Glucagon Deficiency and Hyperaminoacidemia

706 J. Clin. Invest. C) The American Society for clude (a) that pancreatectomized patients are partially glucagon deficient because of diminished basal as well as diminished stimulated glucagon secretion; (b) that fasting concentrations of certain glucogenic amino acids are elevated in pancreatectomized patients probably as result ofreduced hepatic gluconeogenesis; and (c) that the RCS-5 antiserum is not "pancreatic glucagon" specific. INTRODUCTION It has recently been shown that glucagon plays an important role in the control of glucose homeostasis (1) and ketone body production (2) in human subjects. Moreover,Unger and Orci (3) have described diabetes mellitus as a bihormonal disease characterized not only by insulin deficiency but also by glucagon excess. This view has been challenged by Barnes and Bloom (4) who found that totally pancreatectomized patients had no circulating plasma immnunoreactive glucagon (IRG)' but readily developed hyperglycemia and ketoacidosis if deprived of exogenous insulin. Others, however, have detected varying amounts of glucagon in plasma of pancreatectomized patients (5-8). Thus, the solution to the question of whether or not glucagon remains in circulation of patients after total pancreatectomy has becomne important for the evaluation of the role ofglucagon in the pathogenesis ofdiabetes mellitus. There is also some evidence to suggest that glucagon, besides its effects on glucose and ketone metabolism, may play an important role in human amino acid metabolism. For instance, infusion of large glucagon doses lowers plasma amino acids (9); patients with glucagonIAbbreviations used in this paper: IRG, imuntinoreactive glucagon; IRG3500, 3500-dalton IRG; NPH, neuitral protamine Hagedorn (instilin). r Clinical Investigation, Inc. 0021-9738/8010310706/11 $1.00 Volume 65 March 1980 706-716 secreting islet cell tumors (glucagonoma) have severely depressed blood amino acid levels and advanced muscle wasting (10, 11). However, this aspect of glucagon action has been relatively neglected and the evidence remains incomplete. Most of the previous work was done with pharmacological doses of glucagon and the significance of these studies for human physiology can be seriously questioned (12). Sherwin et al. (13) infused glucagon into normal overnight-fasted volunteers at a rate of 3 nglkg per min, which raised plasma glucagon concentrations from about 100 pg/ml to slightly above 300 pg/ml. They observed no consistent changes in amino acid concentrations except for a 7% decrease in serine concentration during the 150-180-min infusion period. Doubling of the infusion rate, however, resulted in a 10-19% reduction in glycine, serine, and threonine concentrations. Effects of infusions of physiologic doses of glucagon on plasma amino acids have also been studied in obese subjects after prolonged fasting (14). Results in this group can be expected to be different because obesity (15) as well as fasting (16) have effects of their own on amino acid metabolism. The effects of glucagon deficiency on amino acids have never been studied. It appears, therefore, that the evidence for a physiologic role of glucagon in amino acid metabolism could be strengthened considerably if it could be demonstrated that chronic glucagon deficiency has effects that are opposite to those seen during chronic glucagon excess (glucagonoma). This study was, therefore, designed to answer the following questions: (a) Are pancreatectomized patients glucagon deficient, and if so, to what extent? (b) Do these patients have abnormal amino acid profiles, and if so, can these abnormalities be related to glucagon deficiency? METHODS Patients. Clinical data on the nine pancreatectomized patients (three males, six females) studied are listed in Table I. All underwent total pancreatectomy, duodenectomy, gastrectomy, and splenectomy. In addition, three had partial jejunostomy, five had cholecystectomny, and three had vagotomy. The reasons for these procedures were: adenocarcinoma in six patients, recurrent pancreatitis with intractable pain, insulinoma, and suspected vipoma in one patient each. Preoperatively, TABLE I Clitnical Data of Nine Panicreatectom ized Patienits Percent Insulin treatmnent ideal Studied FBS dav Patients Sex Age weight Reason for Px Operationi after Px of studv a.m. Noon p.m.