Effect of hyperinsulinemia during hemodialysis on the insulin-like growth factor system and inflammatory biomarkers: a randomized open-label crossover study

Mark Reinhard, Jan Frystyk, Bente Jespersen, Mette Bjerre, Jens S Christiansen, Allan Flyvbjerg, Per Ivarsen, Mark Reinhard, Jan Frystyk, Bente Jespersen, Mette Bjerre, Jens S Christiansen, Allan Flyvbjerg, Per Ivarsen

Abstract

Background: A marked reduction in serum levels of bioactive insulin-like growth factor-I (IGF-I) has been observed in fasting hemodialysis (HD) patients during a 4-h HD session. The aim of the present study was to investigate the beneficial effect of hyperinsulinemia during HD on bioactive IGF-I and inflammatory biomarkers.

Methods: In a randomized cross-over study, 11 non-diabetic HD patients received a standardised HD session with either: 1) no treatment, 2) glucose infusion (10% glucose, 2.5 mL/kg/h), or 3) glucose-insulin infusion (10% glucose added 30 IU NovoRapid® per litre, 2.5 mL/kg/h). Each experiment consisted of three periods: pre-HD (-120 to 0 min), HD (0 to 240 min), and post-HD (240 to 360 min). A meal was served at baseline (-120 min); infusions were administered from baseline to 240 min. The primary outcome was change in bioactive IGF-I during the experiment. Secondary outcomes were changes in high-sensitivity C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor α. Comparisons were performed using mixed-model analysis of variance for repeated measures.

Results: From baseline to the end of study, no significant differences were observed in the changes in either serum bioactive IGF-I or total IGF-I between study days. Overall, serum bioactive IGF-I levels rose above baseline at 120 to 300 min with a maximum increase of 20% at 120 min (95% confidence interval (CI), 9 to 31%; p < 0.001), whereas total IGF-I levels rose above baseline at 180 to 300 min with a maximum increase of 5% at 240 min (95% CI, 2 to 9%; p = 0.004). A significant difference was observed in the changes in serum IGF-binding protein-1 (IGFBP-1) between study days (p = 0.008), but differences were only significant in the post-HD period. From baseline to the end of HD, no significant difference was observed in the changes in serum IGFBP-1 levels between study days, and in this time period overall serum IGFBP-1 levels were below baseline at all time points with a maximum decrease of 51% at 180 min (95% CI, 45 to 57%; p < 0.001). None of the investigated inflammatory biomarkers showed any differences in the changes over time between study days.

Conclusions: Postprandial insulin secretion stimulated the IGF-system during HD with no further effect of adding glucose or glucose-insulin infusion. Hyperinsulinemia during HD had no effect on biomarkers of inflammation.

Trial registration: ClinicalTrials.gov registry: NCT01209403.

Figures

Figure 1
Figure 1
Experimental design. Abbreviations: F, fasting samples; B, blood glucose; A, ABL gas analyzer; H, hormones; I, inflammatory biomarkers; AV, both arterial and venous sites for insulin/insulin aspart samples.
Figure 2
Figure 2
Blood glucose and serum insulin levels. Blood glucose levels (A), glucose infusion rates (B), and serum total insulin levels (C) during the experiments on no treatment (NT) (black circles), glucose infusion (G) (open circles), and glucose-insulin infusion (GI) (black triangles) study days. In plot C dark bars equal insulin and light bars equal insulin aspart levels. αp < 0.001 vs NT and βp < 0.001 vs G study days at same time point. Data are expressed as means.
Figure 3
Figure 3
Serum bioactive IGF-I, total IGF-I, IGFBP-1, and IGFBP-2. Bioactive IGF-I (A), total IGF-I (B), IGFBP-1 (C), and IGFBP-2 (D) changes during the experiments on no treatment (black circles), glucose infusion (open circles), and glucose-insulin infusion (black triangles) study days. αp < 0.003 for NT vs G and βp < 0.02 for NT vs GI study days. Data are expressed as mean ± SEM.
Figure 4
Figure 4
Relative changes in serum bioactive IGF-I and IGFBP-1. Relative changes in bioactive IGF-I (A) and IGFBP-1 (B) on no treatment (black circles), glucose infusion (open circles), and glucose-insulin infusion (black triangles) study days in the present study compared with relative changes in our previous study on fasting patients (empty triangles and dashed line). Data are expressed as mean ± SEM.

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