Search

This investigation was designed to examine the contribution of glucagon to the regulation of free fatty acid (FFA) metabolism in man. The acute effects of exogenous glucagon upon the concentration of plasma FFA and its metabolites: acetoacetic acid (AcAc), beta hydroxybutyric acid (BOH), and triglyceride (TG) were assessed in five normal male subjects. The threshold of response was determined by administering intravenous glucagon in a graded dose-response fashion, andassessing the magnitude of change in FFA and its metabolites. A prompt rise in FFA concentration occurred after glucagon injection, and was associated with a synchronous elevation in both AcAc and BOH concentration in plasma. The rise in FFA concentration was maximal with the glucagon dosage of 0.5 mug./kg. with no greater FFA response seen athigher hormone dosage. In contrast, the rise in plasma ketones was linearly related to thedosage of glucagon but not to the corresponding rise in FFA concentration. The behavior of plasma triglyceride concentration following glucagon challenge also contrasted with the linear rise in ketone concentration. At the lowest dosage of glucagon, TG concentration rose transiently, while at the highest two dosages the concentration of TG was reduced. The transitional dosage of hormone at which no change in TG concentration was observed was approximately 0.5 mug./kg. Comparing our in vivo data with the conclusions reached from published liver perfusion studies, it can be suggested that in the dosages employed, glucagon acutely elevates plasma FFA concentration and modulates their metabolism by augmenting conversion to AcAc and BOH while tending to reduce conversion to TG in man.

To evaluate the effect of contraceptive steroids on endogenous glucagon and insulin secretion, theta-arginine was infused intravenously in normal young women before and during selective steroid treatment. The effect of the combination of an estrogen derivative (mestranol), plus norethindrone (Norinyl, Syntex) was compared to the effect of ethinyl estradiol alone and to norethindrone alone. All three steroid schedules resulted in suppression of aminogenic insulin secretion. However, glucagon secretion was reduced only with ethinyl estradiol alone or the combination of mestranol plus norethindrone. In accordance with previous reports, treatment with an ethinyl estradiol derivative alone or in combination with norethindrone resulted in a tendency for elevated serum lipid concentration, while norethindrone alone resulted in a significant reduction in serum lipid concentration. These observations suggest an inverse relationship between aminogenic glucagon secretion and serum lipid concentration as influenced by contraceptive steroids. It is suggested that the metabolic effects of these steroids may be mediated in part by the associated alterations in pancreatic hormone secretory capacity.

The potential role of glucagon in the pathogenesis of diabetic ketogenesis was examined by intravenous glucagon administration (1.0 mug/kg. body weight) in five insulin-dificient diabetic subjects. The metabolic response was defined by examining the changes in the plasma concentration of insulin, glucose, free fatty acids (FFA), triglycerides, betahydroxybutyrate, and acetoacetate in comparison to those changes occuring in five nondiabetic control subjects tested under identical experimental conditions. Our results demonstrate that in the absence of endogenous insulin secretion, exogenous glucagon administration results in an enhanced ketonemia indipendent of the rise of FFA substrate. This augmented ketogenic response to glucagon in diabetic subjects was not reflected in the dynamics of glucose regulation, with similar changes in blood glucose concentration occurring in both diabetic and nondiabetic populations. These data demonstrate that glucagon may potentiate ketonemia in insulin-deficient diabetics, although the mechanism mediating this augmentation is not defined. Since the rise in FFA substrate was indistinguishable in the diabetic as compared to the control group, increased hepatic conversion of FFA substrate into ketone bodies is suggested.

This study was done to explore the role of physiologic elevations of glucagon concentration in plasma ketone body concentration in normal man. During the period of hormone elevation, plasma free fatty acids were pharmacologically elevated to ensure adequate free fatty acid substrate delivery to the liver to support hepatic ketogenesis. Eighty-minute infusions of glucagon resulted in a plasma hormone concentration of approximately 300 pg./ml. During the infusion, ketone bodies declined from their basal concentration and remained below basal for the duration of the infusion. An acute heparin-induced pharmacologic elevation of plasma free fatty acid concentration resulted in a transient rise in plasma ketone body concentration, but at no time did it attain the concentration observed during the control saline infusion. Plasma glucose concentration was not altered by glucagon infusion, but plasma insulin concentration rose by approximately 2.5 muU./ml. These results suggest that glucagon is not ketogenic in normal man as has been previously reported in insulin-deficient diabetics. The glucagon-induced rise in plasma insulin concentration may participate in the observed reduction in plasma ketone body concentration.

The effect of medroxyprogesterone acetate (MPA) on basal circulating lipids, arginine-stimulated glucagon and insulin secretion, and glucose tolerance was studied in normal women. After 5 days of oral MPA treatment (10 mg/day), there was a small but significant decline in basal circulating triglycerides. No changes were observed in fasting plasma concentrations of cholesterol, free fatty acids, glucagon, insulin, or glucose; in the plasma glucagon, insulin, or glucose responses during L-arginine infusion; or in the plasma insulin or glucose responses during oral glucose tolerance tests. There was no correlation of any of these parameters with the observed decline in fasting plasma triglyceride concentrations. These results confirm previous reports of no consistent changes in lipid or glucose homeostasis in women using derivatives of 17alpha-acetoxyprogesterone derivatives for contraceptive purposes, and suggest that MPA may be a suitable alternative for those women who develop hyperlipemia or glucose intolerance when they use contraceptive agents which contain derivatives of ethinyl estradiol and nortestosterone.

This study examines insulin and glucagon secretion in the basal state and in response to clofibrate therapy in patients with angiographically proven coronary artery disease. When compared with weight matched subjects without coronary artery disease, neither insulin nor glucagon secretion were abnormal in response to L-arginine stimulation. However, in response to clofibrate, a marked reduction in insulin secretion and simultaneous elevation in glucagon secretion characterized all patients. Our data suggest the hypothesis that altered insulin and glucagon secretion in response to clofibrate therapy may participate in the reduction of new coronary events reported to occur during therapy with this drug.

The magnitude and direction of the lipolytic and ketogenic responses following exogenous glucagon administration is controversial and consideration of the possible role of endogenous insulin secretion upon these events has not been clarified. The present study examines the role of endogenous insulin secretion in modulating the net lipolytic and ketogenic activity of glucagon. Three groups characterized by different levels of endogenous insulin secretory capacity were studied. In all three groups, the responses in plasma insulin, betahydroxybutyrate, and free fatty acids were observed following bolus administration of 1.0 mug/kg glucagon. In the obese subjects with increased endogenous insulin secretion, glucagon administration resulted in a decline below basal levels of both free fatty acid and betahydroxybutyrate. In the diabetic subjects with no demonstrable endogenous insulin secretion, glucagon administration was followed by a rise in plasma free fatty acids and an exaggerated rise in plasma betahydroxybutyrate. The normal control group exhibited a response in betahydroxybutyrate midway between the obese and diabetic groups. These obwervations support the thesis that the magnitude of endogenous insulin secretion modulates the lipolytic and ketogenic actions of glucagon in man.

The tissue response to exogenously administered glucagon was examined in 5 obese subjects (180 plus or minus 20 percent ideal body weight) and compared with the response in 5 normal weight controls (plus or minus 10 percent of ideal body weight). In all control subjects, glucagon (1 mug/kg) caused an increase in plasma free fatty acids and betahydroxybutyrate concentrations. In contrast, not only did the obese subjects fail to demonstrate a similar catabolic response, but 4 of the 5 obese subjects actually responded with a depression of plasma free fatty acid concentration and 3 of the 5, a decrease in betahydroxybutyrate. The potential mechanisms responsible for this defect are discussed, and it is suggested that the observation of an abnormal tissue response to a pharmacological stimulus warrants further investigation utilizing physiological lipolytic stimuli.

A porcine burn model demonstrates hypoglycemia in spite of hyperglucagonemia. The ketone response to free fatty acids is defined for the normal and burned pig. Ketogenesis is augmented beyond that expected from free fatty acids during the postburn period. These metabolic changes may be related to the hyperglucagonemia and/or the relative hypoinsulinemia observed in the burned pig.

The influence of Halofenate therapy on insulin and glucagon secretion was examined in the Zucker rat with genetic endogenous hyperlipemia. Coincident with the lipid lowering effects of Halofenate, the net change in the basal bihormonal axis favored glucagon, with the I/G molar ratio (Insulin/Glucagon) decreasing from 2.72 +/- 0.53 to 0.96 +/- 0.20 during treatment with this drug. Following arginine stimulation the I/G ratio remained reduced at 0.87 +/- 0.13 in Halofenate treated animals, contrasting with the statistically greater ratio of 2.5 +/- 0.55 in control animals. The Halofenate induced state of reduced insulin:glucagon was associated with hypolipemia, postarginine hyperglycemia, and hyperketonemia,-three metabolic parameters characteristic of glucagon excess relative to insulin. It is suggested that the lipid-lowering action of Halofenate in genetic hyperlipemia may reflect the altered bihormonal axis induced by the drug.

The present study was designed to test the hypothesis that physiological concentrations of glucagon may increase plasma ketone body concentration when sufficient free fatty acid substrate is available to support hepatic ketogenesis. Physiological elevations of plasma glucagon concentration were produced by a constant infusion of hormone, and increased plasma-free fatty acid availability was produced by simultaneous heparin injection to induce intravascular lipolysis. In the five insulin-dependent subjects studied, when plasma glucagon concentration remained at the normal basal level of 72+/-14 pg/ml during control saline infusion, the heparin-induced increase in free fatty acid availability resulted in approximately a 20% increase in plasma ketone body concentration. In contrast, when plasma glucagon concentration was elevated by hormone infusion to the physiological level of 215+/-35 pg/ml, the heparin-induced increases in free fatty acid availability resulted in approximately an 80% increase in plasma ketone body concentration. These results suggest that physiological elevations in plasma glucagon concentration may augment ketonemia in diabetic man when simultaneous elevations in plasma-free fatty acid arepresent.

The role of glucagon in regulating plasma lipid concentrations (nonesterified fatty acids, ketone bodies, and triglycerides) is reviewed. The effects of glucagon-induced insulin secretion upon this lipid regulation are discussed that may resolve conflicting reports in the literature are resolved. In addition, the unresolved problem concerning the pharmacologic versus physiologic effects of glucagon is stressed. Glucagon's role in stimulating lipolysis at the adipocyte serves two important functions. First, it provides plasma nonesterified fatty acids for energy metabolism and secondly, it ensures substrate for hepatic ketogenesis. In vitro, glucagon's lipolytic activity has been consistently observed, but in vivo, this activity has sometimes been obscured by the effects of glucagon-induced insulin secretion. Frequently, a biphasic response has been reported in which a direct lipolytic response is followed by a glucagon-induced insulin suppression of plasma nonesterified fatty acid concentration. When the glucagon-induced insulin secretion has been controlled by various in vivo techniques, glucagon's lipolytic activity in vivo has frequently been demonstrable. In the 1960s, in vitro liver perfusion experiments demonstrated that glucagon enhanced hepatic ketogenesis independent of glucagon's lipolytic activity. However, this direct effect of glucagon on the hepatocyte was not universally accepted because of conflicting reports in the literature. Failure to observe an in vitro ketogenic effect of the hormone in some studies may have been due to suboptimal experimental conditions. Certain factors are now known to influence the ketogenic response, such as the concentration of fatty acids in the media and the nutritional status of the animal. Under optimal in vitro conditions with liver preparations from fed animals, the ketogenic response to physiologic concentrations of glucagon has been demonstrated. However, further study is necessary to define the quantitative ketogenic role of the hormone. In spite of this early in vitro work, glucagon was not definitely shown to be ketogenic in vivo (independent of fatty acid availability) both in the rat and in diabetic man until 1975. Since these observations, several reports have confirmed the ketogenic action of glucagon in vivo by direct hepatic catheterization experiments. Glucagon's role in decreasing hepatic triglyceride synthesis and secretion in vitro has been repeatedly shown but the mechanism is unresolved. This lipid regulatory action of glucagon has been more difficult to demonstrate in vivo because of the many variables that affect triglyceride synthesis. Under specific experimental conditions, however, glucagon has been shown to decrease plasma triglyceride concentration in man at both physiologic and pharmacologic concentrations. Hepatic catheterization experiments have also confirmed this effect in man. The regulation of lipids by glucagon fits well into its role as a stress hormone...

To explore the effect of physiological elevations of glucagon on plasma triglyceride concentration, glucagon was infused for thirty minutes at 3.0 ng/kg/min into both normal and insulin dependent diabetic subjects. The effects of this hormonal infusion on plasma triglyceride, free fatty acids, glucose, and insulin were compared to a control saline infusion study. A differential effect of glucagon on plasma triglyceride concentration between normal and diabetic subjects was observed. In normal subjects, glucagon infusion was accompanied by a concomitant increase in endogenous insulin secretion and free fatty acid levels, and no observable effect on circulating plasma triglyceride concentration. In contrast, in diabetic subjects, no change in insulin or free fatty acid concentration occurred during glucagon infusion and circulating plasma triglyceride concentration declined after twenty minutes of hormone infusion. These results suggest that plasma triglyceride concentration may be modulated, at least in part, by alterations in circulating plasma glucagon in concert with insulin secretion and free fatty acid availability in man.

Glucagon concentration and regulation were examined in the Zucker rat, in which obesity and hyperlipemia are phenotypic expressions of an autosomal recessive gene. Using littermate animals which are phenotypically thin and normolipemic as controls, we observed reduced basal plasma glucagon levels in the obese lipemic rats. In response to fasting, obese lipemic animals inappropriately demonstrated a further reduction in plasma glucagon concentration. In response to pharmacologic glucagon stimulation (arginine), a subnormal rise in plasma glucagon concentration was observed in the obese, lipemic animals. Glucagon suppressibility with exogenous glucose remained intact. The reduced secretion of glucagon may be a consequence of the abnormal elevation in concentration of plasma insulin, free fatty acids, and glucose, which are characteristic of the obese, lipemic animal. A possible role of glucagon deficiency in the evolution or maintenance of the lipemic state is suggested.

The effect of glucagon on serum lipids and very low density lipoproteins (VLDL) has been examined in the eulipemic and the hyperlipemic rat. An inhibition of amino acid incorporation into hepatic lipoprotein apoprotein was observed, with an associated decrease in circulating VLDL apoprotein, decreased serum triglyceride concentration, and a loss of the pre-beta band as judged by serum lipoprotein electrophoresis. The data suggest that an important action of this hormone is to decrease the synthesis of the protein moiety of the VLDL; this may contribute to the hypolipemic action of glucagon by introducing a limitation in hepatic lipoprotein production.