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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
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↗
PubMed1985

Naloxone increases blood flow in the human hand.

Intravenous injection of 2 mg naloxone produced a rapid and pronounced rise of blood flow (6.3 +/- 5.0 to 67.0 +/- 15.1 ml min-1 100 ml-1) and skin temperature (28.3 +/- 3.0 to 32.4 +/- 1.2 degrees C) in the finger and hand of seven of ten normal volunteers. In the other three there was only a small response. Skin temperature did not change in either the face or the foot. Three responding subjects who were retested with 0.4 mg naloxone showed a smaller and briefer response. To exclude a local effect of naloxone on skin blood flow due to release of histamine, responders and non-responders were tested with naloxone and morphine pricked into the skin of the hand and forearm. All showed a weal and flare reaction to morphine which was not abolished by mixture with naloxone; none showed any reaction to naloxone alone. These results suggest that, in some subjects at least, skin blood flow in the hand may be under endogenous opioid control and they raise the possibility that opioid antagonists might have value in the treatment of disorders of skin blood flow such as Raynaud's disease.

Adult↗
PubMed1984

Pathogenesis of insulin-dependent diabetes: a role for activated T lymphocytes.

Expression of HLA DR antigens on T lymphocytes indicates that these cells are actively involved in an immune response. Raised levels of activated T lymphocytes were found in 14 of 15 recently diagnosed but in only 7 of 28 long-standing insulin-dependent diabetics. 9 of the recently diagnosed patients retested 6 months later still had high levels of activated T lymphocytes. Even long-standing insulin-dependent diabetics had significantly higher levels of activated T lymphocytes than non-insulin-dependent diabetics and healthy controls. 5 of 7 unaffected co-twins of recently diagnosed insulin-dependent diabetics had high levels of activated T cells; this increase persisted in 2 retested 6 months later, when mildly impaired glucose tolerance had developed. These results confirm that there is an active cellular immune reaction in newly diagnosed insulin-dependent diabetics which may precede the disease and persist for at least 6 months after its appearance.

Adolescent↗