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Biomedical subjects

D A Pyke

Publications and source records attributed to D A Pyke.

At least 19 recordsLinked to original sources
PubMed1992

Altered islet beta-cell function before the onset of type 1 (insulin-dependent) diabetes mellitus.

To define the glucose to insulin dose-response relationship before the onset of diabetes, we studied 22 non-diabetic co-twins of patients with Type 1 (insulin-dependent) diabetes mellitus and nine control subjects. All had intravenous glucose tests at 0.02, 0.1 and 0.5 g/kg and were followed-up prospectively for at least 6 years. Seven twins developed diabetes a mean of 7 months later; the remaining 15 are now unlikely to develop diabetes. The seven pre-diabetic twins had higher fasting insulin levels than control subjects (4.2 +/- 2.0 vs 1.8 +/- 1.8 nmol/l; p less than 0.05); but lower glucose clearance (1.0 +/- 0.5 vs 1.9 +/- 0.7 %/min; p less than 0.05), first phase insulin response at 0.5 g/kg (21.1 +/- 23.2 vs 143 +/- 50 nmol/l; p less than 0.0001), and total insulin responses at 0.1 g/kg (p less than 0.05) and 0.5 g/kg (p less than 0.00005). Using a curve-fitting programme, the normal glucose to insulin relationship was lost in prediabetic twins who had lower coefficient of determination (R2) than control subjects (p less than 0.01). In contrast, 15 low-risk twins and their nine control subjects had similar fasting glucose and insulin levels, glucose clearance, R2 and insulin secretory responses to different glucose loads. The positive predictive values of subnormal R2 and subnormal first phase insulin response were 67% and 58% respectively. These observations demonstrate an altered glucose to insulin dose-response relationship and loss of maximum insulin secretory response to glucose before the onset of Type 1 diabetes.

Adolescent↗
PubMed1991

Decreased growth velocity before IDDM onset.

Diabetes can retard growth. Growth was studied prospectively in 12 nondiabetic identical twins aged less than 14 yr and in their co-twins with insulin-dependent diabetes mellitus (IDDM) to determine whether changes in growth occur before the onset of IDDM. Seven of the 12 nondiabetic twins subsequently developed IDDM; the remainder are now unlikely to become diabetic. A significantly reduced growth velocity was observed more frequently in the nondiabetic twins (7 of 12) than in their diabetic co-twins (1 of 12; P = 0.03). Of the 7 nondiabetic twins who were prediabetic, 6 had a reduction in growth velocity to below the 3rd percentile before the onset of diabetes compared with 1 of their diabetic co-twins (P = 0.03). However, only 1 of the 5 nondiabetic twins who did not develop diabetes showed a reduction in growth velocity. The nadir of growth in the twins who developed diabetes occurred a mean of 1.2 yr before diagnosis (range 0.3-2.3 yr). All 7 of the prediabetic twins had islet cell antibodies when first seen, and 3 had them before they showed either decreased growth velocity or impaired glucose tolerance. In 4 prediabetic twins, the decreased growth preceded impaired glucose tolerance. The prediabetic twins tested had lower testosterone or estradiol levels at the time they showed decreased growth than their diabetic twins. We conclude that decreased growth velocity is an early sensitive marker of IDDM.

Adolescent↗
PubMed1990

Impaired glucose tolerance precedes but does not predict insulin-dependent diabetes mellitus: a study of identical twins.

Non-diabetic identical twins of insulin-dependent diabetic patients were studied within five years of the diagnosis of their index twin in order to determine whether changes in intermediary metabolism precede the onset of insulin-dependent diabetes mellitus. Two studies were performed: a cross-sectional study of 12 non-diabetic twins and a prospective study of a separate group of 41 non-diabetic twins. Of the 12 twins tested in the cross-sectional study six developed insulin-dependent diabetes and six did not; the six who developed diabetes were given an oral glucose load a mean of 10 months before diagnosis; they then had normal fasting blood glucose levels but worse glucose tolerance than control subjects (120 min post-load (mean +/- SD) blood glucose 8.5 +/- 3.5 vs 4.9 +/- 0.9 mmol/l respectively, p less than 0.05). However, blood lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate and serum insulin levels were similar. In contrast, the six twins in this cross-sectional study who did not develop diabetes and are now unlikely to do so, as a group, had no significant changes compared with the control subjects though one had impaired glucose tolerance. To determine the predictive value of impaired glucose tolerance a separate group of 41 non-diabetic twins was studied prospectively for 8 to 22 years having a total of 147 glucose tolerance tests in this period; in this group six developed diabetes. Eight of the 41 had impaired glucose tolerance; impaired glucose tolerance was found in four of the six who developed diabetes as compared with only four of the 35 who did not (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Are thyrogastric autoantibodies associated with an increased susceptibility to developing type 1 (insulin-dependent) diabetes? A study in identical twins.

To examine whether the presence of thyrogastric autoantibodies is associated with an increased susceptibility towards developing type 1 diabetes we have tested for thyroid (microsomal and thyroglobulin) and gastric-parietal cell antibodies in 86 pairs of identical twins, 47 discordant and 39 concordant for type 1 diabetes. Autoantibodies were detected in both twins of a pair in 35 and in neither twin in 45 pairs. In only 6 pairs (3 discordant) was there a discrepancy in the antibody results between co-twins. The frequency of antibodies was similar in twin pairs discordant, (21/44, 48%), and concordant, (14/36, 39%), for diabetes. Thyrogastric antibodies were not more frequent in pairs that were female, diagnosed above the age of 20, or had HLA DR3 as opposed to DR4. We conclude that thyrogastric autoantibodies are common in both type 1 diabetic patients and their non-diabetic identical twins. Their presence appears to be genetically determined but does not increase the susceptibility of developing diabetes. The presence of autoantibodies does not appear to indicate a separate aetiological type of diabetes.

Autoantibodies↗
PubMed1990

Transfer from animal insulins to semisynthetic human insulin: a study in four centres.

The effects of transfer from animal insulin to semisynthetic human insulin on glycaemic control, insulin dose and anti-insulin antibodies were investigated in a total of 108 patients at four centres in a double-blind controlled study of eight months duration. Six months after transfer from porcine to human insulin there was a mean (+/- SE) increase in pre-breakfast blood glucose of 1.1 +/- 0.6 mmol l-1 (vs a reduction of 1.6 +/- 0.7 mmol l-1 in controls) (p less than 0.01), and a mean increase of pre-lunch blood glucose of 0.9 +/- 0.7 mmol l-1 (vs a reduction of 1.14 +/- 0.7 mmol l-1 in controls) (p less than 0.05). Six months after transfer from bovine to human insulin, there were no significant changes in blood glucose. Glycated haemoglobin showed no significant change six months after transfer from either bovine or porcine to human insulin. Hypoglycaemic symptoms, the total daily insulin dose, and the ratio of short- to intermediate-acting insulin did not change significantly after transfer from either bovine or porcine to human insulin. Transfer from bovine to human insulin resulted in a significant decline in anti-human insulin antibodies (mean (range): 50.5(14.8-125)% of initial levels), vs controls (113(43.4-234)% of initial levels; p = 0.034), and a non-significant decline in anti-bovine insulin antibodies (52.2(25.8-111)% vs 81.7(42.5-128)%; p = 0.082).

Adult↗
PubMed1989

B-cell responses to intravenous glucose and glucagon in non-diabetic twins of patients with type 1 (insulin-dependent) diabetes mellitus.

The B-cells of patients with recently diagnosed Type 1 (insulin-dependent) diabetes may have no response to glucose when the response to glucagon is present but attenuated. This observation suggests that the recognition of glucose is more severely affected than that for non-glucose stimulants. To determine whether a similar selective decrease in glucose response was present before the onset of diabetes we studied two groups of non-diabetic identical twins of patients with recently diagnosed Type 1 diabetes: one group with complement-fixing islet cell antibodies who were at high risk of developing diabetes (four of the five have already developed diabetes) and a group without such antibodies at low risk of developing diabetes. In addition, a group of patients with chronic pancreatitis were studied to control for non-specific damage to the B-cell. Responses to i.v. glucose and i.v. glucagon were compared. Patients with chronic pancreatitis has similar responses to both glucose and glucagon and the responses did not differ from control subjects. The B-cells of the immune positive group showed evidence of pathology because the insulin and C-peptide responses to both stimuli were reduced when compared to either their control subjects or the immune negative twin group. However, the B-cell response to both glucose and glucagon in the immune positive twins was similar. Because the B-cell response to glucose was not less than that to glucagon, a selective destruction of the glucose recognition system cannot be a characteristic of all twins throughout the period before they develop Type 1 diabetes.

Adult↗
PubMed1989

Islet-cell antibodies as predictors of the later development of type 1 (insulin-dependent) diabetes. A study in identical twins.

To determine the value of islet-cell antibodies, both complement-fixing and non-complement-fixing, in predicting the later development of Type 1 (insulin-dependent) diabetes, we studied different groups of identical twins. Twelve twins have developed diabetes and 11 of these had non-complement-fixing islet-cell antibodies before diagnosis, and eight out of nine tested had complement-fixing islet-cell antibodies. Of the twins who have remained non-diabetic for many years and are now unlikely to develop diabetes, twelve have had non-complement-fixing islet-cell antibodies at some stage but only four have ever had complement-fixing antibodies. In 29 non-diabetic co-twins tested within 5 years of the diagnosis of diabetes in the affected twin the presence of islet-cell antibodies, especially complement-fixing, predicted the progression to frank diabetes with a high specificity (100%), sensitivity (88%) and predictive value (100%). In pairs remaining discordant the antibodies were found more frequently in the diabetic than the non-diabetic twin. We conclude that the presence of islet-cell antibodies is not genetically determined and can occur without progression to diabetes. However, the presence of islet-cell antibodies, especially complement-fixing, in non-diabetic twins tested soon after the diagnosis of their co-twin, indicates a high risk for the development of diabetes.

Autoantibodies↗
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↗