Non-insulin-dependent diabetes mellitus (type 2 diabetes): causes, diagnosis, treatment

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Non-insulin-dependent diabetes mellitus (type 2 diabetes): causes, diagnosis, treatment

Etiology and incidence of non-insulin-dependent diabetes mellitus (NIDDM) . Diabetes mellitus is a heterogeneous disease, divided into type I diabetes (IDDM) and type II diabetes (IDDM) (see table. C-30). NIDDM (MIM No. 125853) accounts for 80 to 90% of all cases of diabetes and is found in the US in 6-7% of adults. For reasons unknown so far, there is a strikingly high incidence of the disease among Pima Indians in Arizona, accounting for almost 50% by the age of 35-40 years.  

About 5-10% of patients with non-insulin-dependent diabetes mellitus have adult type 2 diabetes mellitus (MODY, MIM No. 606391); 5-10% – rare genetic diseases; the remaining 70-85% is a “typical form” of non-insulin-dependent type II diabetes mellitus, characterized by a relative lack of insulin and increased resistance to it. The molecular and genetic basis of a typical non-insulin-dependent diabetes mellitus remains poorly understood.  

Pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)

Non-insulin-dependent diabetes mellitus NIDDM ) is caused by impaired insulin secretion and resistance to its action. Normally, the main secretion of insulin occurs rhythmically, in response to a load of glucose. In patients with non-insulin-dependent diabetes mellitus (NIDDM), the basal rhythmic release of insulin is impaired, the response to glucose loading is inadequate, and the basal level of insulin is elevated, although it is relatively lower than hyperglycemia. 

First, persistent hyperglycemia and hyperinsulinemia appear , initiating the development of non-insulin-dependent diabetes mellitus (NIDDM). Persistent hyperglycemia decreases the sensitivity of islet b-cells, leading to a decrease in insulin release for a given blood glucose level. Similarly, chronically elevated basal levels of insulin inhibit insulin receptors, increasing their insulin resistance.  

In addition, since insulin sensitivity is reduced, glucagon secretion increases; an excess of glucagon increases the release of glucose from the liver, which increases hyperglycemia. In the end, this vicious cycle leads to non-insulin-dependent diabetes mellitus.  

A typical non-insulin-dependent diabetes mellitus occurs due to a combination of genetic predisposition and environmental factors. Observations supporting a genetic predisposition include differences in concordance between monozygous and dizygotic twins, family accumulation, and differences in prevalence in different populations.  

Although the type of inheritance is regarded as multifactorial , the identification of the main genes, complicated by the influence of age, gender, ethnicity, physical condition, diet, smoking, obesity and the distribution of fat, has achieved some success. 

Full genome screening showed that polymorphic alleles of short tandem repeats in the intron of the transcription factor TCF7L2 are closely linked in the Icelandic population with non-insulin-dependent diabetes mellitus. Heterozygotes (38% of the population) and homozygotes (7% of the population) have an increased risk relative to non-carriers of NIDDM by approximately 1.5 and 2.5 times, respectively.  

An increased risk in carriers of the TCF7L2 variant has also been found in Danish and American cohorts of patients. The risk of NIDDM associated with this allele is 21%. TCF7L2 encodes a transcription factor involved in the expression of the glucagon hormone, which increases the concentration of blood glucose, acting opposite to the action of insulin, which reduces the level of blood glucose. Screening of the Finnish and Mexican groups revealed another predisposition, the mutation of Prgo12A1a in the PPARG gene, which is obviously specific for these populations and provides up to 25% of the population risk of NIDDM.  

The more frequent proline allele occurs with a frequency of 85% and causes a slight increase in the risk (1.25 times) of diabetes mellitus.  

The PPARG gene is a member of the nuclear hormone receptor family and is important for regulating the function and differentiation of fat cells.  

Confirmation of the role of environmental factors includes less than 100% concordance in monozygotic twins, differences in distribution in genetically similar populations, and associations with lifestyle, nutrition, obesity, pregnancy, and stress. It has been experimentally confirmed that although a genetic predisposition is a prerequisite for the development of non-insulin-dependent diabetes mellitus, the clinical expression of non-insulin-dependent diabetes mellitus (NIDDM) is highly dependent on the influence of environmental factors.  

Phenotype and development of non-insulin-dependent diabetes mellitus (NIDDM)

Typically, non-insulin-dependent diabetes mellitus (NIDDM) occurs in obese people of middle age or older, although the number of sick children and young people is growing due to an increase in the number of obese and lack of mobility among young people.  

Type 2 diabetes mellitus has a gradual onset and is usually diagnosed by elevated glucose levels with a standard examination. Unlike patients with type 1 diabetes, patients with non-insulin-dependent diabetes mellitus (NIDDM) usually do not develop ketoacidosis. Basically, the development of non-insulin-dependent diabetes mellitus (NIDDM) is divided into three clinical phases. 

At first, the blood glucose concentration remains normal, despite elevated insulin levels, indicating that the target tissues of insulin remain relatively resistant to the influence of the hormone. Then, despite an increased concentration of insulin, hyperglycemia develops after exercise. Finally, impaired insulin secretion causes hunger hyperglycemia and a clinical picture of diabetes.  

In addition to hyperglycemia, metabolic disorders caused by islet b-cell dysfunction and insulin resistance cause atherosclerosis, peripheral neuropathy, renal pathology, cataracts and retinopathy. One in six patients with non-insulin-dependent diabetes mellitus (NIDDM) develops renal failure or severe vascular pathology requiring amputation of the lower extremities; one in five goes blind due to the development of retinopathy. 

The development of these complications is determined by the genetic background and the quality of metabolic control. Chronic hyperglycemia can be detected by determining the level of glycosylated hemoglobin (HbA1c). Strict, as close to normal as possible, maintaining glucose concentration (not more than 7%), with the determination of the level of HbA1c, reduces the risk of complications by 35-75% and can extend the average life expectancy, which is currently an average of 17 years after establishment diagnosis for several years.  

Features of phenotypic manifestations of non-insulin-dependent diabetes mellitus : • Onset age: from childhood to adulthood • Hyperglycemia • Relative insulin deficiency • Insulin resistance • Obesity • Skin acanthosis blackening 

Treatment of non-insulin-dependent diabetes mellitus (NIDDM)

Decrease in body weight , increased physical activity and dietary changes help most patients with non-insulin dependent diabetes mellitus (NIDDM) markedly improve insulin sensitivity. Unfortunately, many patients are unable or unwilling to radically change their lifestyle in order to improve, and require treatment with oral hypoglycemic drugs, such as sulfonylureates and biguanides. A third class of drugs, thiazolidinediones, reduces insulin resistance by binding to PPARG. 

You can also use the fourth category of drugs – a-glucosidase inhibitors, which act by slowing the intestinal absorption of glucose. Each of these drug classes is approved as monotherapy for non-insulin-dependent diabetes mellitus (NIDDM). If one of them does not stop the development of the disease, a drug from another class can be added.  

Oral hypoglycemic drugs are not as effective at controlling glucose levels as weight loss, increased physical activity, and dietary changes. To achieve glucose control and reduce the risk of complications, some patients require insulin therapy; however, it enhances insulin resistance by increasing hyperinsulinemia and obesity.  

Risks of inheritance of non-insulin-dependent diabetes mellitus (NIDDM)

The population risk of non-insulin-dependent diabetes mellitus (NIDDM) is very dependent on the population being studied; in most populations, this risk is from 1 to 5%, although in the United States it is 6-7%. If the patient has a sick siblings, the risk increases to 10%; the presence of a sick siblings and another relative of the first degree of kinship increases the risk to 20%; if a monozygotic twin is sick, the risk rises to 50-100%.  

In addition, since some forms of non-insulin-dependent diabetes mellitus (NIDDM) overlap with type 1 diabetes, children of parents with non-insulin-dependent diabetes mellitus (NIDDM) have an empirical risk of 1 in 10 for developing type 1 diabetes.

An example of non-insulin-dependent diabetes mellitus . M.P., a healthy 38-year-old man, an American Indian Pima tribe, consults about the risk of developing non-insulin-dependent diabetes mellitus (NIDDM). Both of his parents suffered from non-insulin-dependent diabetes mellitus; father died at 60 from myocardial infarction, mother at 55 from renal failure. A paternal grandfather and one of the older sisters also suffered from non-insulin-dependent diabetes mellitus, but he and his four younger siblings are healthy.

Medical examination data were normal, with the exception of minor obesity ; fasting blood glucose levels are normal, but an increase in blood insulin and glucose levels has been detected after an oral glucose load. These results are consistent with early manifestations of a metabolic state, probably leading to non-insulin-dependent diabetes mellitus. His doctor advised the patient to change their lifestyle, lose weight and increase physical activity. The patient sharply reduced fat intake, started cycling to work and running three times a week; his body weight decreased by 10 kg, and glucose tolerance and insulin levels in the blood returned to normal. 

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