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P J Avery

Publications and source records attributed to P J Avery.

15 recordsLinked to original sources
PubMed2006

Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes.

AIMS/HYPOTHESIS: Animal models indicate that even exposure to mild maternal hyperglycaemia in utero is detrimental to the beta cell function of the offspring, but evidence of this in humans is limited. In Europids who are diagnosed with type 2 diabetes before the age of 50 years, the risk of diabetes in the offspring of the diabetic mothers is greatly increased compared with the risk in those born to diabetic fathers. We hypothesised that offspring born to mothers with young-onset type 2 diabetes would have been exposed to mild hyperglycaemia in utero, so we studied the impact of this on their beta cell function. SUBJECTS AND METHODS: We measured beta cell function using early insulin response (EIR) after oral glucose; insulin resistance using HOMA; and HbA(1c) in 568 non-diabetic adult offspring born to parents with type 2 diabetes (mean age 55.8 years), split according to which parent was affected (in 327 it was the mother) and parental age of diagnosis: <50 years (n=117) or > or =50 years. To reduce the impact of genetic susceptibility, the offspring of affected fathers were used as control subjects. RESULTS: Offspring of mothers with young-onset type 2 diabetes had lower EIR (log EIR 4.32, 95% CI [4.14-4.51] vs 4.63 [4.43-4.83] p=0.02) and higher HbA(1c) (4.89% [4.79-4.99] vs 4.68% [4.57-4.79] p=0.02) than the offspring of fathers with young-onset type 2 diabetes. Insulin sensitivity was similar in the two groups. There were no differences in EIR or HbA(1c) between the offspring born to mothers and fathers who were diagnosed after the age of 50 years. CONCLUSIONS/INTERPRETATION: We conclude that the offspring of mothers with young-onset type 2 diabetes have a reduction in beta cell function. This is consistent with exposure to mild maternal hyperglycaemia programming beta cell function.

Adult↗
PubMed2004

Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to measure the heritability estimates for metabolic traits and the features of the insulin resistance syndrome in families with an increased genetic susceptibility to Type 2 diabetes. METHODS: A total of 811 non-diabetic relatives from 278 pedigrees of northern European extraction in which there was a sib-pair with Type 2 diabetes were recruited and studied at the six Diabetes UK Warren Type 2 diabetes centres. Heritability estimates were calculated, allowing for key covariates (age, sex, BMI and recruitment centre). Values greater than 0.10 were considered statistically significant in comparison to zero. RESULTS: Fasting glucose concentration and homeostasis model assessment of pancreatic beta cell function (HOMA %B) had the highest heritability estimates of 0.72 and 0.78 respectively. Heritability estimates for the features of the insulin resistance syndrome (BMI, WHR, systolic and diastolic blood pressure, serum lipids and homeostasis model assessment of insulin sensitivity [HOMA %S]) were also high. The heritability estimate for fasting glucose was markedly higher in the present study (0.77 vs 0.21 adjusted for age and sex; p<0.001) than in a comparable study of families from the same background population but with no increased susceptibility to diabetes. However, the estimates for the features of the insulin resistance syndrome were similar in the two studies. CONCLUSIONS/INTERPRETATION: In families with a high risk of Type 2 diabetes, the heritability estimates for fasting glucose, pancreatic beta cell function and the features of the insulin resistance syndrome were all high. The higher heritability estimate for pancreatic beta cell function suggests that this resource may be most effective when investigating genetic susceptibility to beta cell dysfunction.

Adult↗
PubMed1998

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance.

Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.

Adult↗
PubMed1997

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families.

Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3%, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion.

Adult↗
PubMed1996

Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families.

Insulin receptor substrate-1 (IRS-1) occupies a key position in the insulin-signalling pathway. Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Insulin resistance has been described in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examined the relationships between the two mutations and insulin sensitivity in 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess insulin sensitivity (K(ITT)) were performed. Basal insulin sensitivity was assessed by homeostasis model assessment (HOMA). Comparisons were made between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without either (n = 80). General linear model analysis was used to compare K(ITT) and HOMA between the subgroups with the anthropometric variables known to influence insulin sensitivity as covariates. There were no significant differences between the subgroups for K(ITT) and HOMA. In conclusion, the 513 and 972 mutations, alone and in combination, are not associated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.

Adult↗
PubMed1992

The effect of forage and forage-concentrate diets on rumen fermentation and metabolism of nutrients by the mesenteric- and portal-drained viscera in growing steers.

Growing Friesian steers chronically catheterized in the anterior mesenteric and portal veins were used to study the influence of feeding with either a forage or forage-concentrate diet on nutrient utilization by mucosal tissue. When animals were consuming the forage-concentrate diet the molar proportion of propionate in rumen fluid was significantly increased, although production rate as measured by isotope dilution was not altered. Net rates of absorption of VFA into portal blood when compared with rumen production rates underlined the extent to which metabolism within mucosal tissue modifies the propionate supply to the liver. Net glucose utilization by splanchnic tissue was shown to be significantly lower on the forage-concentrate diet. There were no effects of diet on whole-body glucose turnover or on the proportion of glucose derived from propionate. Animals fed on the forage-concentrate diet had significantly lower concentrations of circulating essential amino acids, due mainly to a reduction in branched-chain amino acid levels. There was net absorption of all amino acids by animals on both diets except for glutamate, glutamine and taurine in forage-fed animals.

Amino Acids↗
PubMed1987

The analysis of intron data and their use in the detection of short signals.

In order to examine whether certain short DNA sequences (putative splice signals) occurred in a certain region of an intron more often than would be expected by chance, intron data were examined to see what structure they took. There were significant departures from equal nucleotide frequency, and successive nucleotides clearly did not occur independently in the rat and mouse introns examined. The nonindependence was mainly due to a CG shortage and a less marked TA shortage. However the pairwise frequencies explained almost all the variability in triplet frequencies in the data and so the data could be approximately modeled by using nucleotide frequencies conditional on what the previous nucleotide was. Some coding DNA was also examined and the pairs in second and third positions, and third and first positions in a codon, showed similar departures from independence to those of the intron data. Using the probability model derived for intron data, expected frequencies of putative signals were derived and compared with the observed frequencies.

Base Sequence↗
PubMed1978

On estimating number of genes by genotype assay.

The method of genotype assay, proposed by Jinks and Towey (1976) for estimating the number of effective factors in a polygenic system, assumes independent segregation if applied to number of genes. Their results are extended to include the case of linked genes, and the ratio of expected number of effective factors to number of genes is computed for a range of models. Unless all genes are on different chromosomes or many generations of inbreeding are used, the estimate of gene number is biased downwards.

Genes↗
PubMed1978

Variability of chimaeras and mosaics.

Aggregation chimaeras and X-inactivation mosaics in mice are alike in general appearance, but chimaeras are very much more variable in the proportions of the cell types (p) seen for example in coat pigmentation. The distribution of p in chimaeras is not binomial, but is uniform, or flat, between the two extremes. The greater variability of chimaeras arises from two sampling events that occur when cellular heterogeneity is already present in chimaeras but before it arises in mosaics. These are the differentiation of the inner cell mass from the trophectoderm and of the primary ectoderm from the primary endoderm. The second of these generates the flat distribution of chimaeras as a consequence of the two cell types being unmixed at that time. The two sampling events generate single-colour individuals in roughly the proportions observed. Consideration of the second sampling event provides evidence that the primordial germ cells must originate in the primary ectoderm and not in the yolk-sac. Estimation of numbers of progenitor cells on the supposition of binomial sampling is not valid unless the clone-size is known or the cells in the sample are not contiguous. Data on coat pigmentation are consistent with the assumptions that X-inactivation is random in about 21 cells, that the sampling of melanoblasts is binomial (because they are not contiguous), and that the melanocytes of the head and body are descended from about 34 progenitor cells.

Animals↗