D. R. Matthews

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

SummaryType 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 μg/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. Recombinant insulin-like growth factor I in a s. c. dose of 40 μg/kg body weight leads to a significant reduction in overnight growth hormone levels and insulin requirements in adolescents with Type 1 diabetes.

The Dawn Phenomenon Is Related To Overnight Growth Hormone Release In Adolescent Diabetics

We have investigated the relation between nocturnal insulin requirements and nocturnal growth hormone (GH) release in 26 diabetic adolescents at various puberty stages and have examined the effect of nocturnal GH suppression on pre‐breakfast insulin requirement. In all the studies, euglycaemia was maintained overnight using a computer‐calculated variable‐rate insulin infusion, and 15‐min blood samples were collected for GH assay. During initial clamp studies, insulin infusion rates were greater from 0500–0800 h (15.22 ± 0.95 mU/kg/h, mean ± SEM) than from 0100–0400 h (12.42 ± 0.84 mU/kg/h, P < 0.001). The increase in insulin infusion rate correlated with mean overnight GH concentration (r = 0.68, P < 0.001), and was maximal at puberty stage 3 in both sexes. In seven of the subjects, a second identical clamp was performed following administration of 100 mg oral pirenzepine. During these studies, mean overnight GH levels were reduced by 11–85%, from 17.6 ± 1.6 to 7.5 ± 2.2 mU/l; P < 0.01. Insulin requirements were not significantly different between the periods 0100–0400 and 0500–0800 h during these studies, and the reduction in pre‐breakfast (0500–0800 h) insulin requirement when compared with the baseline studies correlated with the fall in GH secretion (r, = 0.82, P < 0.01). The dawn increase in insulin requirement in adolescents with IDDM is related to the overnight GH secretion during puberty, and pre‐breakfast insulin requirement can be reduced by suppressing nocturnal GH release.

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.

Evidence for a Role for Insulin and Growth Hormone in Overnight Regulation of 3-Hydroxybutyrate in Normal and Diabetic Adolescents

Objective— To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. Research Design and Methods— We studied overnight changes in plasma ketones—3-hydroxybutyrate and acetoacetate—in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Results— Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 ± 5 μM), reaching a peak at 0200 (103 ± 16 μM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = −0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. Conclusions— We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

The frequency and amplitude of growth hormone secretory episodes as determined by deconvolution analysis are increased in adolescents with insulin dependent diabetes mellitus and are unaffected by short‐term euglycaemia

OBJECTIVE High overnight plasma growth hormone (GH) levels in insulin‐dependent diabetes mellitus (IDDM) are reflected in both an increase in the GH pulse amplitude and elevated baseline GH concentrations. To determine whether these are a result of an increase in GH secretory episodes, we undertook deconvolution analysis of overnight GH profiles using previously determined half‐life data.

Contrasting metabolic effects of continuous and pulsatile growth hormone administration in young adults with Type 1 (insulin-dependent) diabetes mellitus

SummaryPlasma growth hormone profiles in adolescents with Type 1 (insulin-dependent) diabetes mellitus are characterized by both increases in pulse amplitude and higher baseline concentrations. To determine which of these abnormalities adversely affect metabolic control, we studied six young adults overnight on three occasions. On each night somatostatin (50–100 μg·m2−1·h−1) and glucagon (1ng· kg−1·min−1) were infused continuously and 18mU/kg of growth hormone was given as either: three discrete pulses of 6 mU·kg−1· h−1 at 180-min intervals or a 12-h infusion (1.5 mU·kg−1· h−1) or buffer solution only on a control night. Euglycaemia was maintained by an insulin-varying clamp. Blood samples were taken every 15 min for glucose and growth hormone and every hour for intermediate metabolites and non-esterified fatty acids. Comparable normoglycaemic conditions were achieved on all three nights. Growth hormone levels achieved (mean±SEM) on study nights were: 32.8±2.2 mU/l (peak level during growth hormone pulses); 9.8± 0.8 mU/l (continuous growth hormone) and 1.1±0.3 mU/l (control level). Pulsatile growth hormone administration led to an increase in insulin requirements (mean±SEM: 0.17±0.03 vs control 0.09±0.01 mU·kg−1· min−1, p < 0.05) whereas insulin requirements following continuous growth hormone administration were unchanged. Cross-correlation confirmed an increase in insulin requirements occurring 135 min after a growth hormone pulse (r=0.21, p < 0.001). Growth hormone administration (continuous and pulsatile) led to a significant increase in B-hydroxybutyrate levels compared to the control night: 0.21±0.01 mmol/l (mean±SEM), 0.29±0.01 mmol/l, 0.08±0.01 mmol/l (p< 0.001) during the night with pulsatile growth hormone, continuous growth hormone and control respectively. Mean plasma non-esterified fatty acids were also increased following growth hormone administration: 0.94±0.04 mmol/l (mean±SEM), 1.09±0.07 mmol/l, 0.61±0.05 mmol/l (p<0.003), during the night with pulsatile growth hormone, continuous growth hormone and control respectively. It appears that the pulsatile and baseline growth hormone signals have contrasting metabolic effects in young adults with Type 1 diabetes mellitus.

Impact of increased growth hormone secretion on carbohydrate metabolism in adolescents with diabetes

Growth hormone (GH) and fasting insulin concentrations rise during puberty in normal subjects. Any increase in GH secretion in adolescents with insulin‐dependent diabetes mellitus (IDDM) might be expected to lead to further insulin resistance and metabolic disturbance. Despite the high incidence of delayed growth in IDDM, the relationship between Gli, insulin‐like growth factor I (IGF‐I) and IGF binding protein 1 (IGFBP‐1) has not been clearly established. Twenty‐six adolescents with IDDM and 34 healthy siblings underwent measurement of their overnight GH secretory profiles (20.00–08.00 hours, 15‐minute sampling). The diabetic subjects were studied either on their normal insulin regimen (n = 15) or during a euglycaemic clamp (n = 26). A second clamp study was undertaken (n = 7) with addition of pirenzepine to suppress GH secretion. GH profiles in the diabetic subjects were characterized by increases in both pulse amplitude and baseline GH concentrations . Deconvolution analysis also revealed an increase in the frequency of Gil secretory episodes. In the subjects with diabetes, a direct link between the dawn rise in insulin requirements, increased concentrations of 9‐hydroxybutyrate and the elevated concentrations of GH was established. These abnormalities were reversed by the suppression of GH pulse amplitude following pirenzepine. Serum IGF‐I concentrations and IGF‐I bioactivity in the diabetic subjects were low and were positively correlated with mean GH concentrations. In conclusion, well controlled adolescents with IDDM show persisting abnormalities of GH, β‐hydroxybutyrate and IGF‐I despite normoglycaemia. The role of inappropriate insulin delivery in the development of these abnormalities is discussed.

An unbiased glucose clamp method using a variable insulin infusion: its application in diabetic adolescents

A simple, unbiased insulin‐varying glucose clamp program is described. The aim of the program was to utilize a continuously updated array of data to predict insulin requirements for normoglycaemia. In assessing Type 1 diabetes the quantity of insulin required for maintenance of basal euglycaemia can be more clinically informative than other clamp methods. We present a method which uses an iterative computer program to predict changes in insulin infusion rate required for glucose clamping. After initial parameter estimation, the program uses no fixed algorithm but makes predictions according to previous blood glucose responses to infusion rates. The program has flexible data entry, graphic display, and running statistics including mean infusion data, mean glucose levels, and their respective standard deviations. Data for 26 consecutive overnight clamp studies have been analysed. The median coefficient of variation of glucose values at the end of the clamp was 4.1% (range 1.4–12.0%). The mean bias during the last 2 h was 0.20 ± 0.24 mmol l−1. Cross‐correlation showed that insulin had its maximal effect on the rate of decline of glucose after 15 min, and the nadir of glucose occurred 45 min after a change in insulin infusion rate.

The Use of an Automated Microsampling System for the Characterization of Growth Hormone Pulsatility in Newborn Babies

To overcome the difficulties of studying hormone pulsatility in the newborn, we have developed an automated microsampling system that permits the measurement of hormones in small prediluted samples of blood (40 μL) taken at 10-min intervals over 12 h. The system has been validated in adult volunteers, and the error attributable to the dilution was <4%. Using this method in 10 preterm babies, we have been able to describe pulsatile changes in GH and have demonstrated a clear postprandial elevation in GH levels peaking 60 min after a feed. Fourier transform analysis indicated a pulse periodicity of 180 min in babies who were appropriate for gestational age(n = 6), but faster, co-dominant pulse periodicities of 90-100 and 140 min in babies who were small for gestational age (weight and length below the 10th centile) (n = 4). There was no significant difference between mean, peak, and baseline GH levels between the two groups.

Pattern of secretion of bioactive and immunoreactive gonadotrophins in normal pubertal children

Summary. objective The aim was to investigate the relationship between the nocturnal pulsatile secretory patterns of immunoreactive and bioactive luteinizing hormone In normal children at various stages of puberty.