Lack of energy

Introduction Diabetic patients are mainly caused by the oxidation of glucose, and the body needs insufficient energy, so patients feel hungry and eat more.

Cause

(1) Causes of the disease

The exact etiology and pathogenesis of type 1 diabetes is not well understood. The combination of genetic and environmental factors is mainly due to immune-mediated selective destruction of islet B cells.

Genetic factor

(1) Family history: There is a certain family aggregation of type 1 diabetes. Studies have reported that parents have a history of type 1 diabetes with a history of diabetes. The incidence of type 1 diabetes is 4% to 11%; the incidence of family aggregation of type 1 diabetes among brothers and sisters is 6 %11%; the coincidence of identical twin type 1 diabetes is less than 50%.

(2) HLA and type 1 diabetes: The human leukocyte antigen (HLA) gene is located on the short arm of chromosome 6 as a group of closely linked gene groups. HLA encodes class I gene regions by class IIIIII3 genes including HLA-AHLA-BHLA-C. And other unexplained genes and pseudogenes, which encode antigenic molecules present on the surface of all nucleated cells, are responsible for presenting foreign antigens to CD8 T lymphocytes; the class II gene regions mainly include HLA-DRHLA-DQ and HLA-DP3 The sub-regions encode DRDQ and DP antigens on the surface of mature B lymphocytes and antigen-presenting cells, which are responsible for presenting antigen to CD4 cells; the class III gene regions encode some soluble proteins such as C2C4AC4B tumor necrosis factor including certain complement components. HLA such as (TNF) and heat shock protein (HSP) are restricted by the major tissue-compatible complex (MHC) involved in the interaction of T lymphocyte recognition antigens and other immune cells, as well as the formation and maintenance of self-tolerance in the recognition of self and dissident induction. And it plays an important role in regulating immune response. HLA is very important in the occurrence and development of many autoimmune diseases including type 1 diabetes. status.

It has been confirmed that certain HIAs are strongly associated with the development of type 1 diabetes. In a family with type 1 diabetes, siblings with the same HLA antigen have a chance of developing diabetes of 5% to 10% instead of the same siblings with HLA. The chance of diabetes is less than 1%. In the Caucasian population, 95% of patients with type 1 diabetes have HLA-DR3 or HLA-DR4 instead of diabetes, 45% to 50%; HLA-DR2 has protective effect against type 1 diabetes. -DQ gene is a more specific marker of susceptibility to type 1 diabetes. Determining the susceptibility and resistance of B cells to autoimmune destruction has been reported. Almost 70% of patients with type 1 diabetes HLA-DR3 have HLA-DQw3. .2 and the protective gene HLA-DQw3.1 appeared in the DR4 control study and found that if the 57th position of the two allelic DQ chains is occupied by aspartic acid, it will not easily develop autoimmune diabetes if two isotopes All non-aspartate is strongly susceptible to type 1 diabetes. The 52th arginine of HLA-DQA1 chain is also a susceptibility gene for type 1 diabetes. HLA-DQ1 chain 57 is non-aspartate homozygous and HLA- Individuals with homozygous arginine at position 52 of DQA1 chain have a relative risk of type 1 diabetes The 45-amino acid of the most dangerous DQ chain is recognized as an antigenic determinant by DQw3.2 instead of DQw3.1. The above findings may explain the combined appearance of HIA-DQ and HLA-DR sites. Higher risk.

HLA and type 1 diabetes subtypes: According to HLA phenotype, the subtype of type 1 diabetes is meaningful for clinical and etiological differences. It is generally believed that if HLA is expressed as HLA-DR3/DR3, it will lead to primary autoimmune disease and HLA. -DR4/DR4 represents primary environmental factors as the main cause. Secondary autoimmune response with type 1 diabetes with HLA-DR3 is often associated with other autoimmune diseases (eg, adrenal insufficiency, Hashimoto's thyroiditis, etc.) And patients with type 1 diabetes with older women with more onset of HLA-DR4 have almost nothing to do with other immune endocrine diseases. Men are more common on the onset. 745 cases of type 1 to 19 years old have been reported. According to HLA typing, patients with diabetes mellitus showed that patients with HLA-DR3 had a lower risk of ketosis and subsequent partial relief than HLA-DR4 patients.

2. Environmental factors: Type 1 diabetes is often associated with certain infections or subsequent infections. Common mumps virus rubella virus cytomegalovirus measles virus influenza virus encephalitis virus poliovirus Coxsackie virus and Epstein-Barr virus, etc., but the susceptibility or resistance of diabetes after viral infection may be determined by innate decision. If two people (like a brother or sister) are exposed to the same virus, the infection may show the same increase in viral antibodies. However, diabetes may only This may occur in a person due to the difference in susceptibility to intrinsic genetic susceptibility factors that may imply the sensitivity of B cells to a particular dose of a virus; or to a certain expression in the process of B cell viral antigen or mild B cell damage The released autoantigen has a propensity for an autoimmune response.

Recently, some studies have reported that children who are fed with milk or milk products within 3 months of birth have a higher risk of developing type 1 diabetes. Many studies have concluded that certain protein components in milk may be one of the factors leading to diabetes. Bovine serum albumin has been detected in most type 1 diabetic patients. Antibodies against bovine serum albumin. This antibody can produce precipitated antibodies with molecular weight of 69000 proteins in islet B cell lysates. It is considered to be due to intestinal permeability in infants and young children. The bovine serum albumin that allows the protein to enter the circulation causes lymphocyte sensitization to occur. The humoral and cellular immune responses that cross the islet B cell 69000 protein eventually lead to the destruction of B cells. The other two proteins are beta lactoglobulin and casein. It is considered to be an independent risk factor for type 1 diabetes. It is speculated that milk-fed infants with higher calorie formula may increase insulin secretion and enhance the islet B cell antigen presentation in childhood, but also believe that the relationship between milk and type 1 diabetes is not clear. There is still much debate about the origin of milk protein as a type 1 diabetes Pending further study.

3. Genetic-environmental factors interaction: genetic and environmental factors have different effects on the onset of a type 1 diabetes. How the environmental factors affect the autoimmune response process of islet B cells is still not fully understood. The genetic background of susceptibility is that some environmental substances induce autoimmune hypothesis of B cells with genetic susceptibility: Type 1 diabetes occurs when environmental factors damage B cells more than the tolerance of individual genetically determined B cell damage.

Environmental factors permit the action and determine the initial damage of autoimmune initiation by B cells by releasing cytokines such as interleukin-1 (IL-1) or tumor necrosis factor- (TNF-), such as specific or non-specific damage to B cell genetic factors. A rare case of susceptibility is that a specific B-cell toxic substance crosses autoimmunity and causes a large amount of damage to B cells. It is more common that repeated B cell damage induces secondary anti-B cell autoimmunity in genetically susceptible individuals. The ultimate common pathway by which autoimmunity may also spontaneously occur in the absence of environmental factors may result from the production of excess oxygen free radicals or NO damage to B cells.

The cause of type 2 diabetes is not very clear. It is generally considered to have a strong genetic or multi-gene genetic heterogeneous disease. Environmental factors such as insufficient obesity and aging are mainly due to insulin resistance and insulin-deficient insulin. Resistance is generally preceded by insulin secretion disorders; or insulin secretion is insufficient or not accompanied by insulin resistance. Although type 2 diabetes is genetically heterogeneous, most patients with type 2 diabetes and fasting hyperglycemia are characterized by insulin resistance insulin. Secretory disorders and increased hepatic glucose production.

(two) pathogenesis

It is generally believed that the pathogenesis of type 1 diabetes is mainly mediated by cellular immunity. The authors have proposed the pathogenesis pattern: any external or internal environmental factors (nutrition virus chemical substance IL-1, etc.) will lead to the release of B cell antigen or viral antigen expression. Similarity to B cells or B cell antigens The above antigen may be processed by antigen-presenting cells (macrophages) located in islets into sensitized antigen peptides to further activate antigen-presenting cells to produce and secrete large amounts of cytokines (IL). -1 and TNF, etc.) In addition, T-helper cells (CD8 lymphocytes) that specifically recognize the sensitizing antigen peptides are present in the islets and induce the expression of a series of lymphokine genes, such as TNF, which will provide feedback to stimulate antigen presentation. Cells increase the expression of major histocompatibility complex (MHC) subclasses IL-l and TNF. Other cells outside the macrophage lineage (in islets) also cause cytokine release enhanced by TNF and interferon (IFN). IL-1 exerts cytotoxic effects on B cells by inducing free radical production in islets. As B cell damage (denaturation) aggravates more sensitizing antigens are presented to the immune system. There is a significant increase in the production of IL-1 inducible free radicals produced by the islet-producing and self-limiting forms of islets (superoxide anion hydrogen peroxide hydroxyl radicals, etc.) and IL-1 interferon-gamma (INF-) And TNF- and the like also induce B cell-inducible nitric oxide (NO) synthetase synthesis to produce NO in large quantities (NO-derived peroxynitrite also has obvious toxic effects on B cells) plus human islet B cells have the lowest The scavenging ability of oxygen free radicals is therefore particularly sensitive to the destruction of oxygen free radicals by B cells. Oxygen free radical damage B cell DNA activates polyribosomal synthase to repair damaged DNA. This process accelerates the depletion of NAD. Cell death, free radicals also have a great damage to carbohydrates and proteins in cell membrane lipid cells. In addition, lymphokines and free radicals in the above process also cause CIM4 T lymphocytes to tend to damage and activate while macrophages also CD4 cells activated by viral antigens or damaged B cells are activated by CD4 lymphocytes. Further activation of B lymphocytes produces antiviral antibodies and autoantibodies against B cells also promotes B cells. The destruction. It has been clarified that type 1 diabetes is caused by immune-mediated selective destruction of islet B cells. It has been confirmed that a variety of autoantibodies against B cells such as islet cell antibodies (ICA) can be detected in vivo before and during the onset of type 1 diabetes. Insulin antibody (IAA) glutamate decarboxylase antibody (GAD antibody), insulinoma associated protein antibody, and the like.

1. Islet cell antibody Bottazzo is equivalent to the first description of the presence of anti-islet cell antigen antibodies in type 1 diabetic patients in 1974 and can be detected by immunofluorescence. This method has been used in addition to minor modifications, and has recently been radioimmunoassay and enzyme-linked immunosorbent assay. Examination of such antibodies Clinical studies report: ICA positive rate in general non-diabetic population is less than 3% and ICA positive rate in newly diagnosed type 1 diabetes patients is 60% to 90% ICA is divided into islet cytoplasmic antibodies and islet cell surface antibodies but The detection of islet cell surface antibody is rarely used in clinical clinically difficult to obtain fresh islet or insulinoma cell specimens. Islet cytoplasmic antibody examination is relatively simple and standardized. Therefore, the positive rate of islet cell antibody in clinical use is prolonged with the progression of diabetes. The islet cytoplasmic antibodies in 80% to 90% of patients with type 1 diabetes disappeared after 2 years of onset; 10% to 15% of patients persisted for more than 3 years.

1 autoantibodies to the thyroid and stomach.

2 other autoimmune endocrine diseases.

3 There is a strong family history of other autoimmune diseases.

4 more common in women; 5 is strongly associated with HLA-DR3/B8 but there are also reports of ICA positive in 62% of patients with type 1 diabetes after 3 years of onset.

The detection rate of ICA in the first-degree relatives of type 1 diabetes is significantly higher than that of the general population, and the high titer (such as >80JDF unit) associated with the increase in the risk of ICA detection and subsequent clinical type 1 diabetes is significantly higher. The risk of developing type 1 diabetes in patients with low titers (eg, <20 JDF units) ICA is significantly higher than in those who are transiently positive. Prospective study: ICAs titers in 4 to 9 JDF units and type 1 diabetes greater than 20 JDF units About 5% and 35% of first-degree relatives need insulin therapy in 5 years, and 60%-79% of insulin-dependent patients in 10 years. ICA sustained high titer positive has good predictive value in first-degree relatives of type 1 diabetes but Clinical studies have also found that a small number of high titer ICAs in the islet B cell function can remain stable for several years. The exact mechanism is still unclear. There are a small number of clinical reports that the use of immunosuppressive agents and nicotinamide can significantly prevent or delay high titer ICA positive. Non-diabetic first-degree relatives progress to clinically dominant type 1 diabetes. A wide range of clinical studies are underway. In addition, clinically, a significant proportion (10% to 20%) of non-insulin-dependent diabetes mellitus patients with ICA are detected. In the end, 80% to 85% of patients who require insulin therapy after a few years and only ICA-negative patients believe that clinically non-insulin-dependent diabetes mellitus with ICA positive may actually be "adult occult autoimmune diabetes" (LADA belongs to The category of type 1 diabetes has previously been described as "type 1.5 diabetes" or "slow progression of insulin-dependent diabetes mellitus" (SPIDDM). Other such patients are also often positive for anti-GAD.

1 The age of onset is often >15 years old.

2 onset of non-obese non-insulin dependent diabetes.

3 The disease can be controlled by diet or oral hypoglycemic drugs.

4 often in 1 to 4 years, oral hypoglycemic drugs are ineffective or susceptible to diabetic ketosis and need to rely on insulin.

The low level of 5ICA-positive anti-GAD-Ab positive C-peptide and HLA-DR3/4 are currently consistent with the "LADA" patients. Early use of insulin therapy to delay the destruction of islet B cells in the body.

2. Anti-GAD antibody: glutamic acid decarboxylase (GAD) is a biosynthesis enzyme of the inhibitory neurotransmitter -aminobutyric acid. It has been found in human and animal brain and islet tissues in recent years. The relative molecular weights of the isoforms were 65000 (GAD65) and 67000 (GAD67), respectively, and showed that GAD has many physical and chemical characteristics with the islet 64000 protein antigen in patients with type 1 diabetes. Some studies have jointly identified the disease-associated self in patients with type 1 diabetes. One of the antigens, 64000 protein, is the main self-antigen GAD antibody (GAAs) of GADGAD, which is considered to be the autoimmune response of type 1 diabetes. It is far simpler than the anti--64000 protein assay and is widely used clinically. Its clinical value is similar to ICA but The positive rate and specificity were higher than ICA. GAAs were positive in ICA and IAA in individuals with type 1 diabetes first-degree relatives type 1 diabetes. The positive rate of GAAs in newly diagnosed type 1 diabetes patients was 75%. 90% of patients with type 1 diabetes (3 to 10 years) have a positive rate of 60% to 80%. The detection of GAA is a diagnosis of type 1 diabetes, especially for early recognition of LADA. Important predicted value and relatives of type 1 diabetes in the diabetes risk in clinical current methods for the detection of radioactive GAA various immunoassay methods ELISA and immunofluorescence method, an immunoprecipitation method.

3. Insulin autoantibodies (IAAs): IAA can bind to insulin autoantibodies can occur in type 1 diabetic patients without exogenous insulin and preclinical patients with newly diagnosed type 1 diabetes patients with IAA positive rate of 40 %~50% of the existing methods can not distinguish IAA from insulin antibodies caused by insulin therapy. The natural history of IAA after diagnosis of type 1 diabetes has not been investigated. The production of IAA may be primary from B lymphocytes. Abnormal cloning or damage to islet B cells after islet B cell destruction may result in structurally altered insulin release and be treated as a foreign body by the in vivo immune system; or precursors of proinsulin or earlier biosynthesis are destroyed by B cells Released as an antigen; it has been reported that insulin immunoreactivity (possibly proinsulin precursor) is present on the plasma membrane of B cells and the similarity of foreign antigen molecules not related to insulin can also lead to the production of IAAs in vivo like ICAs and GAAs. It is also important to predict the type of IAA titer in type 1 diabetes as part of the formula for predicting the onset time of type 1 diabetes. The time when the first phase insulin secretion of the group will develop type 1 diabetes (year) = 1.5 0.03 × intravenous glucose tolerance (sum of insulin at 1 min and insulin at 3 min) - 0.008 x (IAA titer) but still needs a large series Prospective studies evaluated this formula for a negative correlation between age and IAAs.

IAAs are common in children and often present high titers. It is thought that IAAs appear in younger non-diabetic individuals more likely to appear in adults than to reflect islet B cell destruction faster and faster to type 1 diabetes associated with type 1 diabetes. IAA is mainly IgG occasionally IgMIAAs can be measured by radioimmunoassay and enzyme-linked immunosorbent assay. Some studies report that IAAs by radioimmunoassay can improve ICAs in the first-degree relatives of type 1 diabetes and the general population to predict the subsequent development of type 1 diabetes. The value of IAAs using enzyme-linked immunoassay seems to have no predictive value for type 1 diabetes, so the International Diabetes Symposium believes that only liquid phase radioimmunoassay is more practical for evaluating autoantibodies associated with diabetes.

4. IA-2 and IA-2 and its antibody IA-2 (insulinoma associated protein 2) and its analog IA-2 are confirmed by GAD and the other two islet cells have their own antigens. The highly homologous conserved region of the acid phosphatase catalytic domain is a new member of the receptor-type protein tyrosine phosphatase superfamily but its catalytic activity for dephosphorylation has not been confirmed to date and physiological functions are not clear. IA-2 and IA- 2 are type I transmembrane glycoproteins each containing 979 and 986 amino acid residues with molecular weights of 106000 and 108000, respectively. The genes encoding genes are located on chromosomes 2 (2q35) and 7 (7q35), respectively. The outer domain has a single transmembrane domain and an intracellular domain. The full-length composition has a 42% identity. 74% homology in the intracellular domain. IA-2 and IA-2 are mainly present in the pancreatic islet cell pancreas . In the neuroendocrine tissues such as pituitary brain tissue and adrenal medulla, IA-2IA-2GAD and insulin are both autoantigens of type 1 diabetes. The IA-2 and IA-2 antigens are located at the carboxy terminus of the intracellular domain. Mainly recognizes the conformational epitopes IA-2 and IA-2 have a common epitope The position and the specific antigenic epitopes reported that IA-2Ah is present in 60% to 80% of newly diagnosed type 1 diabetic patients with a pre-diabetes positive rate of 40% to 60% and a positive rate in healthy people. The positive rate of 1% IA-2Ab in newly diagnosed type 1 diabetes patients was 45% to 60%, which was slightly lower than that of IA-2Ab. The positive rate of both patients increased with the course of disease and the age of type 1 diabetes. The increase in IA-2Ab and IA-2Ab is higher than that in GAD-Ab. In patients with autoimmune disease without type 1 diabetes, the positive predictive value of first-degree relatives is less than 75%. 98% of newly diagnosed type 1 diabetic patients have at least one islet autoantibody positive 80% more than two, and no one in healthy humans has two or more antibodies and three antibodies (IA-2AbGAD-Ab and IAA) are negative. Grade relatives have a risk of developing diabetes less than 0.5% within 5 years. The risk of an antibody-positive disease is 15%. The positive rate of both antibodies is 44%. The risk of positive for all three antibodies is 100%. It is considered that the combined test IA-2AbGAD- Ab and IAA are the most reliable immunological markers for predicting type 1 diabetes due to IA-2 Ab is significantly associated with IA-2Ab, so the combination of IA-2Ab does not further increase the sensitivity and positive predictive value of detection. IA-2Ab and IA-2Ab are mainly detected by enzyme-linked immunosorbent assay (ELISA) and radioligand analysis. The Law (RLA), in which the RLA requires less specimens, can be semi-automated, saving time and effort for screening in high-risk groups and children.

The natural pathogenesis of type 1 diabetes is as follows:

Phase I (genetic susceptibility: related to certain sites of HLA).

Environmental factors such as viral infections.

The second phase (initiating autoimmune response to islet B cell damage).

The third phase (immunological abnormalities: a variety of autoantibody insulin secretion functions against B cells can still be maintained in the circulation).

In the fourth phase (the progressive decrease in the number of islet B cells gradually decreases blood glucose and causes diabetes).

Phase 5 (Clinical Diabetes: Islet B cell residuals are less than 10% significant hyperglycemia with clinical symptoms).

Stage 6 (Clinical Diabetes After a few years or years, B cells completely destroy insulin levels and lose their response to stimuli. Many patients develop various degrees of chronic complications).

Type 5.1 diabetic islet pathology

(1) Early pathological changes: As early as 1910, acute pancreatitis with lymphocytes and macrophage infiltration was recorded in patients with type 1 diabetes. Subsequently, autopsy of individuals who died after 6 months of onset of type 1 diabetes showed that islet 2/ 3 The above-mentioned damage to the survival of B cells less than 10% of the total amount of patients with long course of disease without lymphocytic infiltration in patients with a shorter duration of type 1 diabetes can be seen in the local regeneration of islet B cells but with the progression of disease B cell local regeneration The rarer and more regenerated B cells are also destroyed.

(2) Advanced pathology: autopsy after 1.5 to 34 years of diagnosis in patients with type 1 diabetes shows that atrophy of the exocrine glands due to 98% of the exocrine tissue in the normal pancreas may decrease due to the lack of high concentrations of insulin through the vascular bed itself. Pancreatic perfusion of high insulin concentration in the pancreas has a nutritional effect on itself. This effect is less in patients with type 1 diabetes who cannot be achieved by subcutaneous administration of exogenous insulin and has less weight than normal or type 2 diabetic patients. 1/3B cells are almost completely deficient in islets. Alpha cells and cells are included. The PP cells located at the distal end of the pancreas are normal. The number of cells and cells in each islet is normal or the total amount of and cells in the pancreas is increased. In the normal range.

an examination

Related inspection

Serum glucagon (PG) blood routine

Diabetes patients are mainly caused by the oxidation of glucose, and the body needs insufficient energy. Therefore, patients feel hungry and eat more. Eating more food further raises blood sugar. When blood sugar rises above the renal sugar threshold, urine sugar appears. The large amount of sugar is inevitably taken away. A large amount of water causes polyuria; polyuria loses too much water, blood concentration causes thirst, and therefore more drink; due to the disorder of sugar oxidation and energy supply, a large number of mobilization of body fat and protein oxidation function, due to consumption, the body gradually Weight loss and weight loss. This has formed the "three more and one less" of diabetes, that is, more food, more drink, more urine and weight loss.

Differential diagnosis

Especially easy to be hungry: the energy of human physiological activity is directly derived from the blood sugar of the blood, and the blood sugar is derived from the nutrients obtained from the digestive organs such as the small intestine. The reason why people are hungry is that the blood sugar level in the blood is reduced, and there is a normal physiological reaction. At this time, food should be added (that is, eating). If the food is not immediately replenished at this time, if it is a little longer, the physiological reaction will promote the decomposition of liver glycogen (from the cell fat decomposition product, which is completed by bile). At this time, people will feel hungry, and they will not be hungry.

Diabetes patients are mainly caused by the oxidation of glucose, and the body needs insufficient energy. Therefore, patients feel hungry and eat more. Eating more food further raises blood sugar. When blood sugar rises above the renal sugar threshold, urine sugar appears. The large amount of sugar is inevitably taken away. A large amount of water causes polyuria; polyuria loses too much water, blood concentration causes thirst, and therefore more drink; due to the disorder of sugar oxidation and energy supply, a large number of mobilization of body fat and protein oxidation function, due to consumption, the body gradually Weight loss and weight loss. This has formed the "three more and one less" of diabetes, that is, more food, more drink, more urine and weight loss.

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