Circulating Insulins

Abstract

Plasma insulin has been characterized by its biologic, immunologic, physical, and chemical similarity to pancreatic insulin. A higher molecular weight heterogenous component (peak "b") of pancreatic insulin that contains the biosynthetic precursor of insulin (proinsulin) has recently been described. Plasma insulin as measured by radioimmunoassay is composed of at least two components. Filtration of plasma on G-50 Sephadex yields a major component ("little" insulin) which is indistinguishable from the major component of pancreatic insulin and a second component "big" insulin which is less retarded by the gel similar to peak "b." Both components react strongly with insulin antisera and are secreted by the pancreas in response to stimuli of insulin secretion. The characteristics of these recently described components of pancreatic and of plasma insulin are described and discussed.Despite widespread use of radioimmunoassay for the measure¬ ment of polypeptide hormones in plasma and great advances in meth¬ ods for the fractionation of proteins, very few studies have appeared on the nature of circulating hormones.In trying to characterize plasma hor¬ mones several impediments are en¬ countered. First the concentrations of the polypeptide hormones in plas¬ ma rarely exceed 10_8 M, whereas plasma proteins are present at about 100,000 times greater concentration.In comparison with purification of hormones from glands, not only is it much more difficult to obtain from plasma sufficient material on which to perform studies but the number of individual substances from which the hormone must be separated during purification is much greater. Another impediment is that the biological as¬ says that were developed for the study of hormones that were ex¬ tracted from glands usually lack sufficient sensitivity, specificity, pre¬ cision, or ease of assay to be of use in studying plasma hormone.In our present discussion on the nature of circulating insulin, we have restricted ourselves to those sub¬ stances in plasma that react with antibodies to insulin. The large num¬ ber of substances in plasma that possess biological properties of insu¬ lin but whose biological effects are unaltered by the addition of insulin antibody have been reviewed else¬ where i"3 and will not be discussed.Although our discussion, in effect will be restricted to insulin in plasma detected by immunoassay, it should be noted that findings by immuno¬ assay are closely paralleled by mea¬ surements of suppressible insulin¬ like activity,1 which is the portion of insulin-like biological activity of

Subcellular Localization of Proinsulin to Insulin Conversion in Isolated Rat Islets

“…Insulin precursors also were secreted into the media, an observation which is compatible with those of other investigators, where proinsulin was found in plasma, urine and incubation media of isolated islets (25)(26)(27). However, how and why these precursors are secreted, as well as what role they play in normal and diabetic individuals, remains an intriguing question.…”

“…The relationships of proinsulin and intermediate in the media are not clear. However, their presence in the media is compatible with the observance of circulating big insulin which increases relative to insulin during the later phases of a glucose tolerance test (25). Proinsulin also has been found in human serum and urine and in the incubation media of isolated islets (26,27).…”

Excessive Serum Insulin Response to Oral Glucose in Obesity and Mild Diabetes Study of 501 Patients

“…It is, of course, possible that the secretory mechanism is intact and the failure lies in the inability of the islet cell to convert a proinsulin to an active hormone. 19 ' 20 At this stage of beta cell failure, insulin secretion is normal during the fasting state. The fact that abnormally high secretion after a stimulus is insufficient for homeostasis was shown by the lower than normal insulin/glucose ratios.…”

Significance of Human Plasma Insulin Sephadex Fractions

“…15 The demonstration that immunoreactive insulin in plasma is eluted from Sephadex G-50 gel in a region corresponding to porcine proinsulin 3 has led to the speculation that proinsulin "may account for the high but seemingly ineffective levels of immunoreactive in- sulin which are often noted in the early stages of diabetes and in other diseases with so-called insulin resistance." 4 In a more recent publication Gorden and Roth 16 have concluded that "big insulin" in plasma does not account for the hyperinsulinism observed in thin diabetics, acromegalics, or patients with myotonic dystrophy, but have left open the question of whether big insulin may partially account for the hyperinsulinemia observed in some patients with obesity and normal subjects with starvation diabetes.…”