Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM

Abstract

Low plasma insulin-like growth factor (IGF)-I despite high circulating growth hormone (GH) in insulin-dependent diabetes mellitus (IDDM) indicate a hepatic GH resistance. This state may be reflected by the reduction of the circulating GH binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, and the reduction of insulin-like growth factor binding protein (IGFBP)-3, major IGF-I binding protein, upregulated by GH. We carried out two studies. In the first, plasma GHBP activity was compared in patients with IDDM on continuous subcutaneous insulin infusion (CSII) or on conventional therapy and in healthy subjects. In the second study, the 18 patients on CSII at baseline were then treated by continuous intraperitoneal insulin infusion with an implantable pump (CPII) and prospectively studied for GH-IGF-I axis. Although HbA1c was lower in patients on CSII than in those on conventional therapy, GHBP was similarly reduced in both when compared to control subjects (10.2 +/- 0.8 and 11.6 +/- 0.9% vs 21.0 +/- 1.3, p < 0.01). CPII for 12 months resulted in: a slight and transient improvement in HbA1c (Time (T)0: 7.6 +/- 0.2%, T3: 7.1 +/- 0.2%, T12: 7.5 +/- 0.2%, p < 0.02), improvement in GHBP (T0: 10.2 +/- 0.8%, T12: 15.5 +/- 1.5, p < 0.0001), near-normalization of IGF-I (T0: 89.4 +/- 8.8 ng/ml, T12: 146.9 +/- 15.6, p < 0.002) and normalization of IGFBP-3 (T0: 1974 +/- 121 ng/ml, T12: 3534 +/- 305, p < 0.0001). The hepatic GH resistance profile in IDDM does not seem to be related to glycaemic control, but partly to insufficient portal insulinization. Intraperitoneal insulin delivery, allowing primary portal venous absorption, may influence GH sensitivity, and improve hepatic IGF-I and IGFBP-3 generation.

Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control

“…The significant change in the GHBP level between repaglinide and aspart treatment might reflect an alteration in GH receptors similar to what previously has been shown in type 1 diabetes [21,22,41,42]. There is evidence that insulin down regulates the production of IGFBP-1 [19][20][21][22]. We obtained a tendency to lower IGFBP-1 levels with repaglinide compared to aspart, which might reflect that the higher portal insulin levels during treatment with repaglinide suppress hepatic production of IGFBP-1 [29].…”

“…portal insulin level affected the IGFsystem we determined IGF-I, IGFBP-1 and GHBP. The significant change in the GHBP level between repaglinide and aspart treatment might reflect an alteration in GH receptors similar to what previously has been shown in type 1 diabetes [21,22,41,42]. There is evidence that insulin down regulates the production of IGFBP-1 [19][20][21][22].…”

“…Independent of glycaemic control the mode of treatment, insulin secretagogue versus exogenous insulin, may alter the lipoprotein profile possibly by affecting portal insulin delivery to the liver [15][16][17]. This can also have importance for the GH-IGF axis [18], since insulin up regulates the GHR and GHBP level in the liver and down regulates the production of IGFBP-1 [19][20][21][22].…”

Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes

“…However, there are few studies on the relationship between glycaemic control and plasma concentrations of IGF-I in adult patients with type 1 diabetes. A negative relationship between glycaemic control and circulating IGF-I has been shown by some investigators (13,14,18) but not by others (19,20). In adult patients with type 1 diabetes with good glycaemic control and without endogenous production of insulin, the plasma concentrations of free insulin are normal or increased in the fasting state and between meals, whereas meal-related insulin peaks are low compared with those in non-diabetic control individuals (21).…”

Short-term effects of NPH insulin, insulin detemir, and insulin glargine on the GH–IGF1–IGFBP axis in patients with type 1 diabetes

“…Tight glycemic control appears, however, to be unable to fully normalize the changes of the GH-IGF1-IGFBP axis (8). This may be explained by the inability to normalize portal insulin levels following s.c. insulin administration (13).…”