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

A B S T R A C T The pathogenesis of hyperglucagonemia and of the alterations in the pattern of circulating immunoreactive glucagon (IRG) associated with renal insufficiency was studied in rats in which a comparable degree of uremia was induced by three different methods, i.e., bilateral nephrectomy, bilateral ureteral ligation, and urine autoinfusion. Nephrectomized and ureteral-ligated rats were markedly hyperglucagonemic (575+95 pg/ml and 492+54 pg0ml, respectively), while IRG levels of urine autoinfused animals (208±35 pg/ml) were similar to those of control rats (180±26 pg/ml), indicating that uremia per se does not account for the hyperglucagonemia observed in renal failure. Similarly, plasma IRG composition in this group of animals was indistinguishable from that of controls, in which 88.2±5.9%o of total IRG consisted of the 3,500-mol wt fraction. The same component was almost entirely responsible (82.6±4.1%) for the hyperglucagonemia observed in ligated rats, while it accounted for only 57.6±5.0%o of the circulating IRG in nephrectomized animals. In the latter group, 36.8±6.6% of total IRG had a mol wt of approximately 9,000, consistent with a glucagon precursor. This peak was present in samples obtained as early as 2 h after renal ablation and its concentration continued to increase with time reaching maximal levels at 24 h.These results confirm that the kidney is a major site of glucagon metabolism and provide evidence that the renal handling of the various circulating IRG This study was presented in part at

Immunoreactive plasma glucagon (IRG) in normal subjects and patients with chronic renal failure, diabetic ketoacidosis and diagetic hyperosmolar syndrome circulates in several forms. In the diabetic patients most IRG eluted coincidentally with the extracted, purified pancreatic hormone (MW3500), while in normal subjects a high molecular weight component predominated. In striking contrast, the major component of plasma IRG in patients with chronic renal failure was of intermediate size (MW +/- 9000), consistent with proglucagon. The accumulation of this form of IRG suggests that the kidney plays an important role in its metabolism. If there are differences in the biological activity of the various circulating components of IRG, the significance of immunoreactive glucagon levels in some disease states will require reassessment.

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