Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia

Figures & data

Figure 1. Radiological findings of this case. (A) Abdominal computed tomography revealed multiple metastatic tumors in the liver and (B) thickening of the ascending colonic wall. (B, inset) Total colonoscopy demonstrated a large ulcerated and circumferential tumor at the same region.

Figure 2. Immunohistochemical analysis of tumor cells. (A) The tumor cells were highly atypical small cells with hyperchromatic nuclei and scanty cytoplasm, and strongly positive for synaptophysin and Ki-67 (labeling index; 70%) (×400). (B) The tumor cells were positive for IGF-2, IGF-1R, and phosphorylated IGF-1R (×400).

Table 1. Laboratory data on admission

WBC	25.3 × 10^9	/L	(2.7–10.7 × 10^9)	Glu	24	mg/dL	(65–105)
RBC	4.59 × 10^12	/L	(3.62–5.36 × 10^12)	HbA1c	5.3	%	(4.6–6.2)
Plt	734 × 10^9	/L	(109–384 × 10^9)	Insulin Ab	<0.4	% (NSB)	(<0.4)
AST	42	IU/L	(12–30)	Insulin	0.6	μU/ml	(3–15)
ALT	18	IU/L	(10–42)	CPR	0.57	ng/ml	(1.0–2.5)
LDH	294	IU/L	(124–226)	GH	0.20	ng/ml	(<2.1)
ALP	867	IU/L	(115–359)	IGF-1	30	ng/ml	(59–215)
γ-GTP	655	IU/L	(9–54)	IGF-2	499	ng/ml	(396–1049)
T-Bil	0.3	mg/dL	(0.3–1.3)	IGFBP-2	596	ng/ml	(140–715)
T-Chol	130	mg/dL	(140–220)	IGFBP-3	1811	ng/ml	(1960–4650)
BUN	6	mg/dL	(8–22)	CEA	8.8	ng/ml	(<5.0)
Cre	0.58	mg/dL	(0.6–1.06)	CA19-9	71.1	U/ml	(<37)
CRP	4.6	mg/dL	(<0.2)	NSE	180.20	ng/ml	(<12.0)

The levels of total IGF-2, IGFBP-2, IGFBP-3 were measured using a commercially available ELISA kit (BioVendor, Karasek, Brno, Czech Republic).

Figure 3. Western blot analysis and the kinase receptor activation assay of the patient's serum. (A) High molecular weight (HMW) and mature IGF-2 were detected in serum by western blot analysis using anti-IGF-2 antibody (ab9574). Each serum (40 μg of protein per lane) was separated by 15% SDS-PAGE. (B) IGF bioactivity in the patient's serum was greater than in a normal subject, and increased IGF bioactivity was inhibited to normal bioactivity level by the anti-IGF-2 specific antibody, ab9574, and increased IGF bioactivity was completely inhibited by the anti-IGF neutralizing antibody, KM1468. KRB; Krebs–Ringer bicarbonate buffer as a negative control, Ab; ab9574 (anti-IGF-2 specific antibody, final concentration 10 μg/ml), KM; KM1468 (anti-IGF neutralizing antibody, final concentration 10 μg/ml), hIGF-2; recombinant human IGF-2 (final concentration 10 ng/ml) as a positive control.