Type 1 diabetesE10.90

Type 1 diabetes mellitus is characterized by the destruction of the insulin-producing beta cells of the islets of Langerhans by an immune-mediated (T-cell-mediated) "autoimmune insulism" with absolute insulin deficiency (Wang K et al. (2019). Antibodies against glutamate decarboxylase (GADA) or against insulin (IAA) are always detectable. At a degree of destruction of about 80% of the beta cells, the blood sugar level rises and diabetes becomes clinically relevant. In the initial phase of the disease there may still be a small residual insulin production - measurable via the C-peptide.

Type 1 diabetes: Immunological diabetes

Special forms:

• LADA: Acronym for "Latent Autoimmune Diabetes in Adults". In this latent insulin-dependent diabetes mellitus in adults, antibodies against glutamate decarboxylase (GAD) can typically be detected.
• JODA: Acronym for "Juvenile-Onset Diabetes of the Adults" describes a type 1 diabetes occurring from the age of 40.

In Germany, approximately 7.2% of people between the ages of 18 and 79 suffer from diabetes mellitus. About 90 to 95% are affected by type 2 diabetes, 5-10% by type 1 diabetes. The number of type 1 diabetics in Germany is estimated at about 300,000 people. In 2017 there were > 1.1 million children worldwide with type 1 diabetes (Rosner B et al.). However, there are no reliable figures, as diabetes is not a notifiable disease in Germany.

Aetiopathogenetically, there is an immune-induced destruction of the beta cells of the islets of Langerhans, a cellular and humoral "autoimmune insulism" with a consecutive, absolute insulin deficiency, hence the name "insulin-dependent diabetes mellitus". The cause of type 1 diabetes is understood to be a multifactorial process involving autoimmunological, genetic (in >90% of patients with type 1 diabetes the HLA characteristics DR 3 and/or DR 4 are detectable) and environmental factors. Genetic factors play a predisposing role: 20% of type 1 diabetics have a positive family history. To date, > 50 genes have been identified that have been shown to be associated with the development of type 1 diabetes. The vast majority of type 1 diabetics have a polygenic formation type. In rare cases, monogenetic diabetes forms are present. (see below MODY diabetes).

Immune situation: Antibodies against different types of diabetes are detectable. The most important of these are glutamate decarboxylase antibodies(GAD65) or antibodies directed against insulin(anti-IA-2). This immunological reactivity has been shown to correlate with the IgG titer against rotavirus. A similar mechanism of action is also suspected for other enteroviruses and their vaccination, such as Coxsackie-B viruses (especially B4). Furthermore, associations with autoimmune diseases such as Hashimoto's thyroiditis, type A gastritis, Addison's disease and celiac disease have been proven.

Environmental factors:

Sectio: The risk for children of diabetic parents to also develop diabetes after a caesarean section up to the age of 12 years is 4.8%, twice as high as after a natural birth (2.2%). It is assumed that a sectio changes the composition of the child's intestinal flora and thus promotes the development of autoimmunity.

Maternal obesity: Mothers who are overweight are also at increased risk of a child developing type 1 diabetes during childhood. This is also true for women with existing type 1 diabetes (Hidayat K et al. 2019).

Bafilomycins (group of macrolide antibiotics), which are produced by Streptomyces species, especially on root vegetables (potatoes, carrots), damage (in animal experiments) the cells of Langerhans even in the smallest amounts and lead to glucose intolerance.

Vitamin D deficiency: Vitamin D substitution in young children can reduce the later risk of diabetes. Children who received high doses had the lowest risk of developing the disease. Countries with low UVB solar radiation have a high rate of new cases. Respiratory infections in infancy are also associated with later type 1 diabetes mellitus.

Further environmental factors are discussed:

Cow's milk: Consumption of cow's milk in the first 3 months of life in children with only short lactation.

Gluten: The very early exposure to gluten leads to a specific intestinal flora and is suspected to be the cause for the development of hyperglycaemia and type 1 diabetes in mice.

Man. Type 1 diabetes usually begins in childhood and adolescence. If one parent has the disease, the risk of the children is about 5% if the father is ill and 2.5% if the mother is ill. If both parents are ill, the risk of the children being affected is 20%. The risk of illness for identical twins is 35%.

First manifestation most often between the ages of 11 and 13 (juvenile diabetes).

At the beginning, type 1 diabetes does not cause any symptoms. Only when the insulin production of the pancreas is significantly reduced, the characteristic symptoms may appear:

• Weight loss: Characteristic of the manifestation of type 1 diabetes is marked weight loss within days to a few weeks, associated with exsiccosis, constant feeling of thirst, polyuria.
• General decrease in performance, inappetence (rarer in type 2 diabetes), fatigue and lack of strength, visual disturbances and concentration problems
• Headache, diabetogenic skin changes
• Hyperglycaemia and glucosuria with osmotic diuresis (strong urge to urinate and increased thirst) associated with exsiccosis
• Disturbances of the electrolyte and fluid balance
• Impaired vision and concentration
• Decrease in libido and potency, amenorrhea
• Frequent headaches, pruritus

In freshly manifested diabetes mellitus the following antibodies can be detected in different constellations. While the manifestation of diabetes occurs much later, the autoantibodies responsible for it can often be detected at an age of 6 months to 3 years:

• Cytoplasmic islet cell Ac(ICA) (Gangliosides): 80%+.
• Anti-GAD-Ak (GADA) (glutamate decarboxylase): 80%+
• Anti-IA-Ak(IAA) (antibodies against tyrosine phosphatase): age-dependent 20-90%+
• Insulin Car-Ac
• Anti-ZnT8 (antibodies against the zinc transporter 8): 70%+
• fasting blood sugar, oral glucose tolerance level (OGTT), glycolated hemoglobin (HbA1C), ketones in urine

Infiltration of the islets of Langerhans with autoreactive T lymphocytes.

Blood glucose determination: The most important test is the determination of fasting blood glucose. Plasma glucose fasting > 126mg/dl

OGTT value (oral glucose tolerance value) or occasional value in plasma=/ >200mg mg/dl

HBA1c determination(retroactive determination of the metabolic state of the last 2-3 months.
HBA1c<5.7% excludes diabetes mellitus. HBA1c =/>6.5% is a diagnostic diabetes criterion

Determination of ketone body (acetoaceta, acetone; beta-hydroxybutyrate)

Acute complications:

• One of the most common (occurs in almost all patients) acute complications of type 1 diabetes is hypoglycemia (Kahsay H et al 2019). Ketoacidotic coma. Hyperglycemic coma (coma diabeticum).

Chronic complications:

• Macro- and microangiopathy, premature cardiovascular disease (Schofield J et al 2019).
• Diabetic nephropathy (glomerulosclerosis- M.Kimmelstiel-Wilson).
• Peripheral diabetogenic neuropathy (which occurs in all types of diabetes- Feldman EL et al 2019),
• Diabetogenic retinopathy
• Depression (Wang K et al 2019).
• Diabetogenic skin lesions (see also Diabetes skin lesions).
• Diabetic foot syndrome
• Diabetic cardiomyopathy

Therapy (see below Diabetes mellitus)

• Change of diet
• Physical exercise
• Affected persons need insulin regularly to regulate their blood glucose levels. According to the current guidelines, type 1 diabetics initially require a daily insulin dose that varies between 0.5 to 1.0 IU/kg (Muller M et al. 2018). A minority of patients supply themselves via insulin pump.
• The majority of patients follow the intensified insulin therapy (ICT) regimen. Here, a long-acting insulin is injected 1-2x/day + a dose of a fast-acting insulin is applied at mealtimes. The procedure allows flexible planning of daily life and has therefore replaced more rigid injection regimens as the standard in diabetes therapy (Nally LM et al. 2019). The carbohydrate content of each meal is estimated so that the amount of insulin required can be calculated. It is essential to check blood glucose regularly with this procedure.
• Alternative: Immunomodulatory therapy approaches with cyclosporine A, mycophenolate mofetil, anti-CD20 antibodies, cytotoxic T cells, anti-TNF antibodies, anti-CD3 antibodies, anti-thymocyte globulin, a combined rapamycin/interleukin-2 therapy require further analysis (Xin GLL et al. 2019).
• Experimental: Applications of umbilical stem cells: The application of multipotent CD45+ stem cells and CD90+, mesenchymal stem cells from umbilical cord blood can treat diabetes mellitus. There is a correction of autoimmunological dysfunctions and a supplementation of beta cell functions and numbers (Stiner R et al.2019).

Diabetes type 1 is not curable so far, so patients have to inject insulin throughout their lives. If GADA and anti-IA 2 antibodies are positive in clinically healthy patients, the risk of developing diabetes mellitus within the next two years is 20%.

1. Feldman EL et al (2019) Diabetic neuropathy. Nat Rev Dis Primers 5:41.
2. Dong S et al (2019) Effects of Periodic Intensive Insulin Therapy: An Updated Review. Curr Ther Res Clin Exp 90:61-67.
3. Hidayat K et al (2019) The influence of maternal body mass index, maternal diabetes mellitus, and maternal smoking during pregnancy on the risk of childhood-onset type 1 diabetes mellitus in the offspring: Systematic review and meta-analysis of observational studies. Obes Rev: doi:10.1111/obr.12858.
4. Kahsay H et al (2019) Evaluation of Hypoglycemia and Associated Factors among Patients with Type 1 Diabetes on Follow-Up Care at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. J Diabetes Res 10:9037374.
5. Kallinikou D et al (2019) Diabetic neuropathy in children and adolescents with type 1 diabetes mellitus: Diagnosis, pathogenesis, and associated genetic markers. Diabetes Metab Res Rev:e3178.
6. Muller M et al (2018) The influence of patient variables on insulin total daily dose in paediatric inpatients with new onset type 1 diabetes mellitus. J Diabetes Metab Disord 17:159-163.
7. Nally LM et al (2019) Pharmacologic treatment options for type 1 diabetes: what's new? Expert Rev Clin Pharmacol 12:471-479.
8. Rosner B et al (2019) Health-related quality of life in paediatric patients with type 1 diabetes mellitus using insulin infusion systems. A systematic review and meta-analysis. PLoS One 14:e0217655.
9. Schofield J et al (2019) Cardiovascular Risk in Type 1 Diabetes Mellitus. Diabetes Ther 10:773-789.
10. Stiner R et al (2019) Transplantation of stem cells from umbilical cord blood as therapy for type I diabetes. Cell Tissue Res doi: 10.1007/s00441-019-03046-2.
11. Wang K et al (2019) The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between? Mediators Inflamm 28:2987901.
12. Xin GLL et al. (2019) Current Status on Immunological Therapies for Type 1 Diabetes Mellitus. Curr Diab Rep 19:22.