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Impact of insulin antibodies on insulin aspart pharmacokinetics and pharmacodynamics after 12-week treatment with multiple daily injections of biphasic insulin aspart 30 in patients with type 1 diabetes

J-W Chen, J Frystyk, T Lauritzen, and J S Christiansen

Objective: This study aimed to evaluate the impact of insulin antibodies on insulin aspart pharmaco-kinetics and pharmacodynamics after 12-week multiple daily injections of biphasic insulin aspart 30 (30% fast-acting and 70% protamine-crystallised insulin aspart, BIAsp30) in patients with type 1 diabetes.

Methods: Twenty-three patients (8 women, 15 men) aged 44.8 (20.6–62.5) years (median and range) with diabetes duration of 19.5 (1.6–44.6) years and haemoglobin (Hb)A1C of 9.2% (8.1–12.3%) participated in the study, which consisted of 12-week treatment with multiple injections of BIAsp30. At the end of the treatment period, all patients attended two 24-h profile days 1 week apart for pharmacokinetic and pharmacodynamic assessments. HbA1C and insulin antibodies were also determined.

Results: Patients were stratified into two groups depending on whether the level of insulin binding to insulin antibodies was below or above 75% (moderate vs high (%, median and range): 62 (15–74) vs 80 (75–89)). High levels of insulin antibodies resulted in about threefold increase in AUC(0 – 24 h) (the area under the concentration-time curve during 24 h) for total insulin aspart (analysis of variance, P < 0.05). The differences in free insulin aspart pharmacokinetics, insulin pharmacodynamics and HbA1C were not statistically significant between patients with different levels of insulin antibodies. Total daily insulin dosage was significantly lower in patients with high than moderate levels of insulin antibodies.

Conclusions: In type 1 diabetic patients, high levels of circulating insulin antibodies result in elevated total, but not free, insulin aspart profiles. Consistent with the finding of similar insulin pharmacodynamics, the long-term glycaemic control is not significantly different between patients with different levels of insulin antibodies.

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The metabolic clearance rate, serum half-time and apparent distribution space of authentic biosynthetic human growth hormone in growth hormone-deficient patients

J. O. L. Jørgensen, A. Flyvbjerg, and J. S. Christiansen

Abstract. We studied the metabolic clearance rate (MCR) serum half-time (t½) and apparent distribution space (DS) of unlabelled, authentic, biosynthetic human growth hormone (B-hGH) in 9 GH-deficient patients by means of the constant iv infusion to equilibrium technique. B-hGH was infused for 3 h at a rate of 33 ng · kg−1 · min−1 after which the disappearance from serum of GH was followed for 1 h. The mean ± sem values for MCR, t½ and DS were: 2.3 ± 0.6 ml · kg−1 · min−1, 21.1 ± 1.7 min and 67.6 ± 14.6 ml/kg, respectively. The disappearance of GH was monoexponential for the first 30 min, during which 75% of the GH had been cleared. The disappearance rate during the last 30 min of the observation period was somewhat lower, still approximately 90% of the GH had been eliminated after 60 min.

Free access

Long-term DHEA substitution in female adrenocortical failure, body composition, muscle function, and bone metabolism: a randomized trial

Jens J Christiansen, Jens M Bruun, Jens S Christiansen, Jens Otto Jørgensen, and Claus H Gravholt

Context

Adrenal derived androgens are low in women with adrenal failure. The physiological consequences of substitution therapy are uncertain.

Objective

To investigate the effects of DHEA substitution in women with adrenal failure on body composition, fuel metabolism, and inflammatory markers.

Design, participants and intervention

In this study, ten female patients (median age 38.5 years, range 28–52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study. The participants underwent dual-energy X-ray absorptiometry (DXA) scan, computed tomography scan of abdominal fat, indirect calorimetry, bicycle ergometry, muscle and fat biopsies, and blood samples.

Results

Baseline androgens were normalized to fertile range during active treatment. Anthropometric data were unaffected, but lean body mass (LBM) slightly increased compared with placebo (delta LBM (kg) placebo versus DHEA: −0.48±6.1 vs 1.6±3.4, P=0.02) with no alterations in total or abdominal fat mass. PTH increased with DHEA, but no significant changes were observed in other bone markers or in bone mineral content. The mRNA levels of markers of tissue inflammation (adiponectin, interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1, and tumor necrosis factor α) in fat and muscle tissue were unaffected by DHEA treatment, as was indirect calorimetry and maximal oxygen uptake. A high proportion of self-reported seborrheic side effects were recorded (60%).

Conclusion

In female adrenal failure, normalization of androgens with DHEA 50 mg for 6 months had no effects on muscle, fat, and bone tissue and on fuel metabolism in this small study. A small increase in LBM was observed. Treatment was associated with a high frequency of side effects.

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A radioimmunoassay for bone Gla protein (BGP) in human plasma

Julia S. Johansen, J. E. Mølholm Hansen, and Claus Christiansen

Abstract. To study the value of bone Gla protein (BGP) as a biochemical marker of normal bone physiology and metabolic bone disorders, we have developed a radioimmunoassay (RIA) for the detection of BGP in human plasma. Antibodies were generated in rabbits immunized with purified calf BGP conjugated to thyroglobulin. Human plasma BGP reacted identically with the calf BGP standard, thus demonstrating the suitability of the assay to measure plasma BGP levels in man. The RIA is sensitive, accurate, and technically simple. Plasma BGP levels were determined in normal subjects (N = 35) and in patients with hypothyroidism (N = 10), hyperthyroidism (N = 22) and chronic renal failure (N = 35). The mean (± 1 sem) concentration of plasma BGP in normal subjects was 1.27 ± 0.07 nmol/l. Plasma BGP was significantly increased in patients with hyperthyroidism, 4.04 ± 0.78 nmol/l (P < 0.001) and chronic renal failure, 10.17 ± 2.47 nmol/l (P < 0.001). Low concentrations were found in patients with hypothyroidism, 0.74 ± 0.11 nmol/l (P <0.01). Our studies indicate that plasma BGP provides a useful technique in the diagnosis of patients with bone disease.

Free access

Visceral fat mass is a strong predictor of circulating ghrelin levels in premenopausal women

E Sondergaard, L C Gormsen, B Nellemann, E T Vestergaard, J S Christiansen, and S Nielsen

Objective

A well known inverse relationship exists between obesity and circulating ghrelin concentrations. However, obesity is a heterogeneous disease entity and upper-body obesity (UBO) is associated with more profound metabolic disturbances than lower-body obesity (LBO). We therefore aimed to investigate the impact of body composition on circulating ghrelin levels in women spanning a wide range of body composition phenotypes.

Subjects and methods

Ten (UBO; waist-to-hip ratio (WHR) >0.85, body mass index (BMI) >28 kg/m2), ten LBO (WHR <0.80, BMI >28 kg/m2) and ten lean women (BMI<25 kg/m2) were studied. Total ghrelin levels were measured under basal and hyperinsulinemic (0.6 mU/kg per min) conditions. Body fat distribution was determined by dual X-ray absorptiometry in combination with computed tomography at the L2-L3 level.

Results

As expected, an inverse correlation existed between basal ghrelin concentration and BMI (r=−0.40, P=0.03) and total fat mass (r=−0.39, P=0.04). Visceral fat mass was a strong predictor (r=−0.56, P=0.003) of circulating ghrelin levels, even when adjusted for BMI (P=0.02) or body composition group (P=0.04). The suppressive effect of insulin on ghrelin concentration was significantly diminished in the UBO compared with the lean controls (P=0.012) and a highly significant inverse correlation existed with visceral fat mass (r=−0.52, P=0.004).

Conclusions

Visceral fat mass is a strong predictor of basal ghrelin concentrations and also attenuates the suppressive effect of insulin on ghrelin concentrations. These data provide further evidence that the UBO phenotype is associated with more profound metabolic abnormalities than obesity per se.

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Subcutaneous degradation of biosynthetic human growth hormone in growth hormone deficient patients

J. O. L. Jørgensen, A. Flyvbjerg, T. Lauritzen, H. Ørskov, and J. S. Christiansen

Abstract. The aim of the present study was to look further into the question of local degradation of sc injected human GH in GH deficient patients. A comparison was made of serum GH levels after constant iv and sc infusion of the same amount of GH (33 ng· kg−1·min−1) in the same 9 GH deficient patients. A 3-h lag period was interposed between the iv and the sc infusion. Iv infusion was continued for 3 h. All 9 subjects subsequently received sc infusion for 19 h and five of them continued for additionally 24 h. The mean steady state serum GH level in the nine patients was 23.1 ± 5.1 μg/l after iv and 6.8 ± μg/l after sc administration (P < 0.01). Extension of the sc infusion period in 4 of the subjects did not significantly alter the serum GH level (P > 0.15), implying that a steady state was reached. The GH in the infusion system was stable throughout a 24-h period. We therefore conclude that sc injected GH is degraded locally to a substantial extent.

Free access

Long-term effects of growth hormone (GH) on body fluid distribution in GH deficient adults: a four months double blind placebo controlled trial

J Moller, S Fisker, AM Rosenfalck, E Frandsen, JO Jorgensen, J Hilsted, and JS Christiansen

OBJECTIVE: Short-term growth hormone (GH) treatment normalises body fluid distribution in adult GH deficient patients, but the impact of long-term treatment on body fluid homeostasis has hitherto not been thoroughly examined in placebo controlled trials. To investigate if the water retaining effect of GH persists for a longer time we examined the impact of 4 months GH treatment on extracellular volume (ECV) and plasma volume (PV) in GH deficient adults. DESIGN: Twenty-four (18 male, 6 female) adult GH deficient patients aged 25-64 years were included and received either GH (n=11) or placebo (n=13) in a double blind parallel design. METHODS: Before and at the end of each 4 month period ECV and PV were assessed directly using 82Br- and 125I-albumin respectively, and blood samples were obtained. RESULTS: During GH treatment ECV increased significantly (before: 20.48+/-0.99 l, 4 months: 23.77+/-1.38 l (P<0.01)), but remained unchanged during placebo administration (before: 16.92+/-1.01 l, 4 months: 17.60+/-1.24 l (P=0.37)). The difference between the groups was significant (P<0.05). GH treatment also increased PV (before: 3.39+/-0.27 l. 4 months: 3.71+/-0.261 (P=0.01)), although an insignificant increase in the placebo treated patients (before: 2.81+/-0.18 l, 4 months: 2.89+/-0.20 l (P=0.37)) resulted in an insignificant treatment effect (P=0.07). Serum insulin-like growth factor-I increased significantly during GH treatment and was not affected by placebo treatment. Plasma renin (mIU/l) increased during GH administration (before: 14.73+/-2.16, 4 months: 26.00+/-6.22 (P=0.03)) and remained unchanged following placebo (before: 20.77+/-5.13, 4 months: 20.69+/-6.67 (P=0.99)) leaving no significant treatment effect (P=0.08). CONCLUSION: The long-term impact of GH treatment on body fluid distribution in adult GH deficient patients involves expansion of ECV and probably also PV. These data substantiate the role of GH as a regulator of fluid homeostasis in adult GH deficiency.

Free access

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis

E T Vestergaard, T K Hansen, S Nielsen, N Moller, J S Christiansen, and J O L Jorgensen

Objective: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects.

Design: Seven GH-deficient patients (aged 37 ± 4 years (mean ± s.e.)) were studied on four occasions in a 2 × 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp.

Results: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 ± 120 (−GH − Aci), 711 ± 130 (−GH + Aci), 806 ± 130 (+GH − Aci), 574 ± 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (μg/l): 11.2 ± 4.4 (−GH − Aci), 11.7 ± 4.4 (−GH + Aci), 11.5 ± 4.4 (+GH − Aci), 13.9 ± 4.2 (+GH + Aci), P = 0.005.

Conclusion: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

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Serum profiles and short-term metabolic effect of pituitary and authentic biosynthetic human growth hormone in man

J. O. L. Jørgensen, A. Flyvbjerg, J. Dinesen, H. Lund, K. G. M. M. Alberti, H. Ørskov, and J. S. Christiansen

Abstract. In a double-blind cross-over study we compared pituitary and methionine-free biosynthetic human growth hormone (P-hGH and B-hGH) with respect to pharmacokinetics and short-term metabolic effects in 9 hypopituitary children. They treated themselves for 4 weeks with 2 IU sc daily at 20.00 h. After admittance to hospital 2 IU was given: im the first day, and sc the second. They then switched over to the alternative preparation. The serum profiles of B- and P-hGH were identical. Comparing im and sc adsorption, the latter was slower and resulted in smaller areas under the curves, indicating greater local degradation.

Both preparations caused identical increases in somatomedin-C, but slightly more sustained after sc injection. Plasma glucose, plasma glucagon, and serum insulin fluctuated within normal ranges. The glucose profile pointed at a modest anti-insulin effect of hGH when given in the morning. The concentration in the blood of lactate, alanine, glycerol and B-OH-butyrate, and in serum of triglyceride, cholesterol and carbamide revealed no abnormalities with either hGH preparation. Finally, no development of anti-GH or E. coli polypeptide antibodies was seen. In conclusion, the pharmacokinetics and short-term metabolic effects of B-hGH and P-hGH were identical.

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Diurnal plasma profiles of metabolite and hormone concentration in insulin-dependent diabetic patients during conventional insulin treatment and continuous subcutaneous insulin infusion

K. Hermansen, A. Møller, C. K. Christensen, J. S. Christiansen, O. Schmitz, H. Ørskov, K. G. M. M. Alberti, and C. E. Mogensen

Abstract. In addition to hyperglycaemia, derangement of metabolic and hormonal control may play an important role in the development of microvascular complications in diabetes. Little, however, is known about the impact of insulin pump treatment on metabolic and hormonal parameters. In a 6-month prospective randomized study in insulin-dependent diabetics we therefore investigated the effects of continuous subcutaneous insulin infusion by pump (10 patients) and conventional insulin treatment (10 patients) on the 24-h profiles of blood glucose, glycerol, lactate, 3-hydroxybutyrate, insulin, glucagon and growth hormone by measuring the respective concentrations every 2 h.

We found that average blood glucose levels and HbA1c were significantly lower in the group treated by continuous subcutaneous insulin infusion as compared with the group on conventional insulin treatment. Furthermore, we observed an improvement in diurnal levels of lactate and 3-hydroxybutyrate in the pumptreated group which was not seen in the conventionally treated group. A slight increment in alanine was seen in the group treated with insulin pump. Serum growth hormone, glycerol, plasma free insulin as well as the daily insulin supply were unchanged and identical in the two groups. It is noteworthy that in the pump group, the decrease in blood glucose and 3-hydroxybutyrate takes place concomitantly with a significant suppression of glucagon.