Diabetes Mellitus Type 1: Causes

Pathogenesis (disease development)

The cause of diabetes mellitus type 1 is an absolute insulin deficiency due to the destruction of ß-cells (≥ 80%) in the pancreas (pancreas) by an autoimmunological disorder (type 1a); about 90% of cases). In addition, there is a causative genetic component as well as the influence of environmental factors.The phase of ß-cell destruction begins after birth and lasts months to years (prediabetes type 1). If more than 80 % of the ß-cells are destroyed, the manifest diabetes mellitus type 1 occurs. In connection with this manifestation, an infectious disease or puberty is often the trigger. In about 10 % of the cases an idiopathic disorder is present (type 1b; no autoantibodies can be detected).

The main pathogenetic factors of type 1 diabetes mellitus are:

Immune genetic background (presence of certain HLA traits (HLA-DR3, -DR4, -DQ8) and other autoimmune diseases).
Autoantibodies against ß-cell antigens (these result from autoimmune destruction of ß-cells).
Triggering agent (the following triggering factors are discussed: Viruses, dietary components (gluten, cow’s milk proteins) and environmental toxins.

In the early phase of manifest diabetes, only small amounts of insulin (honeymoon phase) or no insulin may be needed.

Etiology (causes)

The etiology of type 1 diabetes is determined by a genetic disposition (predisposition) and by exogenous (external) factors. In this form of diabetes, a clustering of HLA-DR3 and/or -DR4 can be found in type 1 diabetics. However, the concordance (matching) in monozygotic (identical) twins is only 50%, which means that exogenous factors must be added to initiate the autoimmune destruction of the ß-cells. This progressive destruction of the insulin-producing ß-cells then leads to the clinically evident onset of the disease over a period of months to years. These environmental factors have not yet been identified; viral infections (see below), toxins and chemicals are suspected. Only when 80-90% of the ß-cells have been destroyed does type 1 diabetes manifest itself.Biographical Causes

Genetic burden from parents, grandparents (heritability: low; genes: HLA-associated); monozygotic (identical) twins: 30-50%.
- If both parents were not diabetic but were obese (BMI: > 30 kg/m2): Incidence rate ratio (IRR) values were 1.31 (father obese), 1.35 (mother obese), and 1.33 (both obese).
- Genetic risk dependent on gene polymorphisms:
  - Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
    - Genes: ADA1, CLEC16A, ERBB3, HLA-DQA1, IL2RA, NAA25, PHTF1, PTPN2.
    - SNP: rs6679677 in the PHTF1 gene.
      - Allele constellation: AC (1.8-fold).
      - Allele constellation: AA (5.2-fold)
    - SNP: rs2542151 in the gene PTPN2
      - Allele constellation: GT (1.3-fold).
      - Allele constellation: GG (2.0-fold)
    - SNP: rs17696736 in the gene NAA25
      - Allele constellation: AG (1.34-fold).
      - Allele constellation: GG (1.94-fold)
    - SNP: rs11171739 in the gene ERBB3
      - Allele constellation: CT (1.34-fold).
      - Allele constellation: CC (1.75-fold)
    - SNP: rs2104286 in the IL2RA gene.
      - Allele constellation: AG (1.4-fold).
      - Allele constellation: AA (1.7-fold)
    - SNP: rs17388568 in the gene ADA1
      - Allele constellation: AG (1.3-fold).
      - Allele constellation: AA (1.6-fold)
    - SNP: rs12708716 in the CLEC16A gene.
      - Allele constellation: AG (1.2-fold).
      - Allele constellation: AA (1.6-fold)
    - SNP: rs9272346 in the gene HLA-DQA1
      - Allele constellation: AG (0.3-fold).
      - Allele constellation: GG (0.08-fold)
- Genetic diseases (syndromes associated with diabetes).
  - Huntington’s chorea (synonyms: Huntington’s chorea or Huntington’s disease; older name: St. Vitus’ dance) – genetic disorder with autosomal dominant inheritance characterized by involuntary, uncoordinated movements accompanied by flaccid muscle tone.
  - Friedreich’s ataxia – genetic disease with autosomal recessive inheritance leading to a degenerative disease of the central nervous system.
  - Klinefelter syndrome – genetic disease with mostly sporadic inheritance: numerical chromosomal aberration (aneuploidy) of the sex chromosomes (gonosomal anomaly) occurring only in boys or Men occurs; in the majority of cases characterized by a supernumerary X chromosome (47, XXY); clinical picture: large stature and testicular hypoplasia (small testis), caused by hypogonadotropic hypogonadism (gonadal hypofunction); here usually spontaneous onset of puberty, but poor pubertal progress.
  - Laurence-Moon-Biedl-Bardet syndrome (LMBBS) – rare genetic disorder with autosomal recessive inheritance; according to clinical symptoms is differentiated into:
    - Laurence-Moon syndrome (without polydactyly, i.e., without the appearance of supernumerary fingers or toes, and obesity, but with paraplegia (paraplegia) and muscle hypotonia/reduced muscle tone) and
    - Bardet-Biedl syndrome (with polydactyly, obesity and peculiarities of the kidneys).
  - Cystic Fibrosis (ZF) – genetic disease with autosomal recessive inheritance characterized by the production of secretions in various organs to be tamed.
  - Myotonic dystrophy type 1 (DM1; synonyms: myotonia dystrophica, dystrophia myotonica) – genetic disease with autosomal dominant inheritance; form of myotonic muscle disease with muscle weakness, cataract (cataract) and hypogonadism (hypogonadism).
  - Prader-Willi-Labhart syndrome (Prader-Willi syndrome) – genetic disease with autosomal dominant inheritance, which leads to various malformations such as acromicry (too small hands and feet) and hyperphagia (excessively increased food intake).
  - Porphyria or acute intermittent porphyria (AIP); genetic disease with autosomal dominant inheritance; patients with this disease have a 50 percent reduction in the activity of the enzyme porphobilinogen deaminase (PBG-D), which is sufficient for porphyrin synthesis. Triggers of a porphyria attack, which can last a few days but also months, are infections, drugs or alcohol. The clinical picture of these attacks presents as acute abdomen or neurological deficits, which can take a lethal course. The leading symptoms of acute porphyria are intermittent neurologic and psychiatric disturbances. Autonomic neuropathy is often in the foreground, causing abdominal colic (acute abdomen), nausea (nausea), vomiting or constipation (constipation), as well as tachycardia (heartbeat too fast: > 100 beats per minute) and labile hypertension (high blood pressure).
  - Trisomy 21 (Down syndrome) – genetic disease that usually occurs sporadically; in which the entire 21st chromosome or parts of it are present in triplicate (trisomy) (occurrence usually sporadic). In addition to physical features considered typical for this syndrome, the cognitive abilities of the affected person are usually impaired; furthermore, there is an increased risk of leukemia.
  - Turner syndrome (synonyms: Ullrich-Turner syndrome, UTS) – genetic disorder that usually occurs sporadically; girls/women with this peculiarity have only one functional X chromosome instead of the usual two (monosomy X); inter alia. Among other things, with an anomaly of the aortic valve (33% of these patients have an aneurysm/diseased bulging of an artery); it is the only viable monosomy in humans and occurs approximately once in 2,500 female newborns.
  - Wolfram syndrome (WFS) – rare genetic disorder with autosomal recessive inheritance; neurodegenerative disease with type 1 diabetes mellitus, diabetes insipidus, optic atrophy, and neurologic symptoms.

Behavioral causes

Nutrition
- Early consumption of cow’s milk
- NitrosaminesCured foods and foods high in nitrates and nitritesNitrate is a potentially toxic compound: Nitrate is reduced to nitrite in the body by bacteria (saliva/stomach). Nitrite is a reactive oxidant that reacts preferentially with the blood pigment hemoglobin, converting it to methemoglobin. Furthermore, nitrites (also contained in cured sausage and meat products and ripened cheese) form nitrosamines with secondary amines (contained in meat and sausage products, cheese and fish), which have genotoxic and mutagenic effects.They promote the development of cancer of the esophagus, stomach, pancreas and liver.The daily intake of nitrate is usually about 70% from the consumption of vegetables (lamb’s lettuce, lettuce, green, white and Chinese cabbage, kohlrabi, spinach, radish, radish, beet), 20% from drinking water (nitrogen fertilizer) and 10% from meat and meat products and fish.
- Micronutrient deficiency (vital substances) – see prevention with micronutrients.
Weight gain from birth to twelve months of age: Children who later developed type 1 diabetes mellitus weighed a mean of 240 g (Norwegian Mother and Child Cohort Study, MoBa) or 270 g (Danish National Birth Cohort, DNBC) more at twelve months than children without diabetes.
Childhood obesity: Mendelian randomization analysis: obesity alleles are much more common in individuals with type 1 diabetes in childhood than in the control group (risk of type 1 diabetes increased by 2.7-fold and by about one-third per BMI standard deviation from normal weight)

Disease-related causes

Viral infections mainly with enteroviruses (coxsackie and polioviruses) or rubella viruses; also viral respiratory infections in the first months of life.
Pancreatic diseases
- Cystic fibrosis (cystic fibrosis)
- Pancreatitis (inflammation of the pancreas)
- Pancreatic tumor (tumor of the pancreas)
- Post-pancreatic resection (due to a reduction in beta cell mass).
- Idiopathic hemochromatosis (iron storage disease).
- Fibrocalcifying pancreatitis

Medication

Antibiotics? – the prospective international TEDDY study found no association between type 1 diabetes mellitus and prior antibiotic therapy (cephalosporins, penicillins, or macrolides were used in approximately 70% of cases) in children at high genetic risk for type 1 diabetes, meaning that antibiotic therapy has no effect on autantibody formation.

Operations

Children delivered by caesarean section (sectio caesarea) have more than twice the risk of type 1 diabetes than children delivered spontaneously, according to the BABYDIAB study.

Environmental exposure – intoxications (poisonings).

High levels of particulate matter and nitrogen dioxide lead to earlier manifestation of type 1 diabetes in young children
Nitrosamines (carcinogens).