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Biomedical subjects

R C Turner

Publications and source records attributed to R C Turner.

At least 109 records · Page 6Linked to original sources
PubMed1992

Linkage analysis of maturity-onset diabetes of the young with microsatellite polymorphisms. No linkage to ADA or GLUT2 genes in two families.

MODY is a form of NIDDM inherited as an autosomal dominant condition. We studied the linkage of MODY to two loci: ADA and GLUT2 in two large pedigrees with nonradioactive microsatellite polymorphic systems. A positive linkage of ADA to MODY was recently demonstrated in the large RW pedigree. Formal linkage analysis excluded a tight linkage between ADA and MODY with a LOD score of -5.82 and -2.24 at a recombination fraction of 0.01 in the two families. This result suggests genetic heterogeneity in the molecular basis of MODY. GLUT2 is a candidate gene that is expressed in the liver and beta-cells of pancreatic islets. In the two families studied, the disease did not cosegregate with GLUT2 alleles. The LOD scores for GLUT2 were -7.79 and -1.9 at a recombination fraction of 0.001 in the two families, thus providing evidence against the involvement of GLUT2 in MODY.

Adenosine Deaminase↗
PubMed1992

Elevated plasma concentrations of beta-cell tropin (ACTH22-39) in diet-treated type II diabetic patients.

beta-Cell tropin, the pituitary peptide ACTH22-39, is a potent insulin secretagogue and stimulates lipogenesis in adipose tissue in rodents. Plasma beta-cell tropin was measured fasting and after glucose infusion (5 mg.kg glucose ideal body weight-1.min0-1 for 90 min) in 10 mild diet-treated non-insulin-dependent (type II) diabetic subjects and 10 control subjects (body mass index) (BMI): 26.4 +/- 3.2 and 24.1 +/- 2.0 kg/m-2, NS, fasting plasma glucose 7.8 +/- 2.7 mM and 4.7 +/- 0.3 mM, respectively). The diabetic subjects had raised fasting plasma beta-cell tropin compared with the normal subjects (geometric mean (1 SD range): 0.49 (0.25-0.96) nM and 0.17 (0.10-0.28) nM, respectively, P = 0.007). In response to the glucose infusion, plasma glucose rose higher in the diabetic subjects (mean +/- 1 SD: 13.7 +/- 3.1 and 9.6 +/- 0.9 mM, P = 0.007) and plasma insulin was impaired in the diabetic compared with the nondiabetic subjects (geometric mean (1 SD range): 14 (8-26) and 34 (18-63), P less than 0.01). beta-Cell tropin concentrations in the diabetic subjects rose to 1.31 (0.74-2.30) nM (P = 0.007), whereas beta-cell tropin did not change in the normal subjects at 0.19 (0.11-0.91) nM. There was no overlap between glucose-stimulated plasma beta-cell tropin in the two groups (P = 0.0002). Pituitary-adrenal function, as assessed by plasma cortisol, did not differ between the two groups when fasting and did not change after the glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Decreases in albumin/creatinine and N-acetylglucosaminidase/creatinine ratios in urine samples stored at -20 degrees C.

The effects of storage for 6 months or 2 years at -20 degrees C were studied in urine samples from Type II diabetic patients by assaying albumin by immunoturbidity, N-acetylglucosaminidase (EC 3.2.1.30) by methoxynitrovinylphenol release, and creatinine by the Jaffé method. There were significant decreases (P < 0.001) in albumin/creatinine ratios from 1.14 (0.63-2.98) to 0.83 (0.32-2.12) g/mol (median + interquartile ranges) after 6 months (n = 97), and from 1.64 (0.74-5.72) to 1.00 (0.37-4.54) g/mol after 2 years (n = 89). The percentage of samples with results below the detection limit of the albumin assay (2 mg/L) increased from 5% to 21% after 6 months and from 0% to 34% after 2 years. N-Acetylglucosaminidase/creatinine ratios decreased (P < 0.001) from 520 (358-832) to 380 (263-695) U/mol after 6 months and from 520 (330-865) to 258 (82-462) U/mol after 2 years. The effect of storage was greater in samples with concentrations in the normal range (< 2.5 g/mol for albumin/creatinine, < 500 U/mol for N-acetylglucosaminidase/creatinine). Samples with albumin concentrations more than twice the normal range were still detected as abnormal after storage at -20 degrees C; e.g., 18% were > 5 g/mol (albumin/creatinine) initially, with 17% > 5 g/mol after 6 months of storage. We therefore recommend storage of urine samples at 4 degrees C for no longer than 7 days before assay.

Acetylglucosaminidase↗
PubMed1992

Impact of pharmaceutical company representatives on internal medicine residency programs. A survey of residency program directors.

To survey internal medicine residency program directors regarding interactions between their residents and pharmaceutical company (PC) representatives (PCRs) a questionnaire was sent to the directors of all Accreditation Council for Graduate Medical Education-approved internal medicine residency programs. The survey included 444 program directors, of whom 272 (61.16%) responded. The majority of program directors, 228 (83.8%), allowed PCRs to meet with residents during working hours and 241 (88.6%) permitted PC sponsorship of conferences. About half of the program directors were "moderately" or "very" concerned about the potential adverse effects of PC marketing on resident attitudes and prescribing practices. Seventy percent "agreed" or "strongly agreed" that the benefits of PC sponsorship outweigh the adverse effects and 41.5% believed that refusal to allow PCRs to meet with residents would jeopardize PC funding of other departmental activities. Most program directors reported that alternate funds for conferences were available if PC support was withdrawn. "Unethical" marketing activities were observed by 14.3% of program directors and 37.5% reported that residents had participated in PC-sponsored trips during the 3 years prior to the survey. At the time of this survey, only 35.3% of programs had developed formal policies regulating PCR activities and 25.7% provided residents with formal instruction on marketing issues. Knowledge of the current extent of PCR interactions with residents may be helpful to program directors in developing policies regulating PC-marketing activities.

Attitude of Health Personnel↗
PubMed1991

No glucotoxicity after 53 hours of 6.0 mmol/l hyperglycaemia in normal man.

In vitro and in vivo studies have suggested that metabolic deterioration can be induced by hyperglycaemia per se. The effect of 53 h of 2.2 mg glucose.kg ideal body weight-1.min-1 was examined in four normal male subjects. This produced overnight hyperglycaemia of 6.0 mmol/l on the two nights of the study compared with 4.7 mmol/l on the control night (p less than 0.05). In response there was a sustained, two-fold increase in basal plasma insulin (p less than 0.005) and C-peptide (p less than 0.05) levels. After two days of hyperglycaemia an increased Beta-cell response was demonstrated in response to an additional glucose infusion stimulus (estimated Beta-cell function median of 84% on the control day to 100% after two days glucose infusion). Plasma insulin and C-peptide responses to a 10.0 mmol/l hyperglycaemic clamp increased over the two days of the study (insulin from median 48 mU/l to 73 mU/l and C-peptide from median 2.0 pmol/ml to 2.6 pmol/l). Glucose tolerance to the additional glucose infusion stimulus improved, suggesting that the increased insulin response during hyperglycaemia was enhancing peripheral glucose uptake. The calculated peripheral insulin sensitivity was unchanged during the hyperglycaemic clamp. Thus, in response to the two days of basal hyperglycaemia, both the basal and stimulated Beta-cell responses were enhanced and there was no evidence for 'glucose toxicity' to the Beta-cells.

Adult↗
PubMed1991

Simple empirical assessment of beta-cell function by a constant infusion of glucose test in normal and type 2 (non-insulin-dependent) diabetic subjects.

The plasma insulin or C-peptide response to a 90-min constant glucose infusion 5 mg.kg ideal body weight-1.min-1 provides Beta-cell assessment comparable to more intensive methods. In 14 diet-treated Type 2 (non-insulin-dependent) diabetic subjects and 12 non-diabetic subjects, plasma insulin and C-peptide concentrations gave near linear plots against simultaneous glucose values. The 'glucose-insulin and glucose-C-peptide vectors' (G-I and G-C vectors), could be extrapolated to predict insulin and C-peptide levels during a 12 mmol/l hyperglycaemic clamp. Predicted concentrations correlated with clamp concentrations, r = 0.94 and r = 0.98 respectively, p less than 0.001, validating the vectors as empirical glucose dose-response curves. The vector slopes correlated highly with %Beta, a mathematical model-derived measure of Beta-cell function using constant infusion of glucose model assessment, Spearman r = 0.95 and 0.93 for insulin and C-peptide, respectively. G-I vector slopes in 21 diet-treated Type 2 diabetic subjects with fasting glucose (mean + 1 SD) 7.5 +/- 2.3 mmol/l, were lower than in 28 non-diabetic subjects, (geometric mean, 1 SD range, 8.4 pmol/mmol (3.3-21.0) and 25.1 pmol/mmol (14.3-44.1), p less than 0.001, respectively), indicating an impaired Beta-cell response. The G-I vector slopes correlated with obesity in both groups (r = 0.54 p less than 0.02 and 0.72, p less than 0.001 respectively), and, in 15 non-diabetic subjects, correlated inversely with insulin sensitivity as measured by a euglycaemic clamp (r = -0.66, p less than 0.01). Thus, Beta-cell function needs to be interpreted in relation to obesity/insulin resistance and, taking obesity into account, only 4 of 21 diabetic patients had Beta-cell function (G-I vector slope) in the non-diabetic range. The fasting plasma glucose in the diabetic subjects correlated inversely with the obesity-corrected G-I and G-C vector slopes (partial r = -0.57, p less than 0.01 and -0.86, p less than 0.001, respectively). The insulin or C-peptide response to the glucose infusion provides a direct empirical measure of the Beta-cell function, which can be interpreted in relation to obesity or to insulin resistance to assess underlying pancreatic responsiveness.

Blood Glucose↗
PubMed1991

Multiple restriction fragment length polymorphisms at the GLUT2 locus: GLUT2 haplotypes for genetic analysis of type 2 (non-insulin-dependent) diabetes mellitus.

The liver/islet glucose transporter (GLUT2) is expressed in the liver and in the Beta cells of pancreatic islets and is a candidate gene for the inherited defect in Type 2 (non-insulin-dependent) diabetes mellitus. A series of restriction fragment length polymorphisms have been identified using a GLUT2 cDNA probe with five restriction enzymes in a British white Caucasian population. Five independent restriction fragment length polymorphisms detected by restriction enzymes EcoRI (two restriction fragment length polymorphisms termed EcoRI-1, EcoRI-2), TaqI (two restriction fragment length polymorphisms termed TaqI-1, TaqI-2), and BclI (BclI-2) were used to construct GLUT2 haplotypes. Significant linkage disequilibrium was observed between four polymorphic sites EcoRI-2, TaqI-1, TaqI-2 and BclI-2 but linkage disequilibrium was not observed with EcoRI-1 polymorphic site and the other four sites. The frequencies of GLUT2 restriction fragment length polymorphisms and haplotypes in 50 Type 2 diabetic subjects and 50 non-diabetic control subjects show no significant differences suggesting that it is unlikely that there is a single major defect of this gene contributing to the inherited susceptibility to Type 2 diabetes in a Caucasian population.

Alleles↗
PubMed1991

Non-linkage of the islet amyloid polypeptide gene with type 2 (non-insulin-dependent) diabetes mellitus.

Type 2 (non-insulin-dependent) diabetes is associated with the deposition of islet amyloid. The major formative peptide, islet amyloid polypeptide, has recently been characterised and an abnormality of the structure or expression of this gene is a possible candidate for the inherited component of Type 2 diabetes. A restriction fragment length polymorphism of the gene has been identified with Pvu II. To study the relationship between the islet amyloid polypeptide gene and Type 2 diabetes, two distinct genetic approaches have been undertaken. Firstly, non-linkage has been demonstrated in four pedigrees, with four normoglycaemic first degree relatives having an allele associated with diabetes in other family members, and one affected relative not having the putatively associated allele. The LOD score taking age-related penetrance into account was -1.68, making linkage unlikely (p = 0.02). Secondly, in a population-based restriction fragment length polymorphism survey, no linkage disequilibrium of the alleles was found between a population of unrelated Caucasian subjects with Type 2 diabetes and a normal population. A mutation in or near the islet amyloid polypeptide gene is thus unlikely to be a common cause of Type 2 diabetes.

Amyloid↗
PubMed1991

Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes.

A mathematical model of normal glucose/insulin homoeostasis has been based on the known, experimentally determined responses of the liver and periphery to different glucose/insulin concentrations. Different defects of glucose resistance and insulin resistance have been applied to the model to investigate the degree to which these abnormalities could successfully predict the range of fasting glucose and insulin values found in normal, obese, and diabetic subjects. Modeling glucose resistance or insulin resistance at the liver or the periphery alone did not increase the plasma glucose to levels observed in diabetes, even when associated with marked deficiency of beta-cell function. A defect of either glucose resistance or insulin resistance affecting both periphery and liver allowed a wider range of basal glucose and insulin concentration values, but resulted in unphysiologically low hepatic glucose output: with modeling insulin resistance, hyperglycemia suppressed glucose output, whereas with glucose resistance, raised insulin levels suppressed hepatic glucose output. A wide range of glucose and insulin values, with appropriate basal hepatic glucose output, could only be modeled by insulin resistance at both the liver and periphery with additional glucose resistance at the liver. The modeling results are in accord with investigative studies that suggest secondary hepatic and peripheral glucose resistance in response to hyperglycemia. Modeling provides a systematic means of examining the likely effect of different putative defects in a complex physiological system.

Diabetes Mellitus↗
PubMed1991

Masking of diabetic phenotype on a low-energy diet despite persistence of impaired insulin response.

Type 2 diabetes has been postulated to be a "thrifty genotype" that aids fuel conservation; to investigate this hypothesis, type 2 diabetic and nondiabetic subjects, normal weight and obese, were studied after both 6 days on a 700-calorie diet and 6 days on a 2,800-calorie diet. On 2,800 calories per day, the median basal plasma glucose was raised in diabetics compared with nondiabetic subjects (median, 5.5 and 4.5 mmol/L, respectively; P = .003), but on the low-energy diet there was no difference (4.1 and 3.7 mmol/L, respectively; P greater than .05). Basal plasma insulin levels were similar in the diabetic and nondiabetic subjects and were twofold to threefold higher on the high- than low-energy diet in both diabetic (median, 7.8 and 3.1 mU/L on high- and low-energy diets, respectively; P = .007) and nondiabetic subjects (6.8 and 2.6 mU/L, respectively; P = .005). Similarly, the postprandial insulin concentrations increased to the same degree on the high- compared with the low-energy diet in diabetic (median postprandial increment, 14.9 and 3.4 mU/L; P = .005) and nondiabetic patients (9.5 and 3.0 mU/L; P = .005) and the beta cells in type 2 diabetes appeared to modulate normally to different calorie intakes. On both diets, the diabetic subjects had an impaired first-phase insulin response to an intravenous glucose load compared with nondiabetic subjects (high-energy diet median first-phase increment, 4.3 and 21.2 mU/L in diabetic and nondiabetic subjects, P = .0007; low-energy diet, 4.0 and 20.4 mU/L, respectively, P = .003).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms.

We used the recently described technique of single-stranded conformation-polymorphism (SSCP) analysis to examine the insulin-receptor locus. First, the ability of the method to detect known mutations and polymorphisms in the insulin-receptor coding sequence was assessed. Regions of the insulin-receptor sequence containing 16 different nucleotide changes, 9 in patient genomic DNA and 7 as cloned cDNA in plasmids, were analyzed. All 9 patient genomic DNA mutants and 5 of 7 plasmid mutants exhibited variant SSCP patterns. To investigate the potential of the technique for screening many patients, the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). Exons 17-21 were amplified from genomic DNA with polymerase chain reaction and subjected to SSCP analysis. Exons 19, 20, and 21 revealed no bands of aberrant migration, suggesting a high degree of conservation of these sequences. One diabetic subject had an SSCP variant in exon 18. Direct sequencing of this subject's genomic DNA revealed a heterozygous missense mutation (Lys1068----Glu1068). Five different SSCP patterns were detected in exon 17. Based on direct sequencing, these patterns were explained by combinations of three different nucleotide substitutions, two of which were common silent polymorphisms. One subject had a heterozygous missense mutation Val985---- Met985. Allele-specific oligonucleotide hybridization confirmed the presence of these mutations in the appropriate diabetic subjects and also detected the Val985 mutation in heterozygous form in 1 of 13 nondiabetic white subjects. SSCP analysis is a sensitive rapid method for screening for mutations in the insulin-receptor gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1991

Post-prandial glycaemic reduction by an alpha-glucosidase inhibitor in type 2 diabetic patients with therapeutically attained basal normoglycaemia.

Post-prandial glucose excursions remain elevated in most patients with diabetes even when normal fasting plasma glucose levels have been achieved. In 39 patients with type 2 diabetes who had attained basal normoglycaemia by therapy with diet alone, a sulphonylurea, a basal insulin supplement or basal plus prandial insulin the mean glycosylated haemoglobin (HbA1) values were at the upper end (mean +/- 1SD, 8.1 +/- 1.1%) of the normal range (5.0-8.2%). Miglitol, an alpha-glucosidase inhibitor, given in a dose of 50 mg three times a day was studied in a double blind randomized crossover study. In diet and sulphonylurea treated patients, a mean 25% reduction of the post-prandial plasma glucose excursions was obtained whereas in ultralente treated patients miglitol appeared to reduce basal plasma glucose levels (p < 0.006). Side effects were limited to minor gastrointestinal disturbances, usually ameliorating after the first week of therapy. Alpha-glucosidase inhibition to prevent post-prandial glycaemia may have a role in patients in whom sulphonylurea or diet therapy has been used to obtain normal basal glucose concentrations.

1-Deoxynojirimycin↗
PubMed1990

Islet amyloid polypeptide in diabetic and non-diabetic Pima Indians.

Islet amyloid may have a pathological role in the development of Type 2 (non-insulin-dependent) diabetes mellitus. The prevalence of islet amyloid has been investigated on post-mortem pancreatic tissue from both diabetic and non-diabetic Pima Indian subjects who had previously been assessed by oral glucose tolerance tests. Islets were examined for amyloid deposits and for cellular immunoreactivity to pancreatic hormones and islet amyloid polypeptide, the constituent peptide of islet amyloid. Twenty of 26 diabetic subjects (77%) had islet amyloid, compared with one of 14 non-diabetic subjects (7%). Twelve of the diabetic subjects (46%) had amyloid in more than 10% of their islets, whereas only 4% of islets were affected in a single non-diabetic subject. Positive immunoreactivity for islet amyloid peptide was present in the islet amyloid and in islet cells in 54% of the diabetic and 50% of the non-diabetic subjects. Islet amyloid in diabetic Pima Indians may indicate a primary Beta-cell defect which interacts with insulin resistance to produce diabetes, or may develop as a result of Beta-cell dysfunction induced by insulin resistance and hyperglycaemia.

Aged↗