A B S T R A C T Serum levels of immunoreactive insulinlike growth factors (IGF) I and II were determined by a modified IGF I and a new IGF II radioimmunoassay in normal children and adults, and in patients with acromegaly, isolated growth hormone deficiency, and extrapancreatic tumor hypoglycemia.Serum samples were gel filtered by a simple routine procedure at acidic pH to dissociate and separate IGF from the IGF carrier protein.Mean immunoreactive IGF I levels (±SD; corrected for crossreactivity of IGF II) were 193+58 ng/ml in normal adult subjects, 712+245 ng/ml in acromegalic patients and 24±14 ng/ml in patients with isolated growth hormone deficiency. The lack of growth hormone alone, irrespective of an otherwise normal hormonal status, appears to be responsible for the drastic decrease of IGF I levels.Oversecretion of growth hormone does not increase the levels of immunoreactive IGF II: mean levels (± SD; corrected for crossreactivity of IGF I) in normal and acromegalic subjects are virtually identical (647 ±126 and 641±189 ng/ml, respectively). Apparently, normal growth hormone levels stimulate IGF II production already maximally. However, in growth hormone deficiency immunoreactive IGF II is significantly decreased (252 ±99 ng/ml). Thus, IGF II, like IGF I, is growth hormone dependent. But in contrast to IGF I, the growth hormone dependence of IGF II seems to become apparent only at subnormal growth hormone levels.In normal children IGF I is age dependent: it is low in newborn cord sera (51±20 ng/ml) and gradually rises into the adult range with increasing age. At the onset of and during puberty mean IGF I levels lie above prepubertal values. In contrast, IGF II levels in normal children are independent ofage and pubertal stage beyond the first year of life, whereas newborns have significantly lower IGF II values.Hypoglycemia resulting from extrapancreatic tumors is not associated with increased immunoreactive IGF I or II levels. IGF I is decreased in most of the sera (mean level ±SD:56±39 ng/ml) whereas IGF II lies in the normal range (556±195 ng/ml).

Abstract. The levels of insulin-like growth factors (IGF), two somatomedin-like polypeptides of human serum and of their carrier protein were determined in sera of patients with various metabolic disorders. IGF was measured by 4 different methods (fat pad and fat cell assay and competitive protein binding assay measuring total IGF, and a radioimmunoassay for IGF I) after extraction by acidic gel filtration on Sephadex G-50. This procedure is necessary to separate IGF from the carrier protein, which interferes with all of these assays. 1) In normal serum, immunoreactive IGF I accounts for one third of total IGF determined by the fat pad assay, but only for one fifth to one sixth of immunoreactive IGF I + II. 2) In acromegalics total IGF was increased 1.5- (protein binding and fat cell assay) to 2-fold (fat pad assay), but the increase was solely due to immunoreactive IGF I, which was ∼ 5-times above normal. The IGF binding activity was not elevated. Total IGF and IGF binding were decreased in hypopituitarism, Laron-type dwarfism and in liver cirrhosis. Immunoreactive IGF I was more drastically reduced in these diseases than total IGF. Apparently, only IGF I is under growth hormone control. The liver seems to be involved in the production of IGF. 3) No elevation of total IGF was found in patients with extrapancreatic tumour hypoglycaemia, but IGF binding was reduced. Immunoreactive IGF I was decreased in 5 of 10 patients. These results suggest that tumour hypoglycaemia in our patients is unlikely to be caused by increased IGF levels. 4) In patients with hyperprolactinaemia neither total IGF nor immunoreactive IGF I were elevated, and IGF binding was unchanged. 5) In newly detected insulin-deficient juvenile diabetics total IGF and immunoreactive IGF I levels were within the normal range, although the variation was greater than in normal subjects. However, IGF binding was markedly decreased.

Worsening glycaemic control in type 2 diabetes mellitus relates to a decline in beta-cell function, associated with impaired negative feedback regulation of insulin release. Insulin resistance, the 'traditional' cornerstone defect of type 2 diabetes, leads to an array of adverse effects on beta cells, including hypertrophy, apoptosis and those caused by lipotoxicity and glucotoxicity. In particular, increased levels of free fatty acids and their metabolites are thought to diminish both insulin synthesis and glucose-stimulated insulin secretion. Thiazolidinediones are synthetic peroxisome proliferator-activated receptor-gamma agonists that decrease insulin resistance but, as in vitro and in vivo studies suggest, may have direct beneficial effects on pancreatic beta cells. Troglitazone, for example, demonstrated improvements in insulin secretory capacity in isolated pancreatic islets from Wistar rats and a hamster beta-cell line. In vivo studies reveal thiazolidinediones promote beta-cell survival and regranulation as well as maintenance of beta-cell mass and reduction in amyloid deposition. Clinical evidence for thiazolidinediones is largely derived from comparative trials, mainly against sulfonylureas and metformin. Data at 2 years from a number of trials are now available and establish the positive effects of thiazolidinediones on glycaemic control. Empirical evidence showing decreases in fasting plasma insulin levels with pioglitazone and rosiglitazone indicate thiazolidinediones also improve insulin sensitivity. A possible effect of thiazolidinediones on normalising asynchronous insulin secretion, as assessed in a short-term placebo-controlled study, is less established. However, recent and ongoing clinical studies are focusing attention on verifying animal and other data, which support the notion that thiazolidinediones have beneficial effects on beta-cell function. These clinical studies have shown thiazolidinediones capable of preventing or delaying the development of type 2 diabetes in a high-risk population; restoring the first-phase insulin response; and improving secretory responses to oscillations in plasma glucose levels. Many of these effects appear to be independent of improvements in insulin sensitivity. Other research efforts are examining the potential cardiovascular protective effects of thiazolidinediones. Available data imply thiazolidinediones are associated with cardiovascular risk reduction, although results from large, clinical outcome trials, currently in progress, are still needed. Improved understanding of the role that declining beta-cell function has in the development of type 2 diabetes has drawn attention to the need for hypoglycaemic agents that can address this process. Emerging evidence suggests thiazolidinediones offer specific benefits for preventing or delaying the decline in beta-cell function and, thereby, a substrate for early intervention efforts aimed at lowering the worldwide burden of type 2 diabetes.

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