Heterogeneity of plasma glucagon. Circulating components in normal subjects and patients with chronic renal failure.

Abstract

A B S T R A C T Plasma immunoreactive glucagon (IRG) concentrations were measured in 36 patients with chronic renal failure (CRF) and 32 normal subjects. In addition, the components of circulating IRG were analyzed by gel filtration in the fasting state and after physiological stimuli. Fasting IRG was elevated (P< 0.001) in CRF patients (534±32 pg/ml) compared with the levels found in healthy subjects (113±9 pg/ ml). Oral glucose suppressed plasma IRG in CRF patients from a basal level of 568+52 to a nadir of 354± 57 pg/ml (120 min). This degree of suppression (38%) was comparable to that found in normal subjects (basal = 154±20 to 100±23 pg/ml) at 120 min (35%). Intravenous infusion of arginine (250 mg/kg) resulted in a 71% rise in IRG in CRF patients and a 166% increase in normal subjects.Gel filtration of fasting plasma from CRF patients showed three major peaks. The earliest (A) was found in the void volume (mol wt> 40,000) and constituted 16.5±4.7% of the elution profile. The middle peak (B) eluted just beyond the proinsulin marker (approximately 9,000 mol wt) and constituted the largest proportion of the elution profile (56.5±3.4%). The third peak (C) coincided with the standard glucagon and ['I]glucagon markers (3,485 mol wt) and comprised 27.0±4% of the IRG profile. In contrast, only peaks A and C were found in fasting plasma of normal subjects (53.6±10.4% in A and 46.4±10.4 in C). After oral

Pathogenesis and characterization of hyperglucagonemia in the uremic rat.

“…Plasma immunoreactive glucagon (IRG)' is elevated in uremia (1)(2)(3)(4)(5)(6)(7), and a significant portion of the glucagon immunoreactivity is present in a fraction with a mol wt of approximately 9,000 (4,6), consistent with descriptions of proglucagon (8)(9)(10)(11)(12)(13)(14). While changes in glucagon secretion do not appear to be responsible for the increments in total IRG (5,15), the pathogenesis of the alterations in the composition of the circulating hormone is not well understood.…”

“…They do not appear to represent simple aggregates of the 3,500-mol wt material or noncovalent binding of this glucagon species to other plasma proteins. Exposure of these fractions to trypsin demonstrated that Peak A is resistant to the action of the enzyme, while the material in Peak B can be converted to immunoreactive fragments of smaller mol wt, some of which are similar in size to the native hormone (6). The latter observation lends support to the possibility that the 9,000-mol wt component might be a glucagon precursor.…”

“…2 and 3, respectively. The IRG elution profile in the rat is similar to that of man (4,6) and comprises three peaks (A, B, and C). Peak A eluted in the void volume, coinciding with the y-globulin marker (mol wt >40,000).…”

“…However, in both studies it was assumed that the plasma glucagon immunoreactivity comprised a single species, and that its metabolic clearance was similar to that of endogenous glucagon circulating in the nonuremic state (5). It has been recently reported, though, that the hyperglucagonemia observed in patients with renal insufficiency is accompanied by significant and characteristic changes in the composition of circulating glucagon immunoreactivity (4,6). For these reasons, we studied the pathogenesis of hyperglucagonemia in uremic animals by measuring total plasma IRG, and examining in addition the fractions which contribute to its immunoreactivity.…”

Size heterogeneity of immunoreactive glucagon during bile-duct obstruction in the rabbit.

“…Recent studies have pointed out that plasma glucagon immunoreactivity is heterogeneous (Valverde et al, 1970;Valverde et al, 1974;Weir et al, 1975;Valverde and Villanueva, 1976;Kuku et al, 1976;Jaspan et al, 1977) and has as many as four fractions when determined with antiserum 30K. There is at present little information regarding the immunoreactive nature of Big Plasma Glucagon (BPG) (Valverde et al, 1974) and 2000 mol.…”