Increased Plasma Glucagon Research Articles

Hyperglucagonemia and the immediate fate of dietary leucine: A kinetic study in humans

The possible role of glucagon in determining the fate of dietary absorbed amino acids within the splanchnic bed was investigated in five healthy male volunteers. A kinetic study was performed involving a continuous 240-minute infusion of l-[5,5,5- 2H 3]leucine and d-[6,6- 2H 2]glucose by vein, while l-[1- 13C]leucine was infused by a feeding tube into the duodenum (intragut [IG]) along with a constant intravenous (IV) infusion of somatotropin release-inhibitory factor (SRIF) combined with insulin, growth hormone, and glucagon. In random order, glucagon was infused at a rate of 0.4 ng · kg −1 · min −1 in one experiment and 1.2 ng · kg −1 · min −1 in the other experiment, while insulin and growth hormone were kept at constant serum levels, respectively, 37 ± 13 pmol · L −1 and 5 ± 0.2 μg · L −1. The diet was provided as an l-amino acid solution including 60 μmol · kg −1 · h −1 leucine without fat and carbohydrate. During the higher rate of glucagon infusion, there was an increase in plasma glucagon and glucose concentrations, glucose flux, and net dietary leucine release into the periphery from the splanchnic bed. Splanchnic removal and uptake of leucine were decreased with increased glucagon infusion. There were no statistical differences in the plasma leucine level and IV and IG leucine fluxes at the two glucagon levels, although leucine metabolic clearance increased (0.74 v 0.85 L · kg −1 · h −1, P = .08) in the case of glucagon excess. Plasma glucose increased with glucagon excess and was negatively correlated ( P < .05) with the plasma leucine level ( r = −.348) and IV ( r = −.459) or I.G. ( r = −.359) leucine fluxes. The negative correlation between plasma glucagon and leucine levels was also significant ( r = −.684). No significant correlation was found between dietary leucine splanchnic removal and glucose, glucagon, or leucine plasma concentrations. We conclude that glucagon in excess has only a small quantitative effect on the overall handling of dietary leucine, and hypothesize that more leucine is exported to the peripheral tissues under these hormonal conditions.

Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans.

The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.

Effects of casein, sweet white lupin and sweet yellow lupin diet on cholesterol metabolism in rats

The effect of lupin seed protein on rat cholesterol metabolism has been studied with diets high in fat (20% by weight) and containing cholesterol (1%). The proteins used were characterised by their lysine/arginine ratios (sweet white lupin (SWL) 0·5; sweet yellow lupin (SYL) 0·4; and casein 1·8), because the lysine/arginine ratio is one of the parameters suspected to decrease or increase plasma cholesterol depending on the ratio; the diets were also characterised by their total fibre content (casein diet 5%; SWL 22%; SYL 17%) because chronic fibre intake could improve glucose tolerance and modify glucoregulatory hormone levels. Methionine content of diets was balanced. Differences among the total serum cholesterol levels of rat groups fed these diets for 28 days were not significant. But, compared to the casein diet, both lupin diets increased plasma glucagon levels and faeces. Compared to casein and SYL diets, the SWL diet significantly decreased plasma triglyceride levels and the insulin/glucagon ratio, as well as unesterified liver cholesterol and plasma LDL triglycerides levels. The SYL diet significantly increased plasma glucose and insulin, as well as liver total cholesterol compared to the casein and SWL diets. The total fibre content of the diets could indirectly modulate the effect related to the insulin/glucagon ratio on cholesterol metabolism and explain the differences observed between the SWL and SYL diets. © 1998 SCI.

Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus

Twelve patients with non-insulin dependent diabetes mellitus (NIDDM) under secondary failure to sulfonylureas were studied to evaluate the effects of subcutaneous glucagon-like peptide-1(7-36)amide (GLP-1) on (a) the gastric emptying pattern of a solid meal (250 kcal) and (b) the glycemic and endocrine responses to this solid meal and an oral glucose tolerance test (OGTT, 300 kcal). 0.5 nmol/kg of GLP-1 or placebo were subcutaneously injected 20 min after meal ingestion. GLP-1 modified the pattern of gastric emptying by prolonging the time to reach maximal emptying velocity (lag period) which was followed by an acceleration in the post-lag period. The maximal emptying velocity and the emptying half-time remained unaltered. With both meals, GLP-1 diminished the postprandial glucose peak, and reduced the glycemic response during the first two postprandial hours by 54.5% (solid meal) and 32.7% (OGTT) (P < 0.05). GLP-1 markedly stimulated insulin secretion with an effect lasting for 105 min (solid meal) or 150 min (OGTT). The postprandial increase of plasma glucagon was abolished by GLP-1. GLP-1 diminished the postprandial release of pancreatic polypeptide. The initial and transient delay of gastric emptying, the enhancement of postprandial insulin release, and the inhibition of postprandial glucagon release were independent determinants (P < 0.002) of the postprandial glucose response after subcutaneous GLP-1. An inhibition of efferent vagal activity may contribute to the inhibitory effect of GLP-1 on gastric emptying.

Insulin and glucagon secretion by ganglionic nicotinic activation in adrenalectomized mice

The pancreatic islets are innervated by nerves emanating from intra- and extrapancreatic ganglia. However, the effects of ganglionic activation on insulin and glucagon release in vivo have not been established. We therefore investigated the effects of pharmacological ganglionic activation by the nicotinic agonists DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) and nicotine on insulin and glucagon release in sham-operated and adrenalectomized mice. In sham-operated animals, DMPP (0.5 or 1.6 μmol/kg, i.v.) or nicotine (0.075 or 0.75 μmol/kg, i.v.), did not affect plasma insulin levels, but markedly increased plasma glucagon levels ( P<0.05). In contrast, after adrenalectomy or α 2-adrenoceptor blockade by yohimbine (3.6 μmol/kg), nicotinic activation markedly increased plasma insulin levels ( P<0.05), whereas the glucagon response to nicotinic activation was inhibited under these conditions ( P<0.05). We conclude that pharmacological ganglionic nicotinic activation in mice stimulates insulin and glucagon secretion. The insulinotropic effect is, however, counteracted by a concomitant adrenal activation through an α 2-adrenoceptor-mediated mechanism.

Effects of various beverages on the hormones involved in energy metabolism during exercise in the heat in previously dehydrated subjects.

The objective of our study was to examine the effects of beverage content on hormone responses involved in fuel substrate metabolism (catecholamines, insulin and glucagon) in previously dehydrated subjects exercising at a moderate intensity in the heat. Six healthy men walked for 60-min on five occasions at 50% maximal oxygen uptake in a warm environment (dry bulb temperature 35 +/- 0.2 degrees C, relative humidity 20%). On each occasion, the subjects were dehydrated before exercise (loss of 2% body mass) by passive controlled hyperthermia, which led to a reduction in plasma volume (PV) of about -5% to -9%. In one session, the subjects exercised without rehydration (Dh). In the other sessions, four beverages (650 ml) were given just before the exercise: mineral water (W), a 60 g x l(-1) glucose and 1.2 g x l(-1) NaCl solution (GS), a 60 g x l(-1) maltodextrin solution, and a 60 g x l(-1) maltodextrin and 1.2 g x l(-1) NaCl solution. Compared to Dh and W, carbohydrate supply with or without NaCl induced a higher glycaemia (P < 0.05), a reduced increase in plasma adrenaline concentration (P < 0.05) and a higher plasma insulin concentration (P < 0.05), which lowered plasma free fatty acids and glycerol concentrations (P < 0.05). The lesser increase in plasma noradrenaline concentrations observed during GS compared to Dh and W sessions can be explained by a larger correction in PV which might have induced better haemodynamic conditions. However, the increase in plasma glucagon with carbohydrate supply--compared to Dh and W (P < 0.05)--remains unexplained.

Metabolic and orexigenic effects of intracerebroventricular neuropeptide Y are attenuated by food deprivation.

Administration of neuropeptide Y (NPY) into the hypothalamus or cerebral ventricles has been shown to increase food intake, the secretion of hormones such as insulin, glucagon and corticosterone and to alter the metabolism of carbohydrate and lipids. It has been suggested that metabolic effects of hypothalamic NPY may contribute to fat accretion in some types of obesity and to the metabolic and behavioural adaptation to food deprivation. However, it is currently unknown if different nutritional states alter the responses to hypothalamic NPY. Consequently, we have compared the effects of NPY injected into the third ventricle (ICV) in the fed and overnight-fasted state on ingestive behaviour, on insulin, glucagon and corticosterone secretion before, and following, an IV glucose bolus (IVGTT) and on blood glucose following an intra-arterial insulin bolus (ITT). Studies were performed on conscious, unrestrained adult female rats. In the fed state, 2 and 6 micrograms ICV NPY produced a potent orexigenic and dypsogenic effect. In the fasted state, the 2 micrograms dose had a dypsogenic effect, while only the 6 micrograms dose had a significant orexigenic effect. In the fed but not fasted state, 3 micrograms ICV NPY increased plasma glucagon and corticosterone levels and attenuated the decline in blood glucose during the ITT. By contrast, in both fed and fasted groups, 3 micrograms ICV NPY potentiated the insulin secretory responses during the IVGTT. We conclude that, apart from stimulating insulin secretion, the acute metabolic and orexigenic responses to ICV NPY in this study were substantially reduced or abolished by overnight fasting. Therefore, behavioural and metabolic responses to endogenous hypothalamic NPY may also be more significant in the fed than the fasted state.

Time course of the defective α-cell response to hypoglycemia in diabetic BB rats

Although it is understood that patients with insulin-dependent diabetes mellitus (IDDM) lose the ability to release glucagon during a hypoglycemic challenge, the relationship of this defect to the disease onset and loss of β-cell function is not well defined. To address this issue, we measured the counterregulatory response in three groups of BB/wor rats during sequential 90-minute euglycemic (7 mmol/L) and hypoglycemic (3 mmol/L) insulin clamps (180 pmol/kg · min). Group 1 (n = 8) consisted of nondiabetic BB rats (aged 84 ± 3 days), and groups 2 and 3 were rats studied 1 day (n = 7) or 7 days (n = 6) after diabetes onset. Plasma glucagon concentrations were similar in all groups during euglycemia (244 ± 47 ng/L for nondiabetic, 308 ± 38 for 1 day of diabetes, and 277 ± 30 for 7 days of diabetes). Moreover, after 1 day of diabetes, the increase in plasma glucagon during hypoglycemia was similar to that seen in controls (to 581 ± 94 and 650 ± 118 ng/L, respectively) even though insulin production by the pancreas was virtually absent. However, after 7 days of diabetes, plasma glucagon only increased to 339 ± 59 ng/L during hypoglycemia ( P = nonsignificant v basal), despite normal pancreatic glucagon content (11.5 ± 1.2 v 10.8 ± 0.6 μ/g in nondiabetic controls). In conclusion, the hypoglycemia-associated defect in glucagon release occurs early in the course of diabetes in BB rats and is not associated with decreased baseline plasma or pancreatic glucagon levels. This impairtment, although not immediately linked to the decrease in pancreatic insulin content, occurs soon afterward, implying that the two events are related.

Oral sensory stimulation improves glucose tolerance in humans: effects on insulin, C-peptide, and glucagon.

In animals, bypassing the oropharyngeal receptors by intragastric administration of glucose results in glucose intolerance. To determine whether the absence of oral sensory stimulation alters glucose tolerance in humans, we monitored plasma levels of glucose and hormones after intragastric administration of glucose, with and without subjects tasting food. Plasma glucose area under the curve (AUC) was significantly lower after oral sensory stimulation (3,433 +/- 783 vs. 5,643 +/- 1,397 mg.dl-1. 195 min-1; P < 0.03; n = 8). Insulin and C-peptide AUCs were higher during the first one-half of the sampling period (insulin, 5,771 +/- 910 vs. 4,295 +/- 712 microU. ml-1.75 min-1; P < 0.05; C-peptide, 86 +/- 10 vs. 66 +/- 9 ng.ml-1. 75 min-1; P < 0.03) and lower during the second one-half of the sampling period compared with the control condition (1,010 +/- 233 vs. 2,106 microU.ml-1. 120 min-1; P < 0.025; 31 +/- 8 vs. 56 +/- 18 ng.ml-1. 120 min-1; P < 0.05; insulin and C-peptide, respectively). Oral sensory stimulation markedly increased plasma glucagon compared with the control condition (1,258 +/- 621 vs. -2,181 +/- 522 pg.ml-1. 195 min-1; P < 0.002). These data provide evidence in humans that oral sensory stimulation influences glucose metabolism and suggest that the mechanisms elicited by this cephalic stimulation are necessary for normal glucose homeostasis.

Hyperglucagonaemia in cirrhotic patients and its relationship to the severity of cirrhosis and haemodynamic values.

Plasma glucagon concentrations were measured in 160 cirrhotic patients (Pugh's grade A in 52 patients, Pugh's grade B in 64 patients and Pugh's grade C in 44 patients). These values were compared with plasma glucagon concentrations in 57 age and sex-matched healthy subjects. Systemic and portal haemodynamic measurements, effective renal plasma flow and creatinine clearance were recorded for each patient. Plasma glucagon levels were significantly increased in cirrhotic patients compared with healthy subjects. In addition, plasma glucagon levels were higher in cirrhotic patients with ascites than in those without ascites and were increased in relation to the severity of cirrhosis as assessed by Pugh's score. Multiple linear regression found that only Child-Pugh's score was estimated to be an independent predictor of hyperglucagonaemia in cirrhotic patients. However, in patients with different degrees of oesophageal varices and in patients without oesophageal varices, plasma glucagon concentrations were no different among the different groups of patients, but were still higher than plasma glucagon concentrations in healthy subjects. In contrast, plasma glucagon levels were negatively correlated with mean arterial pressure and systemic vascular resistance. The results of the present study suggest that impairment of liver function plays, in part, a role in increased plasma glucagon levels observed in patients with cirrhosis. In addition, these data support the hypothesis that hyperglucagonaemia may contribute, at least in part, to the pathogenesis of peripheral arterial vasodilatation in cirrhosis with portal hypertension.

Nasal administration of glucagon combined with dimethyl-β-cyclodextrin: Comparison of pharmacokinetics and pharmacodynamics of spray and powder formulations

The effect of increasing amounts of dimethyl-β-cyclodextrin (DMβCD) on the nasal absorption and consequent plasma glucose levels of glucagon as spray solution or powder has been examined in rabbits. Nasal spray was prepared by dissolving commercial glucagon in the manufacturer's solvent containing 2 or 5% w/v DMβCD. Powders were obtained by freeze drying of the spray solutions. In general, glucagon was slightly absorbed in the absence of DMβCD. Increasing the enhancer concentration was shown to increase plasma glucagon and glucose levels while decreasing the times for maximum glucagon peaks (tmaxglucagon) in both spray and powder formulations. Spray solutions produced faster and higher plasma glucagon peaks (Cmaxglucagon) at any enhancer concentration compared to powders, however the AUC0–60 min glucagon and glucose concentrations were not significantly different. The 5% w/v DMβCD resulted in a more pronounced glucagon absorption with corresponding higher plasma glucose levels. The percentage bioavailability of glucagon from formulations containing 2% w/v enhancer were between 42.78 and 44.61% with corresponding AUC plasma glucose of between 78.89 and 80.47% compared to subcutaneous injection. The values for the 5% w/v DMβCD formulations were about 82% with corresponding AUC plasma glucose between 95 and 97% for spray and powder, respectively. Nasal administration was found to initiate serum glucagon and plasma glucose concentrations earlier than those of subcutaneous injection, but the effect of the latter was more sustained. Spray solution and freeze dried powder were equally effective.

Effects of xylitol on urea synthesis in normal humans: relation to glucagon.

Xylitol exerts a nitrogen-sparing effect in stress catabolic states with hyperglucagonemia, but the mechanism(s) is unknown. We examined the effects of xylitol on urea synthesis during physiologic glucagon concentrations and during hyperglucagonemia. Urea synthesis was measured independently of blood amino acid concentration by means of functional hepatic nitrogen clearance (FHNC) (ie, the linear slope of the relation between urea synthesis rate and blood alpha-amino nitrogen concentration during infusion of alanine). FHNC was measured on four separate occasions in each of seven healthy subjects: during constant infusion of alanine alone, alanine superimposed on a constant infusion of xylitol (blood xylitol 1 mmol/L), alanine superimposed on infusion of glucagon, and alanine superimposed on infusions of xylitol and glucagon. During alanine infusion alone, plasma glucagon rose to -170 ng/L, and FHNC was (mean +/- sem) 27.9 +/- 1.3 L/h. Xylitol did not affect plasma glucagon and only moderately reduced FHNC to 24.3 +/- 1.0 L/h (p < .05). Glucagon infusion increased plasma glucagon to -450 ng/L and FHNC twofold to 50.9 +/- 6.2 L/h; this increase was totally prevented by the addition of xylitol that reduced FHNC to 27.4 +/- 2.6 L/h (p < .01). The results show that xylitol only inhibited FHNC minimally during spontaneous glucagon levels. In contrast, xylitol completely inhibits the increase in FHNC by glucagon. This suggests that the mechanism whereby xylitol reduces nitrogen loss in stress catabolic conditions with hyperglucagonemia involves an effect on liver metabolism. The mechanism is unknown but may be related to depletion of hepatocyte adenine nucleotides.

Portal hypertensive colopathy in patients with cirrhosis.

Colonic vascular ectasias and colorectal varices have been observed in patients with cirrhosis. However, the pathogenesis of these vascular lesions has not been established. We enrolled 35 cirrhotic patients and 20 normal controls in this study. All received colonoscopic examinations and measurements of plasma glucagon levels. Portal pressure measurements were performed in all the cirrhotic patients. Colonic vascular ectasias occurred more commonly in cirrhotic patients than in controls (17 of 35 versus 0 of 20; p = 0.009) and more commonly in cirrhotic patients with ascites than in those without (15 of 24 versus 2 of 11; p = 0.038). However, the presence of colonic vascular ectasias was not related to the hepatic venous pressure gradient or plasma glucagon levels. Colorectal varices also occurred more commonly in cirrhotic patients than in controls (16 of 35 versus of 1 of 20; p = 0.034), but the hepatic venous pressure gradient, plasma glucagon levels, and severity of cirrhosis were not related to the presence of colorectal varices. Portal hypertension per se and increased plasma glucagon levels may not play an important role in the pathogenesis of colonic vascular ectasias or colorectal varices in patients with cirrhosis.

Tumor necrosis factor alpha stimulates gluconeogenesis from alanine in vivo.

An increase in gluconeogenesis contributes to the cachexia seen in severe injury, sepsis, and malignancy by converting amino acids from skeletal muscle to glucose. Since tumor necrosis factor alpha (TNF alpha) may mediate this cachexia, we examined the effect of this cytokine on gluconeogenesis. Twenty-eight male Fischer rats were injected intraperitoneally with TNF alpha (250 micrograms/kg) or saline, and after 4 hours, isolated hepatocytes were obtained by in situ collagenase liver perfusion. Hepatocytes were incubated with alanine (10 mM), and rates of gluconeogenesis were determined. Plasma lactate, glucose, insulin, glucagon, cortisol, and amino acids were measured. TNF alpha administration resulted in a 50% increase in gluconeogenesis from alanine (P < 0.05) and a three-fold increase in plasma glucagon (P = 0.01). Total and glucogenic plasma amino acids decreased with TNF alpha injection (P < 0.05). In vivo TNF alpha causes an increase in hepatic gluconeogenesis associated with increased plasma glucagon.

The involvement of the peripheral 5-HT 2A receptor in peripherally administered serotonin-induced hyperglycemia in rats

The mechanism of the hyperglycemic response to intraperitoneally administered serotonin(S-HT) was studied in rats. 5-HT i.p.-induced hyperglycemia was strongly antagonized by the 5-HT 2A receptor antagonist ketanserin. 5-HT did not affect the serum insulin levels and increased plasma glucagon levels only at the high dose of 10 mg/kg. 5-HT dose-dependently induced a remarkable increase in plasma adrenaline levels and these effects were antagonized by ketanserin. 5-HT-induced hyperglycemia was abolished by adrenodemedullation. These results suggest that the hyperglycemic effects of 5-HT are closely related to the release of adrenaline from the adrenal gland, mediated by 5-HT 2A receptors.

The effects of dopamine infusion on the postoperative energy expenditure, metabolism, and catecholamine levels of patients after esophagectomy

Although dopamine is one of the most widely used vasoactive agents, its postoperative thermogenic and metabolic effects have not been studied. In this study, the effects of low-dose dopamine, given at 5 microgram/kg/min, on resting energy expenditure (REE), metabolism, and plasma catecholamine levels were examined in eight postsurgical patients. Dopamine infusion increased REE from 1,839 +/- 171 kcal/day to 2,071 +/- 170 kcal/day, and it decreased to 1,867 +/- 141 kcal/day after cessation of the infusion. Dopamine also increased the plasma levels of glucagon from 109.4 +/- 8.7 pg/ml to 132.5 +/- 8.0 pg/ml, and it decreased to 102.9 +/- 11.1 pg/ml after cessation of the infusion. The plasma levels of dopamine before, during, and after the infusion were 116.1 +/- 18.3, 161.1 +/- 25.6 and 121.4 +/- 17.2 ng/ml, respectively. Insulin and glucose were affected by dopamine, but changes in their plasma levels did not parallel the dopamine levels. Epinephrine and norepinephrine were increased by the infusion of dopamine and continued to increase even after its cessation. The results of this study revealed that low-dose dopamine increased REE in postsurgical patients and that this might be associated with the concomitant increase in plasma glucagon.

Effect of tumor necrosis factor on substrate and amino acid kinetics in conscious dogs.

Two groups of conscious dogs were studied using isotopic tracer techniques to test the hypothesis that tumor necrosis factor (TNF) affects glucose production, lipolysis, amino acid, and protein kinetics. [1-13C]leucine, [15N2]urea, [6,6-2H2]glucose, and [2H5]glycerol were infused to determine the leucine, urea, glucose, and lipid kinetics, and NaH14CO3 was infused to determine the rate of CO2 production. In one group, after a 2-h basal period (period 1), recombinant human TNF was infused (prime, 2.5 micrograms/kg; constant, 62.5 ng.kg-1.min-1) for 2 h (period 2; group 1, n = 15). Group 2 received saline rather than TNF in period 2 (n = 3). TNF infusion caused a significant increase in endogenous glucose production, a significant increase in glucose clearance rate, and a decrease in glycerol flux. Although TNF infusion did not change leucine flux, leucine oxidation increased by 49% (P < 0.0001), and nonoxidative leucine disappearance decreased during TNF infusion by 13% (P < 0.0001). TNF infusion also caused a significant increase (18%) in endogenous urea production. TNF significantly increased plasma glucagon concentration. We conclude that TNF causes a shift toward carbohydrate metabolism and stimulates the oxidation of amino acids. Whereas whole body protein breakdown is not affected by TNF, protein synthesis is impaired, leading to an increase in net protein breakdown.

Impact of chronic stress hormone infusion on hepatic carbohydrate metabolism in the conscious dog

The effects of chronic administration of counterregulatory hormones on hepatic glycogenolysis and gluconeogenesis were investigated. We studied 14 20-h fasted conscious dogs prior to (day 0) and after a 70-h stress hormone (SHI, n = 7) or saline (n = 7) infusion (day 3). Glucose production and gluconeogenesis were assessed using tracer and arteriovenous difference techniques. SHI increased plasma glucagon, cortisol, epinephrine, and norepinephrine levels approximately fivefold. SHI increased the arterial plasma glucose and insulin concentrations (110 +/- 2 to 204 +/- 19 mg/dl and 13 +/- 2 to 36 +/- 3 microU/ml on day 3). Tracer-determined glucose appearance and net hepatic glucose output were increased 80 and 60%, respectively. Net hepatic lactate uptake and fractional extraction were increased by 11.2 +/- 3.8 and 0.51 +/- 0.18 mumol.kg-1 x min-1, respectively, as was net hepatic glycerol uptake (1.0 +/- 0.6 mumol.kg-1 x min-1). Net hepatic fractional alanine extraction was also increased by 0.37 +/- 0.03 mumol.kg-1 x min-1; however, net hepatic alanine uptake was not altered. The efficiency of alanine conversion to glucose almost doubled (0.33 +/- 0.05 to 0.59 +/- 0.09). Renal glucose production was also increased, accounting for 33% of the increase in glucose turnover. This increase was paralleled by an increase in renal gluconeogenic precursor uptake. In conclusion, SHI created marked hyperglycemia and hyperinsulinemia and elevated glucose production from both the liver and the kidney, with gluconeogenesis accounting for approximately 70% of the response.

Glucagon does not increase plasma free fatty acid and glycerol concentrations in patients with noninsulin-dependent diabetes mellitus.

The study was initiated to determine whether physiological elevations of plasma glucagon would increase plasma FFA or glycerol concentrations in patients with noninsulin-dependent diabetes mellitus (NIDDM). To do this, patients were infused for 6 h with somatostatin (SRIF) alone or with SRIF plus glucagon. Furthermore, these studies were performed with an insulin infusion rate that maintains basal insulin levels or without any insulin infusion. Infusion of SRIF alone was associated with an increase in plasma FFA and glycerol concentrations, whereas hepatic glucose production and plasma glucose concentrations fell somewhat. When glucagon was added to SRIF, plasma FFA and glycerol concentrations were again increased, but to a significantly lesser extent. In addition, the addition of glucagon was associated with a modest increase in hepatic plasma glucose production and plasma glucose concentrations. In contrast, plasma FFA and glycerol concentrations fell when SRIF was infused in the presence of basal insulin levels. The decrease in FFA and glycerol levels tended to be accentuated when glucagon was also infused. It should be noted that the increases in hepatic glucose production and plasma glucose concentration after glucagon was added to SRIF were prevented when basal insulin levels were replaced. These results demonstrate that an increase in the plasma glucagon level comparable to that seen in patients with NIDDM was associated with lower, not higher, plasma FFA and glycerol concentrations in patients with NIDDM. Furthermore, these changes were seen in the absence of insulin or when basal insulin levels were replaced. Thus, the higher ambient plasma FFA and glycerol concentrations in patients with NIDDM do not appear to be secondary to increased plasma glucagon levels.

Role of the intestinal acyl-CoA:cholesterol acyltransferase activity in the hyperresponse of diabetic rats to dietary cholesterol.

Contrary to normal rats, diabetic rats are known to develop marked hypercholesterolemia when fed a cholesterol-enriched diet. The triggering factor involved in this hyperresponse has not been identified. With the aim of clarifying the role of the intestinal acyl-CoA:cholesterol acyltransferase (ACAT), we studied the effects of a high fat diet and the changes of intestinal ACAT activity during the early development of streptozotocin-diabetes in rats. Feeding diabetic rats with a diet enriched in cholesterol and saturated fat produced an increase in plasma and in tissue cholesterol as early as 3 days after streptozotocin injection in the absence of hyperphagia. Under these experimental conditions, treatment with insulin or with the ACAT inhibitor CL-277082 significantly reduced the plasma cholesterol to levels measured in nondiabetic rats fed the same high fat diet. An increase in [14C]cholesterol in plasma very low density lipoprotein was observed after oral administration of labeled cholesterol to 3-day diabetic rats. In parallel experiments, the direct measurement of small intestine microsomal ACAT activity revealed an increase, averaging 288% in diabetic rats 3 days after diabetes induction. This change in ACAT activity occurred simultaneously with an increase in plasma glucagon and was normalized by insulin treatment. The induction of intestinal ACAT activity in diabetic rats, its modulation by insulin, and the hypocholesterolemic effects of insulin or CL-277082 treatment clearly indicate that ACAT activity plays a major role in the initiation of diabetes-associated hypercholesterolemia.