic coma.

Diabetic Ketoacidosis: How is it manifested?

The ketoacidosis of type 1 diabetes mellitus occurs due to the accumulation of ketone bodies.

It is metabolic waste induced by the consumption of fats and amino acids for energy purposes. This circumstance manifests itself due to the lack of insulin and the consequent deficiency of glucose in the tissues.

The signs and symptoms of diabetic ketoacidosis include:

  • Xeroderma: dry skin
  • Hyperventilation and tachypnea: deep and rapid breathing
  • Drowsiness
  • Abdominal pains
  • He retched.

Hyperosmolar-Hyperglycemic Coma Non Ketosico

Very often triggered by an infection or by taking drugs in the presence of type 1 diabetes mellitus, it has a mortality that reaches 50%.

The pathological mechanism involves:

  • Excessive glycemic concentration
  • Intense renal filtration for glucose excretion
  • Lack of rehydration.

It often occurs with the appearance of focal or generalized convulsions.

Chronic Complications

The long-term complications of type 1 diabetes mellitus are mainly related to macro and micro angiopathies (complications of blood vessels).

Complications of poorly managed type 1 diabetes mellitus may include:

  • Vascular diseases of macrocirculation (macroangiopathies): stroke, myocardial infarction
  • Vascular diseases of the microcirculation (microangiopathies): retinopathies, nephropathies and neuropathies
  • Other, related or unrelated to the above: diabetic renal failure, sensitivity to infections, diabetic foot amputation, cataract, urinary tract infections, sexual dysfunction, etc.
  • Clinical depression: in 12% of cases.

The pathological basis of macroangiopathies is that of atherosclerosis.

However, cardiovascular disease and neuropathy may also have an autoimmune basis. For this type of complication, women have a 40% higher risk of death than men.

Infections of the Urinary Tract

People with type 1 diabetes mellitus show an increased rate of urinary tract infections.

The reason is a bladder dysfunction related to diabetic nephropathy. This can cause a decrease in sensitivity which, in turn, causes an increase in urinary retention (risk factor for infections).

Sexual Dysfunction

Sexual dysfunction is often the result of physical factors (such as nerve damage and / or poor circulation) and psychological factors (such as stress and / or depression caused by the needs of the disease).

  • Males: the most common sexual problems in males are difficulties with erection and ejaculation (retrograde complication).
  • Females: statistical studies have shown the existence of a significant correlation between type 1 diabetes mellitus and sexual problems in women (although the mechanism is unclear). The most common dysfunctions include reduced sensitivity, dryness, difficulty / inability to reach orgasm, pain during sex and decreased libido.

Diagnosis

Type 1 diabetes mellitus is characterized by recurrent and persistent hyperglycemia, diagnosed with one or more of the following requirements:

  • Fasting blood sugar equal to or above 126mg / dl (7.0mmol / L)
  • Glycaemia equal to or greater than 200mg / dl (11.1mmol / L), 2 hours after oral administration of an oral load equal to 75g of glucose (glucose tolerance test)
  • Symptoms of hyperglycemia and diagnostic confirmation (200mg / dl or 11.1mmol / L)
  • Glycated hemoglobin (type A1c) equal to or greater than 48mmol / mol.

NB . These criteria are recommended by the World Health Organization (WHO).

Debut

About ¼ of patients with type 1 diabetes mellitus begins with diabetic ketoacidosis. This is defined as a metabolic acidosis caused by the increase of ketone bodies in the blood; this rise is in turn caused by the exclusive energetic use of fatty acids and amino acids.

More rarely, type 1 diabetes mellitus may present with hypoglycemic collapse (or coma). This is due to the excessive production of insulin in the few moments preceding the final interruption. This is a rather dangerous circumstance.

Differential diagnosis

The diagnosis of other types of diabetes occurs in different circumstances.

For example, with ordinary screeneng, with random detection of hyperglycemia and by recognition of secondary symptoms (fatigue and visual disturbances).

Type 2 diabetes is often belatedly identified due to the onset of long-term complications, such as: stroke, myocardial infarction, neuropary, foot ulcers or difficulty in healing wounds, eye problems, fungal infections and child birth suffering from macrosomia or hypoglycemia.

A positive result, in the absence of unequivocal hyperglycemia, must however be confirmed by the repetition of a positive outcome.

The differential diagnosis between type 1 and type 2 diabetes mellitus, both characterized by hyperglycemia, mainly concerns the cause of metabolic impairment.

While in type 1 there is a significant reduction of insulin due to the destruction of pancreatic beta cells, in type 2 insulin resistance appears (absent in type 1).

Another factor that characterizes type 1 diabetes mellitus is the presence of antibodies aimed at the destruction of pancreatic beta cells.

Autoantibody detection

The appearance of autoantibodies linked to type 1 diabetes in the blood has been shown to be able to predict the onset of the disease even before the hyperglycemia.

The main autoantibodies are:

  • Anti-insular cell autoantibodies
  • Anti-insulin autoantibodies
  • Autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD),
  • Anti-IA-2 autoantibodies of tyrosine-phosphatase
  • Zinc transporter autoantibodies 8 (ZnT8).

By definition, the diagnosis of type 1 diabetes CANNOT be made prior to the manifestation of symptoms and clinical signs. However, the appearance of autoantibodies can however outline a condition of "latent autoimmune diabetes".

Not all subjects who show one or some of these autoantibodies develop type 1 diabetes mellitus. The risk increases with increasing number; for example, with three or four different types of antibodies, a risk level of 60-100% is reached.

The time interval between the appearance of autoantibodies in the blood and the onset of clinically diagnosable type 1 diabetes mellitus can be a couple of months (infants and young children); on the other hand, in some subjects it can take several years.

Only the assay of insular cell autoantibodies requires conventional immunofluorescence detection, while the others are measured with specific radiobinding tests.

Prevention and Therapy

Type 1 diabetes mellitus is not currently preventable.

Some researchers say it could be avoided if properly treated in its latent autoimmune phase, before the immune system is activated against pancreatic beta cells.

Immunosuppressive drugs

It seems that cyclosporin A, an immunosuppressive agent, is able to block the destruction of beta cells. However, its renal toxicity and other side effects make it highly inappropriate for long-term use.

Anti-CD3 antibodies, including teplizumab and otelixizumab, appear to retain insulin production. The mechanism of this effect is probably attributable to the preservation of regulatory T cells. These mediators suppress the activation of the immune system, maintain homeostasis and tolerance of self-antigens. The duration of these effects is still unknown

Anti-CD20 antibodies to rituximab inhibit B cells, but the long-term effects are unknown.

Diet

Some research has suggested that breastfeeding reduces the risk of developing type 1 diabetes mellitus.

Vitamin D intake of 2000 IU in the first year of life has been shown to be preventive, but the causal relationship between the nutrient and the disease is unclear.

Children with antibodies against beta cell proteins, if treated with vitamin B3 (PP or niacin), show a drastic reduction in the incidence over the first seven years of life.

Stress and Depression

The psychological stress related to the lifestyle of the type 1 diabetic is considerable; not surprisingly, the complications of this pathology include depressive symptoms and major depression.

To avoid this inconvenience, there are preventive measures including: physical exercise, hobbies and participation in charities.

Insulin

Unlike type 2 diabetes mellitus, diet and exercise are not a cure.

For endocrine insufficiency, type 1 diabetics are obliged to inject themselves with insulin either subcutaneously or by pumping.

Today, insulin is synthetic in nature; in the past, hormones of animal origin (cattle, horses, fish, etc.) have been used.

There are four main types of insulin:

  • Fast acting: the effect occurs in 15 minutes, with a peak between 30 and 90 '.
  • Short acting: the effect occurs in 30 minutes, with a peak between 2 and 4 hours.
  • Intermediate action: the effect occurs in 1-2 hours, with a peak between 4 and 10 hours.
  • Long-acting: administered once a day, it has an effect that occurs in 1-2 hours, with a prolonged action that lasts for all 24.

WARNING! An excess of insulin can induce hypoglycemia (<70mg / dl) and, in the most serious cases, hypoglycemic coma.

Food management and blood glucose detection are two very important factors that serve to avoid excess and defect of exogenous insulin.

Regarding the diet, one of the key points is the counting of carbohydrates; for what concerns the glycemic estimation, instead, it is sufficient to use an electronic device (glucometer).

See also: Type 1 diabetes mellitus diet.

The goal of food / hormone management is to maintain a blood sugar level of around 80-140mg / dl in the short term and glycated hemoglobin of less than 7% in order to avoid long-term complications.

To learn more: Type 1 Diabetes Treatment Medicines »

Pancreas transplantation

In type 1 diabetes mellitus, especially in cases where insulin therapy is more difficult, it is also possible to perform a beta cell transplant in the pancreas.

The difficulties are related to the recruitment of compatible donors and the side effects in the use of anti-rejection drugs.

The success rate in the first 3 years (defined as insulin independence) is estimated at around 44%.

Epidemiology

Type 1 diabetes accounts for 5-10% of all diabetes cases, or 11 to 22, 000, 000 worldwide.

In 2006, type 1 diabetes mellitus involved 440, 000 children under the age of 14 and was the primary cause of diabetes in those less than 10 years old.

The diagnoses of type 1 diabetes mellitus increase about 3% every year.

Rates vary greatly from country to country:

  • In Finland, 57 cases per 100, 000 per year
  • In Northern Europe and the United States, 8-17 cases per 100, 000 per year
  • In Japan and China, 1-3 cases per 100, 000 per year.

American Asians, American Hispanics and black Hispanic Americans are more likely to develop type 1 diabetes mellitus than non-Hispanic whites.

Search

Type 1 diabetes research is funded by governments, industry (eg, pharmaceutical companies) and charitable organizations.

Currently, the experiment moves in two different directions:

  • Pluripotent stem cells: these are cells that can be used to generate additional specific beta cells. In 2014, an experiment on mice gave a positive outcome but, before these techniques can be used in humans, further investigation is needed.
  • Vaccine: vaccines to treat or prevent type 1 diabetes are designed to induce immune tolerance on pancreatic beta cells and insulin. After some failures, there is currently no working vaccine. Since 2014, new protocols have been launched.