Jian-Wen Chen

Normal Growth Spurt and Final Height despite Low Levels of All Forms of Circulating Insulin-Like Growth Factor-I in a Patient with Acid-Labile Subunit Deficiency

Background: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. Design and Methods: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. Results: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; –0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. Conclusions: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.

Marked reductions in bioactive insulin-like growth factor I (IGF-I) during hemodialysis.

OBJECTIVE Hemodialysis (HD) patients lose lean body mass, even when they are adequately dialysed. One reason may be a decreased activity of the IGF-system. However, data on changes in bioactive IGF-I during HD are sparse. DESIGN Ten stable, non-diabetic HD patients were studied with 30 min intervals during a scheduled HD, with blood sampling before (-15 and 0 min), during (4 h) and after (1 h) the session. Patients were fasted for at least 6 h before and during the study. Arterial and venous blood was sampled for determination of IGF-I bioactivity, free and total IGF-I and IGF-II, IGF binding protein-1 (IGFBP-1), IGFBP-1 complexed IGF-I and IGFBP-2. RESULTS Total IGF-I and -II decreased marginally (<12%) at the very end of the study (P<0.05). By contrast, at 3 h free and bioactive IGF-I had declined by approximately 35% and 50%, respectively, and levels remained suppressed for the rest of the study (P<0.05). Concomitantly, IGFBP-1 and IGFBP-1:IGF-I complex formation increased 5.0-fold and 2.6-fold, respectively (P<0.05). By contrast, IGFBP-2 did not increase as a result of HD. No major differences between arterial and venous concentrations were observed. CONCLUSION Despite marginal reductions in total IGF-I and -II, bioactive and free IGF-I declined markedly during and after HD. This is likely a consequence of the increase in IGFBP-1, sequestering free IGF-I, and reducing bioactive IGF-I. Based on the present data we hypothesize that the catabolism induced by HD is in part related to the observed reductions in bioactive IGF-I.

Ascites from patients with alcoholic liver cirrhosis contains higher IGF-I bioactivity than serum

Objective  Patients with liver cirrhosis have diminished hepatic IGF‐I generation, resulting in low circulating levels, whereas data on IGF‐I in ascites are sparse. Therefore, we compared the IGF‐system in serum and ascites from cirrhotic patients.

A Comparison of Pharmacokinetics and Pharmacodynamics of Biphasic Insulin Aspart 30, 50, 70 and Pure Insulin Aspart: A Randomized, Quadruple Crossover Study

The purpose of this study was to evaluate pharmacokinetic and pharmacodynamic profiles of pure insulin aspart and three different formulations of insulin aspart and protaminated insulin aspart: biphasic insulin aspart 30 (BIAsp30), biphasic insulin aspart 50 (BIAsp50) and biphasic insulin aspart 70 (BIAsp70). Nineteen type 1 diabetes patients received individually identical doses of the four different insulin aspart preparations on 4 separate days in this randomized crossover study. Having achieved overnight stable blood glucose control by intravenous infusions of human insulin, one of the trial insulins was injected subcutaneously and a standard meal was given in the morning. Plasma glucose and serum insulin aspart were recorded the following 12 hr. During the first 4 hr after injection with the trial insulin, the area under the curve for levels of insulin aspart (AUC(ins)) was significantly higher during insulin aspart treatment as compared to the other three insulin treatments, followed by BIAsp70, BIAsp50 and BIAsp30 (P < 0.05). Over the last 4 hr, the AUC(ins) for BIAsp30 was significantly higher as compared to the other insulin preparations (P < 0.05). By contrast, during the initial 4 hr, the area under the curve for levels of glucose (AUC(glu)) was highest after injection with BIAsp30 compared to the other three treatments (P < 0.05), while during the last 4 hr the highest AUC(glu) was seen following insulin aspart (P < 0.05). We conclude that when insulin aspart is pure or formulated with protamine in three different ratios, the pharmacokinetic profiles are readily distinguishable. These differences in pharmacokinetics are reflected in the pharmacodynamic profiles.

Overnight CSII as supplement to oral antidiabetic drugs in type 2 diabetes.

Aim:  To evaluate the potential advantages of a constant overnight subcutaneous delivery of insulin in type 2 diabetic patients who fail to achieve glycaemic control on oral antidiabetics.

Obesity does not influence the unique pharmacological properties of different biphasic insulin aspart preparations in patients with type 2 diabetes

Aim: To investigate the influence of obesity in type 2 diabetic patients upon pharmacological properties of different biphasic preparations of insulin aspart.

Overnight versus 24 Hours of Continuous Subcutaneous Insulin Infusion as Supplement to Oral Antidiabetic Drugs in Type 2 Diabetes

Background: Basal continuous subcutaneous insulin infusion (CSII) therapy at a fixed rate may effectively improve glycemic control in patients with type 2 diabetes when oral antidiabetic treatment fails. Regimens of simple constant subcutaneous delivery of insulin may provide theoretical advantages in type 2 diabetes. Methods: Ten subjects with type 2 diabetes who obtained insufficient glycemic control on oral antidiabetic drugs were included. Following an initial control day, two periods of 3 days with CSII of a rapid-acting insulin analogue, 1.5 IU/h (dose obtained from a preceding study), for 8 hours overnight and for 24 hours, respectively, were carried out in random order. Profiles of serum insulin aspart, serum endogenous insulin, and plasma glucose were recorded. Results: Compared to the control day, an 8-hour overnight insulin infusion during a 3-day period improved fasting plasma glucose (FPG) (mean differences ± SEM; Δ59.0 ± 10.1 mg/dl; p < 0.01) and 2-hour postprandial plasma glucose (PPPG) (Δ57.8 ± 10.6 mg/dl; p < 0.01) after breakfast. Compared to an 8-hour overnight infusion, a 24-hour infusion further improved all three PPPG values after breakfast, lunch, and dinner (Δ28.8 ± 8.1 mg/dl, Δ30.6 ± 8.1 mg/dl, and Δ35.1 ± 7.9 mg/dl; p < 0.01). During insulin infusion, only one hypoglycemic episode with PG <55.8 mg/dl and mild symptoms was recorded. Conclusion: Continuous subcutaneous insulin infusion with a rapid-acting insulin analogue at a fixed rate of 1.5 IU/h, either overnight or for 24 hours, improved glycemic control without safety concerns in patients with type 2 diabetes who had secondary failure to oral antidiabetic drugs. The effect on FPG was similar for both treatments, whereas the effect on PPPG was superior when insulin was infused during the entire 24 hours.