Diabetes is caused by the reasons?

(A) etiology

The exact cause of type 1 diabetes and pathogenesis is not yet clear, its cause is a common genetic and environmental factors involved. Mainly due to immune-mediated selective destruction of pancreatic B cells caused.

1. Genetic factors

(1) family history: type 1 diabetes have a certain familial aggregation. Some studies report parental history of diabetes, their children with type 1 diabetes incidence rate of 4% to 11%; brothers and sisters of the family aggregation of type 1 diabetes incidence rate of 6% to 11%; with twins occur with type 1 diabetes consistency of less than 50%.

(2) HLA and type 1 diabetes: human leukocyte antigen (HLA) genes located on the short arm of chromosome 6, for a group of closely linked genes, HLA by the Ⅰ, Ⅱ, Ⅲ 3 genes encode. Ⅰ gene region including HLA-A, HLA-B, HLA-C and other features unknown genes and pseudogenes, and its encoded antigen present in all nucleated cells of the surface, is responsible for presenting foreign antigens to CD8 T- lymphocytes; Ⅱ genes, including in the HLA-DR, HLA-DQ and HLA-DP3 sub-regions, respectively, encoding DR, DQ and DP antigen, present in mature B lymphocytes and antigen presenting cells responsible for presenting antigens to CD4 cells; Ⅲ regional coding genes, including some of the complement components, including a number of soluble proteins, such as C2C4A, C4B, tumor necrosis factor (TNF) and heat shock protein (HSP) and so on. HLA by major histocompatibility complex (MHC) restrictions, participation in T lymphocytes and other immune cells recognize antigen interactions, and their formation and maintenance of tolerance, and dissent in the identification of their induction and regulation of immune responses and other aspects play an important role. Visible, HLA in many autoimmune diseases, including type 1 diabetes and the development occupies a very important position.

Now been confirmed that some of the HIA and the incidence of type 1 diabetes has a strong correlation. In a family of type 1 diabetes, the same HLA antigen brothers and sisters the chance of diabetes of 5% to 10%, rather than HLA identical siblings, the chance of diabetes less than 1%. The population in the Caucasus, 95% have type 1 diabetes HLA-DR3 or HLA-DR4, but not diabetes, was 45% ~ 50%; HLA-DR2 to avoid the occurrence of type 1 diabetes has a protective effect. HLA-DQ type 1 diabetes susceptibility gene is a more specific mark, decided to autoimmune destruction of B cells to susceptibility and resistance. Has been reported in type 1 diabetes mellitus associated with HLA-DR3 patients, almost 70% of the identified HLA-DQw3.2, while the gene HLA-DQw3.1 protection was observed in the DR4 controls. Researchers found that if the two other places DQβ chain section 57 is aspartic acid footprint, generally not prone to autoimmune diabetes, if the two other sites are non-aspartic acid is easy to type 1 diabetes strongly sense, HLA-DQA1 chain of arginine is also the first 52 type 1 diabetes susceptibility gene. HLA-DQβ1 chain of 57 non-aspartate homozygotes and HLA-DQA1 chain of 52 arginine homozygous individuals suffering from type 1 diabetes, the highest relative risk. DQβ chain of 45 amino acids on the immune epitopes identified as DQw3.2 not DQw3.1. These findings may explain the HIA-DQ, and HLA-DR loci appear higher than the joint performance alone there are more type 1 diabetes risk.

HLA subtypes and type 1 diabetes: HLA phenotypes according to the subtypes of type 1 diabetes, the cause of the difference between clinical and meaningful. Reflected the general view that if the HLA HLA-DR3/DR3 will cause a primary autoimmune disease, and HLA-DR4/DR4 primary environmental factors on behalf of the main incentives, the result is secondary autoimmune response. HLA-DR3 associated with type 1 diabetes is often associated with the presence of other autoimmune diseases (such as adrenal insufficiency, Hashimoto's thyroiditis, etc.) and more common in women, older onset. The HLA-DR4 associated with type 1 diabetes and other autoimmune endocrine disease is almost nothing to do with male predominance, younger age at onset. Reports of 745 cases of onset from 1 to 19 years old with type 1 diabetes, according to HLA typing showed: HLA-DR3 HLA-DR4 patients than in patients with onset of less severe when, ketones in urine light, followed by partial remission of the tendency of big.

2. Environmental factors, type 1 diabetes usually occurs with some infection or infection ensued. Previous mumps infection common virus, rubella virus, cytomegalovirus, measles virus, influenza virus, encephalitis virus, polio virus, coxsackie virus and Epstein-Barr virus, but the virus infection, diabetes occurs susceptibility or resistance may be caused by genetically determined. If two people (such as brothers or sisters) exposed to the same virus infection, may show the same increase for the HIV antibody, but diabetes may only happen in a person, this may be due to intrinsic differences in genetic susceptibility factors. Susceptibility of B cells could mean a specific dose of a virus sensitivity; or a viral antigen expression in B cells, or minor damage in the release of B cell self-antigen reaction occurs autoimmune tendency.

Recently, some studies within 3 months after birth with formula milk or milk products to feed the children, the type 1 diabetes have a higher risk, caused much concern. Study suggests that certain proteins in milk may be one of the factors leading to diabetes, such as bovine serum albumin, has been in the majority of type 1 diabetes patients to detect antibodies against bovine serum albumin, the antibody can be dissolved with the islet B cells The molecular weight of 69 000 protein precipitation. Antibodies are considered as infant intestinal permeability allows the protein into the circulation, circulating sensitized lymphocytes caused by bovine serum albumin, occurs with the islet B cells 69 000 protein cross humoral and cellular immune response, ultimately leading to B cell damage. The other two kinds of protein β-lactoglobulin and casein, were also considered to be an independent risk factor for diabetes. Have speculated that the higher the heat applied to feed baby milk formula in infancy can lead to increased insulin secretion and islet antigen-presenting role of B cells increased. However, others believe that the milk and type 1 diabetes is not clear, the milk protein as a factor in the origin of type 1 diabetes is still a large debate, needs further study.

3. Genetic - environmental interactions of genetic and environmental factors on an individual incidence of type 1 diabetes varies. Environmental factors related to how to start the islet B cells in autoimmune reaction is still not entirely clear, under normal circumstances, the susceptibility of human l-type genetic background of diabetes requires that some environmental substances induce individuals with a genetic susceptibility to autoimmune B cells. Hypothesis: Once the environmental factors on B cell damage than individual B cells genetically determined level of damage tolerance, type 1 diabetes at this time will be.






Environmental factors, such as through the release of cytokines interleukin -1 (IL-1) or tumor necrosis factor-α (TNF-α) and other specific or non-specific damage to B cells. Genetic factors play a role and decisions to allow B cells to start the initial susceptibility to autoimmune damage. Rare is: B cell-specific autoimmune toxic substances across a lot of damage leading to B cells. More common situation is: Repeated B cell injury in the genetic susceptibility of individuals with secondary anti-B cell induced autoimmune; that autoimmunity may also be without the involvement of environmental factors and occur spontaneously. B final common pathway of cell death may come from the excessive production of oxygen free radical or NO on the B cell destruction.

The etiology of type 2 diabetes is not very clear, is generally considered to be a strong genetic or genetic heterogeneity for the disease, multiple genes, environmental factors are obesity, lack of activity and aging. The disease was mainly due to insulin resistance and insulin secretion mainly lack of insulin resistance usually precedes insulin secretion disorders; or inadequate insulin secretion mainly with or without insulin resistance. Although type 2 diabetes has genetic heterogeneity, but the majority with type 2 diabetes and fasting hyperglycemia characteristic of patients showed insulin resistance, insulin secretion and hepatic glucose production increased barriers.

(B) the pathogenesis of

Is generally believed that the incidence of type 1 diabetes is mainly mediated by the cellular immune. Have proposed the pathogenesis of modes: from any external or internal environmental factors (nutrition, viruses, chemicals, IL-1, etc.) will result in the release of B cell antigen or viral antigen expression in B cells or with B cell antigen with similar , the antigen may be located within the islet antigen presenting cells (macrophages) uptake and processing of sensitized antigen, further activation of antigen presenting cells, resulting in a large number of cytokines and secretion (IL-1 and TNF, etc.) In addition, with specific recognition receptor peptide sensitized T-helper cells (CD8 cells) in pancreatic islets and induce gene expression in a lymph node, one of which, such as TNF, to stimulate the antigen presenting cells to increase feedback major histocompatibility complex (MHC) molecules Asia, IL-l and TNF expression. In addition, macrophage cell lineage (in islet) also led to other cells outside the cytokines. By the TNF and interferon (IFN) enhanced IL-1 by inducing the production of free radicals and the pancreatic islet B cells present on the cytotoxicity. With the B cell damage (degeneration) increase, more allergenic antigens are presented on the immune system, a vicious cycle, showing self-induced and self-limited form. IL-1 produced by pancreatic islets can be induced significantly increased production of free radicals (superoxide anion, hydrogen peroxide, hydroxyl radicals, etc.), addition, IL-1, interferon-γ (INF-γ) and TNF-α and so also B cells induced inducible nitric oxide (NO) synthase synthesis, resulting in substantial NO production (NO-derived peroxynitrite on the B cells also have significant toxic effects), plus a minimum of human pancreatic islet B cells of oxygen free radicals scavenging capacity, thus B cells selectively damaging effects of oxygen free radicals are particularly sensitive. B cells of oxygen free radical damage DNA, activation of starch synthesis enzymes to repair the damage of DNA, this process accelerated NAD depletion, the final B cell death. In addition, free radicals on membrane lipids, carbohydrates and proteins within cells is also of great injury. In addition, in the process, free radicals also lead to lymphatic factors and trends CIM4 T lymphocytes and activation of the lesion, while macrophages or antigen presenting cells in their damaged B lymphocyte antigen to CD4, activated CD4 further activation of B lymphocyte cells produce anti-virus antibody and anti-B cell autoantibodies also promote B cell destruction.

Now almost clear l diabetes is immune-mediated selective destruction of pancreatic B cells caused. Has confirmed that prior to the onset of type 1 diabetes and its duration, the body can detect a variety of antibodies against B cells, such as islet cell antibodies (ICA), insulin antibodies (IAA), glutamic acid decarboxylase (GAD antibodies), and insulinoma associated protein antibodies.

1. Islet cell antibody Bottazzo equal to 1 in 1974 first described the existence of anti-diabetic patients with islet cell antigens, and can be detected by immunofluorescence, this method of eliminating minor modifications, has been in use ever since, recently also by RIA and enzyme-linked immunosorbent inspection of such antibodies. Clinical study: an ordinary ICA positive non-diabetic population is less than 3%, while the newly diagnosed type 1 diabetes ICA positive rate was 60% to 90%. ICA is divided into islet cytoplasmic antibodies and islet cell surface antibodies. However, examination of islet cell surface antibodies rarely used in clinical, clinical difficult to obtain due to fresh islets or insulinoma cell samples, and islet cytoplasmic antibody test is relatively simple and has been standardized, and therefore widely used in clinical practice. Islet cell antibody positive rate of extension of duration of diabetes decreased 80% to 90% of patients with type 1 diabetes onset in vivo islet cytoplasmic antibodies disappear after 2 years; 10% to 15% of patients persisted over three years. In the course of disease similar circumstances, often accompanied by positive antibody: ① thyroid and gastric autoantibodies; ② other autoimmune endocrine disease; ③ have a strong family history of other autoimmune diseases; ④ women more common; ⑤ with HLA-DR3 / B8 strongly related. But there are also reports of type 1 diabetes, 62% 3 years after the onset of ICA-positive patients is not found these differences.

ICA in the clinical degree relatives of type 1 diabetes was higher than that in the general population, and the ICA and the subsequent detection of clinical type 1 diabetes associated with an increased risk of high titer (eg,> 80JDF units) of the forecast value significantly higher than the low titer (eg, <20JDF units), ICA continued positive type 1 diabetes was significantly higher than the risk of a transient positive. Prospective study: ICAs titer of 4 ~ 9JDF units and units greater than 20JDF degree relatives of type 1 diabetes within 5 years of approximately 5% and 35% needed insulin therapy, insulin dependent and 10 years were 60% 79%, ICA remained at a high titer of positive first-degree relatives in type 1 diabetes have better predictive value. But clinical studies have also found that those small number of high-titer ICAs, sustainable islet B cell function remained stable for several years, the exact mechanism is unclear. Now report small clinical application of immunosuppressive drugs and nicotinamide can significantly prevent or delay the high-titer ICA-positive non-diabetic first degree relatives dominant progression to clinical type 1 diabetes, large-scale clinical studies are in progress. In addition, also shows that a considerable proportion of clinical (10% ~ 20%) of non-insulin-dependent diabetic patients detected ICA, these patients eventually have 80% to 85% in the years after the need for insulin therapy, and ICA-negative patients only 15%. With ICA is that the positive clinical effect of non-insulin-dependent diabetes may be "latent autoimmune diabetes in adults" (LADA, are areas of type 1 diabetes), had previously been described as "type 1.5 diabetes" or "slow progress in insulin-dependent diabetes "(SPIDDM). In addition, these patients also often has positive anti-GAD. Its characteristics: ① age of onset usually> 15 years; ② non-obese non-insulin-dependent diabetes mellitus onset; ③ early disease can be controlled diet or oral hypoglycemic medication therapy; ④ often occur in 1 to 4 years, failure of oral hypoglycemic drugs or ketosis prone diabetes and insulin-dependent; ⑤ ICA-positive, anti-GAD-Ab positive, C peptide and low levels of HLA-DR3 / 4 and so on. For the "LADA" patients are more consistent view is that early use of insulin therapy to delay the in vivo destruction of residual islet B cells.

2. Anti-GAD antibodies glutamic acid decarboxylase (glutamic acid decarboxylase, GAD) is the inhibitory neurotransmitter γ-aminobutyric acid biosynthesis enzyme, present in human and animal brain and pancreatic tissue. In recent years, found that the form of two isomers, the relative molecular weight of 65000 (GAD65) and 67000 (GAD67), and displays the GAD and type 1 diabetic patients 64 000 protein antigens share many physical and chemical characteristics. Joint identification of a number of studies show that patients with type 1 diabetes, the body and disease-related autoantigen one of the 64,000 protein is GAD, GAD is considered a type of autoimmune response to the major autoantigen. GAD antibodies (GAAs) Determination of protein than the determination of anti -64,000 simple, practical, and thus gradually been widely used in clinical. The clinical value of ICA similar, but the positive rate and specificity of higher than ICA. Degree relatives of type 1 diabetes in type 1 diabetes in preclinical individuals, GAAs positive, sometimes negative and ICA and IAA; in newly diagnosed type 1 diabetes GAAs positive rate of 75% to 90%, in the long course (3 ~ 10 years) with type 1 diabetes positive rate up to 60% to 80%. GAA in the detection of type 1 diabetes diagnosis, especially for early identification of LADA important value and the relatives of type 1 diabetes predicted the risk of diabetes. Current clinical detection methods for GAA immunoprecipitation, radioimmunoassay, enzyme-linked immunosorbent assay and immunofluorescence assay and other methods.

3. Insulin autoantibodies (IAAs) IAA, can be combined with insulin autoantibodies, can be seen in unused exogenous insulin in patients with type 1 diabetes and preclinical patients, newly diagnosed with type 1 diabetes positive rate of IAA 40% to 50%. Existing methods can not due to IAA treatment of insulin from insulin antibodies distinguish. Meanwhile, after diagnosis of type 1 diabetes, IAAs of Natural History has not been investigated. IAA production may be primary, from the abnormal clone in B lymphocytes, or after islet B cell damage caused. Islet B cell damage may lead to structural changes in insulin release, and is the immune system as foreign bodies; or insulin or earlier precursor biosynthesis in B cells are released when damage and as antigen; immune response to reports of insulin activity (possibly proinsulin precursors) present in the B cytoplasmic membrane, addition, and insulin independent of foreign antigen similarity may lead to their bodies IAAs. The same as the ICAs and GAAs, IAAs in the prediction of type 1 diabetes is also important. IAA titers of type 1 diabetes prediction of time as part of the formula, the formula taking into account the high risk of the first phase insulin secretion, there will be time for type 1 diabetes (years) = 1.5 0.03 × intravenous glucose tolerance (1min when insulin and When insulin and 3min) -0.008 × (IAA titer), but still needs a large series of prospective studies conducted to evaluate this formula. Age was negatively correlated with the IAAs, IAAs common in children, and often has high titer. Have that IAAs in non-diabetic individuals younger than in the adult islet B cell damage better reflect the rapid and quickly progressed to type 1 diabetes. With type 1 diabetes is mainly related to the IAA IgG, occasionally as IgM. IAAs generally radioimmunoassay and enzyme-linked immunosorbent assay. A number of studies by the radioimmunoassay of IAAs can improve the ICAs degree relatives of type 1 diabetes in the general population and the subsequent prediction of the value of the type 1 diabetes, while enzyme-linked immunosorbent assay of IAAs appear to type 1 diabetes no predictive value. So that only the International Diabetes Workshop evaluation phase radioimmunoassay of autoantibodies associated with diabetes are more practical.

4.IA-2 and IA-2β and antibody IA-2 (insulinoma associated protein 2) and its analogues IA-2β is the second GAD was later confirmed by two other islet cell autoantigen, both with the protein casein acid phosphatase catalytic domain highly homologous conserved regions, the receptor type protein tyrosine phosphatase superfamily new members, but its phosphatase catalytic activity has not been confirmed that the physiological function is not clear. IA-2 and IA-2β were type Ⅰ transmembrane glycoprotein, each containing 979 and 986 amino acid residues, with molecular weights of 106,000 and 108,000, respectively, in the human gene coding No. 2 (2q35) and 7 (7q35 ) chromosome. Taken by an extracellular domain, a single transmembrane domain and an intracellular domain composed of 42% of the coherence length in the intracellular domain of 74% homology. IA-2 and IA-2β mainly in islet α, β, δ cells, pancreatic α, β cell tumor, pituitary, brain and adrenal medulla and other neuroendocrine tissues. Now that the IA-2, IA-2β, GAD and insulin are of type 1 diabetes autoantigen, IA-2 and IA-2β antigens are located in the intracellular domain of the C-terminal, and their antibodies primarily recognize conformational epitopes IA-2 and IA-2β have a common antigen epitope, and their specific epitopes. IA-2Ah literature exists in 60% to 80% of newly diagnosed type 1 diabetes patients, early in diabetes was detected in 40% to 60% in the healthy population, the positive rate of about 1%. IA-2βAb in newly diagnosed type 1 diabetic patients positive rate of 45% to 60%, slightly lower than the IA-2Ab positive rate, both the positive rate with the duration of the extension and the onset age of type 1 diabetes increases gradually declining. IA-2Ab and IA-2βAb specificity than the GAD-Ab high, not with type 1 diabetes patients with autoimmune disease was found in less of a relative positive predictive value was 75%. Recent study found that 98% of newly diagnosed type 1 diabetes islet autoantibody at least there is a positive, there are two or more 80%, while none of healthy people the existence of two or more antibodies. Three kinds of antibodies (IA-2Ab, GAD-Ab and IAA) were negative, a relative risk of diabetes within 5 years is less than 0.5%, only one kind of antibody-positive cancer risk was 15%, two kinds of antibodies for the 44%, three antibodies were positive 100% risk. Is that the combined detection of IA-2Ab, GAD-Ab and IAA is the prediction of type 1 diabetes, the most reliable immunological marker, as IA-2Ab and IA-2βAb significantly correlated, so in the United IA-2βAb not further increase the sensitivity of detection and positive predictive value. IA-2Ab and IA-2βAb detection mainly ELISA method (ELISA) and radioligand analysis (RLA), which RLA specimens required less can be semi-automatic operation, saving time and labor, and suitable high-risk groups and children in the census.

The natural incidence of type 1 diabetes process is as follows:

Phase I (genetic susceptibility: some sites related with HLA)

Environmental factors such as viral infection → ↓

Phase II (start autoimmunity, islet B cell damage)

Phase III (immunological abnormalities: a loop, there may be a variety of antibodies against B cells, insulin secretion is still normal) ↓

Phase IV (pancreatic islet B cells decreased progressively, its functions are reduced, blood sugar, resulting in diabetes) ↓

Fifth (clinical diabetes: islet B cell survival is less than 10%, with significant clinical symptoms of high blood sugar) ↓

Sixth (clinical diabetes after several years or many years later, B cells completely destroyed, the extremely low level of insulin, loss of response to stimuli, and many patients had various degrees of chronic complications)

5.1 diabetes islet pathology

(1) Early pathological changes: As early as 1910 that is documented in patients with type 1 diabetes in lymphocytes and macrophage infiltration of acute pancreatic inflammation, and then report the incidence of type 1 diabetes 6 months after the autopsy showed the death of the individual islet 2 / 3 of the above damage, the survival of B cells in less than 10% of the total. However, patients with long duration without lymphocytic infiltration. Short duration type 1 diabetes seen in patients with partial regeneration of pancreatic islet B cells, but as the disease progressed, B cells become increasingly rare in the local regeneration, and regeneration of B cells subsequently been destroyed.

(2) advanced pathology: diagnosis of type 1 diabetes from 1.5 to 34 years after the autopsy showed: As 98% of total normal pancreatic exocrine tissue atrophy, the pancreas weight decreased. Exocrine gland atrophy may be due to a lack of high concentrations of insulin by vascular perfusion bed of the pancreas itself, pancreatic insulin concentrations in the role of their own nutritious, and the role of subcutaneous administration of exogenous insulin treatment to succeed. Type 1 diabetes islet small and small, weighing less than normal or type 2 diabetes 1 / 3, B cells were almost completely lacking. Pancreatic islet cells and almost only contains α σ cells and in cells in the pancreas head and distal PP. Each islet α cells, and σ the normal or increased number of cells, pancreas cells in the total amount of α and σ in the normal range.