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Biomedical subjects

D A Pyke

Publications and source records attributed to D A Pyke.

At least 37 records · Page 2Linked to original sources
PubMed1988

The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins.

We studied prospectively 49 non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients for up to 24 years (median 9 years). During this time 15 developed Type 1 diabetes. Actuarial analysis indicates that by 12 years 34% of the twins will have developed Type 1 diabetes and that thereafter only another 2% will do so. Inevitable bias in ascertainment of the twins makes it likely that the true figure is less. We conclude that factors which are not genetically determined must be important in the pathogenesis of the disease. The rates of developing Type 1 diabetes in the co-twins declines sharply in the years after diagnosis of the index twin, which suggests that the initiation of the process leading to Type 1 diabetes occurs within a finite, and not a prolonged, period.

Adolescent↗
PubMed1988

Increased proinsulin levels as an early indicator of B-cell dysfunction in non-diabetic twins of type 1 (insulin-dependent) diabetic patients.

Glucose tolerance and insulin secretion were studied in two groups of non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients: (1) a group of 5 twins with islet cell antibodies, and (2) a group of 6 twins without. Despite similar fasting glucose, insulin and C-peptide concentrations both groups of twins had significantly higher fasting proinsulin concentrations than the control group (p less than 0.05). The twins with complement-fixing islet cell antibodies had reduced glucose tolerance and clearance, whilst the twins without islet cell antibodies did not. Neither group of twins showed any abnormality in insulin, C-peptide or proinsulin response to oral or intravenous glucose. We conclude that increased fasting proinsulin levels precede abnormalities of insulin secretion, and are an early indication of minor B-cell damage in these twins irrespective of their risk of developing diabetes.

Blood Glucose↗
PubMed1988

Low serum haemolytic function of the fourth complement component (C4) in insulin dependent diabetes.

Low serum concentrations of the fourth component of complement (C4) are found in insulin dependent diabetes, and may be important in the aetiology of the disease. To ascertain whether function of C4 is also impaired both its haemolytic activity and its concentration were measured in 34 insulin dependent diabetics, 15 non-insulin dependent diabetics, 20 healthy subjects, and 12 pairs of monozygotic twins discordant for insulin dependent diabetes. C4 function was measured by a radial immune haemolytic assay, and C4 concentration by laser nephelometry. Both measurements were significantly lower in insulin dependent diabetics (C4 function: median 47%, range 4-100%; C4 concentration: 0.22 g/l, 0.10-0.38 g/l) than in non-insulin dependent diabetics (67%, 33-138%, p less than 0.01; 0.27 g/l, 0.16-0.50 g/l, p less than 0.02) and controls (74%, 33-138%, p less than 0.01; 0.27 g/l, 0.18-0.40 g/l, p less than 0.03). C4 function and concentration were lower in both diabetic (48%, 12-100%; 0.17 g/l, 0.08-0.31 g/l) and non-diabetic twins (47%, 12-100%; 0.17 g/l, 0.07-0.36 g/l) than controls (p less than 0.01; p less than 0.01). Thirteen (38%) of the insulin dependent diabetics had a reduction in either C4 function or concentration, but in only five were both features reduced. Values of function and concentration were strongly correlated in both diabetic and non-diabetic twins (r = 0.95, p less than 0.001; r = 0.92, p less than 0.001). These results show defects in C4 function and concentration in insulin dependent diabetes, which--being present in the non-diabetic co-twin of diabetics--may represent a genetic predisposition to the disease.

Adult↗
PubMed1988

Alterations in T-lymphocyte subpopulations in type I diabetes. Exploration of genetic influence in identical twins.

To evaluate factors influencing the alteration in subsets of T-lymphocytes, we studied 24 pairs of identical twins discordant for insulin-dependent (type I) diabetes mellitus. Subsets were assessed by monoclonal antibodies and a pure preparation of peripheral blood mononuclear cells obtained by centrifugation of heparinized whole blood with a Ficoll/Triosil gradient. In 12 pairs studied within 5 yr of diagnosis, we observed a reduction in the percentage of cells reacting with OKT8 (recognizing the CD8 antigen present on the suppressor/cytotoxic subset) (P less than .05), but a similar level was detected in their nondiabetic cotwins. In 12 pairs studied greater than 5 yr after the diagnosis and in whom the nondiabetic twin is less likely to develop diabetes, the percentage of cells reacting with OKT8 was reduced in both the diabetic (P less than .05) and the nondiabetic (P less than .01) twins. Reductions were also seen with OKT3 (recognizing the CD3 antigen present on the total T-lymphocyte population) and OKT4 (recognizing the CD4 antigen present on the helper/inducer subset), but only in the diabetic twins from the group with longer discordance. We conclude that a reduced percentage of suppressor/cytotoxic cells is associated with type I diabetes, but the reduction appears to be genetically determined. Total T-lymphocytes are also reduced but mainly in the helper/inducer subset and only in diabetic patients of long duration. Such a reduction cannot therefore be primarily genetically determined.

Adolescent↗
PubMed1988

Characterization of islet cell antibody in insulin dependent diabetes: evidence for IgG1 subclass restriction and polyclonality.

Using an indirect immunofluorescence technique we have investigated the titre, immunoglobulin class, complement-fixing ability, light chain type and IgG subclass of islet cell antibodies (ICA) in the sera of 21 recently diagnosed insulin-dependent diabetics and four non-diabetics before they developed diabetes. In the recently diagnosed patients titres of ICA ranged from 1/10 to 1/640. ICA belonged to the IgG class in all cases and fixed complement in 14 (67%). In all patients tested both kappa and lambda light chains were found, indicating that the antibody is polyclonal. IgG subclasses of ICA were investigated using specific murine monoclonal antibodies. All patients had ICA of the IgG1 subclass and in 16 (76%) this was the only subclass detected. In the remainder, one or more of the other IgG subclasses were found in association with IgG1. In the four pre-diabetic patients ICA fixed complement, was polyclonal and in all cases was of the IgG1 subclass. These characteristics of ICA, therefore, precede the onset of diabetes. The titre of ICA in the pre-diabetics tended to be greater (range 1/320 to (1/1280) than in the recently diagnosed diabetics. These results demonstrate restriction of ICA to the IgG1 subclass.

Adolescent↗
PubMed1987

Evidence of beta cell dysfunction which does not lead on to diabetes: a study of identical twins of insulin dependent diabetics.

Ten non-diabetic identical twins of insulin dependent diabetics were studied to see whether they showed changes in insulin secretion. The twins were selected because more than 11 years had elapsed since the diagnosis of the diabetic twin and they were therefore unlikely to develop diabetes, and they had had islet cell antibodies. Despite similar glucose concentrations to the controls the twins had greater total immunoreactive insulin responses to both oral (mean 3280 (SD 699) versus 2338 (1110) pmol/dl at 180 minutes; p less than 0.05) and intravenous (1346 (690) versus 699 (294) pmol/dl at 30 minutes; p less than 0.05) glucose challenge. The C peptide responses to intravenous glucose were also increased consistent with increased insulin secretion. In addition, basal serum proinsulin concentrations in the twins were increased (2.1 (1.2) versus 1.0 (0.3) pmol/dl; p less than 0.01) and remained so throughout both tests. These twins, who were unlikely to develop insulin dependent diabetes, showed evidence of beta cell dysfunction which does not progress to diabetes.

Adolescent↗
PubMed1987

Evidence that the reduced number of natural killer cells in type 1 (insulin-dependent) diabetes may be genetically determined.

Viruses may cause Type 1 (insulin-dependent) diabetes. We wondered whether the number and function of natural killer cells, which are important in anti-viral defense, are disturbed in diabetic patients. We studied 16 recently diagnosed Type 1 diabetic patients, 18 Type 1 diabetic patients diagnosed more than 15 years previously, 18 Type 2 (non-insulin-dependent) diabetic patients and 23 control subjects. We determined the number of natural killer cells (expressed as log10%) using anti-Leu 11 monoclonal antibody and the function (in log10 lytic units) concurrently using a 51Cr release assay with K562 as target cells. We found that the number of natural killer cells was reduced in Type 1 diabetes (1.01 +/- 0.04) as compared with Type 2 diabetic patients (1.16 +/- 0.04, p = 0.004) and normal control subjects (1.16 +/- 0.04, p = 0.006). To establish whether the reduced natural killer cell number is genetically determined we studied 19 identical twin pairs discordant for Type 1 diabetes; we found that even the non-diabetic co-twins had a reduced natural killer cell number (0.93 +/- 0.05, p = 0.0006) as compared with normal control subjects. Natural killer cell function was similar in all groups while natural killer activity per cell was significantly increased in the recently diagnosed diabetic patients (1.63 +/- 0.07) as compared with long-standing diabetic patients (1.26 +/- 0.26, p = 0.03) and controls subjects (1.36 +/- 0.07, p = 0.006). In conclusion the reduced number of natural killer cells in Type 1 diabetes appears to be genetically determined while their activity at diagnosis is increased.

Adolescent↗
PubMed1987

Chlorpropamide alcohol flushing: a normal response?

The relationship between chlorpropamide alcohol flushing and non-insulin dependent diabetes remains uncertain. It is known, however, that the frequency of facial flushing with alcohol and the temperature response depend upon both the plasma level of chlorpropamide and the starting facial temperature [10]. We tested 23 young adult non-diabetic subjects with 8 g of ethanol after a dose of chlorpropamide 250 mg twice daily for 2 days or a placebo, in a double blind, cross-over manner. Previously, nine other subjects had participated in a pilot study to assess the safety of the chlorpropamide dose and to ensure that adequate plasma chlorpropamide levels were achieved. No subject was negative for chlorpropamide alcohol flushing, as defined by the following criteria: facial temperature rise of 35% or more of maximum possible rise, observer assessment or subject assessment. In 26 of the total 32 subjects, all three criteria were fulfilled. Thus, among young, healthy non-diabetic adults chlorpropamide alcohol flushing would appear to be a normal phenomenon.

Adult↗
PubMed1987

T cell receptor beta chain polymorphisms are associated with insulin-dependent diabetes.

We investigated the T cell receptor constant beta chain (TCR C beta) genes of patients with insulin dependent diabetes mellitus (IDDM) using DNA restriction fragment length polymorphism (RFLP) analysis. Genomic DNA from patients and controls was digested with the restriction endonuclease Bg1 II and transferred to nylon filters using the Southern blot procedure. This enzyme identifies a polymorphic site between the two TCR C beta chain genes. We have found a highly significant increase in the frequency of the 10.0; 9.2 kilobase heterozygous phenotype in patients with IDDM (62.7% versus 42.0% in normal controls; P = 0.0006). In identical twin pairs, this association was most striking in those concordant for IDDM (79.2% versus 42.0% in controls; P = 0.0006).

Adolescent↗
PubMed1986

Immune changes associated with insulin dependent diabetes may remit without causing the disease: a study in identical twins.

Activation of T lymphocytes and islet cell antibodies were studied in two groups of insulin dependent diabetics and their non-diabetic identical cotwins. Group 1 comprised 12 "short term" twin pairs (diabetic twin diagnosed less than five years previously) in whom only a third of the cotwins were likely to develop diabetes; 10 of the 12 non-diabetic cotwins showed increased values of activated T lymphocytes, islet cell antibodies, or both. Group 2 comprised 10 "long term" twin pairs (diabetic twin diagnosed more than 11 years previously) in whom none of the non-diabetic cotwins was likely to develop diabetes; these pairs were selected because all the non-diabetic cotwins had shown islet cell antibodies at some time in the past, but only two still did so (one with an increased value of activated T cells). There was relative glucose intolerance in the cotwins of the short term group but not in those of the long term group. Non-diabetic cotwins of diabetics may show the immune changes associated with insulin dependent diabetes and relative glucose intolerance, but these changes may remit without leading to diabetes.

Adolescent↗
PubMed1986

The genetics of diabetic complications.

Duration of disease is the major susceptibility factor for microangiopathy. Microangiopathy does not occur without the metabolic abnormality of diabetes and there is much circumstantial evidence to implicate poor diabetic control in its pathogenesis. The rate of development and severity of complications, however, are variable even in patients with apparently similar control and about 25% of diabetics will never develop clinical evidence of microangiopathy. Studies of identical twins suggest a genetic component in the pathogenesis of retinopathy in NIDDM, and less so in IDDM, but increased capillary basement membrane thickness does not occur in the non-diabetic identical co-twins of insulin dependent diabetics. There may also be genetic heterogeneity not only of diabetes, but also of its complications, although for a given type of diabetes the prevalence of microangiopathy is often very similar in different racial groups. Associations between several different HLA molecules (particularly DR4) and microangiopathy in IDDM have been reported but not consistently confirmed. Recently the finding of an increased frequency of the B3 allotype of the fourth component of complement C4B3 in subjects with retinopathy has suggested that there is an HLA linked association. Both complement and the immunoglobulins are concerned with humoral immunity and the report of an association between a phenotype of the IgG heavy chain markers on chromosome 14 and retinopathy is of particular interest. These associations appear to be additive but independent. These reports need confirmation but provide the best evidence we have for an immunogenetic component (HLA and non-HLA linked) of the aetiology of microangiopathy, at least in IDDM. The studies of identical twins, HLA and Gm associations provide good evidence that genetic factors are involved in susceptibility to microangiopathy, at least in some diabetics, although the most relevant genes may not have been identified. Searches for better genetic markers must continue in order to identify those patients at increased risk of developing microangiopathy.

Chromosomes, Human, Pair 6↗
PubMed1986

Chlorpropamide-alcohol flush reaction and isoenzyme profiles of alcohol dehydrogenase and aldehyde dehydrogenase.

To investigate the enzymatic basis of the chlorpropamide-alcohol flush reaction (CPAF) we compared the isoenzyme profiles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from liver biopsies, and of ALDH alone from erythrocytes and leucocytes, in CPAF-positive and CPAF-negative subjects. No differences were seen in ADH or ALDH phenotypes, or in the relative activities of the isoenzymes, between the two groups before chlorpropamide was given; in particular, no subjects showed the 'null' ALDH phenotype that is associated with the alcohol flush reaction in oriental subjects. There was a significant decrease in erythrocyte ALDH activity after 7 days' treatment with chlorpropamide in CPAF-positive individuals but no such difference was seen in CPAF-negative subjects. These results indicate that CPAF has a different enzymatic basis from the alcohol flush reaction of oriental subjects and suggest that in CPAF-positive subjects erythrocyte ALDH may be particularly susceptible to inhibition by chlorpropamide.

Alcohol Dehydrogenase↗
PubMed1985

Value of insulin autoantibodies as serum markers for insulin-dependent diabetes mellitus.

Insulin autoantibodies (IAA) were studied in newly diagnosed insulin-dependent diabetics before the start of insulin treatment and in unaffected identical twins of insulin-dependent diabetics. In 15 of the 40 (38%) diabetics and 27 of the 58 (47%) twins IAA levels exceeded those of 100 controls. Frequency of IAA in unaffected twins was not related to duration of diabetes in their affected twin. In 11 unaffected twins, IAA levels differed in two samples taken 1-12 years apart; IAA were detected at least once in all twins and in one on both occasions. IAA in the twins were not related to the presence of islet-cell antibodies or to HLA-DR 3 or 4. As the unaffected twins of longstanding diabetics are unlikely to develop diabetes, these observations suggest that IAA do not always presage diabetes and are probably not a consequence of the disease; they may reflect an inherited autoimmune tendency to diabetes.

Adolescent↗
PubMed1985

Height at diagnosis of diabetes in children: a study in identical twins.

The height at diagnosis of 16 insulin dependent diabetics aged under 19 was compared with that of their unaffected identical cotwins measured at the same time. In eight pairs the diabetic was shorter, and in the remainder the cotwins were the same height. In those diabetics who were shorter than their cotwins at diagnosis the average period of growth delay before diagnosis was at least 35 weeks; by contrast, the mean duration of symptoms was only six weeks. No cause for the growth delay other than the diabetes was known in any of the twins. These findings show that the onset of insulin dependent diabetes may be a slow process, with growth delay occurring several months before symptoms appear.

Adolescent↗