Mature-onset diabetes in young adults
Introduction
Introduction to adult-onset diabetes in young people Young adult onset diabetes, abbreviated as MODY (maturityonsetdiabetesoftheyoung). In 1975, Fajans and Tattersall analyzed the series of reports from the 1950s. This type of non-insulin-dependent diabetes mellitus, which has an early onset age and is characterized by autosomal dominant inheritance, is named MODY. In 1985, the WHO classification was non-insulin dependent. A subtype of type 2 diabetes. Recently, with the progress of molecular genetics and the in-depth study of the etiology and pathogenesis of diabetes, the 1997 ADA and 1999 WHO diabetes experts reported that they were classified as special types, which are genetic defects of islet -cell function with single gene mutation. Cause diabetes. basic knowledge The proportion of illness: 0.005% Susceptible people: no specific population Mode of infection: non-infectious Complications: diabetic nephropathy, retinopathy, hypertension
Cause
Causes of adult-onset diabetes in young people
(1) Causes of the disease
With the advancement of biology and genetics, the genetic etiology and single-gene mutation of MODY have been confirmed, but the real-variant gene has genetic heterogeneity. The earliest established relationship between MODY gene and disease was studied by GL Bell in 1991. In the family, they conducted a 30-year review and follow-up study of 360 family members of the family for 5 generations. The familial diabetes and the long arm of the 20th long arm (20q12-q13.1) were first discovered. There is a close linkage relationship between the regions of the adenosine deaminate (ADA) gene. Therefore, the diabetes associated with this region is called MODY1. Further studies have found that MODY1 is a nuclear factor of the transcription factor present in this region. 4 (hepatic nuclear factor-4, HNF-4) gene mutation, with the development of molecular biology techniques and advances in genetic statistics, and people's understanding of the high heterogeneity of MODY, more and more MODY families are At least 6 MODY subtypes have been discovered, including MODY2/glucokinase (GCK), MODY3/hepatocyte nuclear factor 1 (HNF-1) in addition to MODY1. , MODY4 / insulin promoter factor 1 (IPF1), MODY5 / hepatocyte nuclear factor 1 (HNF-1), MODY 6 / neurogenic differentiation factor 1 (NeuroDL / BETA2), in addition, 16% ~ 45% of the families have typical clinical manifestations and genetic characteristics of MODY, but the molecular genetic mechanism is not yet clear, called MODY-X. Each of the MODY subtypes has different genetic backgrounds, and the clinical phenotypes also have their own characteristics. Heterogeneous chronic hyperglycemia syndrome.
(two) pathogenesis
Among the six MODY subtypes, except for MODY 2, which is involved in mutations in the glucokinase gene, all of which are transcription factor variants that regulate insulin gene expression. Glucose kinase is the first rate-limiting enzyme in glucose glycolysis, in islet beta cells and liver. The cells catalyze the conversion of glucose into glucose-6-phosphate. The glucokinase in islet cells is regulated by the blood glucose concentration. The increase of blood glucose can directly enhance the glucokinase activity, accelerate the metabolism of glucose, and further promote the secretion of insulin. The glucokinase in cells is called glucose receptor; the glucokinase in the liver is regulated by insulin, the blood sugar is increased after eating, the insulin secretion is increased, the glucokinase activity is enhanced, and the synthesis of glycogen in hepatocytes is promoted. It can lead to an increase in postprandial blood glucose. Studies have shown that a slight decrease in beta-cell glucokinase activity will increase the threshold of glucose-induced insulin secretion, which is the main mechanism of MODY 2 development. More than 130 types of MODY 2 have been found. Glucose kinase mutations, including nonsense mutations, missense mutations, deletions Mutations, etc., by changing the enzyme activity and the binding ability of the enzyme to glucose or adenosine triphosphate, the "sensitivity" of glucokinase selectively to the blood glucose concentration is decreased, the rapid phase of insulin secretion is delayed or disappeared, and the secretion rate is decreased. , resulting in inadequate insulin secretion, while beta cells respond normally to other insulin-promoting secretions such as arginine. In addition, decreased activity of hepatic glucokinase leads to glucose 6-phosphate production and hepatic glycogen synthesis. Slower speed is also the cause of high blood sugar.
The other two MODY subtypes associated with transcription factor variation are pathophysiological based on primary insulin secretion deficiency rather than insulin resistance, but the specific pathogenesis is still unclear. These transcription factors are mainly in the liver, kidney, and gastrointestinal tract. And expression in pancreatic cells, forming a mutually regulated network system, which plays an important role in embryonic pancreas development, pancreatic islet cell proliferation and differentiation, and regulation of glucose and lipid metabolism related genes. For example, HNF-1 is mainly composed of The three functional regions are composed of a dimerization region at the amino terminus, a transactivation region at the carboxy terminus, and an intermediate nucleic acid binding region, which is mainly regulated by a homodimer or a heterodimer with HNF-1. The corresponding gene fragments are combined; while HNF-4 is an upstream regulator of HNF-1, and the decrease in HNF-1 expression caused by HNF-4 gene mutation is one of the causes of glucose metabolism disorder, and the mutation of these transcription factors causes diabetes. Mechanisms, knockout animal models, and in vitro results provide some clues, such as HNF-1-deficient mouse beta cells failing Glycolysis produces reduced nicotinamide-adenine dinucleotide (NADH), which in turn reduces glucose-induced adenosine triphosphate production and decreases insulin secretion; whereas functional HNF-4-deficient embryonic stem cells are affected by this The genes regulated by transcription factors include glucose transporter-2, aldolase B, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase, which affect the glucose transport and glycolysis process, resulting in insulin secretion. In addition, HNF-4 also regulates the expression of apoprotein CIII (Apo C III) gene in the lipid metabolism pathway. It was found that certain MODY 1 mutation carriers had significantly lower concentrations of blood triglyceride and Apo C III. For non-diabetic members of the non-diabetic family, this may be related to a decrease in Apo C III expression caused by HNF-4 mutation, which in turn leads to an increase in lipoprotein lipase activity and a decrease in triacylglycerol levels. IPF1 develops embryonic pancreas and Transcriptional regulation of endocrine-specific genes in adult pancreas plays an important role. Loss of expression of this protein during embryonic stage can lead to pancreatic dysplasia However, its heterozygous mutations affect insulin secretion by down-regulating the expression of related genes.
At least 120 mutations related to MODY 3 have been found, and MODY 1 caused by HNF-4 mutation is relatively rare. So far, 13 families have been reported globally, and MODY 4-6 is less, about 1 to 2 cases each. Mutations include frameshift mutations, deletion mutations, missense mutations, nonsense mutations, etc. It is generally believed that missense mutations occur mostly in the DNA junction region and homologous structural regions of transcription factors, mainly by reducing transcription factors and target gene fragments. Ligation reduces the expression of downstream genes; while nonsense mutations and frameshift mutations less affect the connection of target genes, mainly due to the presence of mutations, changing the sequence of the transactivation region, thereby deleting the transcriptional function of the protein, and additionally the mutant protein. It is also possible to compete with the wild-type protein for the binding site of the target gene by a dominant negative effect, thereby reducing the expression of the target gene.
Prevention
Adult onset diabetes prevention among young people
Early lifestyle interventions and monitoring and tracking of unaffected mutation carriers in the family can delay or even reverse the disease.
1. Reasonable diet excessive calorie intake, overnutrition, obesity, lack of exercise is an important cause of the disease. Proper calorie intake, low salt, low sugar, low fat, high fiber, and sufficient vitamins are the best dietary compatibility.
2. Protecting the eyes, you may not understand that if there are some diseases in the eyes, it will lead to the disease. If you want to prevent diabetes, you should pay attention to avoid wearing contact lenses. It is recommended to wear spectacles because wearing contact lenses will increase the weight. Eye symptoms can also affect the risk of diabetic patients controlling blood sugar, infection or the appearance of diabetic eyes.
Complication
Adult onset diabetes complications in young adults Complications diabetic nephropathy retinopathy hypertension
1. Microvascular complications include diabetic retinopathy, diabetic nephropathy is rare and prognosis is good, and risk factors associated with macrovascular complications, such as hypertension, obesity, dyslipidemia, etc., are less likely to accumulate in MODY 2 patients, so Related cardiovascular and cerebrovascular complications are also rare. In addition to the increase in blood glucose, glucokinase gene mutations also affect embryonic development and lead to low birth weight, which may be the result of insufficient insulin secretion during the fetal period. This phenomenon is rare in other MODY subtypes.
2. MODY1 and MODY3 disease with age, prone to diabetic retinopathy and diabetic nephropathy.
Symptom
Symptoms of adult-onset diabetes in young people Common symptoms Increased blood sugar in polyuria
MODY is a group of chronic hyperglycemia syndrome characterized by defects in insulin secretion. The insulin deficiency is between type 1 and type 2 diabetes. The clinical manifestations have some characteristics of the two, which constitute the middle of the spectrum of diabetes diseases. Transition type.
The genetic heterogeneity of MODY determines the heterogeneity of its clinical phenotype. It is generally believed that MODY 2, which is associated with glucokinase gene mutation, is clinically less severe due to elevated blood glucose, and less than half of patients present with dominant diabetes. The subtype has a high and complete penetrance rate. Most of the mutation carriers have a mild increase in blood glucose levels during puberty, which is undetected asymptomatically. About 50% of women with mutations pass glucose tolerance during pregnancy. Screening tests found diabetes, and the smallest MODY 2 patients diagnosed by family surveys are 1 year old, and MODY 2 progresses slowly. Many patients can maintain glucose tolerance or mild fasting hyperglycemia for a long time. Microvascular complications include diabetic retina. Lesions, diabetic nephropathy are rare and have a good prognosis, and risk factors associated with macrovascular complications, such as hypertension, obesity, and dyslipidemia, are less likely to accumulate in MODY 2 patients, so the associated cardiovascular and cerebrovascular complications Symptoms are also rare. In addition to causing an increase in blood glucose, glucokinase gene mutations also affect embryonic development and lead to neonatal Low body weight, which may be insufficient fetal insulin secretion results, but this phenomenon in other MODY subtypes are rare.
The clinical manifestations of MODY 1 and MODY 3 caused by mutations in hepatocyte nuclear factor are similar, the penetrance rate is relatively low and incomplete, the time of hyperglycemia occurs slightly later than MODY 2, and 60% to 70% of the mutation carriers are before 25 years old. Diagnosed as diabetes, the rest were diagnosed at 25 to 60 years old, and a few non-existing mutation carriers did not develop diabetes for life. The hyperglycemia of these two subtypes was more serious, and the insulin secretion function was degraded by 1% to 4%. The sensitivity of insulin is relatively normal. Most patients have low body mass index, obvious clinical symptoms, and the condition is aggravated with age. The blood sugar control is often progressively worsened. It is easy to be complicated with diabetic retinopathy and diabetic nephropathy. Half of the patients eventually need insulin therapy. A small number of patients with high penetrance due to small onset age, severe disease and rapid progress, easily misdiagnosed as type 1 diabetes, and because HNF-1 is also expressed in the kidney, HNF-1 gene defects can be changed by changing the renal distal convoluted tubule The expression of sodium-glucose co-transporter reduces the ability of the kidney to reabsorb glucose, thereby lowering the renal sugar threshold, which is also the characteristic of MODY 3 clinical manifestations. One.
IPF1 is an important transcription factor for pancreatic development and islet endocrine-specific gene expression. Currently, only one case of MODY 4 family caused by IPF1 heterozygous mutation has been found. Its clinical manifestations are not strictly in accordance with the diagnostic criteria of MODY, such as the average incidence. Later in age, about 35 years old, in recent years, some mutations in this gene seem to be related to the susceptibility to late-onset type 2 diabetes. MODY-1 gene mutation caused by MODY 5 is mainly in Japanese families. It has been found that in addition to the common genetic characteristics of common MODY, most of the cases are mild, which may be accompanied by renal congenital lesions (such as polycystic kidney disease) and renal insufficiency. These kidney changes may occur earlier than hyperglycemia. Some patients with advanced stage may require insulin therapy. The MODY 6 family associated with NeuroDL/BETA2 mutations only reported 2 cases, one of which is similar to MODY 3, and the other is closer to common type 2 diabetes, ie, the age of onset is later. , obesity and normal insulin secretion.
In addition to the overall clinical phenotypic heterogeneity between the above-mentioned common different MODY subtypes, the clinical manifestations of different families within the same MODY subtype, or different members of the same family, are often inconsistent, such as the age of onset and The severity of diabetes, etc., in addition to considering the impact of mutation types on phenotype, environmental factors such as different lifestyles and dietary habits may be one of the reasons for the disease penetrance. In addition, some minor gene mutations Although it is not enough to cause diabetes, it can modify the clinical phenotype of MODY and affect the severity of hyperglycemia.
The clinical manifestations of different types of MODY1~6 are as follows:
The characteristics of MODY1 are as follows: 1 is the transcription factor HNF4a gene mutation. In 1991, the mutant gene was found to be located on chromosome 20q; 2 was found in the earliest reported American RW family, the frequency of occurrence was 5% in the United States, and the age of onset was younger (young people), the minimum age for diagnosis. It is 9 years old; 3 diabetes is generally mild (post-prandial hyperglycemia is the main), but because B cells stimulate the secretion reaction disorder of blood sugar, causing progressive glucose metabolism disorder, about 30% often require insulin treatment; 4 abnormal lipid metabolism And vascular complications.
The characteristics of MODY2 are as follows: 1 is the glucokinase gene (GCK) mutation. It was first identified in the French MODY family in 1992. The mutant gene is located on chromosome 7p. 2GCK is a key enzyme regulating glucose metabolism. It acts as a glucose sensor in B cells. Mutation-induced GCK activity is reduced, B cells (abnormal secretion) decrease glucose-stimulated insulin secretion and fasting hyperglycemia occurs, the frequency of occurrence (UK%) is 12.5, and the 3GCK gene mutation points are more than 40 different, but the clinical manifestations are similar. High blood sugar occurs early (childhood), and can be found after birth. The minimum age for diagnosis is 1 year old, and the condition is not serious (blood sugar is generally 6-8 mol/L, rarely >10 mol/L). The course of the disease is good. Even for life without diabetes symptoms, and few vascular complications, most do not require special treatment, about 2% with insulin treatment.
The characteristics of MODY3 are: 1 gene transcription factor HNF1a gene mutation, which was confirmed in the non-GCK MODY family in France in 1996. The mutation gene is located on chromosome 12q, and the incidence rate of 2 is 65% in the UK. It is the most common genetic mutation in European white MODY, 3 Due to changes in insulin gene expression and affecting pancreatic embryo development, resulting in B cell dysplasia and loss of function, diabetes occurs, and diabetes is gradually aggravated, hyperglycemia is obvious, but no ketosis, early dietary regulation and oral hypoglycemic agents can be used. Insulin treatment is needed as the condition worsens. 4 More patients with small vessel disease have more than MODY2, and 14% have retinopathy in the UK. 5HNF-1 transcription factor can alter the expression of some other genes in different tissues (liver, kidney and pancreas). It can affect the external organs of the pancreas. In Isoma et al. reported in 1998, the disease has tubular dysfunction of glucose absorption and a decrease in renal sugar threshold. Therefore, patients have obvious polyuria and polydipsia in the early stage.
MODY4 is characterized by: mutation of the IPF-1 gene of the hematodomine transcription factor, which regulates early development of the pancreas and -cell-specific genes, mainly leading to gene expression disorder of insulin. 2 The age of onset is relatively late, average 35 years old (young people), clinical manifestations similar to MODY1, milder diabetes, no ketosis and other insulin deficiency, rare complications, 3 generally with dietary regulation and oral hypoglycemic agents.
The characteristics of MODY5 are: 1 line HNF-1 gene mutation, the mutation gene is located on chromosome 12q, and is also a frame shift mutation, which expresses and regulates islet gene expression in islets. In 1998, Horikawa et al. and Nishigori et al. First reported that 2 the age of onset <35 years old, the frequency of occurrence in the United Kingdom is 2.5%, 3 clinical manifestations of high blood sugar levels vary, treatment according to the discretion, 4 early or prior to diabetes can occur renal changes.
MODY6 is characterized by mutation of beta A2/NEORODI gene, which causes damage to insulin secretion. The age of onset is young, the frequency of occurrence is 2% in the UK, the severity of diabetes varies, and diabetic complications can occur (nephropathy, retinopathy). ).
In summary, the above 6 species are the MODY genetic variants reported so far, but not all transcription factor mutations that regulate the insulin gene can cause MODY. It should be noted that some mutations are not related to MODY. Clinically, suspected MODY patients can further do Genetic identification is used to determine the type of genetic mutation associated with the diagnosis and resolution.
Examine
Examination of adult-onset diabetes in young people
According to the performance of the performance selection, do the following checks:
1. Fasting blood glucose measurement and blood glucose measurement 2 hours after meal.
2. Oral or injection glucose tolerance test.
3. Plasma insulin determination, serum C-peptide determination of diabetes typing, treatment and prognosis.
4. Liver and kidney function tests.
5. Blood total cholesterol, triglyceride determination.
6. Urine volume qualitative, quantitative examination and urine ketone body timing check.
7. Abdominal B-ultrasound to timely understand the qualitative changes of liver, kidney and organs.
8. Fundus examination to detect early fundus complications.
9. Determination of glucokinase activity.
Diagnosis
Diagnosis and diagnosis of adult onset diabetes in young people
1. Non-glucose urine such as lactose urine is found in breastfeeding or pregnant women and infants. Fructose and pentose urinary occasional are very rare congenital disorders after eating a large amount of fruit. When the diabetes is positive, it should be analyzed and judged according to the clinical situation, and it should not be confirmed as diabetes immediately. Identification methods include biochemical and fermentation tests.
2. Non-diabetic glucoseuria
(1) Hunger Diabetes: When the hunger is quite high, a large amount of sugary foods will be rushed in the future. Insulin secretion can not be adjusted at one time, and diabetes can be produced, and glucose tolerance can be reduced. When analyzing, pay attention to the analysis of the condition, pay attention to the diet history, the total amount of food intake, and the fasting blood glucose is often normal. Can be low.
(2) Postprandial diabetes: Diabetes occurs after eating a large amount of sugary foods, or because the absorption is too fast, the blood sugar concentration rises temporarily beyond the renal sugar threshold and diabetes occurs, but the fasting blood glucose and glucose tolerance tests are normal.
(3) Renal glucosuria: due to the reduced ability of renal tubules to reabsorb sugar, the renal sugar threshold is low, although the blood sugar is normal and there is diabetes. When a small number of pregnant women have temporary renal sugar threshold reduction, postpartum follow-up must be performed to identify. Nephritis, kidney disease, etc. may also occur due to renal tubular resorption function damage renal renal diabetes, should be differentiated from diabetic glomerulosclerosis. True renal glucosuria such as Fanconi syndrome is a defect in the renal tubular enzyme system, which is quite rare. The fasting blood glucose and glucose tolerance test are completely normal, and the renal sugar threshold can be measured, and the maximum glucose absorption rate of the renal tubule can be determined.
(4) neuroglycemia: seen in cerebral hemorrhage, brain tumor, intracranial fracture, asphyxia, anesthesia, sometimes blood glucose is temporarily too high with diabetes, can be identified in the follow-up of the disease.
3. Secondary diabetes mellitus caused by pancreatitis, cancer, pancreatic excision, etc. should be considered in combination with medical history analysis. Hemochromatosis patients with pigmentation, hepatosplenomegaly, diabetes and iron metabolism disorders, should be noted, but less common. Other endocrine diseases have their own characteristics, and there is no difficulty in combining the disease analysis. Stress hyperglycemia or gestational diabetes should be followed up and identified, usually recovered 2 weeks after the disappearance of stress, or identified during follow-up after delivery.
