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K Silver

Publications and source records attributed to K Silver.

At least 37 records · Page 2Linked to original sources
PubMed1998

Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women.

There is controversy regarding the role of the Trp64Arg variant of the beta3-adrenergic receptor (beta3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 +/- 6 yr old) heterozygous for the beta3AR variant and in 14 women (57 +/- 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in beta3AR heterozygotes (241 +/- 135 mg/min) vs. normal homozygotes (379 +/- 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 +/- 27 mg/min) and normal homozygotes (164 +/- 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 +/- 57 mg/min) and normal homozygotes (56 +/- 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 +/- 111 mg/min) than for normal homozygotes (441 +/- 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the beta3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.

Aged↗
PubMed1998

Congenital bilateral perisylvian polymicrogyria presenting as congenital hemiplegia.

We report three children with pure congenital hemiplegia found to have congenital bilateral perisylvian polymicrogyria (CBPP). None of our patients had the seizures, oromotor dysfunction, or cognitive impairment usually associated with CBPP. CBPP may be more common and heterogeneous than previously thought, is easily recognized by MRI, and should be included in the differential diagnosis of the young child presenting with congenital hemiplegia.

Cerebral Aqueduct↗
PubMed1997

Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.

Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.

Adult↗
PubMed1997

The beta3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64.

The beta3-adrenergic receptor (ADRbeta3) is a seven-membrane spanning, G-protein linked receptor expressed in brown adipose tissue in rodents, and visceral adipose tissue in humans. Stimulation of the receptor by norepinephrine leads to lipolysis and thermogenesis. In rodent models of obesity and diabetes, administration of beta3-agonists results in weight loss and improved glucose tolerance. Studies indicate that the pharmacological properties of the ADRbeta3 differ markedly between rodents and humans, making generalizations of rodent studies to humans difficult. We hypothesized that the obesity and diabetes prone rhesus monkey (Macaca mulatta) would provide an excellent animal model to study the role of the ADRbeta3 in the development of obesity and diabetes as well as for assessment of the therapeutic efficacy of beta3-agonists. We sequenced the entire coding region of the rhesus ADRbeta3 gene. Like humans, the rhesus ADRbeta3 has two exons. There is 89% amino acid (aa) identity between human and rhesus compared to 82% aa identity between human and mouse. A single base deletion results in divergence of the intracellular carboxy terminus accounting for 26 of the 45 aa changes and 10 additional aa. Of the 15 rhesus monkeys studied, all were homozygous for Arg64. In humans, Arg64 (rather than Trp) is associated with increased body mass index, insulin resistance, and an earlier onset of type II diabetes mellitus. We conclude that the rhesus ADRbeta3 is more similar to the human ADRbeta3 than to the rodent ADRbeta3 suggesting that this primate model may be more appropriate for physiologic and therapeutic studies of the ADRbeta3 axis, and that Arg64 may influence susceptibility in this species to obesity, insulin resistance, and type II diabetes.

Amino Acid Sequence↗
PubMed1997

TRP64ARG beta 3-adrenergic receptor and obesity in Mexican Americans.

The beta 3-adrenergic receptor (beta 3AR) is expressed in visceral fat and is a regulator of resting metabolic rate, thermogenesis, and lipolysis. We genotyped 61 unrelated Mexican Americans for a variant in the beta 3AR gene (codon 64 TGGTrp-->CGGArg; TRP64ARG). The allele frequency was 0.13. The TRP64ARG variant was significantly associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (41.3 +/- 4.6 years vs 55.6 +/- 2.6 years; P < 0.02) and in non-diabetics, with elevated 2-h insulin levels during an oral glucose tolerance test (810 +/- 120 pmol/l vs 384 +/- 6 pmol/l; P < 0.005). Non-diabetic subjects with the variant allele tended to have higher body mass indices (BMI), waist-to-hip ratios, and diastolic blood pressures. The study group was expanded to include 421 related subjects from 31 families in the San Antonio Family Diabetes Study. Using a measured genotype analysis approach to estimate genotype-specific means for each trait, those who were homozygous for the TRP64ARG variant had significantly higher 2-h insulin levels (P = 0.036) and trends towards higher BMI compared to the other two genotypes. We detected no associations of these traits in the TRP64ARG heterozygotes in the larger group. We conclude that the TRP64ARG beta 3AR variant is a susceptibility gene for several features of the insulin resistance syndrome in Mexican Americans. Since its effects are modest, study design (e.g., subject selection, genetic background, and statistical analyses) may influence which traits are associated with this variant and whether or not the effect is detectable in heterozygotes.

Arginine↗
PubMed1997

Molecular scanning of beta-3-adrenergic receptor gene in total congenital lipoatrophic diabetes mellitus.

Total congenital lipoatrophic diabetes is characterized by absence of subcutaneous adipose tissue, hypertriglyceridemia, and insulin resistance. We hypothesized that mutations in the beta-3-adrenergic receptor (beta 3AR) gene might result in the lipoatrophic phenotype by preventing triglyceride storage in adipocytes; thereby, resulting in secondary insulin resistance. We screened the beta 3AR gene in 7 subjects with total congenital lipoatropic diabetes. We found a heterozygous substitution of a guanine to cytosine at position -153 (G-153C) in the 5'-untranslated region of 3 African-American lipoatrophic siblings and 1 sibling without lipoatrophy but with insulin resistance. To determine whether the base change was related to the lipoatrophic phenotype, we genotyped 69 African-Americans without lipoatrophy and found the G-153C substitution in 2 control subjects (allele frequency = 0.01). No other single-stranded polymorphism variants were found in any of the 7 lipoatrophic subjects. Direct sequencing of both alleles of 1 lipoatrophic subject demonstrated a thymidine insertion at position -300 in both alleles. All lipoatrophic subjects along with 20 African-American control subjects were homozygous for the base insertion, suggesting an error in the published sequence. In conclusion, mutations in the beta 3AR gene do not appear to be involved in the development of congenital total lipoatrophy.

Alleles↗
PubMed1996

Molecular scanning for mutations in the beta 3-adrenergic receptor gene in Nauruans with obesity and noninsulin-dependent diabetes mellitus.

We recently identified a mutation in the human beta 3-adrenergic receptor (beta 3AR) gene (codon 64 TGGTrp -> CGGArg; TRP64ARG) that associates with features of the insulin resistance syndrome and an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM). We scanned the beta 3AR gene for mutations by single stranded conformational polymorphism analysis in 20 Nauruans with obesity and NIDDM. No mutations were identified. Sixty-five Nauruan subjects were genotyped for the TRP64ARG beta 3AR. All subjects were homozygous for the normal allele. We genotyped Samoans and Asians for the TRP64ARG beta 3AR. Seven of 52 Samoans were heterozygous for the mutant arginine allele (allele frequency, 0.07). Of these, 5 were diabetic and 2 were nondiabetic (by Fisher's exact test, P = 0.4). There were trends toward increased body mass indices, waist to hip ratios, and 2-h insulin levels during oral glucose tolerance tests in Samoans with the mutation; however, the limited number of subjects available for study precluded rigorous statistical analysis. The TRP64ARG beta 3AR was also detected in Chinese, Chinese Americans, and subjects from the Indian subcontinent. In conclusion, the TRP64ARG beta 3AR mutation or any other mutation in the beta 3AR gene is not a major contributor to genetic susceptibility to NIDDM and obesity likely in Nauruans.

Adult↗
PubMed1995

A mutation in the beta 3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects.

The Trp 64 Arg mutation in the beta 3-adrenergic receptor (beta 3AR) gene was investigated in 350 Japanese subjects. This mutation was not associated with non-insulin-dependent diabetes mellitus (NIDDM). In 191 subjects without NIDDM, body mass index (BMI) was significantly higher in subjects homozygous for this mutation than in those homozygous for the normal allele (24.7 +/- 1.4 vs 22.1 +/- 0.2 kg/m2, p = 0.009). Moreover, the frequency of the mutant allele in obese subjects (BMI > 26.4) was significantly higher than that in non-obese subjects (BMI < 22) (0.37 vs 0.15, p = 0.009). The presence of this mutation was also accompanied by significantly higher fasting (p = 0.000) and 2 hrs (p = 0.018) serum insulin levels during an oral glucose tolerance test. The beta 3AR may be one of the loci contributing to obesity and hyperinsulinemia/insulin resistance in Japanese subjects.

Adult↗
PubMed1995

Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene.

BACKGROUND: The beta 3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis. METHODS: To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). RESULTS: A missense mutation was identified in the gene for the beta 3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/- SD) age at the onset of NIDDM was significantly lower (36 +/- 10 years) than in Trp64Arg heterozygotes (40 +/- 10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance). CONCLUSIONS: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Adult↗
PubMed1995

Pelizaeus-Merzbacher disease in a family of Portuguese origin caused by a point mutation in exon 5 of the proteolipid protein gene.

Single-strand conformational polymorphism analysis of an affected male with Pelizaeus-Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G-->A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435-442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes.

Child, Preschool↗
PubMed1995

Association of cerebral dysgenesis and lactic acidemia with X-linked PDH E1 alpha subunit mutations in females.

We describe an infant girl who presented at age 4 1/2 months with developmental delay, infantile spasms, hypotonia, and elevated lactate levels in the blood and cerebrospinal fluid. She had minor dysmorphic features. Muscle phosphorus magnetic resonance spectroscopy demonstrated reduced phosphocreatine and increased inorganic phosphate, suggesting a defect in oxidative energy metabolism. Pyruvate dehydrogenase activity in cultured fibroblasts was reduced (0.35 nmol/mg mitochondrial protein/min; controls 0.7-1.1 nmol/mg mitochondrial protein/min). Immunoblotting demonstrated a reduced amount of pyruvate dehydrogenase (PDH) E1 alpha immunoreactive protein with normal amounts of E2 protein. Single-strand conformational polymorphism analysis of E1 alpha cDNA prepared from fibroblasts disclosed an abnormal migration pattern, suggesting heterozygosity for a mutant allele. Dideoxy-fingerprinting of PCR-amplified genomic DNA was used to localize the mutation to exon 10. Direct sequencing demonstrated a novel 13-bp insertion mutation that would lead to premature termination of the protein product. This study further extends the allelic heterogeneity underlying PDH deficiency. The demonstration of bioenergetic abnormalities in muscle emphasizes that hypotonia in PDH deficiency may have combined peripheral and central etiologies. The results further suggest that the association of cerebral dysgenesis with lactic acidemia in females may be a useful clue to PDH deficiency.

Acidosis, Lactic↗
PubMed1995

Imaging of axonal damage in vivo in Rasmussen's syndrome.

We obtained magnetic resonance spectroscopic images (MRSIs) in three patients with Rasmussen's syndrome. The relative resonance intensity of N-acetylaspartate (NAA) to creatine (NAA:Cr), an index of neuronal loss or damage, was determined for various regions within the brain, and the affected:unaffected hemisphere asymmetry ratio was determined. All three patients had decreased relative NAA signal intensity over the entire affected hemisphere. The decrease in NAA:Cr involved cortex and white matter, was most prominent in the anterior periventricular region, and showed a tendency to be worse in patients with longer duration of disease. 1 year follow-up MRSI showed further reduction of the relative NAA signal in all patients, indicating progression of the disease. All patients were free of seizures for at least 48 h before the first MRSI, but two of them had epilepsia partialis continua (EPC) during the follow-up examination. There was no significant increase of the lactate resonance intensity, except in the two MRSIs performed during EPC. This indicates that lactate accumulation results from repetitive seizures rather than from the disease process itself. The spatial distribution of the metabolic abnormality on MRSI was more widespread than that of the structural abnormality on MRI. The relative NAA resonance intensity was not reduced in the contralateral hemisphere. Our findings indicate that MRSI can identify and quantify neuronal damage and loss throughout the affected hemisphere of patients with Rasmussen's syndrome, including areas that appear normal on conventional MRI.

Adolescent↗
PubMed1995

Lack of IRS-1 codon 513 and 972 polymorphism in Pima Indians.

Insulin receptor substrate-1 (IRS-1), an endogenous substrate for the insulin receptor tyrosine kinase, mediates many or all of the metabolic actions of insulin. Recently, polymorphism at codons 513 and 972 of the IRS-1 gene resulting in 2 amino acid substitutions that were associated with type II diabetes were found in a Caucasian population. Using allele specific oligonucleotide (ASO) hybridization, we screened 242 diabetic and 190 nondiabetic Pima Indians, a population with a very high prevalence of type II diabetes. Neither of the two mutations was present in either diabetic or nondiabetic subjects. We conclude that polymorphism at codons 513 and 972 of the IRS-1 gene observed in certain Caucasian populations is very rare or absent in Pima Indians.

Adult↗
PubMed1994

Fulminant hepatic failure associated with status epilepticus in children: three cases and a review of potential mechanisms.

Fulminant hepatic failure is a rare complication of status epilepticus. Although many of the anticonvulsants used to treat the seizures are known to have hepatotoxic properties, the exact mechanism leading to massive destruction of the liver following a prolonged seizure remains unclear. Three children are presented who developed fulminant hepatic failure following status epilepticus and subsequently died of multiple organ failure. The literature is reviewed with particular attention to the possible interaction between the anticonvulsants and the metabolic consequences of status epilepticus. We postulate that it is a combination of hypoxia and ischemia that occurs during a prolonged seizure with altered metabolism of free radicals secondary to the anticonvulsant drugs which leads to widespread hepatocyte membrane damage.

Anticonvulsants↗