Insulin glargine is more potent in activating the human IGF-I receptor than human insulin and insulin detemir.

OBJECTIVE: To investigate whether human insulin (HI) and insulin analogues differ in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor A (IR-A) and the human insulin receptor B (IR-B) in vitro. METHODS: HI, short-acting insulin analogues (insulin aspart; insulin lispro) and long-acting insulin analogues (insulin glargine; insulin detemir) were compared by using kinase receptor activation (KIRA) bioassays specific for IGF-IR, IR-A or IR-B, respectively. These assays quantify ligand activity by measuring receptor auto-phosphorylation upon ligand binding. HI and insulin analogues were tested in a range from 0.1 to 100 nM. RESULTS: Short-acting analogues: Overall, short-acting insulin analogues did not differ substantially from HI, nor from each other. Insulin lispro was slightly more potent than HI and insulin aspart in activating the IGF-IR, only reaching statistical significance at 100 nM (p<0.01). Long-acting analogues: At <10 nM insulin glargine was as potent as HI in activating the IRs and IGF-IR. At 10-100 nM insulin glargine was significantly more potent than HI in activating the IR-B (p<0.05) and IGF-IR (p<0.001). Insulin glargine was more potent than insulin detemir in activating all three receptors (p<0.001). Insulin detemir was less potent than HI in activating the IRs at 1-10 nM (p<0.01) and IGF-IR at >1 nM (p<0.05). CONCLUSIONS: Insulin glargine was more potent in activating the IGF-IR than HI and insulin detemir. Since KIRA bioassays do not mimic the exact in vivo situation, further research is needed to find out whether our data have implications for clinical use of insulin glargine.

Heterophilic antibodies may be a cause of falsely low total IGF1 levels.

BACKGROUND: A low serum total IGF1 is considered as a diagnostic indicator of GH deficiency (GHD) in the presence of hypopituitarism. Introduction of IRMA and chemiluminescent immunometric assay (CLIA) IGF1 immunoassays has introduced endogenous antibodies as a new source of interference. In general, this goes unnoticed and might lead to unnecessary diagnostic and therapeutic interventions. CASE: A 56-year-old man was referred with a decline in physical performance, unexplained osteopenia, and weight loss of 3 kg over the past 8 months. Although clinical signs and symptoms were unremarkable, laboratory results pointed to secondary hypothyroidism and secondary hypogonadism. In addition, the serum total IGF1 level (CLIA; Siemens Medical Solutions Diagnostics) was in the low normal range. Two GH stimulation tests were performed, but these tests did not support the diagnosis GHD. Moreover, IGF1 bioactivity measured by the kinase receptor activation assay was normal. Interference of heterophilic antibodies was considered. After pretreatment with specific heterophilic blocking tubes that contain blocking reagents to eliminate heterophilic antibodies, serum-free thyroxine, testosterone, and IGF1 levels turned out to be normal. CONCLUSION: To the best of our knowledge, we here describe the first case in the literature of a patient with low serum total IGF1 levels due to interference from heterophilic antibodies in the used IGF1 immunoassay. When confronted with low-IGF1 levels that do not fit the clinical picture, interference of heterophilic antibodies should be considered in the differential diagnosis.

Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality.

CONTEXT: Low IGF-I signaling activity prolongs lifespan in certain animal models, but the precise role of IGF-I in human survival remains controversial. The IGF-I kinase receptor activation assay is a novel method for measuring IGF-I bioactivity in human serum. We speculated that determination of circulating IGF-I bioactivity is more informative than levels of immunoreactive IGF-I. OBJECTIVE: Our objective was to study IGF-I bioactivity in relation to human survival. DESIGN, SETTING, AND STUDY PARTICIPANTS: We conducted a prospective observational study at a clinical research center at a university hospital of 376 healthy elderly men (aged 73-94 yr). MAIN OUTCOME MEASURES: IGF-I bioactivity was determined by the IGF-I kinase receptor activation assay. Total and free IGF-I were determined by IGF-I immunoassays. Mortality was registered during follow-up (mean 82 months). RESULTS: During the follow-up period of 8.6 yr, 170 men (45%) died. Survival of subjects in the highest quartile of IGF-I bioactivity was significantly better than in the lowest quartile, both in the total study group [hazard ratio (HR) = 1.8; 95% confidence interval (95% CI) = 1.2-2.8; P = 0.01] as well as in subgroups having a medical history of cardiovascular disease (HR = 2.4; 95% CI = 1.3-4.3; P = 0.003) or a high inflammatory risk profile (HR = 2.3; 95% CI = 1.2-4.5; P = 0.01). Significant relationships were not observed for total or free IGF-I. CONCLUSION: Our study suggests that a relatively high circulating IGF-I bioactivity in elderly men is associated with extended survival and with reduced cardiovascular risk.