Insulin-dependent diabetes mellitus (type I diabetes): causes, diagnosis, treatment

Etiology and incidence of insulin-dependent diabetes mellitus . Insulin-dependent diabetes mellitus (IDDM) (also called type I diabetes mellitus, MS No. 222100) is usually caused by autoimmune destruction of islet pancreatic beta cells; the mechanism of initiation of this autoimmune reaction is unknown.  

The death of islet b-cells leads to a lack of insulin , and as a result to impaired anabolism and catabolism, resulting in metabolic changes similar to those observed during fasting. 

Among North American Caucasians, insulin-dependent diabetes mellitus (IDDM) is the second most common childhood illness, increasing with a frequency of 1 in 2500 at 5 years of age to 1 in 300 at 18 years of age.  

Pathogenesis of insulin-dependent diabetes mellitus

Usually insulin-dependent diabetes mellitus (IDDM) is associated with a combination of genetic predisposition and subsequent environmental effects, and only very rarely isolated environmental exposure or only a genetic mutation.  

Although approximately 90% and non-insulin-dependent diabetes mellitus (IDDM) occurs in patients without diabetes in family history, observations proving a genetic predisposition include differences in concordance between monozygous (33-50%) and dizygotic twins (1-14%), familial accumulation and differences in prevalence in different populations. In humans, more than 13 different genetic loci of predisposition were found, although several of them were identified sequentially and repeatedly. 

One of the proven loci is the HLA locus, which provides 30 to 60% of the genetic predisposition. Approximately 95% of white patients express the DR3 or DR4 allele, or both, compared to 50% in the control; Obviously, this association does not arise due to the fact that DR3 and DR4 are real predisposition alleles, but because of the disequilibrium linkage between DR and DQ. The primary predisposition alleles were the DQb1 * 0201 allele, which segregates with DR3, and DQb1 * 0302, which segregates with DR4. Conversely, the DQb1 * 602 allele linked to DR2 turned out to be a protective allele; those. the presence of these two alleles negates the predisposition effect.  

Both alleles of the DQb1 predisposition have a neutral amino acid at position 57, a site within the borders of the proposed gap that binds to the antigen, while the protective or neutral alleles of DQb1 have aspartic acid at position 57. It is believed that this substitution of an aspartic neutral amino acid changes the specificity of the antigen binding to the DQ molecule.  

Confirmation of the influence of environmental factors in the development of insulin-dependent diabetes mellitus in genetically predisposed patients is a concordance in less than 50% of monozygotic twins, seasonal changes in the incidence and increased incidence of diabetes among children with congenital rubella. Estimated environmental factors are viral infections and early exposure to bovine albumin. The action of viruses and cow albumin can cause autoimmune destruction of b-cells due to molecular mimicry, i.e. the similarity of antigenic determinants between b-cell proteins and a viral or cow protein.  

Approximately 80-90% of newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) have anti-island antibodies. These autoantibodies recognize cytoplasmic and surface cell determinants, for example, glutamic acid decarboxylase, carboxypeptidase H, ganglioside antigens, islet cell antigen 69 (ICA69), and tyrosine phosphatase protein. Glutamic acid decarboxylase and ICA69 antigen share epitopes with Coxsackie virus type B4 and bovine serum albumin, respectively.  

As a result, insulin-dependent diabetes mellitus is an autoimmune disease, although the exact role of autoantibodies to islet cells remains uncertain. Additional confirmation of the autoimmune mechanism in insulin-dependent diabetes mellitus is the increased spread of other autoimmune diseases, mononuclear islet infiltration and repeated death of b-cells after transplantation from a monozygous twin. However, two facts suggest that the development of insulin-dependent diabetes mellitus is more than the development of autoantibodies.  

Firstly, less than 1% of the general population has diabetes , although autoantibodies to islets have 10%, and secondly, relatives of patients of the first degree of kinship have antibody remission rates of 10 to 78%. 

Phenotype and development of insulin-dependent diabetes mellitus

The development of insulin deficiency occurs over several, often many, years. The earliest sign of the disease is the appearance of autoantibodies to islet tissue, while the concentration of blood glucose, glucose tolerance (the ability to maintain normal blood glucose levels after sugar loading) and the insulin response to glucose are normal. This period is followed by a phase of decreased glucose tolerance, but a normal concentration of glucose on an empty stomach.  

As b-cells continue to die , eventually fasting hyperglycemia develops, but enough insulin is still produced to prevent the development of ketosis; during this period, patients have non-insulin-dependent diabetes mellitus (NIDDM). 

In the end, insulin synthesis falls below a critical threshold, and patients become dependent on the administration of external insulin, a tendency to ketoacidosis appears. Younger patients usually go through these phases faster than older ones.  

Although acute complications of diabetes can be controlled by insulin administration, the loss of endogenous insulin synthesis causes many problems, including atherosclerosis, peripheral neuropathy, kidney pathology, cataracts and retinopathy. Approximately 50% of patients die from kidney failure. The development and severity of these complications is determined by the genetic background and the quality of metabolic support. Strict blood glucose control reduces the risk of complications by 35-75%.  

Features of phenotypic manifestations of insulin-dependent diabetes mellitus : • Age of onset: from childhood to adulthood • Polyuria, polydipsia, polyphagia • Hyperglycemia • Ketoacidosis • Weight loss 

Treatment for insulin-dependent diabetes mellitus

Although transplantation of the pancreas or islet tissue can cure insulin-dependent diabetes mellitus, tissue deficiency for transplantation and complications of immunosuppression limit this treatment. Most patients are treated with intensive correction of blood glucose by the administration of external insulin.  

The fact of the development of islet autoantibodies several years before the onset of the clinical manifestations of insulin-dependent diabetes mellitus led to the emergence of screening techniques to predict and prevent the treatment of insulin-dependent diabetes mellitus. It turned out that the administration of insulin or nicotinamide in some patients delays the development of insulin-dependent diabetes mellitus.  

The risks of inheriting insulin-dependent diabetes mellitus

The risk of insulin-dependent diabetes mellitus in the general population is approximately 1 in 300. If a sick siblings are present, the risk increases to 1 in 14 (1 to 6, if HLA antigens are identical, 1 to 20, if the HLA haplotype is identical).  

The risk increases to 1 in 6 in the presence of a second sick relative of the first degree of kinship and to 1 to 3 if a monozygotic twin is ill. Children of a sick mother have a risk of developing insulin-dependent diabetes mellitus from 1 in 50 to 1 in 33, while children of a sick father – 1 in 25 – 1 in 16. A higher risk in a sick father is limited to fathers with the HLA DR4 allele.  

An example of insulin-dependent diabetes mellitus . F.C., a 45-year-old father with a late form of diabetes, was referred to the endocrinology clinic for advice on the risk of developing diabetes in his children. The patient developed reduced glucose tolerance (inability to maintain a normal sugar curve after exercise) at the age of 39 years and hyperglycemia at 45 years. There were no therapeutic or surgical problems in the patient’s personal history.

Medical examination data is normal , with the exception of moderate obesity in the abdomen; body mass index [weight in kg / (height in m) 2] is 31.3 with excess fat, mainly distributed around the waist. At F.Ts. five children in two marriages; children from each marriage to 10 years of life developed insulin-dependent diabetes mellitus. His sister developed insulin-dependent diabetes mellitus in childhood, she died in her youth due to diabetic ketoacidosis. 

The geneticist said that, judging by the family history , the patient is likely to have a late form of insulin-dependent diabetes mellitus and that his NIDDM probably precedes the development of insulin-dependent diabetes mellitus. After discussing the possible causes and methods that delay the development of insulin-dependent diabetes mellitus, the patient agreed to enroll himself and all his minor children in a research program that studies the prevention of insulin-dependent diabetes mellitus. 

As part of this study, F.Ts. and children were tested for anti-island antibodies . Both he and the healthy daughter had a high titer of anti-islet antibodies; the daughter also showed an abnormal glucose tolerance test result, but fasting hyperglycemia was not found. As part of the study protocol, small doses of insulin are prescribed to the patient and his daughter.

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