C-Terminal Fragment of Adiponectin Receptor Clinical Correlations

Specimen type

Patient group

–

Ig CTF ng/mL

Aver

min

max

Serum

Normal

322.5

173.4

55.5

778.8

Serum

Liver disease

1141.2

1514.3

293.8

6854.7

Serum

Breast cancer

794.6

260.7

340.7

1140.0

Serum

Pancreatic cancer

581.2

430.5

293.2

1330.7

–

Plasma

Normal

727.5

343.0

290.2

1723.4

Plasma

Anti TNF α therapy

404.1

130.1

194.1

601.0

Plasma

Pre-diabetic (IGT)

119

349.5

268.1

95.1

2346.3

Plasma

Pre-diabetic (IFG)

100

335.3

256.4

99.0

2346.3

Plasma

Diabetic

268.0

141.1

91.3

645.7

–

Whole blood

Normal

101

1234.1

651.9

178.6

4758.9

Whole blood

Inflammation

402.1

173.6

145.2

713.2

Whole blood

Immunosuppressant

566.0

361.1

160.7

1427.1

Whole blood

Pre-diabetic

527.0

195.6

250.9

1055.2

Whole blood

Diabetic

222.3

97.3

51.6

444.1

The values for Ig-CTF were measured in serum, plasma and whole blood for patients and health donors. Patients were characterized by oral glucose tolerance test if sample was plasma. Donors lacked inflammatory conditions (CBC & CRP normal) unless indicated. The HbA1c and FBG was measured if the sample was whole blood. Matching samples for all three sample type were compared across 25 health donor and 48 pre-diabetics and produce values similar to those shown

Sample collection had to be optimized to reduce within patient variability to <10 % to suppress coagulation. We found plasma with activated platelets caused 4-fold increase in Ig-CTF values compared to the same plasma with deactivated platelets. Activation caused a visible cloudiness to occured in diluted sample. The impact on the assay was explained by IgG binding to Fc receptors on platelets and causing platelet aggregation artificially elevating values (Worth et al. 2006). Complement components also bind to activated normal platelets and promote binding of immunoglobulin through C1 q (Hamad et al. 2010). As a control it was verified neither C1q nor Adpn bound to Ig-CTF as tested by ELISA and platelet binding Ig-CTF is a likely through the immunoglobulin Fc receptor

The values for Ig-CTF were next compared with patients undergoing glucose and HbA1c testing. The Ig-CTF plasma values for patient with pre diabetes and diabetes were significantly lower than patients with normal glucose tolerance (P > 0.01). Overnight fasting did not impact Ig-CTF values in health donors or diabetics with all values within 9–14 % of non-fasting values. The Ig-CTF values did not change during the 120 min following glucose administration. Values did not change over 45 days. This is consistent with the 14 day plasma half-life of immunoglobulin (Hinton et al. 2006). Values did changed in a patients who underwent significant a weight change (>20 % drop) after 45 days. This contrasts the rapid changes of free CTF measured in animals during the 120 min following glucose administration (See Chap. 5). Ig-CTF appears to be more a chronic phase marker.

6.3.2 Correlation to Inflammation

The values for Ig-CTF measured shown for normal and diabetic donors were in cases lacking inflammation. Inflammatory conditions were ruled out by a CPR <5 mg/dl or CBC of <10 white blood cells/mL. These cut-off do not rule out mild elevation of inflammation. The patients with significant inflammation, as indicated a CRP and CBC positive, did exhibited a significantly lower Ig-CTF (P > 0.01) than normal patients (Table 6.1). This decrease was of a similar magnitude to a decrease in the Ig-CTF seen in diabetes.

Patients using anti-inflammatory therapies such as Remicade® (Infliximab) exhibited suppressed Ig-CTF values. Transplant patients on immunosuppressants also had suppressed Ig-CTF values. The impact of anti-TNF alpha inhibitor drugs, would be expected to prevent CTF formation by inhibition of TACE. Others drug expected to impact the assay would include adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), or etanercept (Enbrel). Immunosuppressants would also be expected to lower immunoglobulin levels and suppress Ig-CTF formation.

Patients who had diseases that would be expected to increase blood immunoglobulin levels, also had changes in the values for Ig-CTF. Liver diseases represent a significant inflammatory disease group. Liver diseases (Hepatitis & cirrhosis) elevate serum immunoglobulin. Values for Ig-CTF were significantly increased with auto-immuno hepatitis patients having the highest values (Table 6.2). Patients with leukemia, multiple myeloma, and lymphoma were excluded as these cancers would clearly elevate immunoglobulin levels. However, cancer is generally associated with greater blood immunoglobulin levels and many patients with breast and pancreatic carcinomas did exhibited increased Ig-CTF values.

Table 6.2

The predictive values of CTF-Ig for in gestational study

	Study 1	Study 2
TN	95	110
FN	0	10
FP	7	10
TP	64	84
Sens	100.0 %	89.4 %
Spec	93 %	92 %
PPV	90 %	89 %
NPV	100 %	92 %

Study 1 is a comparison of normal vs. diabetics with pre-diabetic considered normal and diagnosis based solely on FBG and HbA1c values. Study 2 is a comparison of normal vs. diabetics with IGT pre-diabetics considered positive with diabetic and diagnosis based solely on OGTT and HbA1c values.

The efficiency of ruling in and out impaired glucose tolerance (IGT) was also tested. Of the 48 patients flagged by FBG as impaired, only 2 patients were confirmed by OGTT as a diabetic and 30 were classifieds as impaired glucose tolerance (IGT). The Ig-CTF value eliminated 10 of the 30 follow ups flagged by FBG and agreed with 13 of the 16 patients correctly rule out by FBG

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