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PubMed1999

[NIDDM susceptibility genes].

Non-insulin dependent diabetes mellitus (NIDDM) is a heterogeneous disorder and both genetic and nongenetic factors are associated with the development of diabetes. Until now five genes (HNF-4 alpha, glucokinase, HNF-1 alpha, IPF-1 and HNF-1 beta), whose mutation can result in MODY, insulin and insulin receptor genes, and mitochondria DNA have been reported to be responsible for diabetes. Furthermore the mutations in some genes which work for insulin secretion or action also have been reported. This review discusses our current knowledge of these NIDDM susceptibility genes.

Diabetes Mellitus, Type 2↗
PubMed1999

[Childhood diabetes mellitus].

Long-term check of 68 type 1 diabetes patients (1978-1998); 23 under age 19, mean age 13.4 +/- 4.1 (group A) and 45 above age 20, mean age 26.7 +/- 4.9 (group B) were analyzed. 1) Mean onset age were 5.5 +/- 3.9 years old in group A whereas 7.8 +/- 3.5 in B. 2) In all type 1 diabetes high prevalences of positive HLA-DQ region gene and ICA and/or GADA were found. About 11% of all these patients showed the clinical pattern of slowly progressive variants. 3) Treatment modalities in individuals were successfully selected out of various combinations of insulin and multiple daily injection (MDI) styles. 4) Late complication prevalences were none in A and very little in B (8.9% background and none proliferative retinopathy, 2.2% nephropathy and 2.2% hypertension). 5) Five married females were able to have 7 normal babies. Sixteen type 2 diabetes patients, including one MODY 2, were successfully treated with combinations of sulfonylureas/alphaglucosidase inhibitors/insulin.

Adolescent↗
PubMed2000

Genetics of type 2 diabetes mellitus.

Type 2 diabetes mellitus is a heterogeneous disease that is caused by both genetic and environmental factors. Only a minority of cases of type 2 diabetes are caused by a single-gene defect, such as maturity-onset diabetes of youth (mutated MODY gene), syndrome of insulin resistance (insulin receptor defect), and maternally inherited diabetes and deafness (mitochondrial gene defect). The genetic component of the more common form of type 2 diabetes is probably complex and involves the interactions of multiple genes and environmental factors. The candidate gene approach has identified several genes that regulate insulin signalling and secretion, but their contributions to diabetes are small. Recent genome scan studies have been conducted to identify major susceptibility loci that are linked with type 2 diabetes. This information would provide new insights into the identification of novel genes and pathways that lead to this complex disease.

Amyloid↗
PubMed1997

[Retroviral vector mediated gene transfer and expression of human GM-CSF in HL-60 leukemic cells].

OBJECTIVE: To study the condition and possibility for introducing foreign gene into myeloid leukemic cells and gene therapy for malignant tumors in hematology. METHODS: With Lipofectin technique, N2A/CMV/hGM-CSF was transfected into packaging cell line PA317 and recombinant retrovirus were obtained. Then the human myeloid leukemic cells HL-60 were infected with recombinant retroviral supernatant. Positive cells were obtained through the neomycin analogue G418 selection. RESULTS: Successful integration of GM-CSF gene into HL-60 cell genome was verified by PCR and Southern Blot, while no specific fragments were amplified by PCR test in HL-60 cells without being transferred or transferred with empty vector N2A. With measurement by GM-CSF dependent cell line TF-1, the level of GM-CSF released by the GM-CSF gene modi-fied HL-60 cell line was 60-200 ng.ml-1.10(-6).24 h-1, while the supernatant of HL-60 cells without being transferred or transferred with empty vector N2A. CONCLUSION: hGM-CSF gene mediated by retroviral vector can achieve efficient transfer and expression in HL-60 leukemic cells.

Gene Transfer Techniques↗
PubMed2000

The role of C-peptide in the classification of diabetes mellitus.

We investigated twenty-one insulin-using patients, who had all been labelled as having insulin dependent diabetes mellitus (IDDM) or type 1 diabetes. Physicians have been erroneously using the term IDDM loosely to include all diabetics on insulin. The clinical criteria of the National Diabetes Data Group/WHO were used to reclassify these patients. Only thirteen were found to have IDDM and eight non-insulin dependent diabetes mellitus (NIDDM). Using fasting C-peptide values, only five of the thirteen with clinical IDDM truly had IDDM, the others might have maturity onset diabetes of the young (MODY) or diabetes in the young. Of the eight with clinical NIDDM seven had normal to high C-peptide values; the lone patient with low C-peptide values had diabetes diagnosed at age 64 years. We conclude that the clinical classification of diabetes mellitus may be inaccurate and that C-peptide evaluation improves the accuracy of the classification.

Adolescent↗
PubMed2000

Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations.

The glucokinase gene is expressed not only in pancreatic B cells and in the liver, but also in pancreatic alpha cells, and in some cells of the central nervous system. A decreased glucokinase activity in the latter cell types may interfere with counterregulatory responses to hypoglycemia. In order to assess functional consequences of glucokinase mutations, counterregulatory hormones secretion and glucose production (6,6(- 2) H glucose) were monitored during an hyperinsulinemic clamp at about 2.4 pmol.kg(- 1).min(- 1) insulin with progressive hypoglycemia in 7 maturity onset diabetes of the young (MODY) type 2 patients, 5 patients with type 2 diabetes, and 13 healthy subjects. Basal glucose concentrations were significantly higher in MODY2 patients (7.6 +/- 0.4 mmol.l(- 1) ) and type 2 diabetic patients (12.4 +/- 2.3 mmol.l(- 1) ) than in healthy subjects (5.3 +/- 0.1 mmol.l(- 1), p<0.01) but counterregulatory hormones concentrations were identical. Insulin-mediated glucose disposal and suppression of endogenous glucose production at euglycemia were unchanged in MODY2 patients, but were blunted in type 2 diabetes. During progressive hypoglycemia, the glycemic thresholds of MODY2 patients for increasing glucose production (5.0 +/- 0.4 mmol.l(- 1) ) and for glucagon stimulation (4.5 +/- 0.4 mmol. l(- 1) ) were higher than those of healthy subjects and type 2 diabetic patients (3.9 +/- 0.1 and 4.1 +/- 0.1 mmol.l(- 1) respectively for glucose production and 3.7 +/- 0.1 and 3.5 +/- 0.1 mmol.l(- 1) for glucagon stimulation, p <0.02 in both cases). These results indicate that counterregulatory responses to hypoglycemia are activated at a higher plasma glucose concentration in MODY2 patients. This may be secondary to decreased glucokinase activity in hypothalamic neuronal cells, or to alterations of glucose sensing in pancreatic alpha cells and liver cells.

Adult↗
PubMed2000

Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice?

The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic B-cells to compensate by adequate insulin secretion. Here, we review studies obtained from genetically engineered mice that have helped dissect the pathophysiology of this disease. Transgenic/knockout models with monogenic impairment in insulin action and insulin secretion have highlighted potential molecular mechanisms for insulin resistance and suggested a mechanism for the development of MODY in humans. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, pointing out the importance of interactions of different genetic loci in the production of diabetes. Tissue-specific knockouts of the insulin receptor have challenged current concepts on the regulation of glucose homeostasis and have highlighted the importance of insulin action in pancreatic B-cells and brain. The impact of the genetic background on insulin action, insulin secretion and the incidence of diabetes is also evident in these models. These findings highlight potential new therapeutic targets in the treatment of type 2 diabetes.

Animals↗
PubMed2000

[Molecular background and clinical characteristics of autosomal dominant type 2 diabetes mellitus].

Type 2 diabetes is a complex disease and genetic as well as environmental factors play a role in its pathogenesis. Six different genes have been identified so far to be responsible for rare forms of autosomal dominant, early onset type 2 diabetes mellitus. All but one are transcription factors which influence expression of the other genes through the regulation of mRNA synthesis. These are hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, insulin promoter factor (IPF)-1 and HNF-1 beta, which are associated with MODY1, 3, 4, 5 respectively. MODY1 is a relatively rare and usually severe form of diabetes. It is associated with progressive hyperglycemia and frequent chronic complications. The HNF-4 alpha gene is localized on chromosome 20q. Similar clinical characteristics apply to the MODY3 form, however the latter is much more frequent among early onset, autosomal dominant type 2 diabetes (20-40%). HNF-1 alpha gene is localized on chromosome 12q. HNF-1 beta (MODY5 locus on chromosome 17q) is a protein which forms heterodimers with HNF-1 alpha. This rare form of diabetes has a clinical picture similar to MODY1 and MODY3. It is sometimes accompanied by symptoms of early kidney damage which are independent from diabetes. The other two transcription factors responsible for the development of autosomal dominant type 2 diabetes are proteins which bind directly to the insulin promoter. MODY4 (IPF-1, chromosome 13q) is a rare form and of a typical middle and late onset type 2 diabetes. BETA 2/Neurod1 has been recently associated with MODY by Dr Krolewski's group from Joslin Diabetes Center, Boston, MA, USA. BETA 2 is responsible for about 2% of autosomal dominant type 2 diabetes. The clinical characteristics depend on the localization of the mutations in the specific functional domains of the protein. Mutations identified in the glucokinase gene are associated with the MODY2 form. Glucokinase is an enzyme involved in the first level of glucose metabolism in b-cells-enzymatic phosphorylation. MODY2 is a modest form of diabetes. It is characterized by mild hyper-glycemia, mainly fasting, and the chronic complications are very rare. Glucokinase gene is localized on chromosome 7p. It is expected that in the nearest future more type 2 susceptibility genes will be identified.

Adolescent↗
PubMed2000

[The role of genetic studies in finding the etiopathogenesis of diabetes mellitus].

The role of genetic investigations in diabetes one can describe in aspect of their role in the pathogenesis of type 1 and type 2 as well as in pathogenesis of chronic complications and gene therapy of diabetes. There is not only one gene responsible for type 1 diabetes. Similarly there are many gene-candidates in type 2 diabetes. Only in 6 types of MODY the genes responsible for beta-cell dysfunction were described. In diabetic complications some role e.g. in retinopathy may be played by genes of growth factors, heparan sulfate synthesis as well as genes of adrenergic receptor beta 3. In diabetic nephropathy the genes of renin synthesis, converting enzyme, aldose reductase or angiotensin receptor can be of importance. It should be emphasized that identification of human genome and genes responsible for diabetes can contribute to introduction of gene therapy in diabetes.

Diabetes Mellitus, Type 1↗
PubMed2000

[Genetics of type II diabetes].

Type 2 diabetes is a multifactorial disease composed of subtypes strongly associated with environmental factors at one end of the spectrum and highly genetic forms at the other hand. The former forms have been largely elucidated in the last years by the identification of the 5 genes responsible for the autosomal dominant MODY subtype: glucokinase, and 4 transcription factors which play a key role in the development of the endocrine pancreas or in the expression of glucose metabolism genes. Apart from the monogenic forms of type 2 diabetes little is known about the nature of the genetic factors involved. Minor contributors include insulin, sulfamide receptor and some others. Genome scans of diabetic families have revealed susceptibility loci on chromosome 1q, 2p, 2q (where the gene calpain 10 was recently cloned), 3q, 12q and 20. The identification of diabetes susceptibility gene is the first step to define targets of new drugs against diabetes.

Adolescent↗
PubMed2001

Genetic aspects of diabetes mellitus.

Practically all types of diabetes mellitus (DM) result from complex interactions of genetic and environmental factors. Multifactorial and polygenic Type 1 DM is strongly influenced by genes controlling the immune system, mainly HLA-DQ and DR. In addition to this, many other predisposition loci, interacting with each other, have some influence on susceptibility to DM. Heterogeneous Type 2 DM, accounting for about 85% of all diabetic patients, is supposed to be induced by multiple genes defects involved in insulin action and/or insulin secretion. Other genetically influenced traits like obesity and hyperlipidemia are strongly associated with the Type 2. The group called Other specific types of DM include monogenic forms MODY 1-5 and many various subtypes of the disease, where the specific gene mutations have been identified. Both genetic and intrauterine environmental influences are likely to contribute to the abnormalities defined as Gestational DM.

Diabetes Complications↗
PubMed2000

[Neonatal diabetes, heterogeneous syndrome].

Neonatal diabetes (ND) is a rare condition of hyperglycaemia which occurs, generally, within the first month of life, requires insulin therapy and lasts more than two weeks. The pathogenesis is uncertain and the different clinical variants are heterogeneous; both a "permanent" and a "transient" form of ND exist. We report the clinical history of three neonates (A.L., A.B. and V.I.) in which a tout-court diagnosis of ND was done; the follow-up allowed us to reevaluate the initial diagnoses and suppose different ethiopathogenic mechanisms. Clinical observations, insulin requirement and biochemical data obtained during the years of follow-up allowed to distinguish three different situations: a "permanent" ND (A.L.), a "transient-recurrent" ND (A.B.), and a Maturity Onset Diabetes of the Young (MODY) (V.I.).

Diabetes Mellitus↗
PubMed2001

Volume sonography of the pelvic floor in nulliparous women and after elective cesarean section.

OBJECTIVE: To describe the sonographic appearance of the pelvic floor which has not been stressed by forces of labor or vaginal delivery in pregnant women and after childbirth. SUBJECTS AND METHODS: In a prospective observational study 14 nulliparous women during first trimester pregnancy and 26 primiparous women after elective cesarean were examined within the first week postpartum. The integrity of the internal anal sphincter expressed as the ratio between the anterior and the posterior internal anal sphincter muscle thickness (a/p-ratio), asymmetry of the levator ani muscle and the paraurethral fixation of the lateral vaginal edges at the arcus tendineus were assessed using volume sonography. RESULTS: The a/p-ratio in nulliparous women was significantly higher (p<0.01) than after elective cesarean section. Asymmetry of the levator ani muscle did not differ between both groups but was more frequently in the nulliparous patients with an odds-ratio of 1.16 (CI 0.74-1.82). In both groups of women the paraurethral fixation of the lateral vaginal edges were above the suburethral level of the vagina. CONCLUSIONS: This study gives sonographic features of the pelvic floor in nulliparous women and in primigravidae after elective cesarean section. Data from the post-cesarean group can serve as reference values for further studies evaluating pelvic floor damage after various modi of vaginal delivery.

Adult↗
PubMed1975

[Clinical and histopathological findings in mycoplasmal polyarthritis of rats. I. Course of infection during the first 8 days (author's transl)].

Polyarthritis in rats could be induced by intraperitoneal infection with M. arthritidis. The mycoplasma culture alone or in combination with infusorial earth was used as inoculum. The histopathological changes consisted of initial lesions in the transitional zone of the articular capsule which could be attributed to disturbances of vascular permeability. After two days suppurative arthritis occurred, which was accompanied by massive inflammatory lesions of the articular capsule and of the periarticular tissues. Towards the end of the observation period erosions of cartilage, pannus formation and periarticular foci of purulent necrobiosis were found. Especially the synovial membrane was subjected to profound changes and dense cellular infiltration. The cell infiltration, mesenchymal proliferation and changes of vascular permeability showed variations in timing and degree depending on the modi of infection. The histological examinations of organs indicated generalization of the infection.

Animals↗
PubMed2000

[The studies on human endogenous retrovirus gene expression, distribution of the genome and association with IDDM and other inheritance- related diseases].

OBJECTIVE: The mechanism for type 1 diabetes still remains unclear. This study was focused on the viral morphology, endogenous retrovirus expression, immunology and molecular biology. METHODS: Type C retrovirus-like particles were observed in beta cells of the diabetic pancreases under electron microscope. Human endogenous retroviral pol gene expression was detected by PCR in cDNA libraries from IDDM pancreases, brain, splenocytes and control subjects. These DNA segments were sequenced. RESULTS: ERV9, HERV-K-MIN, HERV-K10, RTVL related sequences were significantly higher in IDDM group than control subjects and DR2-related MMTV-like sequences were significant lower in IDDM group than control subjects. ERV9- related genes, gag, pol, env and 3' LTR were amplified and sequenced by PCR from cDNA libraries of 2 newly onset diabetic pancreases. Retrovirus sequences were further searched for their distribution on the chromosome genome and their locations at the centromeres, telomeres, immune reaction genes (MHC, TCR, Ig autoantigens) and at many disease loci, such as the loci for IDDM, Mody, the candidate genes for NIDDM, diabetic complications, autoimmune diseases, cancer and other genetic diseases. CONCLUSIONS: These facts indicate that the endogenous retrovirus genes may be the important genetic factor of IDDM and play key role in the structure and physical function of chromosome and the pathogenesis of genetic-related diseases.

Chromosomes, Human↗
PubMed2001

Lack of association between hepatocyte nuclear factor-1beta gene and common forms of type 2 diabetes in the Japanese population.

Mutations in the hepatocyte nuclear factor-1beta (HNF-1beta) gene have been shown to be a cause of maturity-onset diabetes of the young (MODY). We studied the contribution of the HNF-1beta gene to susceptibility to common forms of Type 2 diabetes in the genetically homogeneous Japanese population, by investigating the allelic association of Type 2 diabetes with two markers in the HNF-1beta region. The frequency of a nonsense mutation, R177X, which was previously reported in a Japanese family, was also studied by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using a mismatch primer. A total of 200 subjects were studied. There was no significant difference in allele frequencies of either of the two polymorphisms studied between patients with Type 2 diabetes and control subjects, or between subgroups of patients subdivided by the presence of mild or severe diabetic nephropathy. None of the subjects studied had R177X mutation, giving a frequency of less than 1.1% in common forms of Type 2 diabetes in Japan. These results suggest that mutations in the HNF-1beta gene derived from a limited number of founders are not a major cause of common forms of Type 2 diabetes, even in the genetically homogeneous Japanese population.

Adult↗
PubMed2002

Prevalence of the missense mutation Gly574Ser in the hepatocyte nuclear factor-1alpha in Africans with diabetes.

BACKGROUND: Clinical presentation and natural history of diabetes are somewhat different in Black Africans compared to Caucasians. This peculiar disease course could be at least partly related to a specific genetic profile that has not been studied in this population. METHODS: Medical backgrounds, anthropometric and biologic parameters were obtained from 69 diabetic subjects in Dakar, Senegal, in 1998. Blood anti GAD and Islet Cell Antibodies were studied, using RIA and immunofluorescence assay. The HNF-1alpha gene was sequenced searching the Gly574Ser mutation, previously described in MODY 3. RESULTS: Among these 69 diabetic patients, 11 (16%) were found to have the G574S mutation affecting the HNF-1alpha. These 11 patients carrying the mutation were compared respectively with the 58 non carriers. Mean age (57.5 yr. +/- 11 vs 51.1 yr. +/- 15) and duration of diabetes (11.9 vs 6.7 yr), were similar in the two groups. BMI was not different in patients with the mutation (26.3 vs 23.3, p=0.06). Metabolic control (Glycosylated hemoglobin) was poor in the two groups (9.5% vs 9.2%). Chronic complications were equally found in the patients, but no mutation carrier had macroangiopathy. None of the anti GAD positive or ICA positive patients had the mutation. CONCLUSIONS: The HNF-1alpha Gly574Ser mutation was found in 16% of cases in a 69 diabetic patients group in Senegal. Diabetes was as severe as in non carriers of mutation. This mutation has been implicated in atypical diabetes of Afro-American children. The study confirms its prevalence in Africans with diabetes.

Adult↗
PubMed2002

[Clinical heterogeneity of childhood diabetes in Baranya county].

INTRODUCTION: Immune mediated type 1 diabetes is the most frequent form of childhood diabetes while type 2 and other forms are more rare in childhood in the Caucasian population. Differentiation of various diabetes subtypes has importance in the choice of treatment and prognosis. AIMS: The aim of the study was to describe clinical heterogeneity of childhood diabetes and to evaluate possibilities of phenotypical classification. METHODS: Two hundred twenty eight children (128 girls and 100 boys) with diabetes diagnosed at the Department of Pediatrics, University of Pécs, in the period of 1978-2000 were examined. Glycated hemoglobin levels, insulin requirement, body weight at diagnosis and association of type 1 diabetes with other disorders were analysed. RESULTS: Thirty one patients (13.6%) had permanently low (< 8%) glycated hemoglobin levels. Low glycated hemoglobin level associated with low insulin requirement (< 0.5 U/kg/day) was observed in three patients (1.4%) with 4 years of disease duration and in 2 patients (0.9%) during the whole disease course. These patients can be classified as non-classical type 1 diabetes cases. Obesity associated with less than 0.5 U/kg/day insulin requirement observed at least for two years from diagnosis was found in 2 cases (0.9%). These cases may be diagnosed as having childhood type 2 diabetes. The authors identified two diabetes patients with Down syndrome while MODY and transient neonatal diabetes were observed in one cases each. Diabetes associated conditions diagnosed in single cases each were as follows: thymus tumor, Duchenne muscular dystrophy, autoimmune polyglandular syndrome type 2, and T-cell lymphoma. CONCLUSIONS: Childhood diabetes cases can be classified into several subgroups on clinical grounds, insulin requirement, and glycemic control. The data suggest that the prevalence of type 2 and non-classical type 1 diabetes is probably only a few percent among children with diabetes in Hungary. Due to phenotypic overlap between different forms of diabetes, measurement of beta-cell specific autoantibodies and C peptide levels can be recommended for etiologic classification.

Adolescent↗