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Biomedical subjects

G I Bell

Publications and source records attributed to G I Bell.

At least 55 records · Page 3Linked to original sources
PubMed1998

A missense mutation, Val62Ala, in the glucokinase gene in a Norwegian family with maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a form of diabetes mellitus characterized by autosomal dominant inheritance, onset usually before 25 y of age and a primary defect in glucose-stimulated insulin secretion. It is a heterogeneous disorder both with respect to aetiology and clinical features. Mutations in the genes encoding the glycolytic enzyme glucokinase, the liver-enriched transcription factors, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-1beta and HNF-4alpha, and the transcription factor, insulin promoter factor-1 (IPF-1) have all been associated with MODY. Here, we report a family, Norway-2 (N2), characterized by the presence of a mild, complication-free form of diabetes with autosomal dominant inheritance. Sequencing of the glucokinase gene in the proband revealed a T-to-C mutation in codon 62 which resulted in a valine-to-alanine substitution, designated Va162Ala (V62A). The V62A mutation, which has not been previously reported, cosegregated with diabetes in the N2 family. The results presented here indicate that the glucokinase form of MODY occurs in Norway. Moreover, screening the glucokinase gene for mutations in other families with clinical features similar to those of the N2 family could lead to improved treatment for patients with this form of diabetes.

Adult↗
PubMed1998

Adaptation to hyperglycemia enhances insulin secretion in glucokinase mutant mice.

The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice. Insulin secretion and intracellular calcium ([Ca2+]i) were measured as the glucose concentration was increased from 2 to 26 mmol/l in islets from heterozygous glucokinase (GK)-deficient mice (GK+/-) and their wild-type littermates (GK+/+). Results obtained in islets incubated in 11.6 or 30 mmol/l glucose for 48-96 h were compared. GK+/- islets that had been incubated in 30 mmol/l glucose showed improved although not normal insulin secretory and [Ca2+]i responses to the standard glucose challenge as well as an enhanced ability to sense small amplitude glucose oscillations. These effects were associated with increased glucokinase activity and protein. In contrast, exposure of GK+/+ islets to 30 mmol/l glucose increased their basal insulin secretion but reduced their incremental secretory responses to glucose and their ability to detect small amplitude glucose oscillations. Thus exposure of GK+/- islets to 30 mmol/l glucose for 48-96 h enhanced their ability to sense and respond to a glucose stimulus, whereas similar exposure of GK+/+ islets induced evidence of beta-cell dysfunction. These findings provide a mechanistic framework for understanding why glucokinase diabetes results in mild hyperglycemia that tends not to increase over time. In addition, the absence of one allele of the glucokinase gene appears to protect against glucose-induced beta-cell dysfunction (glucose toxicity).

Animals↗
PubMed1997

Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene.

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic disorder characterized by autosomal dominant inheritance, onset usually before 25 yr of age, and abnormal pancreatic beta-cell function. Mutations in the hepatocyte nuclear factor(HNF)-4alpha/MODY1, glucokinase/MODY2, and HNF-1alpha/MODY3 genes can cause this form of diabetes. In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree. Here we report the identification of a second family with MODY1 and the first in which there has been a detailed characterization of hepatic function. The affected members of this family, Dresden-11, have inherited a nonsense mutation, R154X, in the HNF-4alpha gene, and are predicted to have reduced levels of this transcription factor in the tissues in which it is expressed, including pancreatic islets, liver, kidney, and intestine. Subjects with the R154X mutation exhibited a diminished insulin secretory response to oral glucose. HNF-4alpha plays a central role in tissue-specific regulation of gene expression in the liver, including the control of synthesis of proteins involved in cholesterol and lipoprotein metabolism and the coagulation cascade. Subjects with the R154X mutation, however, showed no abnormalities in lipid metabolism or coagulation except for a paradoxical 3.3-fold increase in serum lipoprotein(a) levels, nor was there any evidence of renal dysfunction in these subjects. The results suggest that MODY1 is primarily a disorder of beta-cell function.

Adult↗
PubMed1997

Increase in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats.

Pregnancy is a physiological state associated with significant changes in appetite, thermogenesis, and lipid metabolism, functions which are regulated in part by a hormone, leptin, secreted by adipocytes. Leptin has also been shown to have a role in reproduction, promoting centrally-regulated maturation of the reproductive system and signaling the presence of adequate maternal energy stores for fertility. Here we demonstrate that serum leptin levels are modulated during normal rat pregnancy with a 1.8-fold increase during pregnancy followed by a decrease just before parturition. Leptin receptor mRNA levels in the uterus are also regulated with an increase about 2.7-fold during this same period, whereas there is no change in other tissues examined. The results suggest that leptin may play a role during pregnancy, perhaps regulating energy utilization.

Animals↗
PubMed1997

Cloning and characterization of exodus, a novel beta-chemokine.

Chemokines are a family of related proteins that regulate leukocyte infiltration into inflamed tissue. Some chemokines such as MIP-1 alpha also inhibit hematopoietic progenitor cell proliferation. Recently, three chemokines, MIP-1 alpha, MIP-1 beta, and RANTES, have been found to significantly decrease human immunodeficiency virus production from infected T cells. We report here the cloning and characterization of a novel human chemokine termed Exodus for its chemotactic properties. This novel chemokine is distantly related to other chemokines (28% homology with MIP-1 alpha) and shares several biological activities. Exodus is expressed preferentially in lymphocytes and monocytes, and its expression is markedly upregulated by mediators of inflammation such as tumor necrosis factor or lipopolysaccharide. Purified synthetic Exodus was found to inhibit proliferation of myeloid progenitors in colony formation assays. Exodus also stimulated chemotaxis of peripheral blood mononuclear cells. The sequence homology, expression, and biological activity indicate that Exodus represents a novel divergent beta-chemokine.

Amino Acid Sequence↗
PubMed1997

The length distribution of perfect dimer repetitive DNA is consistent with its evolution by an unbiased single-step mutation process.

We have examined the length distribution of perfect dimer repeats, where perfect means uninterrupted by any other base, using data from GenBank on primates and rodents. Virtually no lengths greater than 30 repeats are found, except for rodent AG repeats, which extend to 35. Comparable numbers of long AC and AG repeats suggest that they have not been selected for special functions or DNA structures. We have compared the data with predictions of two models: (1) a Bernoulli Model in which bases are assumed equally likely and distributed at random and (2) an Unbiased Random Walk Model (URWM) in which repeats are permitted to change length by plus or minus one unit, with equal probabilities, and in which base substitutions are allowed to destroy long perfect repeats, producing two shorter perfect repeats. The source of repeats is assumed to be from single base substutions from neighboring sequences, i.e., those differing from the perfect repeat by a single base. Mutation rates either independent of repeat length or proportional to length were considered. An upper limit to the lengths L approximately 30 is assumed and isolated dimers are assumed unable to expand, so that there are absorbing barriers to the random walk at lengths 1 and L + 1, and a steady state of lengths is reached. With these assumptions and estimated values for the rates of length mutation and base substitution, reasonable agreement is found with the data for lengths > 5 repeats. Shorter repeats, of lengths </= 3 are in general agreement with the Bernoulli Model. By reducing the rate of length mutations for n </= 5, it is possible to obtain reasonable agreement with the full range of data. For these reduced rates, the times between length mutations become comparable to those suggested for a bottleneck in the evolution of Homo sapiens, which may be the reason for low heterozygosity of short repeats.

Animals↗
PubMed1997

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.

Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G-->T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50% of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro- and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM.

Adolescent↗
PubMed1997

Genetic variation in the hepatocyte nuclear factor-1 alpha gene in Danish Caucasians with late-onset NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) is a phenotypically and genetically heterogeneous disorder. A recent random genome mapping study has localized a locus termed NIDDM2 that maps to the region of chromosome 12 that includes MODY3, one of the three genes responsible for maturity-onset diabetes of the young, a monogenic form of NIDDM characterized by early age of onset and autosomal dominant inheritance. These findings suggest that NIDDM2 and MODY3 may represent different alleles of the same gene. MODY3 has recently been shown to be the gene encoding the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) thereby allowing us to determine whether mutations in the HNF-1 alpha gene are present in subjects with late-onset NIDDM. We screened 84 white NIDDM patients of Danish ancestry and found four nucleotide substitutions that changed the sequence of HNF-1 alpha, Ile27-->Leu, Ala98-->Val, Ser487-->Asn and Arg583-->Gln, five nucleotide substitutions that were silent and did not change the amino acid, Leu17, Gly288, Leu459 and Thr515, and five substitutions in the intron regions. The frequencies of the codon 27, 98 and 487 amino acid variants were similar in 245 unrelated NIDDM patients and 242 age-matched control subjects. The Arg583-->Gln mutation was found in 2 of 245 NIDDM patients and in none of the control subjects. Thus, genetic variation in the HNF-1 alpha gene is not a common factor contributing to NIDDM susceptibility in white subjects of Danish ancestry.

Age of Onset↗
PubMed1997

Identification of gestationally regulated genes in rat myometrium by use of messenger ribonucleic acid differential display.

OBJECTIVE: We hypothesized that the proteins contributing to myometrial changes during gestation could be identified indirectly by analyzing the changing pattern of messenger ribonucleic acid expression in the myometrium during pregnancy. STUDY DESIGN: Ribonucleic acid was extracted from myometrium of timed pregnant Sprague-Dawley rats on days 12, 16, 20, 21, and 22 of pregnancy and on day 1 post partum. The technique of messenger ribonucleic acid differential display, a simple and sensitive polymerase chain reaction-based method for rapidly identifying messenger ribonucleic acids whose levels increase or decrease, was performed with the nine different anchoring primers (oligodeoxythymidine11 VN: V = G, A, or C; N = G, A, or C) in combination with 24 different 10-base oligonucleotides of random sequence. The polymerase chain reaction products were separated by electrophoresis on a 5% polyacrylamide sequencing gel, and those whose levels changed were then cloned, sequenced, and compared with those in the GenBank database to determine whether they corresponded to a known sequence in the database or were novel. Semiquantitative reverse transcriptase-polymerase chain reaction was used to confirm differential expression of selected products. RESULTS: Messenger ribonucleic acid differential display revealed > 500 polymerase chain reaction products that were differentially expressed during gestation, 179 of which were cloned and sequenced. Of these, 157 were from messenger ribonucleic acids whose levels increased during gestation, and 22 were from transcripts that decreased. Eighty-seven (49%) were related to sequences in the GenBank database, of which 62 (35%) were from messenger ribonucleic acids encoding known proteins and 25 (14%) corresponded to known expressed sequence tags. The technique of semiquantitative reverse transcriptase-polymerase chain reaction confirmed the increased expression of messenger ribonucleic acids encoding beta-tropomyosin, type II phosphatidyl inositol-4-phosphate 5-kinase, and a novel myometrial messenger ribonucleic acid named RPU0901AC. CONCLUSION: Messenger ribonucleic acid differential display is a simple and sensitive method for rapidly identifying myometrial messenger ribonucleic acids that are differentially regulated during pregnancy. The identification of these differentially expressed messenger ribonucleic acids may lead to a better understanding of the molecular basis of normal and abnormal parturition.

Aging↗
PubMed1997

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4alpha) and hepatocyte nuclear factor 1 alpha (HNF-1alpha) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers for MODY3 for mutations in the HNF-1alpha gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.

DNA-Binding Proteins↗
PubMed1997

Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene.

Nondiabetic subjects with the Q268X mutation in the hepatocyte nuclear factor (HNF)-4alpha/MODY1 gene have impaired glucose-induced insulin secretion. To ascertain the effects of the nonglucose secretagogue arginine on insulin and glucagon secretion in these subjects, we studied 18 members of the RW pedigree: 7 nondiabetic mutation negative (ND[-]), 7 nondiabetic mutation positive (ND[+]), and 4 diabetic mutation positive (D[+]). We gave arginine as a 5-g bolus, followed by a 25-min infusion at basal glucose concentrations, and after glucose infusion to clamp plasma glucose at approximately 200 mg/dl. The acute insulin response (AIR), the 10-60 min insulin area under the curve (AUC), and the insulin secretion rate (ISR) were compared, as were the acute glucagon response (AGR) and glucagon AUC. The ND[+] and D[+] groups had decreased insulin AUC and ISR and decreased glucose potentiation of AIR, insulin AUC, and ISR to arginine administration when compared with the ND[-] group. At basal glucose concentrations, glucagon AUC was greatest for the ND[-] group, intermediate for the ND[+] group, and lowest for the D[+] group. During the hyperglycemic clamp, there was decreased suppression of glucagon AUC for both ND[+] and D[+] groups compared with the ND[-] group. The decreased ISR to arginine in the ND[+] group compared with the ND[-] group, magnified by glucose potentiation, indicated that HNF-4alpha affects the signaling pathway for arginine-induced insulin secretion. The decrease in glucagon AUC and decreased suppression of glucagon AUC with hyperglycemia suggest that mutations in HNF-4alpha may lead to alpha-cell as well as beta-cell secretory defects or a reduction in pancreatic islet mass.

Adult↗
PubMed1997

Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Adolescent↗