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PubMed2002

[Physiological basis of insulin secretion abnormalities].

The pathogenesis of type 2 diabetes is complex, with two distinct mechanisms: insulin resistance (decrease of insulin action on peripheral tissues) and insulin deficiency (impaired insulin secretion by pancreatic beta-cells). These abnormalities are due to genetic and environmental factors. Type 2 diabetes is a heterogeneous disease: besides the common form with obesity, monogenic forms (such as MODY) exist. Knowledge of these forms has permit a better understanding of the genetic factors involved in diabetes, and of their relationship with insulin resistance. In this review, we discuss the main data available on genetics of type 2 diabetes, as well as the various research approaches. Today, the genetic determinism of functional abnormalities of pancreatic beta-cell is no longer discussed. However, it is also clearly established that acquired metabolic factors may contribute to pancreatic beta-cell failure. Hyperglycaemia, even moderate, induces a reduced insulin biosynthesis potential (glucotoxicity), and the increased free fatty acid flux accelerates pancreatic beta-cell apoptosis (lipotoxicity). The role of these metabolic abnormalities in the development of type 2 diabetes is briefly described.

Animals↗
PubMed2003

[Gene therapy in the treatment of diabetes mellitus].

Multiple genetic factors are involved in the pathogenesis of type 1 and 2 diabetes mellitus. A defect, which could be ascribed to a single or only few genes, has not been established yet. An exception represents the Maturity Onset Diabetes of the Young (MODY) which is rather rare and is caused by mutations in some of 6 known genes. Principles of gene therapy focus mainly on generation of replenishable sources of insulin producing tissue. Which could be used for replacement of the destroyed or failing beta-cells. Current approaches include stimulation of embryonic or adult stem cell proliferation and differentiation into beta-cells, beta-cell proliferation, transdifferentiation of non-islet cells into glucose-sensitive insulin-producing cells and xenotransplantation. Genetic modification is being studied to prevent islet rejection (e.g. local expression of immuno-suppressive cytokines or ligands inducing T-cell apoptosis, knock-out of specific animal genes or transfer of human genes into animal tissue donors) or to construct "superislets" resistant to apoptosis or oxidative stress. For prevention of type 1 diabetes and perhaps for induction of specific immune tolerance vaccination with DNA fragments encoding for specific auto or alloantigens represents a promising approach. In addition, gene therapy offers some hope for the future treatment of diabetic vascular complication, neuropathy and syndromes of insulin resistance.

Diabetes Mellitus↗
PubMed1992

Importance sampling. I. Computing multimodel p values in linkage analysis.

In linkage analysis, when the lod score is maximized over multiple genetic models, standard asymptotic approximation of the significance level does not apply. Monte Carlo methods can be used to estimate the p value, but procedures currently used are extremely inefficient. We propose a Monte Carlo procedure based on the concept of importance sampling, which can be thousands of times more efficient than current procedures. With a reasonable amount of computing time, extremely accurate estimates of the p values can be obtained. Both theoretical results and an example of maturity-onset diabetes of the young (MODY) are presented to illustrate the efficiency performance of our method. Relations between single-model and multimodel p values are explored. The new procedure is also used to investigate the performance of asymptotic approximations in a single model situation.

Diabetes Mellitus, Type 2↗
PubMed1992

[Neonatal diabetes mellitus and microcephaly. Indications for autosomal recessive inheritance].

Still, there are a lot of questions about the pathogenesis of neonatal diabetes mellitus. In the author's opinion neonatal diabetes mellitus is a distinct entity which differs from the well-known types of diabetes in children (type 1 diabetes, MODY-diabetes) and transient neonatal hyperglycemia regarding pathogenesis, pathophysiology and prognosis. Casuistics of three children two of whom were sibs are reported in detail to demonstrate the characteristics of neonatal diabetes mellitus. Regarding the reported sibs we suppose genetic origin of the disease. Autosomal-recessive mode of inheritance must be assumed.

Abnormalities, Multiple↗
PubMedDate not supplied

Increased placental expression of tissue factor is associated with abnormal uterine and umbilical Doppler waveforms in severe preeclampsia with fetal growth restriction.

BACKGROUND: This study investigated whether modifications of placental expression of endothelin-1 (ET-1), nitric oxide synthase (NOS) and tissue factor (TF) are associated with abnormal Doppler waveforms. METHODS: Fourteen pre-term severe preeclamptic (PE) women with fetal growth restriction (FGR) and 14 normal preg nant women underwent serial Doppler examination of the uterine and umbilical arteries (UA). Placental ET-1 and T expression was evaluated by in situ hybridization, NOS by NADPH-diaforase staining and in situ hybridization Doppler evaluation was extended to 11 female kidney transplant recipients (Tx), without FGR and/or PE, in wh we previously demonstrated a strong modification of placental ET-1/NOS vasoactive balance. RESULTS: PE women showed a marked reduction of endothelial constitutive NOS (ecNOS) expression in the syncy tiotrophoblast layer of all villi, whereas ET-1 expression was unchanged. All cases showed abnormal uterine artery blood flow velocimetry, 13 out of 14 PE women showed abnormal UA Doppler waveforms. In contrast, all Tx women showed normal UA blood velocimetry, all but one woman displayed a normal uterine artery waveform pattern. The Doppler velocimetry abnormalities were significantly associated with only TF expression, which was markedly increased, exclusively, in the endothelial cells within the basal decidua of PE women. CONCLUSIONS: The modification of ET-1/NOS vasoactive balance, per se, did not lead to Doppler impedance modifica tions in the UA and uterine arteries, observed in pre-term PE women with FGR. Instead, Doppler velocimetry modi fications appeared to correlate with endothelial cell activation, as revealed by increased TF expression.

Adult↗
PubMed2003

The genetics of diabetes mellitus.

Genes play an important role in the development of diabetes mellitus. Putative susceptibility genes could be the key to the development of diabetes. Type 1 diabetes mellitus is one of the most common chronic diseases of childhood. A combination of genetic and environmental factors is most likely the cause of Type 1 diabetes. The pathogenetic sequence leading to the selective autoimmune destruction of islet beta-cells and development of Type 1 diabetes involves genetic factors, environmental factors, immune regulation and chemical mediators. Unlike Type 1 diabetes mellitus, Type 2 diabetes is often considered a polygenic disorder with multiple genes located on different chromosomes being associated with this condition. This is further complicated by numerous environmental factors which also contribute to the clinical manifestation of the disorder in genetically predisposed persons. Only a minority of cases of type 2 diabetes are caused by single gene defects such as maturity onset diabetes of the young (MODY), syndrome of insulin resistance (insulin receptor defect) and maternally inherited diabetes and deafness (mitochondrial gene defect). Although Type 2 diabetes mellitus appears in almost epidemic proportions our knowledge of the mechanism of this disease is limited. More information about insulin secretion and action and the genetic variability of the various factors involved will contribute to better understanding and classification of this group of diseases. This article discusses the results of various genetic studies on diabetes with special reference to Indian population.

Diabetes Mellitus↗
PubMed2004

[Diabetes mellitus, but which type?].

In three patients with an unusual presentation of diabetes mellitus, the classification of their diabetes was troublesome. An adolescent male with slightly elevated blood-glucose levels turned out to have excellent glycaemic control on sulphonylurea derivatives only. When he was 40 years of age, his diabetes was finally diagnosed as 'maturity onset diabetes of the young' (MODY). A non-obese 41-year-old man was initially diagnosed with type-2 diabetes. Therapy with oral hypoglycaemic agents was unsuccessful and he was subsequently classified as having 'latent autoimmune diabetes of adults' (LADA) based on the presence of antibodies against glutaminic acid decarboxylase. A 29-year-old man presented with severe ketoacidosis and was initially believed to have type-1 diabetes. The patient himself discontinued insulin therapy and he was eventually diagnosed as having type-2 diabetes. A careful classification may have clinical consequences. Patients with MODY3, for example, respond to sulphonylurea derivatives. In MODY2, treatment with diet alone is often sufficient. In patients with LADA, insulin therapy is the treatment of choice. The recognition of diabetes mellitus type 2 as the underlying illness in some patients who present with ketoacidosis means that these patients can be specifically treated for their basic problem, which is insulin resistance. For them, weight reduction is essential and metformin is the drug of choice as far as pharmacotherapy is concerned, but of course attention must also be given to cardiovascular risk factors such as hypertension and dyslipidaemia.

Adolescent↗
PubMed2004

[Etiological dissection in common anti-islet autoantibody-negative patients with type 1 diabetes].

OBJECTIVE: To explore the immunological and genetic factors of common anti-islet autoantibody-negative patients with type 1 diabetes. METHODS: Specimens of peripheral blood were collected from 33 common autoantibody (GAD-Ab, IA2-Ab, IAA, TGA and TPO-Ab) negative diabetic patients with new-onset of unprovoked ketosis (or ketoacidosis), and genome DNA was extracted. The antibodies to carboxypeptide-H (CPH) and SOX13 (ICA12) were detected by radioligand assay. The gene mutations of MODY3 (HNF-1alpha) and MODY6 (NeuroD1/Beta2) were detected by PCR-SSCP sequencing. Mitochondrial gene mutations were analyzed with PCR-RFLP. RESULTS: Two (6%) of the patients were SOX13-Ab positive, while none of them was positive for CPH-Ab. Gene mutation detection found one case of a new mutation, R321H (CGC-->CAC) in the exon 5 of HNF-1alpha gene and one case with ND1 mt3316 G-->A mutation in mitochondrial DNA. In addition to the diabetes-associated mutations described above, seven polymorphisms of HNF-1alpha gene, including L17L, I27L, L459L, S487N, IVS5 + 9 C > G, IVS6-42 G > T, and IVS7 + 7 G > A, and one NeuroD1/Beta2 gene polymorphic variant Ala45Thr, were found. CONCLUSION: Autoimmunity and gene mutations (such as MODY3 and mitochondrial genes mutations) may be etiological in a few cases initially diagnosed as autoantibody-negative type 1 diabetes. Autoimmunity and MODY and mitochondrial diabetes should be excluded if idiopathic type 1 (type 1B) diabetes is diagnosed.

Adolescent↗
PubMed2004

[Physiopathological mechanisms in type 1 and type 2 diabetes].

Type 1 and type 2 diabetes have different clinical presentations in their common forms. The absence of biological tests for diagnosis of type 2 diabetes, for reliable evaluation of insulin secretion and, beta-cell mass or for diagnosis of insulitis and the limited sensitivity of antibody tests in type 1 diabetes explain the difficulty of classifying a large number of cases of diabetes and the identification of questionable clinical entities: LADA (Latent Autoimmune Diabetes in Adult), non-insulin dependant diabetes in coloured people. Hyperglycaemia may also be observed in genetic diseases affecting insulin secretion (MODY, mutations of mitochondrial DNA), complex genetic diseases, pancreatic, endocrine and iatrogenic affections. Type 1 diabetes is characterised by the destruction of, beta-cells while type 2 diabetes combines abnormal insulin secretion and insulin resistance. The reduction of the beta-cell mass in type 2 diabetes remains controversial. These different conditions are examples of multifactorial diseases during which several physiopathological processes are disturbed in association with the expression of multiple genes, of normal structure and function, but variants of which copy for a number of partial phenotypes the association of which causes the disease. Some hypotheses suggest that type 2 diabetes is the consequence of the selection of variants of genes involved in energetic storing and responsible for defence against infection and of the recent very rapid changes in the environment.

Diabetes Mellitus, Type 1↗
PubMed2005

[Research development of Mendelian inherited diabetes].

Diabetes mellitus is a chronic syndrome of abnormal metabolism, determined by interaction of multifactorial genetic and environmental factors. Some specific types of diabetes, such as MODY, Leprechaunism, lipoatrophic diabetes, and Rabson-Mendenhall syndrome, are monogenic forms of diabetes and are inherited as a Mendelian pattern. The article reviews the research development of these Mendelian inherited diabetes will be reviewed.

Diabetes Mellitus, Type 2↗
PubMed2005

Modeling the distribution of Schistosoma mansoni and host snails in Uganda using satellite sensor data and Geographical Information Systems.

The potential value of MODIS satellite sensor data on Normalized Difference Vegetation Index (NDVI) and land surface temperatures (LST) for describing the distribution of the Schistosoma mansoni-"Biomphalaria pfeifferi"/Biomphalaria sudanica parasite-snail system in inland Uganda, were tested by developing annual and seasonal composite models, and iteratively analysing for their relationship with parasite and snail distribution. The dry season composite model predicted an endemic area that produced the best fit with the distribution of schools with > or =5% prevalence. NDVI values of 151-174, day temperatures of 26-36 degrees C, and night temperatures of 15-20 degrees C were used as criteria for the prediction model. Using the same approach with host snail data indicated that most of Uganda is suitable "B. pfeifferi"/B. sudanica habitat, except for possibly the north-eastern region of the country. The parasite, however, appears to be restricted in its distribution in both the north-eastern and the south-western regions of Uganda. The absence of disease in the south-west can not be attributed to the absence of snail hosts. Results suggest a combination of satellite sensor data on temperature and standard climate data on precipitation, as the best ecological determinants of the S. mansoni-"B. pfeifferi"/B. sudanica system. Satellite composite models and logistic regression analysis, suggest low night time temperature as one of the significant factors inhibiting S. mansoni transmission in the south-western highland areas of Uganda. The developed models are, however, unique, representing species-specific ecologic preferences of the S. mansoni-"B. Pfeifferi"/B. sudanica system in inland Uganda. Further validation studies are needed to test the value of the model in other countries in East Africa.

Animals↗
PubMed2005

[Molecular diagnostics in diabetes mellitus].

BACKGROUND: Genetic factors are involved in the development of diabetes. We here evaluate the possibilities for a genetic diagnosis of diabetes. METHODS: This overview is based on a limited literature search in PubMed as well as our own experience. RESULTS AND INTERPRETATION: Sequence variations in a number of genes and genomic regions result in an increased risk for development of type 1 and type 2 diabetes. With the exception of the HLA genes and their association with type 1 diabetes, these sequence variations each cause only a modest increase in diabetes risk. In contrast, disease-causing mutations can be identified in six genes associated with maturity-onset diabetes of the young (MODY). In most countries, MODY2 and MODY3 are the most frequent subtypes. Sulphonylurea may be the drug of choice when treating MODY3 because sensitivity for the drug is preserved even after long duration of diabetes. Neonatal diabetes is often caused by mutations in a component (Kir6.2) of the potassium channel of the beta cell. Patients can be managed on oral sulphonylurea with sustained metabolic control rather than on insulin injections.

Adolescent↗
PubMed2005

Type 2 diabetes mellitus: from genes to disease.

The development of type 2 diabetes (T2DM) is determined by two factors: genetics and environment. The genetic background of T2DM is undoubtedly heterogeneous. Most patients with T2DM exhibit two different defects: the impairment of insulin secretion and decreased insulin sensitivity. This means that there are at least two pathophysiological pathways and at least two groups of genes that may be involved in the pathogenesis of T2DM. As far as genetic background [corrected] of T2DM is concerned, the disease may be divided into two large groups: monogenic and polygenic forms. In this review, we present genes known to cause rare monogenic forms of diabetes with predominant insulin deficiency (MODY - maturity-onset diabetes of the young, MIDD - maternally inherited diabetes with deafness) and uncommon syndromes of severe insulin resistance. We also describe some of the main approaches used to identify genes involved in the more common forms of T2D and the reasons for the lack of spectacular success in this field. Although major genes for T2DM still await to be discovered, we have probably established a "road map" that we should follow.

Deafness↗
PubMed2004

Insulins and oral hypoglycemic medications.

The management of childhood diabetes is rapidly evolving, reflecting both the recognition of new types of diabetes in pediatrics and the availability of new insulins. Over the past two decades there have been increasing numbers of children affected by type 2 diabetes, maturity onset diabetes of youth (MODY), and medical diabetes secondary to medication usage (e.g. prednisone) or disease process (e.g., cystic fibrosis). These forms of diabetes require familiarity with medications other than insulin and an understanding of appropriate treatment strategies. Simultaneously, after years of little change, there has been the relatively rapid introduction of new insulins (e.g., lispro, aspart, glargine) and more sophisticated means of insulin delivery (e.g., pumps, pens, inhalers). Taken as a whole, these trends present a challenge to the pediatric diabetes specialist. In this article, the medications that are now frequently used in diabetes treatment are reviewed, including the indications for use, the usual dose, dose adjustment strategies, common side effects and anticipated outcomes. The diabetes literature on the new insulins and diabetes medications is reviewed, with an emphasis on the limited pediatric data. The goal is to familiarize the practicing pediatric diabetes specialist with these medications and their usage.

Administration, Oral↗
PubMed2005

[Spatial-temporal dynamics of landscape fragmentation in North Shannxi Loess Plateau].

The study of landscape fragmentation is an important means to reveal regional ecological processes. By using the remote sensing data of 1987, 1997 and 2002, and the GIS tools, some representative quantitative indices of the landscape spatial structure and landscape fragmentation in North Shannxi Loess Plateau were calculated, aimed to investigate the relationships between landscape ecological structure and landscape pattern in this area. The results showed that cropland contributed most to the extent of landscape fragmentation, but unused land lacked obvious relationship with it. To get large-area images accurately and promptly is very important for monitoring ecological process in regional scale. Moderate-Resolution Imaging Spectroradiometer (MODIS) images in 2003 were used to derive monthly landscape fragmentation information calculated with Local Index of Spatial Associations (LISA) based on Spatial Statistical Analysis (SSA). The analysis of the fragmented landscape types showed that human disturbance had a main contribution to the seasonal landscape fragmentation. Furthermore, with the increasing percentages of cropland and unused land, landscape became more fragmented, while forestland coverage had inverse effects on the fragmentation.

China↗
PubMed2006

[Diabetes mellitus: simple classification and corresponding treatment].

The classification of diabetes mellitus is not always straightforward but is of clinical importance in view of the differences in treatment, prognosis and inheritance. In young patients with acute signs ofhyperglycaemia and a low bodymass index (BMI), diabetes type 1 is the evident diagnosis, and insulin therapy should be initiated as quickly as possible. Deafness in patients with mild symptoms and a highly positive family history suggests the presence of a mitochondrial or maternally inherited type of diabetes: maternally inherited diabetes and deafness (MIDD). In the absence of deafness, maturity onset diabetes of the young (MODY) should be suspected in the same group of patients. In case of a non-acute presentation of hyperglycaemia without an evident family history of diabetes, the BMI can be helpful in the next steps of the diagnostic process. In practice, the proposed flow chart can readily be applied for the classification and treatment of patients with hyperglycaemia.

Body Mass Index↗
PubMed2006

[Evaluation of eco-environmental quality based on artificial neural network and remote sensing techniques].

In the present study, vegetation, soil brightness, and moisture indices were extracted from Landsat ETM remote sensing image, heat indices were extracted from MODIS land surface temperature product, and climate index and other auxiliary geographical information were selected as the input of neural network. The remote sensing eco-environmental background value of standard interest region evaluated in situ was selected as the output of neural network, and the back propagation (BP) neural network prediction model containing three layers was designed. The network was trained, and the remote sensing eco-environmental background value of Fuzhou in China was predicted by using software MATLAB. The class mapping of remote sensing eco-environmental background values based on evaluation standard showed that the total classification accuracy was 87. 8%. The method with a scheme of prediction first and classification then could provide acceptable results in accord with the regional eco-environment types.

Climate↗
PubMed1991

[Diabetes mellitus and molecular biology].

There are two approaches to identify diabetes-susceptibility genes. One approach is to isolate and characterize genes expressed in the beta-cell and in insulin target tissues whose mutation or altered expression may contribute to the development of diabetes mellitus. Another approach is to clone a diabetes-susceptibility gene by a reverse genetic strategy. The first step for this strategy is to identify a DNA polymorphism that is linked to the disease locus. Using the strategy of the first approach, several candidate genes were examined. Among these genes, the mutation of insulin genes and insulin receptor genes was found in the patient with diabetes. By cDNA cloning or PCR-direct sequencing methods, we identified several mutations in the insulin receptor genes of four insulin-resistant diabetic patients. At least two mutants of insulin receptor genes were expressed in Chinese hamster ovary cells and these mutated receptors showed impaired ability to transduce insulin action in these cultured cells. The expression of these mutant genes in animals such as transgenic mice will be indispensable to establish the relationship between the gene mutation and the abnormality found in the patient. Using the strategy of the second approach, Bell et al. recently reported that the gene responsible for MODY (maturity-onset diabetes of the young) is tightly linked to the adenosine deaminase gene on chromosome 20q. However, this strategy will not be applicable for identification of diabetes-susceptibility genes of NIDDM, since this disorder is likely to be genetically heterogenous, with mutations in several different genes able to cause hyperglycemia, and this heterogeneity could confound the linkage analysis.

Diabetes Mellitus↗