Biomedical subjects

D B Dunger

Publications and source records attributed to D B Dunger.

At least 91 records · Page 5Linked to original sources

PubMed1999

Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group.

OBJECTIVE: The predictive value of microalbuminuria (MA) in children with type 1 diabetes has not been defined. We describe the natural history of MA in a large cohort of children recruited at diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: Between 1985 and 1996, 514 children (279 male) who developed type 1 diabetes before the age of 16 years (91% of those eligible from a region where ascertainment of new cases is 95%) were recruited for a longitudinal study with central annual assessment of HbAlc and albumin excretion (three urine samples). Dropout rates have been < 1% per year, and 287 children have been followed for > 4.5 years. RESULTS: MA (defined as albumin-to-creatinine ratio > or = 3.5 and > or = 4.0 mg/mmol in boys and girls, respectively) developed in 63 (12.8%) and was persistent in 22 (4.8%) of the subjects. The cumulative probability (based on the Kaplan-Meier method) for developing MA was 40% after 11 years. HbAlc was worse in those who developed MA than in others (mean difference +/- SEM: 1.1% +/- 0.2, P < 0.001). In subjects who had been 5-11 years of age when their diabetes was diagnosed, the appearance of MA was delayed until puberty, whereas of those whose age was < 5 years at diagnosis of diabetes, 5 of 11 (45%) developed MA before puberty. The adjusted proportional probability (Cox model) of MA was greater for female subjects (200%), after pubertal onset (310%), and with greater HbAlc (36% increase for every 1% increase in HbAlc). Despite earlier differences based on age at diagnosis of diabetes (< 5, 5-11, and > 11 years), the overall cumulative risks in these groups were similar (38 vs. 29 vs. 39%, respectively) after 10 years' duration of diabetes. CONCLUSIONS: Prepubertal duration of diabetes and prepubertal hyperglycemia contribute to the risk of postpubertal MA. The differences in rates of development of MA relating to HbAlc, sex, and age at diagnosis relative to puberty may have long-term consequences for the risk of subsequent nephropathy and for cardiovascular risk.

Adolescent↗

PubMed1999

Counterregulation during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes.

OBJECTIVE: To examine counterregulatory responses during spontaneous nocturnal hypoglycemia in prepubertal children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 29 prepubertal patients with type 1 diabetes underwent two overnight profiles. Data were analyzed from 16 children (median [range] 8.7 [5.9-12.9] years of age) with a night of hypoglycemia and a nonhypoglycemic night. Children hypoglycemic (< 3.5 mmol/l) on night 1 were given 25% extra carbohydrate as uncooked cornstarch with their usual evening snack on night 2 to avoid hypoglycemia. Glucose, growth hormone, and cortisol were measured every 15 min, catecholamines every 30 min, and glucagon, pancreatic polypeptide, insulin, and ketones every 60 min. A group of 15 healthy control subjects, aged 9.5 (5.6-12.1) years, underwent one overnight profile. RESULTS: Median duration of hypoglycemia was 225 (30-630) min, and glucose nadir was 2.0 (1.2-3.3) mmol/l. Insulin levels were not different on the two nights (P = 0.9, analysis of variance), but children with diabetes had higher insulin levels than normal control subjects between 2300 and 0300, maximal at 0200 (mean +/- SEM 57.4 +/- 5.7 vs. 31.6 +/- 5.0 pmol/l, P = 0.002). Peak epinephrine was higher on the night of hypoglycemia (0.98 [0.52-2.09] nmol/l) versus nonhypoglycemia (0.32 [0.21-0.62] nmol/l), P = 0.001, but norepinephrine (1.29 [1.07-2.64] vs. 1.26 [1.04-1.88] nmol/l, P = 0.5), glucagon (93 [64.2-125.6] vs. 100.5 [54.6-158] ng/l, P = 0.6), pancreatic polypeptide (410.2 [191-643.2] vs. 270.8 [158.2-777.8] ng/l, P = 0.5), and cortisol (513 [300-679] vs. 475 [235-739] nmol/l, P = 0.6) were not different. Glucose threshold for epinephrine release was very low, 1.9 +/- 0.2 mmol/l. There was a short-lived rise in growth hormone from 75-105 min after onset of hypoglycemia, maximal at 90 min (7.8 +/- 1.2 vs. 3.5 +/- 0.9 ng/ml, P = 0.02). CONCLUSIONS: The prolonged nature of nocturnal hypoglycemic episodes may be explained in part by defective counterregulation. The risk of nocturnal hypoglycemia needs to be reduced before intensification of insulin therapy can be contemplated in this age-group.

Blood Glucose↗

PubMed1998

Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet.

A total of 167 children and adolescents with insulin-dependent (Type 1) diabetes mellitus (97 males; age range 1.9-22.4 yrs) in a UK paediatric diabetic clinic were screened for coeliac disease using the IgA endomysial (EMA) test, or, in IgA deficient subjects, the IgG antigliadin (AGA) test. Antibody positive subjects were selected for small bowel biopsy, and confirmed coeliac cases started on a gluten free diet. Clinical features, height (Ht) standard deviation score (SDS), body mass index (BMI) SDS, HbA1c, insulin requirements' haemoglobin (Hb), mean red cell volume (MCV), serum folate and ferritin levels were evaluated at diagnosis and thereafter at 3-6 month intervals. A total of 156 subjects (93.4%) were antibody negative. Eleven (6.6%) were antibody positive (10 EMA/1 AGA; 6 males), of whom 9 had biopsies: 1 normal: 8 coeliac (4.8%; 5 males; 1 'classical'; 1 anaemia; 3 'atypical'; 3 asymptomatic). Seven coeliac subjects were followed during 12-24 months of dietary therapy. Pretreatment mean (range) Ht SDS = 0.08 (-1.66 to 1.88); BMI SDS = 0.32 (-0.82 to 1.29); HbA1c = 8.9 (6.2 to 11.3%); insulin dose = 0.98 (0.51 to 1.29) U kg(-1) day(-1). During treatment antibody status reverted to and remained negative, and symptoms resolved. By 24 months, there was a trend towards increased BMI SDS (mean (range) 1.31 (0.47 to 2.29), p = 0.248) and to reductions in HbA1c (8.1 (6.4-10.8), p = 0.697). Repeat small bowel biopsies were normal in 6 subjects (1 refused). No statistically significant changes occurred in any other parameters. In conclusion, serological screening is effective, although the therapeutic benefit of dietary therapy in asymptomatic cases remains uncertain.

Adolescent↗

PubMed1998

Mortality in patients with congenital adrenal hyperplasia: a cohort study.

OBJECTIVE: To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population. DESIGN: We identified 333 children with CAH, treated at several pediatric endocrinology departments in the United Kingdom since 1964, and monitored their mortality to mid 1996. Standardized mortality ratios were calculated, comparing mortality in the cohort with that in the general population, adjusted for sex, age, and calendar period. RESULTS: All-cause mortality in the cohort was 3 times that expected. Mortality was significantly increased at ages 1 to 4 years (standardized mortality ratio = 18.3) but not at older ages and was significantly increased in patients of Indian-subcontinent ethnicity (standardized mortality ratio = 20.4), particularly in girls. From case notes and death certificates, it appears that most deaths were caused by adrenal crisis, often after infection. CONCLUSIONS: Although survival of patients with CAH has greatly improved since steroid therapy has been used, this disease can still have fatal consequences. The high mortality rate in Indian ethnic girls may well reflect lack of parental acceptance and understanding of the disease, as well as of the action required when their child becomes acutely ill. Better communication with and education of parents of children with CAH, especially those from immigrant ethnic minorities, is important.

Adolescent↗

PubMed1998

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus.

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.

3-Hydroxybutyric Acid↗

PubMed1998

Recombinant human insulin-like growth factor-I abolishes changes in insulin requirements consequent upon growth hormone pulsatility in young adults with type I diabetes mellitus.

To investigate whether recombinant human insulin-like growth factor-I (rhIGF-I) has direct effects on the insulin requirement to maintain euglycemia independent of the growth hormone (GH) level, nine subjects with insulin-dependent diabetes mellitus ([IDDM] seven females; median (range) age, duration of diabetes, and hemoglobin A1C [HbA1C], 16.9 (12.5 to 21.9) years, 11.8 (4.6 to 16.8) years, and 9.8% (7.9% to 14.1%), respectively) underwent two euglycemic studies (6:00 PM to 8:00 AM) after double-blind subcutaneous administration of rhIGF-I/placebo (40 microg/kg). Octreotide infusion (300 ng/kg/h) suppressed endogenous GH, and three identical discrete GH pulses were infused on both nights. Variable-rate insulin infusion maintained euglycemia. Samples were taken every 15 minutes (glucose and GH), 30 minutes (insulin and intermediate metabolites), and 60 minutes (IGF-I and nonesterified fatty acids [NEFA]). Variables were analyzed during the steady-state period of euglycemia (4:00 to 8:00 AM). Data are expressed as the mean +/- SEM. The insulin infusion rate and free-insulin level were both significantly reduced after rhIGF-I administration (0.13 +/- 0.03 v placebo 0.23 +/- 0.05 mU/kg/min, P = .04, and 8.4 +/- 1.3 v placebo 12.1 +/- 1.4 mU/L, P = .03, respectively). GH pulse-related changes in the insulin requirement observed after placebo were not present after rhIGF-I. Glucagon levels were equally suppressed on both nights. Insulin clearance was not altered after rhIGF-I administration. NEFA and ketone levels also were not different on the 2 nights. In conclusion, in adolescents and young adults with diabetes, rhIGF-I administration directly affected insulin requirements independent of GH levels, but had no effect on fatty acid or ketone levels. This difference is related to the abolition of changes in the insulin requirement after GH pulses, and would suggest a complex interaction between GH and IGF-I on insulin action.

Adolescent↗

PubMed1998

Islet amyloid polypeptide decreases the effects of insulin-like growth factor-I on glucose transport and glycogen synthesis in skeletal muscle.

Previous studies have shown that islet amyloid polypeptide (IAPP) is co-secreted with insulin from the beta-cell. IAPP reduces insulin-stimulated rates of glycogen synthesis in skeletal muscle but the mechanisms are unclear. Insulin-like growth factor I (IGF-I) is an important regulator of glucose metabolism in skeletal muscle and acts through its own receptor, which has many structural and functional similarities with the insulin receptor. Despite this, the effects of IGF-I on glucose utilization are not identical to those of insulin. The aim of the study was to determine the effects of IAPP on IGF-I-stimulated rates of glucose transport and metabolism (measured by 3-O-methyl[3H]glucose and [U-14C]glucose, respectively) in rat soleus muscle, and compare them with those simulated by insulin. IAPP (10 nM) decreased the sensitivity of 3-O-methylglucose transport, the flux of glucose to hexosemonophosphate and the sensitivity of glycogen synthesis to IGF-I. In contrast, IAPP had no effect on IGF-I-stimulated rates of lactate formation (i.e., glycolysis). IAPP decreased the sensitivity of 3-O-methylglucose transport and glycogen synthesis to insulin. It is concluded that IAPP blunts the stimulation of glucose uptake and deposition by IGF-I or insulin in skeletal muscle. These observations expand those made initially for IAPP and insulin and suggest that IAPP affects IGF-I- or insulin-stimulated glucose metabolism in muscle by a mechanism which is common for both hormones. These experiments may serve as a framework for future studies in order to clarify the mechanisms by which IAPP affects glucose metabolism in skeletal muscle.

Amyloid↗

PubMed1998

Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.

Birth Weight↗

PubMed1998

Genetic testing for maturity onset diabetes of the young in childhood hyperglycaemia.

Mild hyperglycaemia is a common finding during minor illness in children. The differential diagnosis includes maturity onset diabetes of the young (MODY), which can be a difficult diagnosis to make clinically. As most genes resulting in MODY have been identified, it is possible to make a firm diagnosis using mutation detection. A case is reported of a 4 year old girl in whom a diagnosis of MODY2 was established by the finding of a heterozygous missense mutation in exon 7 of the glucokinase gene, resulting in the substitution at codon 259 of alanine by threonine (A259T). Observations from other glucokinase families suggest that hyperglycaemia in this child is likely to be stable and will not require intensive medical follow up, whereas other forms of MODY (1, 3, and 4) might carry a different prognosis.

Child, Preschool↗

PubMed1998

Hypertonic saline test for the investigation of posterior pituitary function.

The hypertonic saline test is a useful technique for distinguishing partial diabetes insipidus from psychogenic polydipsia, and for the diagnosis of complex disorders of osmoreceptor and posterior pituitary function. However, there is little information concerning its use in childhood. The experience of using this test in five children (11 months to 18 years) who presented diagnostic problems is reported. In two patients, in whom water deprivation tests were equivocal or impractical, an inappropriately low antidiuretic hormone (ADH) concentration (< 1 pmol/l) was demonstrated in the presence of an adequate osmotic stimulus (plasma osmolality > 295 mosmol/kg). In two children--one presenting with adipsic hypernatraemia and the other with hyponatraemia complicating desmopressin treatment of partial diabetes insipidus--defects of osmoreceptor function were identified. Confirming a diagnosis of idiopathic syndrome of inappropriate ADH secretion (SIADH) was possible in a patient with no other evidence of pituitary dysfunction. The hypertonic saline test was well tolerated, easy to perform, and diagnostic in all cases.

Adolescent↗

PubMed1998

Insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn.

The relationship between GH, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin may be critical to the understanding of variation in early growth, especially in the small for gestational age (SGA) baby. To investigate these relationships, we have undertaken 12-h hormone profiles in 26 babies (13 SGA) at a median of 4.5 days of age. GH levels were measured every 10 min; insulin and IGFBP-1 were measured every 20 min. Mean levels of these hormones and IGF-I levels (from a single sample) were related to size at birth. The GH data were analyzed by Pulsar and time series analysis to characterize hormone pulsatility and relationship with feeds. IGF-I levels correlated with birth weight and length (r2 = 0.47; P = 0.004, and r2 = 0.5; P = 0.0005, respectively, after allowing for gestation), whereas mean GH levels were negatively related to birth size (r2 = -0.18; P = 0.04 and r2 = -0.2; P = 0.03 for weight and length, respectively). No direct relationship between mean GH levels and IGF-I was identified. IGF-I levels were higher in appropriate for gestational age (AGA; mean +/- SD, 82+/-61 ng/mL) than in SGA (34+/-22 ng/mL; P = 0.03) babies. Baseline (mean +/- SD, 25.9+/-11.9), mean (33.9+/-14.0), and peak (45.0+/-18.1 microg/L) GH levels were higher in SGA than in AGA babies [17.1+/-8.2 (P = 0.04), 22.5+/-10.4 (P = 0.03), and 30.7+/-15.4 microg/L (P = 0.04), respectively]. Mean IGFBP-1 levels were also higher in SGA than AGA babies (157.4+/-90.7 vs. 62.7+/-43.8 ng/mL; P = 0.01). A positive correlation was identified between changes in insulin and coincident pulses of GH (r = 0.147; P < 0.01), whereas there was an inverse relationship between insulin and IGFBP-1, with a lag time 120 min (r = -0.33; P < 0.0001). In conclusion, these studies indicate that the GH-IGF-I axis is closely related to feeding in the newborn. In SGA babies, low IGF-I and elevated IGFBP-1 reflect the slow growth, but elevated GH and rapid GH pulsatility may be a signal for lipolysis.

Eating↗

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↗

PubMed1998

Pubertal growth in IDDM is determined by HbA1c levels, sex, and bone age.

OBJECTIVE: In cross-sectional studies of subjects with IDDM, the relationship between suboptimal pubertal growth, glycemic control, and abnormal insulin-like growth factor I (IGF-I) levels has proved difficult to define. The objective of this study was to examine these relationships in a longitudinal prospective study. RESEARCH DESIGN AND METHODS: A total of 46 children (23 boys) were measured every 3 months, and their bone age was assessed annually. Blood samples were obtained for HbA1c, IGF-I, and C-peptide. Growth data were compared with national standards, and IGF-I data were compared with a parallel longitudinal study of normal schoolchildren. Data were analyzed as SD scores (mean +/- SD). RESULTS: The onset of puberty was not delayed, although in the girls, bone age was advanced (bone age, 11.48 +/- 1.01 years vs. chronological age, 10.93 +/- 0.86 years [mean +/- SD]; P = 0.04). The timing of peak height velocity (PHV) was normal in both sexes, but the magnitude was reduced in girls (PHV SDS = -0.56 +/- 0.90, P < 0.02), and reductions in height SDS between diagnosis and final height were observed (P = 0.014). At PHV, IGF-I levels were reduced in both sexes, and there were no sex differences in HbA1c levels and insulin doses. IGF-I SDS correlated with insulin dose (r = 0.47, P = 0.004) but not with PHV SDS, whereas HbA1c correlated negatively with PHV SDS in both sexes (r = -0.35, P = 0.03). In a stepwise multiple regression analysis, the major determinants of PHV SDS were HbA1c (P = 0.04), sex (P = 0.0007), and bone age (P = 0.01). CONCLUSIONS: We conclude that the magnitude of the pubertal growth spurt is related to HbA1c levels in both sexes, but it is reduced only in girls. This sexual dimorphism cannot be explained by differences in IGF-I levels and may relate to the bone age advance at the onset of puberty in the girls.

Body Height↗

PubMed1998

IGF-I and diabetes in adolescence.

Adolescents with insulin-dependent diabetes mellitus (IDDM) often experience difficulties achieving good glycaemic control, and attempts at intensifying insulin therapy may increase the risk of hypoglycaemia and weight gain. Abnormalities of the GH/IGF-I axis may contribute to these problems. Insulin-like growth factor-I (IGF-I) levels and IGF bioactivity are invariably reduced despite growth hormone (GH) hypersecretion, and these abnormalities are only partially corrected by intensified insulin therapy. The administration of recombinant human IGF-I (rhIGF-I) as an adjunct to insulin therapy can restore circulating IGF-I levels and thus suppress GH levels and improve insulin sensitivity. Randomised placebo-controlled clinical trials of daily subcutaneous rhIGF-I therapy (40-80 micrograms/kg/day) have demonstrated that significant reductions in HbA1c can be achieved without evidence of toxicity or exacerbation of diabetic complications. RhIGF-I used in conjunction with insulin may therefore provide an additional approach to the management of IDDM during adolescence, although further studies are required to determine the ideal dose regimen and confirm beneficial effects without adverse effects on microvascular complications in these subjects.

Adolescent↗

PubMed1997

Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus.

BACKGROUND: Good glycaemic control in insulin-dependent diabetes mellitus (IDDM) to prevent complications may be difficult to achieve during adolescence, because abnormalities in production of growth hormone or insulin-like growth-factor-I (IGF-I) can lead to lower insulin sensitivity. Recombinant human IGF-I (rhIGF-I) given as an adjunct to insulin therapy in IDDM, might improve glycaemic control in adolescents; we investigated the effects of the addition of IGF-I in a randomised, double-blind, placebo-controlled trial. METHODS: 53 patients with IDDM (26 male, 27 female) with a median age of 16.1 years (range 10.8-20.6) and diabetes of more than 2 years' duration were randomly assigned subcutaneous rhIGF-I (20 or 40 microg/kg daily [n=18, n=18, respectively]) or placebo (n=17), both in addition to multiple-injection insulin therapy for 24 weeks. The primary endpoint, glycated haemoglobin (HbA1c) and routine biochemistry were measured every 4 weeks. Retinal photographs and glomerular-filtration rates were assessed at base line and at the end of the study. Data were analysed by intention to treat. FINDINGS: With a dose of 40 microg/kg rhIGF-I daily, we found significant reductions in HbA1c compared with placebo (p=0.03), without changes in body-mass index, rate of hypoglycaemia, insulin dose, or circulating concentrations of IGF-binding proteins 1 and 3. The greatest median change in HbA1c of -0.6% (range -2.8 to -1.5%) was seen with rhIGF-I 40 microg/kg at week 12, but was not sustained at week 24. The greatest reductions in HbA1c at week 24 were seen among patients with the greatest changes in IGF-I concentrations (r=-0442, p=0.002). Retinal photographs, renal function (glomerular filtration rate and urinary albumin excretion), and routine biochemistry showed no adverse events. INTERPRETATION: Our data confirm that rhIGF-I as an adjunct to insulin therapy can improve HbA1c values in adolescents with IDDM without overt toxic effects, but they raise questions about whether these effects can be sustained in cases of poor compliance or reduced bioefficacy.

Adolescent↗

PubMed1997

Does recombinant human insulin-like growth factor-1 have a role in the treatment of diabetes?

The structure of IGF-I is similar to that of insulin, having 43% sequence homology with human proinsulin. Both peptides can induce metabolic and mitogenic effects through their own specific receptors, which also share many structural and functional similarities. Primarily involved in the regulation of growth, IGF-I may have a role in the control of glucose homeostasis, facilitated by changes in its binding proteins. RhIGF-I can reduce hyperglycaemia in patients with severe insulin resistance by direct effects mediated via the IGF-I receptor. Improvements in insulin sensitivity, and reductions in blood glucose levels and HbA1c values have also been seen in subjects with NIDDM. Enhanced insulin sensitivity with low dose rhIGF-I has been observed in adolescents and young adults with IDDM. These effects are closely related to reductions in growth hormone levels, but there is also evidence of complex interactions with insulin at the post receptor level and with IGFBP-1. In recent randomised, double-blind, placebo controlled trials, rhIGF-I given as an adjunct to insulin therapy reduced to HbA1c values. Although the ideal dosage to obtain therapeutic efficacy without complications has yet to be determined, rhIGF-I may have an important role in the treatment of hyperglycaemia and insulin resistance in diabetes.

Adolescent↗

PubMed1997

Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus.

Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non-diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non-nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK.

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↗