Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature.

BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ± 11 to ± 38% (median ± 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours. CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase.

AIMS/HYPOTHESIS: The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period. METHODS: All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. RESULTS: Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. CONCLUSIONS/INTERPRETATION: The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Target setting in intensive insulin management is associated with metabolic control: the Hvidoere childhood diabetes study group centre differences study 2005.

OBJECTIVE: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. METHODS: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. RESULTS: A total of 2062 adolescents completed questionnaires (age 14.4 +/- 2.3 yr; diabetes duration 6.1 +/- 3.5 yr). Mean HbA 1c = 8.2 +/- 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). CONCLUSIONS: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.

Basal lipolysis, not the degree of insulin resistance, differentiates large from small isolated adipocytes in high-fat fed mice.

AIMS/HYPOTHESIS: Adipocytes in obesity are characterised by increased cell size and insulin resistance compared with adipocytes isolated from lean patients. However, it is not clear at present whether hypertrophy actually does drive adipocyte insulin resistance. Thus, the aim of the present study was to metabolically characterise small and large adipocytes isolated from epididymal fat pads of mice fed a high-fat diet (HFD). METHODS: C57BL/6J mice were fed normal chow or HFD for 8 weeks. Adipocytes from epididymal fat pads were isolated by collagenase digestion and, in HFD-fed mice, separated into two fractions according to their size by filtration through a nylon mesh. Viability was assessed by lactate dehydrogenase and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium assays. Basal and insulin-stimulated D-[U-(14)C]glucose incorporation and lipolysis were measured. Protein levels and mRNA expression were determined by western blot and real-time RT-PCR, respectively. RESULTS: Insulin-stimulated D-[U-(14)C]glucose incorporation into adipocytes isolated from HFD-fed mice was reduced by 50% compared with adipocytes from chow-fed mice. However, it was similar between small (average diameter 60.9 +/- 3.1 microm) and large (average diameter 83.0 +/- 6.6 microm) adipocytes. Similarly, insulin-stimulated phosphorylation of protein kinase B and AS160 were reduced to the same extent in small and large adipocytes isolated from HFD-mice. In addition, insulin failed to inhibit lipolysis in both adipocyte fractions, whereas it decreased lipolysis by 30% in adipocytes of chow-fed mice. In contrast, large and small adipocytes differed in basal lipolysis rate, which was twofold higher in the larger cells. The latter finding was associated with higher mRNA expression levels of Atgl (also known as Pnpla2) and Hsl (also known as Lipe) in larger adipocytes. Viability was not different between small and large adipocytes. CONCLUSIONS/INTERPRETATION: Rate of basal lipolysis but not insulin responsiveness is different between small and large adipocytes isolated from epididymal fat pads of HFD-fed mice.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?

AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.

P450c17 deficiency: clinical and molecular characterization of six patients.

CONTEXT: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development. OBJECTIVE: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients. DESIGN AND PATIENTS: We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension. MAIN OUTCOME MEASUREMENTS: Genotype-phenotype correlation was measured. RESULTS: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins. CONCLUSION: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

Inhibition of the action of nonsuppressible insulin-like activity on isolated rat fat cells by binding to its carrier protein.

Nonsuppressible insulin-like activity extracted and purified from human serum (NSILA-S) mimics all insulin-like effects in vitro and, after injection, in vivo in the presence of excess insulin antibodies. However, there is no evidence that it exerts acute insulin-like effects in its native form in the circulation, where it is almost completely bound to a specific large molecular weight carrier protein. In this paper we show that partially purified NSILA-S-carrier protein, devoid of endogenous insulin-like activity, inhibits the stimulatory effect of NSILA-S, but not of insulin, on 3-0-methylglucose transport and on lipogenesis from [U-(14)C]glucose in isolated rat fat cells. Concomitantly, it prevents binding of (125)I-labeled NSILA-S to the insulin receptor and to the NSILA-S-binding site. The following explanation is, therefore, offered for the absence of acute insulin-like effects of native NSILA-S in vivo: In native serum NSILA-S occurs almost exclusively as NSILA-S-carrier complex. According to recent findings the passage of this complex through blood capillaries is restricted. The present results indicate that, in addition, it is metabolically inactive, or, at least, possesses reduced metabolic activity. The well-known phenomenon that whole serum, nevertheless, exerts pronounced nonsuppressible insulin-like effects on adipose tissue in vitro seems, therefore, to be mainly caused by the presence of a large molecular weight insulin-like protein not identical to the NSILA-S-carrier complex.

Epidemiology of IDDM in Switzerland. Increasing incidence rate and rural-urban differences in Swiss men born 1948-1972.

OBJECTIVE: To determine the incidence of insulin-dependent diabetes mellitus (IDDM) in Switzerland by undertaking a retrospective analysis of the registry of the Swiss army, which contains updated medical files for all male Swiss citizens. Nation-wide data for IDDM epidemiology have not been available in Switzerland. RESEARCH DESIGN AND METHODS: Every male Swiss citizen is obliged to enlist in the Swiss military service at 19 years of age, when a personal, continuously updated medical file is established. Diabetes is an exclusion condition for military service and is clearly marked in the file. A total number of 514,747 files, corresponding to birth year cohorts 1948-1950, 1955-1957, 1962-1964, and 1970-1972, have been manually checked for the diagnosis of IDDM. RESULTS: IDDM was identified in 926 cases in the four groups of three age-cohorts. The incidence at < or = 15 years (per 100,000/year) was 4.5 in the age cohorts 1948-1950 and 7.2 in the age cohorts 1970-1972 (P < 0.005). An additive age-cohort Poisson regression model fits the nationwide incidences adequately, neither a period effect nor age x cohort interactions being required. In the oldest age cohorts, the age-specific incidence of IDDM was calculated up to the age of 43 and was approximately 7/100,000/year in men between 20 and 40. In these age cohorts, we found an approximately 50% higher risk to develop IDDM at age < or = 19 for men living in an urban region and a significantly (P < 0.005) increased incidence between 20 and 40 years in rural regions compared with urban regions. CONCLUSIONS: The incidence of IDDM in Switzerland is comparable to other countries in central Europe and has been increasing in the last 20 years. This is in accordance to most recent epidemiological studies worldwide. In addition, the data suggest exogenous factors inducing IDDM at a younger age in urban regions.

Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes.

OBJECTIVE: It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families. RESEARCH DESIGN AND METHODS: The study involved 2,101 adolescents, aged 10-18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA(1c) was analyzed centrally (normal range 4.4-6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires. RESULTS: Mean HbA(1c) was 8.7% (range 4.8-17.4). Lower HbA(1c) was associated with lower impact (P < 0.0001), fewer worries (P < 0.05), greater satisfaction (P < 0.0001), and better health perception (P < 0.0001) for adolescents. Girls showed increased worries (P < 0.01), less satisfaction, and poorer health perception (P < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P < 0.0001). Patients from ethnic minorities had poorer scores for impact (P < 0.0001), worries (P < 0.05), and health perception (P < 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores. CONCLUSIONS: In a multiple regression model, lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.

Persistent differences among centers over 3 years in glycemic control and hypoglycemia in a study of 3,805 children and adolescents with type 1 diabetes from the Hvidøre Study Group.

OBJECTIVE: Twenty-one international pediatric diabetes centers from 17 countries investigated the effect of simple feedback about the grand mean HbA(1c) level of all centers and the average value of each center on changes in metabolic control, rate of severe hypoglycemia, and insulin therapy over a 3-year period. RESEARCH DESIGN AND METHODS: Clinical data collection and determination of HbA(1c) levels were conducted at a central location in 1995 (n = 2,780, age 0-18 years) and 1998 (n = 2,101, age 11-18 years). RESULTS: Striking differences in average HbA(1c) concentrations were found among centers; these differences remained after adjustment for the significant confounders of sex, age, and diabetes duration. They were apparent even in patients with short diabetes duration and remained stable 3 years later (mean adjusted HbA(1c) level: 8.62 +/- 0.03 vs. 8.67 +/- 0.04 [1995 vs. 1998, respectively]). Three centers had improved significantly, four centers had deteriorated significantly in their overall adjusted HbA(1c) levels, and 14 centers had not changed in glycemic control. During the observation period, there were increases in the adjusted insulin dose by 0.076 U/kg, the adjusted number of injections by 0.23 injections per day, and the adjusted BMI by 0.95 kg/m(2). The 1995 versus 1998 difference in glycemic control for the seven centers could not be explained by prevailing insulin regimens or rates of hypoglycemia. CONCLUSIONS: This study reveals significant outcome differences among large international pediatric diabetes centers. Feedback and comparison of HbA(1c) levels led to an intensification of insulin therapy in most centers, but improved glycemic control in only a few.

In vivo control of insulin-sensitive phosphodiesterase in rat adipocytes by growth hormone and its parallelism to glucose transport.

As shown previously in adipocytes of hypophysectomized (hypox) rats, 3-O-methyl-glucose transport is already maximal in the basal state and insensitive to insulin. It is normalized by prolonged administration of GH to hypox rats. This study shows glucose transport in the presence and absence of phosphodiesterase (PDE) inhibitors in the fat cells of normal and hypox rats. Enhanced glucose transport in insulin-stimulated normal fat cells as well as enhanced glucose transport in adipocytes of hypox rats is inhibited by PDE inhibitors. The low Km phosphodiesterase activity, which is known to be acutely stimulated by insulin in normal adipocytes, is found to be increased in the fat cells of hypox rats, and further stimulation by insulin is not possible. Normalization occurs after GH administration for 4 days. Then, the low Km PDE activity is again low and stimulated in the presence of insulin. The similarity between the behavior of the activity of the glucose carrier system and that of the low Km PDE suggests that both may be dependent on a GH-induced membrane factor which would be acutely inhibited by insulin.

Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche.

CYP17 is a microsomal enzyme embodying two distinct activities, 17alpha-hydroxylase and 17,20-lyase, essential for the synthesis of cortisol and sex hormone precursors, respectively. The two activities are differentially regulated in a tissue and developmental stage-dependent fashion. Leptin might play a role in such differential control. Low dose leptin caused a significant increase in 17,20-lyase activity in adrenal NCI-H295R cells expressing leptin (OB) receptor (OB-R), without significant sustained influence on the 17alpha-hydroxylase activity. To analyze the time dependence of this leptin effect, the impact of long and short-term leptin treatment was studied. To assess the relationship with the OB-R signal transduction pathway, the same experiments were performed in intact cells and in a reconstituted system. The long- and short-term studies in intact cells and in microsomes suggest that the 17alpha-hydroxylase activity of CYP17 can be promptly stimulated by leptin, but that the effect is transient. In contrast, physiological doses of leptin steadily enhance 17,20-lyase activity. This influence is direct, OB-R specific and dependent on the integrity of the signal transduction pathway. The 17,20-lyase activity stimulation relies on phosphate incorporation, as demonstrated by the loss of leptin-dependent 17,20-lyase stimulation after phosphate removal, and by the fact that the DHEA production appears to be related exclusively to the presence of phosphorylated CYP17, independently from novel protein synthesis. The mechanism underlying the observed events seems to involve CYP17 phosphorylation, a feature of the OBR signal transduction pathway, and a process already shown to be crucial for 17,20-lyase activity.

Regulation of rat adipocyte glucose transport by growth hormone: no mediation by insulin-like growth factors.

Growth hormone (GH) in vivo is responsible for normal glucose transport in isolated rat fat cells: In fat cells of hypophysectomized (hypox) rats basal glucose transport is maximal and insulin-insensitive. GH treatment of hypox rats restores the basal glucose transport rate towards normal and renders it again insulin-sensitive. The aim of this study was to find out whether these are direct effects of GH or effects that are mediated by GH-dependent insulin-like growth factors (IGF) I or II. Whereas IGF I and II infused into hypox rats stimulate growth, they do not normalize the glucose transport system in fat cells. Thus, the restriction of basal glucose transport in adipocytes seems to be directly controlled by GH.

Effects of insulin on glucose metabolism and glucose transport in fat cells of hormone-treated hypophysectomized rats: evidence that growth hormone restricts glucose transport.

In earlier studies we have shown that insulin does not stimulate glucose incorporation in adipocytes of hypophysectomized (hypox) rats. Basal glucose incorporation is decreased, although basal 3-O-methylglycose transport is very rapid and cannot be further stimulated by insulin. In this study we treated hypox rats with human GH, ACTH, and T3, alone or in combination, and examined the effects of insulin on glucose incorporation into fat cells and on 3-O-methylglucose transport. The results show that chronic administration of T3 alone to hypox rats partially restores glucose incorporation into fat cells and, in combination with ACTH, completely restores this incorporation. The two hormones have no effect on the glucose carrier system. The transport rate under T3 and ACTH replacement therapy continues to proceed at a maximal rate, so that basal glucose incorporation is high but not further enhanced by insulin. In contrast, administration of human GH to hypox rats does not influence glucose incorporation but has a marked effect on glucose transport. The basal glucose transport rate returns toward normal and again responds to insulin. This suggests 1) that enzyme activities responsible for the lipogenetic capacity of the fat cell are decreased in hypox rats and returned toward normal by the combined T3/ACTH treatment, and 2) that the limitation of glucose transport in the fat cell is controlled by GH. GH seems to induce a change of the glucose-carrier system; it leads to a restriction of glucose transport, which is acutely modulated by insulin.

Growth hormone requirement for a normal human adipocyte glucose carrier function.

One of the most prominent actions of insulin is stimulation of the glucose carrier in different cell types, especially adipose cells. However, the exact mechanism of the mode of action of insulin, between receptor binding and stimulation of glucose transport, is not understood in detail. We have shown earlier, that GH plays an important role in the control of the insulin-sensitive glucose carrier system in rat fat cells. In this study, we measured glucose transport in fat cells of normal probands, GH-deficient (GHD) and GH-treated GHD patients. From sc fat tissue biopsies of three GHD patients, fat cells were isolated after digestion with collagenase. In normal fat cells, basal glucose transport was slow (t/2 = 2.5 min) and stimulated by insulin (t/2 = 0.8 min), as expected. In fat cells of GHD patients glucose transport was maximal already in the basal state (t/2 = 0.8 min) without an additional effect of insulin. After GH administration during several months to GHD patients, glucose transport was again slow in the basal state (t/2 = 3.2 min) and could be stimulated by insulin (t/2 = 0.7 min). These results confirm our earlier findings in rat adipocytes for human adipocytes: GH in vivo is responsible for a glucose transport-limiting factor in the plasma membrane that restricts basal glucose transport and is acutely inhibited by insulin resulting in enhanced glucose transport. These results demonstrate the physiological importance of GH for a normal function of the insulin transmembrane signaling system in fat tissue and indicate a possible benefit of GH administration in adult GHD patients.

Replacement of growth hormone (GH) in normally growing GH-deficient patients operated for craniopharyngioma.

Removal of a craniopharyngioma usually results in panhypopituitarism. Some children, however, grow normally or even excessively after extirpation of the tumor despite a proven lack of GH and have so far not been treated with hGH. We studied the effects of short (2-day) and long term (1-yr) administration of hGH on metabolism and growth in six patients receiving regular hormonal replacement therapy. During short term human (h) GH treatment, 15N retention was not significantly increased (mean +/- SEM, 115.4 +/- 9.6% of basal balance) and was not different from the control value. In contrast, 15N retention was 210.3 +/- 20.7% in children with GH deficiency from other causes. Long term administration of hGH (2 IU/m2.day, sc, for 12 months) did not influence growth velocity, but increased the calf circumference and decreased the body mass index and skinfold thickness in prepubertal patients. Insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the 150-kilodalton IGFBP complex were decreased before and restored to normal during treatment. The reverse was observed for the 50-kilodalton IGFBP complex. Growth (velocity) in these patients did not correlate with any of the usual indicators of the growth status and remains unexplained. Although hGH did not affect growth, it had other beneficial effects and is recommended for these patients.

Lack of bromocriptine-induced reduction of predicted height in tall adolescents.

Fifteen girls and five boys with excessive predicted adult height (chronological age, 10.1-14.6 yr; bone age, 11.0-14.0 yr) were treated with bromocriptine (two doses; 2.5 mg/day) to reduce their final height. After a mean treatment period of 1.14 yr (range, 0.6-1.75 yr) we did not find a reduction of predicted adult height [difference, -0.5 +/- 3.5 (+/- SD) cm according to Bayley and Pinneau's tables (P = NS) and +0.2 +/- 2.5 (+/- SD) cm according to the method of Tanner (P = NS)]. Mean peak plasma GH concentrations after TRH administration before and during bromocriptine were 51.5 +/- 49.4 and 58.5 +/- 50.7 mU/L, respectively. The wide range of the GH values may be explained by physiological variation in this age group. After ingestion of 2.5 mg bromocriptine a significant increase in plasma GH occurred within 3 h in six adolescents tested. Our results do not support the concept that bromocriptine may reduce predicted adult height in tall adolescents by decreased GH secretion or acceleration of skeletal maturation.

High molecular weight forms of IGF-II ('big-IGF-II') released by Wilms' tumor cells.

Insulin-like growth factor-II (IGF-II) is thought to play a critical role in the development of embryonic tumors such as Wilms' tumor. However, despite highly elevated IGF-II mRNA levels in tumors, IGF-II is not elevated in the serum of patients with Wilms' tumors. Recently high molecular weight forms of IGF-II ('big'- or pro-IGF-II) have been found to be produced by some tumors. In order to prove whether or not high molecular weight forms of IGF-II are produced by Wilms' tumor cells and secreted into the culture medium, we established Wilms' tumor cell lines. After column chromatography of the culture medium, IGF-II and pro-IGF-II concentrations were measured. For pro-IGF-II measurement we established a pro-IGF-II RIA using a rabbit polyclonal antiserum directed against amino acids 7-21 (E7-21) of the E-domain of pro-IGF-II. Gel electrophoresis and Western blotting with anti-IGF-II antibodies revealed a band at 7.5 kDa corresponding to fully processed IGF-II and bands between 10 and 20 kDa. Using pro-IGF-II antiserum, bands between 10 and 25 kDa were detected. We conclude that in vitro cultured Wilms' tumor cells produce and release various forms of 'big IGF-II' with molecular masses between 10 and 25 kDa. It remains uncertain whether these high molecular weight forms of IGF-II represent normal precursors of IGF-II or incorrectly processed IGF-II.

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.