PubMed Health⌕ Search

Biomedical subjects

T D Cheetham

Publications and source records attributed to T D Cheetham.

29 records · Page 2Linked to original sources
PubMed1998

The effects of recombinant human IGF-I administration on concentrations of acid labile subunit, IGF binding protein-3, IGF-I, IGF-II and proteolysis of IGF binding protein-3 in adolescents with insulin-dependent diabetes mellitus.

The long term therapeutic potential of recombinant human (rh) IGF-I administration in insulin-dependent diabetes mellitus (IDDM) may be determined by changes in the IGF binding proteins (IGFBPs) and thus the bioavailability of IGF-I. We have therefore studied the effects of a single subcutaneous dose of rhIGF-I (40 micrograms/kg at 1800 h), when compared with an untreated control night, in 17 subjects with IDDM, on serum concentrations of IGF-I, IGF-II, IGFBP-3, acid labile subunit (ALS), and IGFBP-3 proteolysis. Mean (+/- S.E.M.) IGF-I levels increased from 242 +/- 30 ng/ml to 399 +/- 26 ng/ml (P = 0.01) after rhIGF-I whereas IGF-II levels declined from 600 +/- 45 ng/ml to 533 +/- 30 ng/ml. There was a small overnight reduction in baseline ALS levels from 48 +/- 2.8 to 44.5 +/- 3.2 micrograms/ml (P = 0.04) after rhIGF-I administration. An early fall in IGFBP-3 concentrations on the control night was not seen after rhIGF-I and overall mean levels were increased (5.2 +/- 0.2 micrograms/ml vs 4.9 +/- 0.2 micrograms/ml, P = 0.04, on the control night). On the baseline night, IGFBP-3 levels correlated with the sum of IGF-I and IGF-II (r = 0.73, P = 0.02) and with levels of the ALS (r = 0.7, P = 0.002). However after rhIGF-I, the sum of IGF-I and IGF-II no longer correlated with IGFBP-3, whereas the relationship with ALS was maintained. Immunoblot studies in six subjects indicated that 60%-70% of the IGFBP-3 was detected as a low molecular weight fragment at 1900 h on both study nights, but the amount of fragment declined to approximately 50% at 0100 h and 45% at 0700 h. In conclusion, despite a slight but significant fall in ALS, IGFBP-3 levels rise after rhIGF-I administration in IDDM. This cannot be explained by alterations in IGFBP-3 proteolysis, and may relate to the relative stability of ALS/IGFBP-3 when complexed principally with IGF-I rather than IGF-II.

Adolescent↗
PubMed1997

The relationship between overnight GH levels and insulin concentrations in adolescents with insulin-dependent diabetes mellitus (IDDM) and the impact of recombinant human insulin-like growth factor I (rhIGF-I).

OBJECTIVE: We examined the relationship between GH concentrations and free insulin concentrations, used as an index of insulin sensitivity, before and after recombinant human insulin-like growth factor I (RhIGF-I) administration in adolescents with insulin-dependent diabetes mellitus (IDDM). DESIGN AND PATIENTS: Growth hormone concentrations were assessed by a peak detection programme (Pulsar) on a control night (2000 h-0800 h) and a night when rhIGF-I administered in a subcutaneous dose of 40 micrograms/kg at 1800 h to 16 adolescent subjects. Stable euglycaemia was maintained by a continuous intravenous insulin infusion and changes in free insulin levels on the two nights were compared with growth hormone data. RESULTS: Mean overnight GH concentrations (2000 h-0800 h) on the control night were positively related to glycated haemoglobin (Hba1) concentrations (r = 0.63; P < 0.01) and were reduced following rhIGF-I administration (24.9 +/- 3.6 mU/I on the control night versus 17.4 +/- 2.2 mU/I after administration, P = 0.01). The mean GH pulse amplitude on the control night was related to the change in GH levels after rhIGF-I (rs = -0.66, P < 0.001). Multiple regression analysis revealed that mean GH pulse amplitude was the only determinant of free insulin concentrations (0500 h-0700 h on both study nights (P < 0.01). The percentage change in mean growth hormone pulse amplitude between the two nights was related to the percentage reduction in free insulin concentrations (r = 0.53, P = 0.03). CONCLUSIONS: Growth hormone pulse amplitude is related to early morning insulin sensitivity in adolescents with IDDM on control nights and after rhIGF-I administration. The reduction in insulin levels following rhIGF-I may be linked to the change in GH pulse amplitude and not just to direct insulin-like actions. Individuals with the higher GH (and thus HbA1 levels) were most sensitive to the GH-suppressive effects of rhIGF-I.

Adolescent↗
PubMed1996

Growth hormone insulin-like growth factor I axis in insulin-dependent diabetes mellitus.

Growth hormone (GH) hypersecretion and relative insulin-like growth factor I (IGF-I) deficiency have been implicated in the development of insulin resistance, poor metabolic control, and impaired growth during puberty in insulin-dependent diabetes mellitus (IDDM). Portal levels of insulin are critical for the integrity of the hepatic GH receptor and suppression of the inhibitory IGF-binding protein I. Increasing insulin doses during puberty will result in adequate portal levels of insulin and thus restore IGF-I levels and IGF bioactivity, but at the risk of nocturnal hypoglycaemia and weight gain. Restoration of normal circulating levels of IGF-I using the recombinant peptide will lead to reductions in GH levels and improved insulin sensitivity. Given as a daily subcutaneous injection, low-dose recombinant human IGF-I (40 micrograms/kg/day) could prove to be a useful adjunct to standard insulin therapy during puberty in IDDM. The reduced and more stable insulin requirement might reduce the risks of nocturnal hypoglycaemia and weight gain. However, whereas intensified insulin therapy will reduce the risk of microangiopathic complications, the benefits of combination therapy have not been proven. The role of recombinant human IGF-I in the treatment of IDDM needs to be tested by long-term controlled trials.

Blood Glucose↗
PubMed1995

Insulin-like growth factors (IGFs) and IGF-I treatment in the adolescent with insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) during adolescence is associated with complex derangements of the growth hormone (GH)/insulin-like growth factor (IGF) axis. Despite GH hypersecretion, IGF-I levels and IGF bioactivity are reduced. The diabetogenic effects of GH are well established, and GH hypersecretion has been implicated in the deterioration in glycemic control during adolescence and in the development of microangiopathy. Insulin deficiency or reduced portal delivery of insulin plays a central role in the development of these abnormalities, and although continuous subcutaneous insulin delivery may improve plasma IGF-I levels, it does not necessarily suppress GH levels. Recombinant IGF-I has been proposed as an adjunct to conventional insulin therapy, as restoring circulating IGF-I levels might lead to GH suppression. Placebo-controlled studies have shown a consistent reduction in GH secretion and related improvements in insulin sensitivity following a single subcutaneous IGF-I injection (40 micrograms/kg). Repeated daily subcutaneous IGF-I administration for 1 month resulted in a sustained increase in IGF-I levels, as well as a reduction in GH secretion and insulin requirements. There was no increase in hypoglycemia or other adverse effects. Recombinant IGF-I used in conjunction with insulin may therefore provide an additional approach to the management of IDDM during adolescence, allowing correction of abnormalities in the GH/IGF axis and leading to improved control and, hence, reduced risk of long-term complications. However, this hypothesis needs to be rigorously tested in long-term placebo-controlled studies.

Adolescent↗
PubMed1995

The effects of repeated daily recombinant human insulin-like growth factor I administration in adolescents with type 1 diabetes.

Reduced insulin-like growth factor bioactivity has been linked to poor metabolic control and growth hormone hypersecretion in adolescents with Type 1 diabetes. The safety and efficacy of recombinant human insulin-like growth factor I administered subcutaneously in a dose of 40 micrograms kg-1 for 28 days was studied in a group of 6 adolescent male subjects with Type 1 diabetes (aged 13.6-19.4 years, puberty stage 3-5). After a 4-week run-in period (week -4 day 0) recombinant human insulin-like growth factor I was administered for 4 weeks (day 0 to week +4) before a run-out of a further 4 weeks duration (week +4 to +8). HbA1c levels were measured throughout the study and overnight profiles were undertaken to study levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3, and growth hormone concentrations (week -1, day 0, and week +4). The injections were well tolerated and hypoglycaemia was not problematic at any stage of the study. Recombinant insulin-like growth factor I administration appeared to lead to a sustained increase in insulin-like growth factor I levels (week -1; 198 +/- 16 ng ml-1, week +4; 422 +/- 18 ng ml-1, mean +/- SEM; p = 0.03). Insulin-like growth factor binding protein-3 concentrations (n = 6) increased in 5 subjects (week -1; 4.5 +/- 0.3 micrograms ml-1, week +4; 5.1 +/- 0.4 micrograms ml-1) and mean overnight growth hormone decreased (week -1; 14.0 +/- 3.1 mUI-1, week +4; 7.6 +/- 1.7 mUI-1) during the period of study but these differences were not statistically significant. HbA1c levels fell significantly at the time of rhIGF-I administration (day 0; 10.4 +/- 1.9% vs week +4; 9.4 +/- 1.9%; p = 0.03) despite a reduction in subcutaneous isophane insulin dose from 0.50 +/- 0.02 U kg-1 to 0.41 +/- 0.02 U kg-1 (p = 0.03). There was no significant change in biochemical and haematological indices, glomerular filtration rate or urinary albumin excretion. The restoration of IGF-I levels in adolescents with Type 1 diabetes may have a beneficial impact on glycaemic control.

Aged↗
PubMed1994

The effects of recombinant human insulin-like growth factor I on growth hormone secretion in adolescents with insulin dependent diabetes mellitus.

OBJECTIVE: It has been proposed that low IGF-I levels and reduced IGF-I bioactivity may lead to elevated GH levels in adolescents with insulin dependent diabetes (IDDM). We have therefore studied the effects of human recombinant insulin-like growth factor I (rhIGF-I) administration on GH levels and GH secretion in adolescents with IDDM. PATIENTS: Nine late pubertal adolescents (four male and five female) with IDDM. DESIGN: A double-blind placebo controlled study of rhIGF-I administered subcutaneously in a dose of 40 micrograms/kg body weight at 1800 h. MEASUREMENTS: IGF-I and GH concentrations were measured at regular intervals throughout the study. Twenty-two hour GH secretory rates were calculated by deconvolution analysis. Overnight GH profiles were analysed by distribution analysis, and Fourier transformations were performed on both overnight GH concentrations and GH secretory rates. RESULTS: Mean IGF-I levels over the 22-hour study period were significantly elevated following rhIGF-I administration (350 +/- 26 vs 205 +/- 21 micrograms/l (mean +/- SEM), P < 0.01). Mean 22-hour GH levels were reduced following rhIGF-I administration (19.4 +/- 4.0 compared with 33.6 +/- 5.8 mU/l; P = 0.01). Distribution analysis demonstrated that the reduction in GH levels was due to changes in the proportion of values at both high and low concentrations. Deconvolution analysis also revealed a significant overall reduction in GH secretory rate following IGF-I administration (1.81 +/- 0.30 vs 2.98 +/- 0.47 mU/min, P = 0.01) which was still apparent during the final 5.5 hours of the study period (1.51 +/- 0.30 vs 2.76 +/- 0.61 mU/min, P = 0.02). The dominant periodicity of GH secretory episodes as determined by Fourier transformation was between 120 and 180 minutes after both IGF-I and placebo. CONCLUSIONS: In late pubertal adolescents with IDDM the rise in IGF-I levels following rhIGF-I administration in a subcutaneous dose of 40 micrograms/kg body weight leads to a significant reduction in GH levels and GH secretory rate. The reduction in GH secretion is due to changes in pulse amplitude rather than frequency. A reduction in GH secretion was apparent at the beginning and also towards the end of the 22-hour study period.

Adolescent↗
PubMed1994

Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-I in adolescents with insulin-dependent diabetes mellitus.

OBJECTIVE: It has been proposed that the dissociation between growth hormone secretion and insulin-like growth factor-I (IGF-I) concentrations in insulin-dependent diabetes mellitus arises because of partial resistance at the GH receptor. In order to explore this hypothesis further we have examined the relations between IGF-I, GH-binding protein (GHBP), and GH secretion in normal subjects and patients with diabetes during puberty. DESIGN AND SUBJECTS: Blood samples for the estimation of IGF-I and GHBP levels were obtained from 104 patients with diabetes and 89 puberty matched controls. Thirty-four of the controls and 42 of the patients with diabetes also underwent an overnight GH secretory profile with measurements of GH every 15-20 minutes between 2000 and 0800 h. RESULTS: In multivariate analysis using sex, puberty stage, and presence or absence of diabetes as dependent variables, diabetes was associated with increased GH levels (F = 23.04, P < 0.001), reduced IGF-I (F = 10.89, P < 0.001), and reduced GHBP levels (F = 31.36, P < 0.001). A negative relation between GH and GHBP levels (r = -0.44, P < 0.01) was found in normal subjects but this was absent in those with diabetes. Both GHBP and IGF-I levels in the diabetic subjects were correlated with total insulin dose (r = 0.4, P < 0.001, and r = 0.46, P < 0.001, respectively). Yet there was no direct correlation between GHBP and IGF-I concentrations. The variation in IGF-I levels was also related to glycosylated haemoglobin levels in the diabetics (r = -0.27, P = 0.01). In a stepwise multiple regression analysis insulin dose contributed 23%, HbA1 4.4% and C-peptide levels 3.7% to the variation in IGF-I levels. CONCLUSIONS: In adolescents with insulin dependent diabetes mellitus, the elevated GH concentrations are associated with low circulating IGF-I and GHBP concentrations and the normal reciprocal relation between GHBP and GH is no longer evident. Although IGF-I and GHBP are both related to insulin dose, there is no direct correlation between these variables. This may indicate that GHBP reflects GH receptor numbers but not necessarily post receptor events, and the weak positive correlation between GH and IGF-I indicates that increased growth hormone secretion may compensate for reduced receptor numbers.

Adolescent↗
PubMed1994

The effects of recombinant human insulin-like growth factor-I (IGF-I) administration on the levels of IGF-I, IGF-II and IGF-binding proteins in adolescents with insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) during puberty is associated with a reduction in circulating concentrations of insulin-like growth factor-I (IGF-I) and low IGF bioactivity. Altered levels of the IGF-binding proteins (IGFBPs), including low IGFBP-3 and elevated IGFBP-1, have also been described. These abnormalities have been linked to poor growth and deteriorating blood glucose control. We have therefore examined the effects of recombinant human IGF-I (rhIGF-I) administration on the levels of IGF-I, IGF-II, IGFBP-1, IGFBP-3 and IGF bioactivity in a group of 9 late-pubertal adolescents with IDDM. This was a double-blind placebo controlled study with each individual admitted on two occasions when either rhIGF-I (40 micrograms/kg) or placebo was administered by subcutaneous injection in the thigh at 1800 h. Blood samples were then taken for the subsequent 22 h. The half-life of administered rhIGF-I (12.1-22.2 h) was similar to that previously described in normal subjects. There was a small increase in IGFBP-3 concentrations overnight following rhIGF-I administration when compared to placebo, whereas the levels of IGF-II decreased. Under strict euglycaemic conditions, the relationship between insulin and IGFBP-I did not appear to be affected by rhIGF-I administration although the levels of IGFBP-1 tended to be higher overnight. IGF bioactivity was low during the placebo study, and although within the normal adult range following administration of IGF-I, was still relatively low for adolescents in late puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

The effects of recombinant insulin-like growth factor I administration on growth hormone levels and insulin requirements in adolescents with type 1 (insulin-dependent) diabetes mellitus.

Type 1 (insulin-dependent) diabetes mellitus in adolescence is associated with reduced levels of insulin-like growth factor I, elevated growth hormone concentrations and insulin resistance. In order to determine whether restoring insulin-like growth factor I levels to normal might lead to a reduction in growth hormone levels and insulin requirements, we undertook a double-blind placebo controlled study of a single s.c. dose of recombinant insulin-like growth factor I (40 micrograms/kg body weight) in nine late pubertal subjects with Type 1 diabetes. After administration of placebo or insulin-like growth factor I at 18.00 hours, a variable rate insulin infusion was used to maintain euglycaemia overnight. Plasma insulin-like growth factor I, growth hormone, free insulin, and intermediate metabolite concentrations were monitored throughout the study. Recombinant insulin-like growth factor I led to a rise in plasma concentrations which reached a peak at 5.5 h (413.1 +/- 28.2 ng/ml, mean +/- SEM). Mean growth hormone levels between 20.00 and 08.00 hours were significantly reduced after recombinant insulin-like growth factor I (19.4 +/- 4.0 compared with 33.6 +/- 5.8 mU/l; p = 0.01), as were the insulin requirements for euglycaemia (0.25 +/- 0.02 compared with 0.31 +/- 0.04 mU.kg-1.min-1; p = 0.03). Plasma free insulin levels were lower after recombinant insulin-like growth factor I administration (31.9 +/- 2.7 compared with 67.9 +/- 16.0 mU/l; p = 0.001) but no significant differences in ketone or lactate levels were detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗