Abstract
In diabetes mellitus, it has recently been proposed that in addition to absolute or relative lack of insulin, glucagon is the essential for the development of hyperglycemia.
The present study was designed to define the role of insulin and glucagon in regulating gluconeogenesis in dogs. To accomplish this, somatostatin (ST 0.4-0.8μg/kg/min), a potent inhibitor of insulin and glucagon, was infused peripherally alone or concurrently with glucagon in order to produce respectively either acute deficiency of both hormones or of insulin only in normal dogs.
The metabolic effects of acute insulin deficiency in normal dogs were subsequently compared to acute or prolonged insulin deficient depancreatized dogs where non-pancreatic IRG originates exclusively in the gastrointestinal tract and can not be distinguished from pancreatic glucagon using a variety of techniques.
Gluconeogenesis was monitored by tracter (2-H3-glucose). To assess the importance of glucagon in early diabetes, ST was infused for 50min in 5 conscious normal dogs. ST induced sustained decreases in insulin (IRI)(-67±4%) and glucagon (IRG)(-37±4%), glucose concentration decreased temporarily (-8±1%) because glucose production (Ra) fell transiently. This indicates that at low insulin levels IRI and IRG interact on liver. This was corroborated by infusing glucagon with ST, thus decreasing IRI but not IRG. These experiments demonstrate that basal levels of glucagon are essential for the hyperglycemic effect of acute insulin deficiency.
In acutely insulin deficient depancreatized dogs the secretion of gastrointestinal glucagon (G-IRG) was enhanced by arginine (AR, 12.5mg/kg/min) and suppressed by ST, and an increase or a decrease in plasma G-IRG levels induced, respectively, an increase or a decrease in Ra. Thus, G-IRG has a stimulatory effect on hepatic glucose production. The metabolic clearance (M) of glucose did not fall during the time when plasma G-IRG levels were decreased by ST. Indirect evidence that M fell when levels of G-IRG increased. This suggests that, at low insulin levels, G-IRG has an inhibitory effect on Ra. This effect is probably confined to the liver. Acute insulin deficiency, in depancreatized dogs, did not result in an increase in Ra if plasma G-IRG was maintained at low levels. Thus, basal levels of G-IRG are essential for these acute diabetogenic effects of insulin deficiency in depancreatized dogs. The effects of changes in plasma IRG levels in normal and depancreatized dogs indicated that pancreatic and gastrointestinal glucagon are similar with the respect to in vivo action on glucose turnover.
On the other hand, in prolonged insulin deficiency in depancreatized dogs, the secretion of G-IRG was suppressed by ST, but was enhanced a little by ST, and an increase or a decrease in plasma G-IRG levels did not induce respectively, an increase or a decrease in Ra. Thus the stimulatory effect of glucagon (G-IRG) on hepatic glucose production was reduced in prolonged insulin deficiency.
The lack of insulin is clearly a major factor in the abnormality of A cell function (diabetes mellitus). Under this circumstance A cells respones to arginine or glucose stimulation were exaggeracted and as IRG levels increase, blood glucose levels increase.
Thus in addition to lack of insulin, glucagon is the essential for the hyperglycemic effect.
