Neonatal macrosomia in maternal diabetes

Summary In order to determine the effect of maternal diabetes on the somatic growth of the rat fetus and to elucidate mechanisms underlying the control of fetal growth, concentrations of DNA and proteins and DNA polymerase- activities in neonates were examined. The maternal status was classified as normal (no urinary glucose excretion), mildly diabetic (0.01–0.99 g/day urinary glucose), and severely diabetic (1.00 g/day or more urinary glucose). The total DNA contents in mg/neonate were 26.8 ± 2.2 (mean ± SEM), 31.3 ± 2.5, and 29.4 ± 2.7 for neonates from normal, mildly diabetic and severely diabetic mothers, respectively. The DNA polymerase activities in (cpm/g neonate) x 10^-3 for the same groups of neonates were 432 ± 58, 1,008 ± 74, and 888 ± 118, respectively. These results indicate that the neonatal macrosomia disappears as the severity of maternal diabetes increases. Furthermore, DNA polymerase is one of possible biochemical sites through which macrosomia is manifested in diabetic pregnancies.     

Improvement of lipid profile in Type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I

Summary Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2×120 g insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean ± SD) 3.1±2.6, 1.3±1.0, 6.3±1.3, and 4.5±1.1 mmol/l and decreased to 1.6±0.8, 0.6±0.4, 5.0±1.0, and 3.5±1.1 mmol/l, respectively, on the last treatment day (p<0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48±22 and 32±18% of control (p<0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.     

Elevated plasma insulin-like growth factor binding protein-1 levels in Type 1 (insulin-dependent) diabetic patients with peripheral neuropathy

Summary Previous studies have suggested that nerve regeneration may be defective in patients with diabetic polyneuropathy. Since insulin-like growth factor I (IGF-I) has been shown to stimulate nerve regeneration, and IGF binding protein-1 is acutely regulated by plasma insulin we have investigated the relationships between plasma IGF-I, IGFBP-1, glucose and insulin in Type 1 (insulin-dependent) diabetic patients with peripheral polyneuropathy. Plasma samples were taken at hourly intervals over an 11-h period (08.00–19.00 hours) in order to characterise secretory profiles for 15 Type 1 diabetic patients (eight neuropathic and seven non-neuropathic) and eight non-diabetic control subjects. In the non-diabetic subjects, mean plasma IGF-I levels were stable throughout the 11-h period with a range of 97 g/l–169 g/l. In contrast, mean plasma IGFBP-1 levels declined steadily from a high level of 1.99 g/l at 08.00 hours to approximately one half (0.86 g/l) at 15.00 hours. Comparison of areas under the curves revealed significant negative correlations between IGFBP-1 and glucose (–0.88, p=0.01), IGFBP-1 and insulin (–0.75, p=0.016), and IGFBP-1 and IGF-I (–0.68, p=0.03). A significant positive correlation was found between insulin and IGF-I (+ 0.89, p=0.001). The diabetic patients had markedly elevated plasma IGFBP-1 levels (area under curve, p=0.01) and lower plasma IGF-I levels (p=0.033) even though these patients were hyperinsulinaemic throughout the study period. The neuropathic diabetic patients had grossly elevated IGFBP-1 levels (–X=40 g/l at 08.00 hours) which were significantly higher (area under curve, p=0.05) than in patients without neuropathy (¯X=15 g/l at 08.00 hours). However, plasma levels of insulin and IGF-I in neuropathic and non-neuropathic subjects were similar, suggesting that the regulation of IGFBP-1 is more resistant to insulin in the neuropathic patients. In contrast to the non-diabetic subjects comparison of area under curve values revealed no positive correlation between insulin and IGF-I or negative correlations between IGF-I and IGFBP-1, and IGFBP-1 and glucose. We conclude that in Type 1 diabetes the relationships between plasma glucose, insulin, IGF-I and IGFBP-1 are clearly abnormal, and these abnormalities are more pronounced in patients with peripheral neuropathy.     

Effect of recombinant human growth hormone treatment on insulin-like growth factor (IGF-I) levels in insulin-dependent diabetic patients

Basal and recombinant human growth hormone (rhGH)-stimulated insulin-like growth factor (IGF-I) levels were studied in 19 insulin-dependent diabetic patients and 4 healthy subjects. Diabetic patients were divided according to glucagon test result into CpN (10 patients without residual beta cell activity) and CpP (9 patients with preserved beta-cell activity) groups, and according to age into three groups (A=21–30 years; B=31–40 years; C=41–50 years). All control subjects belonged to group B. Blood glucose and growth hormone were measured at hourly intervals and IGF-I every 6 h during 24 h before and after 7 days treatment with 4 IU of rhGH given subcutaneously at 8 p.m. The age-related decrease in basal IGF-I levels was evident in both CpN and CpP groups of diabetic patients. IGF-I net increase with rhGH treatment was variable and insignificant in comparison with basal value without age-related differences in CpN diabetics. Progressively larger age-related increases in IGF-I concentrations were observed in CpP diabetic patients. This study indicates impairment of hepatic IGF-I generation capacity in diabetic patients without residual beta-cell activity and the importance of simultaneous actions of portal insulin and GH on hepatic IGF-I production.     

Type I and type II insulin-like growth factor receptors and their function in human Ewing's sarcoma cells

Summary Binding studies using recombinant human¹²⁵I-labelled insulin-like growth factor I ([¹²⁵I]IGF-I) revealed IGF-I receptors in three Ewing's sarcoma cell lines withK _d ranging from 74×10^–12 M to 100×10^–12 M andB _max=36–63 fmol/mg cell protein. [¹²⁵I]IGF-I binding was displaced by IGF-I, IGF-II and insulin with IC₅₀ values of 1.5 nM, 6.3 nM and 0.7 M respectively. Recombinant human [¹²⁵I]IGF-II radioligand-binding assays in the cell lines disclosed specific binding sites for IGF-II withK _d=(110–175)×10^–12 M andB _max varying from 21 fmol/mg to 72 fmol/mg cell protein. Neither IGF-I nor insulin displaced [¹²⁵I]IGF-II binding. IGF-I was found to increase basal glucose transport by maximally 1.5 times with EC₅₀=0.9 nM IGF-I. The efficacy and potency of IGF-II on glucose uptake were comparable to those of IGF-I whereas insulin was ineffective. IGF-I and IGF-II also provoked stimulation of glycogen synthesis in Ewing's sarcoma cells. The maximal glycogenic response was reached at 0.01 M IGF-I and 0.1 M IGF-II, the EC₅₀ value being approximately 1 nM IGF-I and 2 nM IGF-II. Insulin did not significantly influence glycogen formation. IGF-I and IGF-II but not insulin increased DNA synthesis in Ewing's sarcoma cells. The maximal mitogenic response was obtained with 10 nM IGF-I or IGF-II with an EC₅₀ value of about 0.7 nM for both peptides. -IR-3, a monoclonal antibody specific for the IGF type I receptor, effectively blocked IGF-I- and IGF-II-mediated metabolic responses. In conclusion, the data show that IGF-I and IGF-II induce rapid and longterm biological responses in Ewing's sarcoma cells exclusively through interaction with IGF type I receptors.     

Insulin-like Growth Factor-I and IGF-I Receptors in Diabetic Patients with Neuropathy

Since a number of animal studies have shown that Insulin-like growth I (IGF-I) stimulates nerve regeneration, the aim of our study was to evaluate the possible relationship between IGF-I and IGF-I receptors in diabetic patients with peripheral neuropathy. One hundred and four patients with Type 2 diabetes (57 with peripheral neuropathy and 47 non-neuropathic) were studied. Controls were 17 non-diabetic persons. After an overnight fast, blood was taken for IGF-I, IGF-I receptors, glucose, HbA₁, C-peptide, and insulin. The neuropathy study group had significantly lower levels of IGF-I:144.5 ng mI^-1 (57.5–363.0, 95% confidence limits) compared to controls: 186.2 ng mI^-1 (93.3–371.5), p<0.01, and to diabetic patients without neuropathy: 173.7 ng mI^-1 (83.1–363.0), p<0.01. The study group also had a lower number of IGF-I receptors per red cell: 22.9 times 10³ (13.08–38.01) vs control subjects: 28.1 times 10³ (18.62–42.65), p<0.01, and non-neuropathic diabetic patients: 26.3 times 10³ (16.59–41.68), p<0.01. In diabetic subjects there was a positive correlation (r = 0.20, p<0.05) between IGF-I and HbA₁, while in the neuropathy group there was a negative correlation between the score for nerve dysfunction with the IGF-I (r = -0.39, p<0.01) and with IGF-I receptors (r = -0.34, p<0.01). We conclude that in diabetic patients with peripheral neuropathy there are abnormalities of IGF-I and IGF-I receptors which may contribute to impaired neuronal regeneration.     

Insulin-like growth factors (IGF) I and II in diabetic pregnancy: Suppression of normal pregnancy-induced rise of IGF-I

Summary The concentrations of somatomedins/insulin-like growth factors were measured by a specific radioimmunoassay for insulin-like growth factor-I and a specific radioreceptor assay for insulin-like growth factor-II in sera of term normal and Type 1 (insulin-dependent) diabetic pregnant women and in various cord sera of their newborn infants. Serum insulin-like growth factor-I levels in normal (non-diabetic) maternal serum were higher than in non-pregnant women (486 ± 26 versus 215 ± 26 ng/ml). The normal pregnancy-induced increment of insulin-like growth factor-I was markedly reduced in diabetic pregnancy. It was not different in patients with good or poor glycaemic control, as judged by normal or elevated blood levels of haemoglobin A_1c content. Insulin-like growth factor-I levels in cord serum of infants of diabetic women with good glycaemic control (86±11 ng/ml) and poor glycaemic control (91±19 ng/ml) were significantly higher (p < 0.01) than in infants of non-diabetic women (43±42 ng/ml). The fetal birth weight ratios were not significantly correlated with insulin-like growth factor-I levels in cord serum. Serum insulin-like growth factor-II levels in maternal and cord serum in diabetic and normal pregnancy were not different from each other or from normal non-pregnant women. The increment in insulin-like growth factor-I levels in maternal serum in pregnancy may influence placental structure and function. Lack of this increment in maternal diabetes may have direct implication in placental abnormalities in diabetes and indirect implications on fetal development and metabolism. The increment in fetal serum insulin-like growth factor-I levels in infants of diabetic mothers might suggest a role for insulin-like growth factor-I in fetal macrosomia. This finding, along with the lack of correlation with maternal glycaemic control, might suggest that fetal hyperinsulinaemia has a greater role than insulin-like growth factor-I in the fetal macrosomia. Serum insulin-like growth factor-II levels do not appear to be influenced by pregnancy or diabetes. The similar levels of insulin-like growth factors-I or II in normal and diabetic non-pregnant women may present some evidence against a major role of both insulin-like growth factors in the chronic complications which may develop in persons with diabetes.     

Relationship between non-enzymatic glycosylation and changes in serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in patients with type 2 diabetes mellitus

The possible occurrence of increased non-enzymatic glycosylation of serum insulin-like growth factor binding protein-3 (IGFBP-3) in vivo and the changes that would simultaneously occur in serum levels of IGFBP-3 and insulin-like growth factor-1 (IGF-I) were investigated. We measured levels of IGF-I and IGFBP-3 and the degree of glycation of total serum protein and IGFBP-3, in serum samples obtained from patients with poorly controlled non-insulin-dependent diabetes (type 2) and from age-matched non-diabetic controls. Type 2 diabetic patients had significantly higher glycated serum protein (GlyP) levels. GlyP significantly correlated with age in the control (r = 0.315, P<0.05) but not in the type 2 diabetes group. Control and diabetic subjects had comparable serum IGF-I levels and in both groups IGF-I levels tended to decrease with age (r = –0.567, P<0.001 and r = –0.465, P<0.05 for control and type 2 diabetic subjects, respectively). In the type 2 diabetes group, IGF-I levels showed a negative correlation with serum GlyP values (r = –0.476, P<0.05). Type 2 diabetic and control patients had comparable serum IGFBP-3 levels, which were significantly higher in diabetic patients in the older age subgroups. A negative correlation was found between IGFBP-3 levels and age in the control (r = –0.705, P<0.001) and in the type 2 diabetes groups (r = –0.463, P<0.05). A significant negative correlation was found between IGFBP-3 levels and GlyP in control (r = –0.449, P<0.002) but not in type 2 diabetic subjects. The mean glycated IGFBP-3 (GlyIGFBP-3) levels were higher in the oldest type 2 diabetic patients. In these patients, GlyIGFBP-3 was negatively associated with IGF-I levels (r = –0.447, P<0.05). The IGF-I/IGFBP-3 molar ratio was significantly reduced in the 46–60-year-old type 2 diabetic group, whereas the IGF-I/IGFBP-3 ratio was positively and significantly correlated with GlyP levels only in the control group (r = 0.489, P<0.01). Our results show that: a) increased non-enzymatic glycosylation of IGFBP-3 occurs in vivo; and b) this effect is accompanied by an increase in IGFBP-3 levels. These results suggest that the IGF-I/IGFBP-3 system is another target for the metabolic derangements of type 2 diabetes. Its alterations might play a role in diabetic complications. Received: 22 September 1997 / Accepted in revised form: 30 April 1998     

Development and validation of a radioimmunoassay for fish insulin-like growth factor I (IGF-I) and the effect of aquaculture related stressors on circulating IGF-I levels

This paper describes the development and validation of a commercially available radioimmunoassay (RIA) for the detection of fish insulin-like growth factor-I (IGF-I). The assay was developed using recombinant barramundi IGF-I as antigen and recombinant tuna IGF-I as radiolabelled tracer and standard. Assay sensitivity was 0.15 ng/ml, inter-assay variation was 16% (n = 9) and intra-assay variation was 3% (n = 10). Cross reactivity of less than 0.01% was found with salmon insulin, salmon IGF-II and barramundi IGF-II, less than 0.5% with human IGF-I and less than 1% with human IGF-II. Parallel dose-response inhibition curves were shown for barramundi (Lates calcarifer), coho salmon (Oncorhynchus kisutch), Southern Bluefin tuna (Thunnus maccoyii), tilapia (Oreochromis mossambicus), and seabream (Pagrus auratus) IGF-I. The assay was then used to measure stress related changes in different aquacultured fish species. Salt water acclimated Atlantic salmon smolts (Salmo salar) bathed for 2 h in fresh water showed significantly lower IGF-I concentrations than control smolts two days after the bath (53.1 compared to 32.1 ng/ml), with levels of IGF-I also lower in smolts exhibiting stunted growth (stunts). Capture and confinement of wild tuna in sea-cages resulted in a significant decrease in IGF-I levels (28 ng/ml) when compared to tuna captured and sampled immediately (48 ng/ml), but had recovered to starting levels after 3 weeks (43 ng/ml). Handling and isolation in silver perch (Bidyanus bidyanus) led to a gradual decline in IGF-I over a 12 h period (36-19 ng/ml) but showed signs of recovery by 24 h (24 ng/ml) and had recovered fully 72 h after treatment (40 ng/ml). A similar trial in black bream (Acanthopagrus butcherii) showed comparable results with IGF-I levels gradually decreasing (40-26 ng/ml) over 24 h, results that were mirrored by cortisol concentrations which increased during this time (1-26 ng/ml). In the studies presented here changes in IGF-I levels were not observed for at least 3 h after exposure to the stressor. We suggest this is due to the endocrine nature of IGF-I regulation and the clearance rate of IGF-I in vivo.     

Human placental growth hormone,insulin-like growth factor I and -II,and insulin requirements during pregnancy in type 1 diabetes

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P < or = 0.021). Serum hPGH correlated to serum IGF-I from wk 24- 35, and changes in IGF-I followed the increase in hPGH between wk 26-35 (r(s) = 0.53; P < 0.001), as did IGF-II (r(s) = 0.37; P = 0.008). Changes in IGF-I and IGF-II between wk 26-35 also correlated to the birth weight z-score (P < or = 0.020), but only hPGH remained significant in multiple regression analysis. Similar results were found in the subgroup delivering at term. Interestingly, the increase in hPGH was not correlated to the increase in insulin requirements, nor was any consistent relationship revealed during each gestational period. In conclusion, our study suggests a role for hPGH in the regulation of both IGFs and fetal growth in type 1 diabetes. In contrast, the increase in insulin requirements during pregnancy in type 1 diabetic subjects could not be related to hPGH levels.     

Somatomedins and insulin in diabetic pregnancies: effects on fetal macrosomia in the human and rhesus monkey

The concentrations of the somatomedins (SMs) insulin-like growth factors I and II (SM-C/IGF-I and IGF-II) were measured by RIA in six normal and seven insulin-dependent diabetic pregnant women and their infants at delivery. SM-C/IGF-I and IGF-II levels in the two groups of women were similar. Maternal IGF-II concentrations correlated with maternal hemoglobin AIc levels (r = 0.68) and infant birth weight ratios (actual birth weight/expected 50th percentile sex-corrected birth weight for gestation age; r = 0.54). SMC/IGF-I and IGF-II levels in umbilical plasma in infants of diabetic mothers did not differ from those in control infants, but were lower than the corresponding maternal values. In contrast, umbilical plasma levels of C-peptide immunoreactivity were significantly elevated in the infants of diabetic mothers (2.25 +/- 1.85 (+/-SD) vs. 0.34 +/- 0.15 pmol/ml; P less than 0.01). The infant birth weight ratio was logarithmically correlated with the umbilical plasma C-peptide immunoreactivity (r = 0.78). SM levels were also measured by radioreceptor assay in five normal and five hyperinsulinemic rhesus monkey fetuses. When chronic hyperinsulinemia was produced by continuous SC infusion of insulin in the fetal rhesus monkey, the fetal birth weight ratio was also found to be logarithmically correlated with the fetal plasma insulin concentration (r = 0.81). The fetal SM peptide content was elevated only in the fetuses with plasma insulin levels greater than 3000 microU/ml. The fetal weight gains in response to hyperinsulinemia in the human and rhesus are similar. Since fetal SM levels in the humans and monkeys were not significantly different in the two groups, our data suggest that insulin plays the predominant role in stimulating human and subhuman primate excess fetal weight gain of the infant of the diabetic mother during the latter part of gestation.     

Study of insulin resistance in relation to serum IGF-I levels in subjects with different degrees of glucose tolerance

AIM:

We studied the correlations between fasting and post-lunch serum IGF-I concentrations, and insulin resistance and insulin sensitivity in subjects with various degrees of glucose tolerance.

MATERIALS AND METHODS:

A total of 12 nondiabetic subjects, 09 subjects with impaired glucose tolerance (IGT) and 18 patients with newly diagnosed type-2 diabetes of either sex (mean age, 46 years) were recruited. None of the participants received any drug treatment at the commencement of the study. Fasting as well as post-lunch blood samples were collected from all the subjects and anthropometric and biochemical parameters were analyzed.

RESULTS:

Fasting serum IGF-I concentrations were negatively correlated with fasting serum glucose, insulin, C-peptide, triglycerides, total LDL and VLDL cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR), and age. Fasting serum IGF-I concentrations were positively correlated with fasting blood HDL cholesterol and homeostatic model assessment of insulin sensitivity (HOMA-S) in only diabetic subjects. Post-lunch serum IGF-I concentrations were positively correlated with HDL and LDL cholesterol. Correlations with HOMA-S with these metabolic anthropometric variables were of similar magnitude and direction as that of IGF-I concentrations. IGF-I concentrations were significantly lower in the subjects with World Health Organization-defined metabolic syndrome compared with the subjects without metabolic syndrome (P < 0.0001).

CONCLUSIONS:

Our data indicate that IGF-I could be a useful marker in the insulin resistance syndrome. The post-lunch low-IGF-I levels help in better identification of subjects at risk for type-2 diabetes mellitus and cardiovascular disease.     

The negative association between plasma ghrelin and IGF-I is modified by obesity, insulin resistance and type 2 diabetes

Aims/hypothesis Ghrelin is a natural growth hormone-releasing peptide thought to be involved in the regulation of energy metabolism. The recent studies concerning the association between ghrelin and insulin-like growth factor-I (IGF-I) concentrations have shown either negative correlation or no correlation at all. The aims of this study were to clarify the association between ghrelin and IGF-I concentrations in a large cohort and to characterize whether obesity, insulin resistance and type 2 diabetes affect this association.Methods We analysed fasting plasma ghrelin and IGF-I concentrations of 1,004 middle-aged subjects of the population-based OPERA study. Insulin resistance was estimated using QUICKI.Results IGF-I concentrations were negatively associated with ghrelin concentrations in the analysis of all subjects before (=–0.32, p<0.001) and after adjustments for BMI, insulin levels, sex and age (=–0.40, p<0.001). The association was particularly strong in males and in the higher BMI tertiles. The degree of association varied in relation to the glycaemic status: no insulin resistance: r²=6.5% (p<0.001), insulin resistance without type 2 diabetes: r²=21.0% (p<0.001), type 2 diabetes: r²=25.4 (p<0.001). IGF-I levels explained larger proportion (r²=9.8%) of the variation in ghrelin concentrations compared to fasting insulin concentration (r²=3.0%) and BMI (r²=1.5%).Conclusions/interpretation There is a negative and independent association between ghrelin and IGF-I concentrations in middle-aged subjects. The interaction between IGF-I and ghrelin is modified by obesity, IR and type 2 diabetes. Further studies are warranted to elucidate the role of ghrelin in the development of these states.     

Insulin sensitivity and secretion in normal children related to size at birth,postnatal growth,and plasma insulin-like growth factor-I levels

Aims/hypothesis Type 2 diabetes risk is associated with low birth weight, rapid weight gain during childhood, and shorter stature and lower circulating IGF-I levels in adults. The largest variations in growth rates occur during the first postnatal years. We hypothesised that early postnatal variations in height and weight gain and IGF-I levels may be associated with risk markers for adult disease.Methods We measured the fasting insulin sensitivity (Homeostasis model) and insulin secretion post-oral glucose (insulinogenic index 0–30 min) in 851 normal 8-year-old children from a prospective birth cohort. We examined associations between size at birth, postnatal weight gain and circulating IGF-I levels with insulin sensitivity and secretion at 8 years of age.Results Fasting insulin sensitivity at 8 years was closely related to current BMI (r=–0.33, p<0.0005). Lower insulin sensitivity and higher BMI and waist circumference were all predicted by greater weight gain between birth to 3 years of age (all p<0.0005); lower birth weight was associated with reduced insulin sensitivity only in the highest current BMI tertile (r=0.17, p=0.006). In contrast, lower insulin secretion was related to smaller size at birth (p=0.01), independent of postnatal weight gain and insulin sensitivity. Lower insulin secretion was also independently related to shorter stature at 8 years of age relative to parental height (p=0.047) and with lower plasma IGF-I levels at 5 years of age (n=252, p=0.004).Conclusions/interpretation Associations between lower birth weight and insulin resistance may be dependent on rapid weight gain during the early postnatal years. However, irrespective of postnatal weight gain, smaller size at birth, lower IGF-I levels and lower childhood height predicted reduced compensatory insulin secretion.Abbreviations ALSPAC Avon Longitudinal Study of Pregnancy and Childhood     

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P 相似文献   

Serum insulin-like growth factor II levels in normal adolescents and those with insulin dependent diabetes mellitus

OBJECTIVE Unlike IGF-I and its principal binding proteins, data regarding IGF-II levels have not been well defined in normal subjects and those with insulin-dependent diabetes mellitus (IDDM). We have therefore measured IGF-II, as well as IGF-I, and IGFBP-3, levels In a large cohort of subjects with IDDM and in age/sex matched controls. PATIENTS One hundred and fourteen patients with IDDM (57 males, 57 females) and 89 control subjects (49 males, 40 females). MEASUREMENTS Random blood samples were obtained from each subject for the measurement of IGF-II, IGF-I and IGFBP-3 levels. RESULTS Mean values of IGF-II (±SEM) were 630 (±27.8) μg/l and 646 (±32.3) μg/l in female and male controls, compared to 569 (±23.3) μg/l and 623.3 (±28.1) μg/l in female and male diabetics respectively. IGF-II levels did not differ significantly between the sexes or show any change with transition through puberty in either control or diabetic groups. In contrast, IGF-I levels increased through puberty peaking at stages 3–5 in controls (P < 0.001) and G4–5 (P= 0.002) in diabetic males but not females. IGF-I levels in all diabetics were generally lower than in controls, differences reaching significance at G4–5 in males (P= 0.002) and B5 in females (P= 0.002). IGFBP-3 levels did not show any variation with puberty stage in diabetics, in contrast to controls where levels increased, peaking at G4–5 in males (P= 0.001) and B3 in females. IGFBP-3 levels were lower in diabetics of both sexes and at all stages compared to controls (P range 0.047 to < 0.001). Multiple regression analysis revealed significant correlations between IGF-II and IGFBP-3 (F= 20.1, P= < 0.001) and reaffirmed previously observed associations for IGF-I and IGFBP-3. The sum of IGF-I and IGF-II (expressed as nmol/l) correlated with IGFBP3; r= 0.47 in controls and 0.60 in diabetics. CONCLUSIONS Insulin-dependent diabetes mellitus is not associated with any significant changes in IGF-II levels during puberty. The binding of IGFBP-3 for both IGF-I and IGF-II is unaltered by insulin-dependent diabetes mellitus.     

The effects of a specific growth hormone antagonist on overnight insulin requirements and insulin sensitivity in young adults with Type 1 diabetes mellitus

Aims/hypothesis Growth hormone hypersecretion in Type 1 diabetes could exacerbate insulin resistance and contribute to declining glycaemic control. Our aim was to determine the effects of specific growth hormone blockade on insulin sensitivity and lipolysis in young adults with Type 1 diabetes.Methods We studied the effects of two doses of a specific growth hormone antagonist (B2036-PEG; Somavert, Pharmacia Corporation, Milton Keynes, UK) on insulin sensitivity in seven young adults (17–22 yrs, 3M) with Type 1 diabetes. Subjects recieved 5 and 10 mg B2036-PEG, in random order for 3 weeks, with a 3-week washout. At baseline and following each treatment block, an overnight (03:00 to 08:00 h) insulin infusion for euglycaemia (5 mmol/l), followed by two-step hyperinsulinaemic euglycaemic clamp, using [6,6 ²H₂] glucose and ²H₅ glycerol to measure glucose and glycerol turnover was performed.Results Compared to baseline, overnight insulin requirements decreased with both doses: (means±SEM) 0.34±0.02 mU/Kg/min vs 0.25±0.01 (5 mg) (p=0.04), and 0.24±0.01 (10 mg) (p=0.004). IGF-I (ng/ml) decreased following 10 mg [223.5±23.9 vs 154.6±28.1 (p=0.005], but not 5 mg. Mean overnight non esterified fatty acid concentrations (mmol/l) decreased with 10 mg [0.51±0.04 vs 0.38±0.04 (p=0.03)], as did -hydroxybutyrate (mmol/l); [0.31±0.04 vs 0.15±0.02 (p=0.004)]. Glycerol production rate, an index of lipolysis, was lower following 10 mg (p=0.04), but insulin sensitivity during the clamp did not change with either dose.Conclusion/interpretation Treatment with both doses of B2036-PEG reduced overnight insulin requirements. The 10 mg dose suppressed lipolysis and reduced IGF-I. Failure to show enhanced insulin sensitivity during the clamp with the 10 mg dose could reflect opposing actions of growth hormone and IGF-I.Abbreviations T1DM Type 1 diabetes mellitus - GH growth hormone - IGF-I insulin-like growth factor 1 - IGFBP-1 IGF binding protein 1 - IGFBP-3 IGF binding protein 3 - NEFA non eosterified fatty acids - OHB -hydroxybutyrate     

Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes

Summary The offspring of mothers with diabetes mellitus during pregnancy are presumed to develop altered glucose homeostasis. We analysed metabolic parameters at birth and glucose tolerance and insulin secretion during oral glucose tolerance tests at 1–9 years of age in 129 children born to mothers with pregestational insulin-dependent diabetes (IDDM) and 69 infants of gestational diabetic mothers. Newborns of IDDM mothers displayed higher insulin (p < 0.001), glucose (p < 0.05), and insulin/glucose ratios (p < 0.002) than newborns of gestational diabetic mothers. During childhood, frequencies of impaired glucose tolerance (IGT) rose in infants of IDDM mothers from 9.4 % at 1–4 years to 17.4 % at 5–9 years of age, while in children of gestational diabetic mothers an increase from 11.1 % up to 20.0 % was observed. Offspring of gestational diabetic mothers displayed higher stimulated blood glucose (p < 0.025) than infants of IDDM mothers, while children of IDDM mothers showed higher stimulated insulin (p < 0.025), accompanied by increased fasting and stimulated insulin/glucose ratios (p < 0.05 and p < 0.02, respectively). Stimulated insulin in childhood was positively correlated to insulin at birth (p < 0.05). Furthermore, insulin/glucose ratio in childhood showed a positive correlation to insulin (p < 0.01) and insulin/glucose ratio at birth (p < 0.005). In conclusion, a pathogenetic role of fetal and neonatal hyperinsulinism for the development of IGT in both groups of infants of diabetic mothers is suggested, in particular for early induction of insulin resistance in the offspring of mothers with pregestational IDDM. [Diabetologia (1997) 40: 1097–1100] Received: 24 February 1997 and in revised form: 7 May 1997