Insulin receptor and IGF-I receptor Bioactivity in Health and Disease

Insulin was discovered in 1921 by Banting and Best and its structure elucidated in 1955. The first insulin bioassays appeared in the 1940s. First, rats were injected with a range of known concentrations of purified commercial or ‘standard’ insulin and the subsequent fall in blood glucose levels was measured. Then an unknown sample of human plasma was administered to a rat and its insulin concentration was assumed to be identical to the standard dilution that caused the same fall in glucose levels. Due to poor correlations between measured blood glucose levels and calculated insulin levels, these bioassays were replaced by in vitro bioassays. Metabolic parameters, such as rate of glucose uptake in response to dose-response curves of known insulin concentrations were measured using isolated tissues, such as the hemidiaphragm or epididymal fat pad from the rat. Also these in vitro bioassays for plasma insulin were not very successful due to high inter-assay variability, their laborious nature and due to a growing doubt that they were not specific for insulin. Maybe even more importantly, in 1959 Leonards described a substance in normal human fasting serum that, like insulin, stimulated glucose oxidation and triglyceride synthesis in adipose tissue but that, unlike insulin, could not be extracted from plasma into acid-ethanol. In 1963, Froesch et. al. found that serum from guinea pigs immunized against insulin, suppressed insulin action in fat tissue, but it had no effect on Leonards’s insulin-like substance and so the term nonsuppressible insulin like activity (NSILA) was born

The insulin-like growth factor-I receptor stimulating activity (IRSA) in health and disease

Determination of true IGF-I bioactivity in serum and other biological fluids is still a substantial challenge. The IGF-IR Kinase Receptor Activation assay (IGF-IR KIRA assay) is a novel tool to asses IGF-IR stimulating activity (IRSA) and has opened a new era in studying the IGF system. In this paper we discuss many studies showing that measuring IRSA by the IGF-IR KIRA assay often provides fundamentally different information about the IGF system than the commonly used total IGF-I immunoassays. With the IGF-IR KIRA assay phosphorylation of tyrosine residues of the IGF-IR is used as read out to quantify IRSA in unknown (serum) samples. The IGF-IR KIRA assay gives information about net overall effects of circulating IGF-I, IGF-II, IGFBPs and IGFBP-proteases on IGF-IR activation and seems especially superior to immunoreactive total IGF-I in monitoring therapeutic interventions. Although the IRSA as measured by the IGF-IR KIRA assay probably more closely reflects true bioactive IGF-I than measurements of total IGF-I in serum, the IGF-IR KIRA assay in its current form does not give information about all the post-receptor intracellular events mediated by the IGF-IR. Interestingly, in several conditions in health and disease IRSA measured by the IGF-IR KIRA assay is considerably higher in interstitial fluid and ascites than in serum. This suggests that both the paracrine (local) and endocrine (circulating) IRSA should be measured to get a complete picture about the role of the IGF system in health and disease

双方向グラフの最大重み最小帰還辺集合問題について

Centenarians' offspring represent a suitable model to study age-dependent variables (e.g. IGF-I) potentially involved in the modulation of the lifespan. The aim of the present study was to investigate the role of the IGF-I in human longevity. We evaluated circulating IGF-I bioactivity measured by an innovative IGF-I Kinase Receptor Activation (KIRA) Assay, total IGF-I, IGFBP-3, total IGF-II, insulin, glucose, HOMA2-B% and HOMA2-S% in 192 centenarians' offspring and 80 offspring-controls of which both parents died relatively young. Both groups were well-matched for age, gender and BMI with the centenarians' offspring. IGF-I bioactivity (p\u30080.01), total IGF-I (p\u30080.01) and the IGF-I/IGFBP-3 molar ratio (p\u30080.001) were significantly lower in centenarians' offspring compared to offspring matched-controls. Serum insulin, glucose, HOMA2-B% and HOMA2-S% values were similar between both groups. In centenarians' offspring IGF-I bioactivity was inversely associated to insulin sensitivity. In conclusion: 1) centenarians' offspring had relatively lower circulating IGF-I bioactivity compared to offspring matched-controls; 2) IGF-I bioactivity in centenarians' offspring was inversely related to insulin sensitivity. These data support a role of the IGF-I/insulin system in the modulation of human aging process

IGF-IR targeted therapy: Past, present and future

The IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons why IGF-I R targeted therapy fails to inhibit growth of human cancers. It has become clear that intracellular signaling pathways are highly interconnected and complex instead of being linear and simple. One of the most potent candidates for failure of IGF-IR targeted therapy is the insulin receptor isoform A (IR-A). Activation of the IR-A by insulin-like growth factor-II (IGF-II) bypasses the IGF-IR and its inhibition. Another factor may be that anti-cancer treatment may reduce IGF-IR expression. IGF-IR blocking drugs may also induce hyperglycemia and hyperinsulinemia, which may further stimulate cell growth. In addition, circulating IGF-IRs may reduce therapeutic effects of IGF-IR targeted therapy. Nevertheless, it is still possible that the IGF-IR may be a useful adjuvant or secondary target for the treatment of human cancers. Development of functional inhibitors that affect the IGF-IR and IR-A may be necessary to overcome resistance and to make IGF-IR targeted therapy successful. Drugs that modify alternative downstream effects of the IGF-IR, so called "biasing agonists," should also be considered

IGF-I bioactivity might reflect different aspects of quality of life than total IGF-I in gh-deficient patients during GH treatment

Context: No relationship has been found between improvement in quality of life (QOL) and total IGF-I during GH therapy. Aim: Our aim was to investigate the relationship between IGF-I bioactivity and QOL in GH-deficient (GHD) patients receiving GH for 12 months. Methods: Of 106 GHD patients, 84 on GH treatment discontinued therapy 4 weeks before establishing baseline values and 22 were GH-naive. IGF-I bioactivity was determined by IGF-I kinase receptor activation assay, total IGF-I by immunoassay (Immulite), and QOL by the disease-specific Question on Life Satisfaction Hypopituitarism (QLS-H) module and by the general SF-36 questionnaire (SF-36Q). Results: IGF-I bioactivity increased after 6 months (-2.5 vs -1.9 SD, P < .001) and did not further increase after 12 months (-1.8 SD, P = .23); total IGF-I increased from -2.3 to -0.9 SD (P < .001) and to -0.6 SD (P < .005), respectively. QLS-H did not change over 12 months (-0.66 ± 0.16 to -0.56 ± 0.17 SD [P = .42] to -0.68 ± 0.17 SD [P = .22]). The mental component summary of the SF-36Q increased from 47.4 (38.7-52.8) to 50.2 (43.1-55.3) (P = .001) and did not further improve (49.4 [42.1-54.1], P = .19); the physical component summary did not change (47.5 [42.0-54.2] vs 47.0 [41.9-55.3], P = .91, vs 48.3 [39.9-55.4], P = .66). After 12 months, IGF-I bioactivity was related to QLS-H (r = 0.28, P = .01); total IGF-I was not (r = 0.10, P = .37). IGF-I bioactivity and total IGF-I were related to PCS

The IGSF1 deficiency syndrome: Characteristics of male and female patients

Context: Ig superfamily member1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods: All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone productionwasdelayed, aswerethe growth spurtandpubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH