Persistent Pancreatic Glucagon but not Insulin Response to Arginine in Pancreatectomized Dogs

Abstract

Effects of total pancreatectomy on plasma glucagon, insulin and glucose responses to arginine were determined in 5 dogs. Portal vein and femoral artery samples were obtained in response to an arginine infusion (10 g/30 min) prior to, 1 h, 1 day and 1 week after pancreatectomy. Glucagon was measured using pancreatic-specific antiserum 30K (Unger, Dallas). Before pancreatectomy arginine significantly increased portal vein glucagon from 373 plus or minus 36 to 595 plus or minus 31 pg/ml and femoral artery levels from 233 plus or minus 28 to 342 plus or minus 74 pg/ml. Portal vein and femoral artery insulin concentrations of 74 plus or minus 21 and 17 plus or minus 3 muU/ml increased significantly to 173 plus or minus 64 and 31 plus or minus 7 muU/ml. Glucose levels did not change. One h after pancreatectomy, portal vein glucagon decreased to 121 plus or minus 15 pg/ml but increased to 230 plus or minus 42 pg/ml after arginine. Elevated blood glucose and the necessity for insulin treatment established the adequacy of pancreatectomy. Furthermore portal vein insulin levels were undetectable and unresponsive to arginine or a combination of glucose, glucagon, and tolbutamide 1 week after pancreatectomy. One day after pancreatectomy arginine significantly increased portal vein glucagon from 343 plus or minus 42 to 776 plus or minus 152 pg/ml. One week after pancreatectomy basal glucagon values were 374 plus or minus 30 in the portal vein and 360 plus or minus 49 in the femoral artery and responded to 1226 plus or minus 641 and 825 plus or minus 270 pg/ml, respectively, with arginine. Chromatography of plasma from one pancreatectomized dog on Sephadex G-50 after arginine stimulation revealed that much of the material cross-reacting with antibody 30K was eluted from the column earlier than either 125I-insulin or 125I-glucagon. In contrast, peak glucagon activity in plasma obtained from a normal human given arginine eluted from the column between the peak of 125I-insulin and 125I-glucagon; glucagon added to human plasma also was recovered in this same area between the 125I-insulin and 125I-glucagon peaks. These results suggest that some of the material that reacted with 30K antibody and which increased after pancreatectomy in response to arginine has a molecular weight greater than pancreatic glucagon. At autopsy no pancreatic tissue could be identified. Thus, after pancreatectomy, validated by absent insulin responses, the glucagon response to arginine was normal or increased. Since arginine is not thought to increase intestinal glucagon-like immunoreactive material, the source and nature of the material measured as glucagon after pancreatectomy is unknown, but may be important to any understanding of plasma glucagon measurements.

Identification of glucagon-producing cells (A cells) in dog gastric mucosa

“…These findings are in accord with data suggesting that the major source of the extrapancreatic glucagon of depancreatized dogs is the gastric oxyntic mucosa (34,16,15,6,18). Ultrastructural evidence for the presence in the gastrointestinal tract of cells resembling pancreatic A cells was first reported in 1967 (20).…”

Effect of acetylcholine on the secretion of gut glucagon immunoreactivity and gut glucagon-like immunoreactivity in pancreatectomized dogs.

“…It has been demonstrated that gut glucagon immunoreactivity (gut GI) as measured with C-terminal specific glucagon antiserum, and gut glucagon-like immunoreactivity (gut GLI) obtained by subtracting GI from total GLI, increased in pancreatectomized dogs untreated with insulin (Matsuyama and Foa, 1974;Vranic et al, 1974;Mashiter et al, 1975;Yoshida, 1977).…”

“…Concerning the regulation mechanism of extrapancreatic glucagon, it has been known that gut GI is inhibited by insulin injection (Matsuyama and Foa, 1974;Vranic et al, 1974) or by somatostatin infusion (Sakurai et al, 1975), but gut GI is promoted by the withdrawal of insulin therapy (Matsuyama and Foa, 1974;Vranic et al, 1974), by the administration of arginine (Mashiter et al, 1975;Matsuyama et al, 1978;Muller et al, 1978), or by the transplantation of hypophysis (Yoshida, 1977 (Botha et al, 1977Ma-tsuyama et al, 1978 reported that the kinetics of the extrapancreatic GI to various stimulants and suppressants was different from that of pancreatic glucagon. However, from our present study, it is concluded that the parasympathetic nervous system might play an important role in the control me.…”

“…Although the high levels of circulating gut glucagon immunoreactivity (gut GI) that was measured using C-terminal specific glucagon antiserum after pancreatectomy, and gut glucagon-like immunoreactivity (gut GLI) that was obtained by subtracting GI from total glucagon-like immunoreactivity (total GLI) which was measured using nonspecific glucagon antiserum, have been demonstrated in pancreatectomized dogs untreated with insulin (Matsuyama and Foa, 1974;Vranic et al, 1974;Mashiter et al, 1975;Yoshida, 1977), the regulation mechanism of the secretion of extrapancreatic glucagon has not been clearly explained. In order to demonstrate whether the secretion of gut GI and gut GLI is influenced by the parasympathetic nervous system, the present investigation was designed to find the effect of acetylcholine on the secretion of gut GI and gut GLI in pancreatectomized dogs.…”

PTEN Deletion in Pancreatic α-Cells Protects Against High-Fat Diet–Induced Hyperglucagonemia and Insulin Resistance

“…However, historically, its main counterregulatory hormone insulin has been a greater focus of diabetes research (19,20). The discovery that hyperglycemia could result from increased glucagon production in pancreatic a-cells and other tissues renewed interest in this hormone (21)(22)(23), particularly when glucagon suppression restored normoglycemia (24). Accordingly, mice with genetic ablation of glucagon signaling have improved peripheral insulin sensitivity (25,26) and are protected against both type 1 and type 2 models of diabetes (27,28).…”