No abstract

Elevated plasma glucagon immunoreactivity (IRG) observed in overt diabetes and during prolonged fasting is assumed to be the result of increased secretion of pancreatic glucagon. In seven healthy mongrel dogs diabetes was induced by total pancrtflteetonij 1 • s During the first two weeks following surgery, porcine NPH (6 to 12 U, once daily) and Regular insulin (6 to 12 U twice daily) were administered. Thereafter, insulin treatment was discontinued and the dogs were fasted for periods up to seven days. Plasma IRG was measured using antiglucagon serum G9-I which is 95 per cent specific for pancreatic glucagon. Fifteen hours after the last insulin injection an intraportal infusion of Regular insulin was given in amounts sufficient to achieve normoglycemia: mean IRG (pg./ml.) was 118 ± 34, a value similar to that observed in the fasting intact animals (134 ± 33). After insulin withdrawal, as fasting continued, plasma IRG increased progressively in all dogs. On Days 5 and 6-7, after insulin withdrawal, when peripheral plasma insulin was undetectable and marked hyperglycemia, hyperlipacidemia and ketonuria prevailed, mean IRG was 624 ± 136 and 986 ± 184, respectively. The highest level of IRG observed was 1450 in one dog on Day 7. These results are confirmed by using three other antiglucagon sera considered to be specific for pancreatic glucagon. We conclude that: 1) Progressively increasing amounts of material crossreacting with "specific" antiglucagon sera appear in plasma of totally depancreatized dogs fasting for up to seven days. 2) This event appears to be the consequence of metabolic derangements induced by insulin lack. 3) Hyp_erglucagonemia can result not nnlv from a defect of the pancreatic a cell, but can also be the consequence of excessive production of T^f r frnm a n sourcejLcould be that glucagon deficiency cannot be easily demmonstrated, because the release of nonpancreatic IRG can compensate for lack of pancreatic glucagon. DIABETES 23:905-12, November, 1974.It was shown previously that in normal dogs arginine infusions increase glucose turnover. 1 In order to find out whether this effect of arginine can be solely attributed to the release of glucagon and insulin, arginine was infused into depancreatized dogs whose metabolism was controlled by basal intraportal insulin infusions. Glucose turnover did not change, but surprisingly glucagon immunoreactivity (IRG) in plasma of these dogs was within the normal range prior to and during arginine administration. 2

Arginine, leucine, or histidine, and glucose were each administered intravenously, in 30-gm. amounts on separate occasions to the same healthy subjects. Each of the amino acids and glucose in these same amounts were administered also as mixtures. Synergism in the stimulation of the release of insulin was demonstrated when the sum of the increases in plasma insulin which resulted from the separate administrations of an amino acid and glucose was exceeded by that obtained when they were administered as a mixture. A synergistic effect was exerted by each of the three amino acid-glucose combinations; it was greatest with arginine and glucose and least with histidine and glucose. Synergism probably results from the effects of these stimuli upon the pancreatic beta cell; it is not dependent upon humoral gastrointestinal factors released after the ingestion of these nutrients. DIABETES 19: 109-15, February, 1970. We have reported that the intravenous administration of individual amino acids, as well as of mixtures of amino acids, induces the release of insulin. 2 " 5 In the course of these studies it was demonstrated that the elevations in blood glucose observed during the infusion of some amino acids cannot be the major cause of the insulin release, which was observed. Although there was not a good correlation between increases in blood glucose and increases in plasma insulin, some of the infusions of individual amino acids and mixtures of amino acids which were accompanied by the larger and more consistent increases in blood glucose were also the more potent in stimulating the release of insulin. This suggested that the insulin-releasing effect of certain amino acids might be potentiated by the concomitant elevations of blood glucose.The present studies were undertaken to determine if certain amino acids might act synergistically with glucose to effect the release of insulin. Three essential amino acids (arginine, leucine, and histidine) and glucose were each administered intravenously in 30-gm. amounts on separate occasions to the same healthy subjects. Glucose and each of the amino acids in the same amounts were • administered also as mixtures. The results demonstrate that a synergistic effect upon the release of insulin is exerted by arginine and glucose, leucine and glucose; and histidine and glucose. 1 The effect was greatest with glucose and arginine and least with glucose and histidine. The synergistic effect appears to result from an action of these stimuli upon the pancreatic beta cell and is not dependent upon humoral, gastrointestinal or other known factors released after the ingestion of these nutrients. MATERIAL AND METHODSEight healthy, nonobese* males, aged twenty to twenty-nine (mean 23.5) years, served as subjects. These active subjects maintained their habitual ad libitum food intake but took no food during the nine hours before they were given the infusions.L-arginine, 1-leucine, 1-histidine, and d-glucose were infused individually in 30-gm. amounts over periods of thirty minutes. Thirty grams of...

We have previously identified in fasting monkeys large amplitude, rapid oscillations in plasma levels of insulin, glucagon, and glucose. To determine whether such spontaneous oscillations also occur in man, we studied 9 healthy normal weight subjects and 11 obese volunteers (145-316% ideal body weight). During the morning hours after a 16-h fast, peripheral venous blood was withdrawn at precise 1- or 2-min intervals over 40-120 min. Spectral analysis of the assay results showed significant oscillations in plasma levels of insulin and glucose, with periods ranging from 8-16 min (P less than 0.05). In this range, the means of the oscillatory periods in normal weight subjects were 12.1 +/- 1.0 min for insulin and 11.2 +/- 0.8 min for glucose. The oscillatory periods on obese subjects were not different from those in normal weight subjects (12.4 +/- 0.7 min for insulin and 12.1 +/- 0.9 min for glucose). Periodicity in plasma levels of glucagon was observed in the range of 12-23 min. Based on cross-correlation analysis, the periodic fluctuations in insulin, glucose, and glucagon showed no consistent relationships; the patterns observed did not support the presence of feedback loops among these parameters as the mechanism of these spontaneous fluctuations. Our data indicate that basal plasma levels of insulin, glucagon, and glucose fluctuate rapidly in man. The physiological function of these oscillations is yet to be identified; they may play a role in the regulation of responsiveness of the respective target tissues or of their own release into the circulation.