Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 2 patients, a 26-year-old woman and a 47-year-old man, diabetes mellitus was diagnosed during their teens, although they had (almost) no symptoms at the time. Since then, the disease was well controlled in both patients with the use of tolbutamide at a low dose. Diabetes occurred in at least 3 generations of both patients' families, inherited as an autosomal dominant trait. Genetic screening in both individuals revealed two separate mutations in the HNF-1 alpha gene, confirming maturity-onset diabetes of the young type 3 (MODY-3). MODY-3 patients are unusually sensitive to the hypoglycaemic effects of sulphonylureas. These agents remain effective in these patients for years, even at low doses.
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PMID:[High sensitivity to sulphonylurea treatment in 2 patients with maturity-onset diabetes of the young type 3]. 1198 Mar 75

The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of beta cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic beta cell growth and function. To investigate whether beta cell failure in Irs2(-/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2(-/-) mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2(-/-) mice, whereas it was expressed normally in islets from wild-type or Irs1(-/-) mice, which do not develop diabetes. Whereas male Irs2(-/-)Pdx1(+/+) mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2(-/-) mice. By contrast, transgenic expression of Pdx1 restored beta cell mass and function in Irs2(-/-) mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.
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PMID:Pdx1 restores beta cell function in Irs2 knockout mice. 1199 8

Mutations in the hepatocyte nuclear factor - 1 beta (HNF-1 beta) gene cause maturity onset diabetes of the young type 5 (MODY 5). A clinical feature of the resulting phenotype besides impaired glucose tolerance is a variety of renal abnormalities, ranging from renal cysts to end-stage renal failure. Using a candidate gene approach we investigated the prevalence of mutations in the HNF-1 beta gene in a group of 63 patients from two different European populations (33 Germans, 30 Czechs) with type 2 diabetes mellitus and diabetic nephropathy diagnosed by increased albuminuria (39 patients) or end-stage renal failure (24 patients). No mutations were found in any of the 9 exons or in a minimal promoter region. Three intronic variants (single nucleotide polymorphisms - SNPs) were detected. The frequencies of these variants showed no difference between the two studied populations and were comparable to data reported from healthy subjects. No association between SNPs or formed haplotypes and any clinical parameters (like age of disease onset, BMI and severity of renal failure) was found. The results confirm that the genetic variations in the HNF-1 beta gene would be a very uncommon cause of progressive nephropathy in patients with type 2 diabetes mellitus.
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PMID:Mutations and intronic variants in the HNF-1 beta gene in a group of German and Czech Caucasians with type 2 diabetes mellitus and progressive diabetic nephropathy. 1201 76

Wide efforts have taken place with complex metabolic disorders to emulate the success that linkage analysis has had in explaining the nature of monogenic metabolic diseases such as MODY (maturity-onset diabetes of the young) and FH (familial hypercholesterolemia). New linkage methods are being specifically developed and tested for complex disorders since some of the basic assumptions of traditional linkage analysis used with Mendelian traits are not valid. The nature of complex diseases precludes the use of extended families under the hypothesis that the same disease allele acts in most affected individuals throughout a pedigree. Rather, a multitude of genes and of rare and common alleles creates an apparently chaotic pattern of heterogeneity within and between families. Therefore, very simple family structures, in many studies even isolated sibling pairs, form the basis of efforts to compare the inheritance of disease with that of the chromosomal regions under investigation. Also, assumptions about how individual loci contribute to the overall disease inheritance used for the models applied in linkage computation have to be kept to a minimum. The overall effect of this, together with the potentially weak influence of many loci, is a heavy toll on the statistical power to detect individual contributing genes. This may be the reason why very few scans so far have yielded disease loci that meet genome-wide significance criteria. The confirmation of original loci in secondary studies has proven, as predicted, to be very difficult. Nevertheless, the overall emerging picture is very encouraging: one of the genome scans in type 2 diabetes has been carried through to the positional cloning of the underlying genetic variant, namely, the calpain 10-associated polymorphism in type 2 diabetes. Several other loci have been detected repeatedly throughout studies in various human racial groups, such as the chromosome 1q and 20q diabetes loci, and have become the target of collaborative fine-mapping efforts. Modifications to present methodology are in development with the goal to increase statistical power: examples are the use of intermediate traits with potentially increased genetic homogeneity, the investigation of admixed populations, and the study of linkage disequilibrium over wide genomic regions.
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PMID:Genetic and molecular analyses of complex metabolic disorders: genetic linkage. 1207 52

Diabetes represents a conglomerate of diseases with chronic hyperglycaemia as hallmark. The present review discusses those diabetic cases that associate with variants in genes that affect the magnitude of the glycolytic flux and oxidative disposal of glucose by mitochondria in pancreatic beta-cells. These genetic variants result in an attenuated secretion of insulin in response to glucose stimulation. The diabetic states that associate with these genetic variants are MODY 2, thiamine responsive anaemia syndrome (TRAS) and mitochondrial diabetes. These disease states highlight the critical contribution of the carbohydrate flux through glycolysis and mitochondria and its coupling to ATP production in determining insulin secretion.
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PMID:Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2. Diseases with common pathophysiology? 1243 22

Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.
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PMID:Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3). 1247 73

Hepatocyte nuclear factor (HNF)-1alpha plays a central role in intestinal and hepatic gene regulation and is required for hepatic expression of the liver fatty acid binding protein gene (Fabpl). An Fabpl transgene was directly activated through cognate sites by HNF-1alpha and HNF-1beta, as well as five other endodermal factors: CDX-1, C/EBPbeta, GATA-4, FoxA2, and HNF-4alpha. HNF-1alpha activated the Fabpl transgene by as much as 60-fold greater in the presence of the other five endodermal factors than in their absence, accounting for up to one-half the total transgene activation by the group of six factors. This degree of synergistic interaction suggests that multifactor cooperativity is a critical determinant of endodermal gene activation by HNF-1alpha. Mutations in HNF-1alpha that result in maturity onset diabetes of the young (MODY3) provide evidence for the in vivo significance of these synergistic interactions. An R131Q HNF-1alpha MODY3 mutant exhibits complete loss of synergistic activation in concert with the other endodermal transcription factors despite wild-type transactivation ability in their absence. Furthermore, whereas wild-type HNF-1alpha exhibited pairwise cooperative synergy with each of the other five factors, the R131Q mutant could synergize only with GATA-4 and C/EBPbeta. Selective loss of synergy with other endodermal transcription factors accompanied by retention of native transactivation ability in an HNF-1alpha MODY mutant suggests in vivo significance for cooperative synergy.
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PMID:HNF-1alpha and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity. 1264 18

Right classification of diabetes is important clinical issue. The aim of present study was to compare clinical, biochemical and immunological features, to analyze their practical use and to establish new decision tree which make the distinction between diabetes type 1, LADA, diabetes type 2 and MODY. We studied 97 not obese (mean BMI 26.3 +/- 4.9 kg/m2) patients aged 14 to 70 years, mean age 43 +/- 11.7 years, 53 women, 44 men. Mean duration of diabetes--2.3 +/- 4.3 years. We measured basal and stimulated C-peptide (6 minutes after 1 mg i.v. glucagon) (ELISA) and antibodies titers to glutamic acid decarboxylase--antiGAD65, tyrosine phosphatase-like molecule--IA2 and insulin--IAA (RIA). Autoimmune diabetes (LADA, type 1) was diagnosed with presence of one or more islet antigen antibodies. The highest frequencies had anti-GAD antibodies 33/97 (34%). The most complicated was to sort out group of patients with LADA. Comparison between this group and patients with diabetes type 2 have shown that BMI, co-existence of autoimmune disease, autoimmune markers and basal and stimulated C-peptide level measured at entry for the classification were useful in differentiation. Moreover we observed significantly lower C-peptide basal, stimulated and over basal level in group with MODY diabetes in comparison to diabetes type 2 patients. In the studied group were 5 patients with diabetes type 2 and obesity, in relatively young age. At the end there was one case of ADM (atypical diabetes mellitus). Clinical criteria for the classification of diabetes not always correlated with diagnosis. Autoimmune markers, basal and stimulated C-peptide were useful specially in differentiation between LADA and diabetes type 2 or diabetes type 1. Autoimmune diabetes co-existe with autoimmune disease. Proposed diagnostic scheme take for consideration presence of autoantibodies as well as C-peptide criteria.
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PMID:[Clinical, biochemical and immunological characteristic of diabetes type I, LADA, diabetes type II, and MODY patients]. 1268 30

The spectrum of diabetes in the young has widened; it now includes monogenic diseases, for example the various forms of permanent and transient neonatal diabetes and MODY as well as the emerging obesity-associated Type 2 diabetes in late childhood, but the main form is still Type 1 diabetes. Age-related major medical, physiological, social and emotional problems make the clinical management of diabetes in children and adolescents a difficult task for the physician and the family. Overall glycaemic control remains moderate or poor despite a treatment schedule, which interferes with several elements of "normal" childhood. There is an up to tenfold geographical variation in the incidence of childhood Type 1 diabetes within Europe with relatively stable incidence rates in some countries (mainly northern), but dynamic increases in incidence in other countries (mainly central European).A number of nongenetic (environmental) factors have been associated with the risk of Type 1 diabetes. Among these, perinatal factors, early nutrition, growth and vaccinations, atopic diseases and vitamin D are discussed in detail. The important interplay between genes, organism and environment is illustrated with new genetic data supporting the importance of environmental pressures in the evolution of this major disease.Although Type 1 diabetes usually accounts for only a minority of the total impact of diabetes in a population, it is the predominant form of the disease in younger age-groups in most developed countries. It is estimated that on an annual basis almost 100 000 children younger than 15 years of age develop Type 1 diabetes worldwide. The autoimmune destruction of the pancreatic beta cells in Type 1 diabetes leads to absolute insulin dependence and a high rate of complications typically occurring at a relatively young age. Therefore, Type 1 diabetes places a particularly heavy burden on the individual, the family and health services.
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PMID:Diabetes in the young: a paediatric and epidemiological perspective. 1269 Apr 39

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.
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PMID:[Physiological basis of insulin secretion abnormalities]. 1270 60


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