Increase In Glucagon Levels Research Articles

Impairment of counterregulatory hormone responses to hypoglycemia in pregnant women with insulin-dependent diabetes mellitus

Intensive insulin therapy directed at elimination of hyperglycemia is advocated during pregnancy in women with insulin-dependent diabetes mellitus. Because such treatment is complicated by frequent hypoglycemic episodes, we evaluated maternal and fetal responses in nine intensively treated pregnant women with insulin-dependent diabetes mellitus during an insulin-induced, gradual, controlled fall in plasma glucose levels. In contrast to values in nonpregnant control women, reductions in glucose to 44 +/- 2 mg/dl in pregnant diabetic patients failed to elicit an increase in glucagon levels. Epinephrine release during hypoglycemia was also markedly suppressed in the pregnant diabetic subjects (106 +/- 32 vs 327 +/- 52 pg/ml in controls, p less than 0.001). Furthermore, the plasma glucose level at which epinephrine and growth hormone were released was 5 to 10 mg/dl lower in the pregnant women with insulin-dependent diabetes mellitus (p less than 0.05). The basal fetal heart rate remained unchanged and continued to manifest accelerations during the hypoglycemic state. We conclude that the high frequency of hypoglycemia in intensively treated pregnant women with insulin-dependent diabetes mellitus may be due in part to impaired counterregulatory hormonal responses.

The influence of vanadate on insulin counter-regulatory hormones in obese fa/fa rats

Vanadate has been shown to improve glucose homoeostasis in mildly glucose-intolerant and severely insulin-resistant fa/fa rats. The present study examined whether changes in insulin counter-regulatory hormones contribute to this beneficial effect of vanadate. Since oral administration of Na3VO4 caused a decrease in food intake and stopped the increase in body weight, vanadate-treated fa/fa rats were compared with both controls with food available ad libitum and pair-fed rats. Slightly lower plasma glucose levels were maintained in conjunction with markedly lower plasma insulin levels in vanadate-treated rats, and this effect was not simply due to the smaller body weight of the animals. Compared with control rats, treatment with vanadate affected neither basal plasma glucagon levels nor the increase in glucagon levels observed after insulin-induced hypoglycaemia or after i.v. injection of arginine. Compared with pair-fed rats, treatment with vanadate prevented the fall in basal plasma glucagon and its exaggerated rise in response to insulin that mere food restriction produced. Plasma corticosterone levels were high in fa/fa rats. Vanadate and pair-feeding similarly decreased basal plasma levels of corticosterone as well as nocturnal corticosteronuria. Thus the attenuation of the hypercorticism of fa/fa rats results from the reduction in body weight gain rather than from a specific action of vanadate. Vanadate did not influence urinary excretion of noradrenaline, an index of neural sympathetic activity, but prevented the increase in adrenaline excretion, an index of adrenal medulla activity, that was produced by food restriction in pair-fed rats. In conclusion, vanadate administration has no or little specific effects on three major insulin counter-regulatory hormones. This reinforces the suggestion that the beneficial effects of vanadate on glucose homoeostasis in fa/fa rats are mainly due to a correction of insulin resistance in peripheral tissues.

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats ( r = 0.44, P < 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 μg/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 ± 0.1 to 6.8 ± 0.2 mM ( P < 0.05), and glucagon from 179 ± 12 to 259 ± 32 pg/ml ( P < 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 μg/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to > 18 mM and glucagon to 249 ± 25 pg/ml ( P < 0.05). In these rats, 10 μg/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 ± 248 pg/ml ) and also increased plasma ACTH. A specific oxytocin analog, Thr 4,Gly 7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 ± 250 pg/ml ), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15–180 min later. Plasma glucose levels dropped to < 2.5 mM by 15 min. Oxytocin levels increased by 150–200% at 30 min; however, the effect was not statistically significant. Finally, the effect of glucose on oxytocin secretion from intact isolated rat hypothalami was tested in vitro. Increasing concentrations of glucose in the incubation medium significantly decreased basal oxytocin secretion within 30 min ( r = 0.62, P < 0.01) with half-maximal inhibition at approx. 4.5 mM. We conclude that oxytocin has only very moderate acute glucoregulatory actions in normal rats, and only at high concentrations; however, normal resting levels of glucose can feedback to inhibit further secretion of oxytocin from the hypothalamus/median eminence; and the effects of oxytocin on glucagon secretion are augmented in insulin-deficient diabetic rats.

INSULIN AND GLUCAGON LEVELS IN RELATIONSHIP WITH PLASMA AMINO ACID IMBALANCE IN LIVER CIRRHOSIS

Alterations in insulin and glucagon levels might accout for the plasma amino acid imbalance in cirrhotics. In order to verify this hypothesis we evaluated basal insulin, glucagon, branched-chain amino acids and aromatic amino acids in 10 controls and 17 cirrhotics. Tyrosine and aromatic amino acids significantly correlated with I/G ratio. On the other hand, insulin did not correlate with any of the plasma amino acids. Our data suggest that the catabolic state associated with increased glucagon levels may account for some of the alterations in the plasma amino acid profiles in cirrhotics.

Role of insulin in the blunted glucose metabolic response of septic rats to epinephrine

Epinephrine produces smaller incremental increases in plasma glucose concentration and rate of glucose appearance (Ra) in septic rats compared with nonseptic animals. In the present study, we investigated the role of insulin in the diminished response of septic rats to epinephrine-induced increases in glucose turnover. Glucose kinetics were assessed by the infusion of [6- 3H]-glucose in conscious catheterized rats made septic by subcutaneous injections of live Escherichia coli. Epinephrine was infused at 1 μg/min/kg for 2 hours in the presence and absence of somatostatin and mannoheptulose (SRIF + MH). In comparison to nonseptic control animals, epinephrine-induced increases in plasma glucose concentration and glucose Ra were blunted by more than 50% in the septic rats. Infusion of SRIF + MH with epinephrine restored the blunted response to normal. During the infusion of epinephrine alone, the plasma insulin concentration in the septic rats was 2.8-fold higher than the nonseptic controls. SRIF + MH lowered the plasma insulin concentrations in both the nonseptic and septic rats to less than 10 μU/mL. SRIF + MH reversed the sepsis-induced hyperglucagonemia, but did not prevent a slight increase in glucagon levels during the epinephrine infusion in the nonseptic rats. In a second study, septic rats infused with SRIF + MH and replacement insulin showed a smaller increase in glucose concentration and glucose production in response to epinephrine than did septic animals administered SRIF + MH and no insulin. These results indicate that insulin plays an important role in the diminished response of septic rats to epinephrine.

The maintenance of increased glucagon levels preclude the effects of somatostatin on splanchnic haemodynamics in portal hypertensive rats

The maintenance of increased glucagon levels preclude the effects of somatostatin on splanchnic haemodynamics in portal hypertensive rats

Superactive somatostatin analog decreases plasma glucose and glucagon levels in diabetic rats

The action of the new analog of somatostatin, D-Phe- Cys-Tyr-D-Trp-Lys-Val-Cys -Trp-NH 2 (RC-160), on plasma glucagon and glucose levels was evaluated in streptozotocin-diabetic rats. The effect of this analog on the insulin-induced hypoglycemia in diabetic rats was also investigated in order to evaluate the risk of exacerbating hypoglycemia. Administration of analog RC-160, in a dose of 25 μg/kg b.wt. SC, inhibited plasma glucagon secretion and decreased plasma glucose levels. This effect also occurred when plasma glucagon and glucose levels were first elevated by arginine infusion, 1000 mg/kg/hr for 30 min. Subcutaneous injection of regular insulin, 15 U/kg b.wt., produced hypoglycemia with a progressive increase in glucagon levels. Analog RC-160 completely suppressed the hypoglycemia-induced glucagon release for up to 150 min after injection of the analog or insulin. A greater decrease in the plasma glucose level was observed in the group treated with insulin and the analog than in the group injected only with insulin. These results indicate that somatostatin analog RC-160 can produce a marked and prolonged inhibition of glucagon release and a decrease in the plasma glucose level in diabetic rats. This analog may be useful as an adjunct to insulin in the treatment of diabetic patients, although caution should be exercised, to prevent hypoglycemia when using somatostatin analogs together with insulin.

Glucagon Binding and Lipolytic Response in Isolated Adipocytes from Streptozotocin-diabetic Rats.

Evidence for pre-receptor, receptor and post-receptor glucagon defects was investigated in adipocytes from streptozotocin-diabetic rats. For this purpose male Wistar rats were injected by cardiac puncture with streptozotocin (65 mg/Kg body-weight) or saline solution and sacrificed after 7 and 15 days of drug administration. Increased glucagon levels and increased glucagon degradation in serum together with a decrease in glucagon binding were found in both groups of diabetic rats. The decrease in glucagon binding was related to a decrease in the number of glucagon receptors/cell rather than to a change in receptor affinity. The lipolytic response of glucagon was increased. However, the ability of glucagon to increase basal or theophylline-stimulated cAMP accumulation in the incubation medium of adipocytes from diabetic rats was decreased. Such alterations could represent a counter-regulatory mechanism of the hyperglucagonemia detected in streptozotocin-diabetic rats.

Major operative trauma increases peripheral amino acid release during the steady-state infusion of total parenteral nutrition in man.

The effect of major operative trauma on skeletal muscle metabolism was examined in nine patients receiving a constant infusion of calories (1460 kcal/m2/day) and protein (75 gm of amino acids/m2/day) for 5 days before and 4 days after an operation. Compared with the preoperative state, 72 hours after the operation there was a significant rise in arterial levels of glucagon, cortisol, norepinephrine, and inactive triiodothyronine and a drop in concentrations of insulin, active triiodothyronine, and amino acids. Forearm blood flow increased, as well as the efflux from forearm muscle of lactate, taurine, serine, glycine, valine, methionine, isoleucine, leucine, phenylalanine, lysine, arginine, and total amino acid nitrogen (440%). This loss of muscle protein after trauma is associated with increased muscle proteolysis, as measured by increased urinary 3-methylhistidine excretion (83%), and accounts for increased nitrogen loss (54%) from the body. Increased activity of the sympathetic nervous system is manifested by increased levels of epinephrine and norepinephrine, a relative lack of insulin, and increased levels of glucagon. This hormonal milieu plays an important role in the production of hypoaminoacidemia, increased efflux of amino acids and lactate from muscle, and negative nitrogen balance observed in these traumatized patients.

Role of the endocrine pancreas in the kalemic response to acute metabolic acidosis in conscious dogs.

Metabolic acidosis due to organic acids infusion fails to elicit hyperkalemia. Although plasma potassium levels may rise, the increase is smaller than in mineral acid acidosis. The mechanisms responsible for the different effects of organic acid acidosis and mineral acid acidosis remain undefined, although dissimilar hormonal responses by the pancreas may explain dissimilar hormonal responses by the pancreas may explain the phenomena. To test this hypothesis, beta-hydroxybutyric acid (7 meq/kg) or hydrochloric acid (3 meq/kg) was infused over 30 min into conscious dogs (n = 12) with chronically implanted catheters in the portal, hepatic, and systemic circulation, and flow probes were placed around the portal vein and hepatic artery. Acid infusion studies in two groups of anesthetized dogs were also done to assess the urinary excretion of potassium (n = 14), and to evaluate the effects of acute suppression of renal electrolyte excretion on plasma potassium and on the release/uptake of potassium in peripheral tissues of the hindleg (n = 17). Ketoacid infusion caused hypokalemia and a significant increase in portal vein plasma insulin, from the basal level of 27 +/- 4 microU/ml to a maximum of 84 +/- 22 microU/ml at 10 min, without changes in glucagon levels. By contrast, mineral acid acidosis of similar severity resulted in hyperkalemia and did not increase portal insulin levels but enhanced portal glucagon concentration from control values of 132 +/- 25 pg/ml to 251 +/- 39 pg/ml at 40 min. A significant decrease in plasma glucose levels due to suppression of hepatic release was observed during ketoacid infusion, while no changes were observed with mineral acid infusion. Plasma flows in the portal vein and hepatic artery remained unchanged from control values in both acid infusion studies. Differences in renal potassium excretion were ruled out as determinants of the disparate kalemic responses to organic acid infusion compared with HCl acidosis. Evaluation of the arteriovenous potassium difference across the hindleg during ketoacid infusion demonstrates that peripheral uptake of potassium is unlikely to be responsible for the observed hypokalemia. Although the tissue responsible for the different kalemic responses could not be defined with certainty, the data are compatible with an hepatic role in response to alterations in the portal vein insulin and/or glucagon levels in both acid infusion studies. We propose that cellular uptake of potassium is enhanced by hyperinsulinemia in ketoacid infusion, and release of potassium results from increased glucagon levels in HCl acidosis. Whether the changes in plasma potassium that other types od organic acid acidosis produce are accounted for by a similar hormonal mechanism remains to be determined.

Serum branched chain amino and keto acid response to fasting in humans

Eight healthy individuals were fasted for 72 hours. The concentrations of the branched chain keto acids (BCKA), branched chain amino acids (BCAA), C peptide, and glucagon were determined in peripheral venous blood. α-ketoisocaproic acid, α-keto-β-methyl-n-valeric acid, and α-ketoisovaleric acid increased significantly within 36 hours along with the corresponding amino acids. After 60 hours of starvation, the concentrations of BCKA and BCAA declined despite the fact that the subjects were still in the fasting state. These changes were accompanied by a decrease in the concentrations of C peptide and an increase in glucagon levels. It is suggested that in starving man (1) insulinopenia may contribute to the rise in BCKA concentrations and that (2) the increase in BCKA may be a mechanism to reduce proteolysis.

Minimal increases in glucagon levels enhance glucose production in man with partial hypoinsulinemia

Minimal increases in glucagon levels enhance glucose production in man with partial hypoinsulinemia

Minimal increases in glucagon levels enhance glucose production in man with partial hypoinsulinemia.

In man a small dose of somatostatin (50 micrograms/h) suppressed moderately basal insulin (5 microU/ml) and glucagon (40 pg/ml) levels. This resulted in a short-lasting hypoglycemia, which was then followed by marginal hyperglycemia throughout the experiment. The addition of a minimal dose of glucagon (0.50 ng/kg/min) to somatostatin normalized basal glucagon levels and resulted in a significant and sustained hyperglycemia. During the first 2 h, hyperglycemia was mainly due to increased glucose production, whereas later on it was maintained by decreased glucose uptake. We conclude that, in man moderately deprived of insulin, even a marginal change in glucagon level induces a long-lasting hyperglycemia.

Possible role of glucagon in cyproheptadine-induced increase of insulin secretion.

In order to test the hypothesis that insulin secretion may be affected by increased glucagon levels during cyproheptadine (CPH) administration, an arginine-glucose test was performed in 8 normal women and repeated after three days of CPH administration at a dose of 16 mg/day. Both the glucagon and the insulin response were increased by CPH treatment and so were their incremental areas. For glucagon, the increase was present at all times tested, for insulin this rise was significant only during the first 60 min of the arginine test and during the rapid secretory phase following glucose injection. The difference between the incremental areas of glucagon before and after CPH treatment was significantly correlated to the above mentioned insulin areas and to insulin peak values. These data are in agreement with the hypothesis that in vivo CPH action on insulin secretion may be partly mediated by its effects on circulating glucagon levels.

Glucoregulation and simulated diving in the harbor seal Phoca vitulina.

Plasma glucose, glucagon, and insulin concentrations were measured in the harbor seal, Phoca vitulina, during a 6-min dive and a 30-min recovery period. Studies were performed in the fasting state and following intravenous glucose. During diving in the fasting state, values of plasma glucose, glucagon, and insulin are not significantly different from prediving values, presumably because of the loss of perfusion to the pancreas. In the postdiving period, plasma glucagon increases significantly. The increased glucagon levels reach a peak at 6 min into the postdiving period. By 4 min postdiving, plasma glucose values increase. The hyperglycemia appears to be at least partially related to hyperglucagonemia. Despite hyperglycemia, insulin levels do not change significantly. The net effect is to increase glucose availability, particularly for non-insulin-requiring tissues (brain). Preadministration of glucose eliminates the postdiving increase in glucagon. Plasma glucose and insulin concentrations also show no significant changes during the diving and postdiving periods. These results suggest that hormonally mediated glucose conservation serves to maintain brain glucose supplies and to restore peripheral carbohydrate stores during the postdiving period.

Effect of indomethacin on the metabolic and hormonal response to a standardized breakfast in normal subjects.

We have investigated the influence of a single oral administration of indomethacin on blood glucose, plasma free fatty acids (FFA), alpha-amino-nitrogen, insulin and glucagon concentrations in young healthy subjects. Two groups of 6 subjects were studied, the first received a standardized 500 kcal mixed meal without any previous drug administration (controls) whereas the second group received 50 mg indomethacin 2 h before ingesting an identical meal. Plasma indomethacin concentration reached its maximum (2.36 +/- 0.36 micro g/ml) 15 min after administration and declined to 0.45 +/- 0.04 micro g/ml after 2 h. Indomethacin ingestion was followed by a significant increase in blood glucose and plasma FFA reaching their maximum value at 45 min and returning to basal levels at 120 min. No simultaneous changes in plasma alpha-amino-nitrogen, insulin or glucagon levels were detected during this period. The meal was followed by a rise in blood glucose and plasma insulin as well as by a decrease in plasma FFA concentration. No significant differences were detected between the controls and the subjects receiving indomethacin. In controls, the meal was followed by a rise in plasma alpha-amino-nitrogen and a modest although significant increase in glucagon levels. In indomethacin-treated subjects, the increment of alpha-amino-nitrogen was less marked and the increase in plasma glucagon was not observed. Thus, indomethacin by itself can exert several metabolic effects; however, it does not deteriorate the blood glucose or insulin profile after a regular meal. The present work is the first to demonstrate that an inhibitor of prostaglandin synthesis inhibits the plasma glucagon rise occurring after a physiological stimulus such as a normal meal. On the basis of previous in vitro experiments, we suggest that this effect results from an inhibition of glucagon secretion by the PG synthesis inhibitor.

A model of sustained activation of the symphatetic nervous system (SNS) using anterior hypothalamic cooling in the baboon

A model has been developed to simulate central activation of the sympathetic nervous system (SNS) in unanesthetized baboons. By continuously cooling the preoptic anterior hypothalamus with an implanted thermode, a chronic heat production response is generated. In the primate, SNS activation is a major feature of the response to cold stress. During central cooling, oxygen consumption and catecholamine excretion doubled. These responses have been sustained for 30 days. Metabolic and endocrine changes accompanying chronic SNS activation include (1) an early period of basal hyperinsulinemia followed by restoration of normal insulin sensitivity, (2) an unexpected maintenance of normal (or even increased) responsiveness to isoproterenol (heart rate, insulin secretion and lipolysis, (3) increased glucagon levels throughout, (4) a persistent and progressive fall in T3 without change in T4 which was not explained by decreased food intake since this did not diminish, and weight was maintained. The model may prove useful in characterizing the adaptations and maladaptations which accompany sustained increases in central SNS activity in primates.

Differential time course of glucagon's effect on glycogenolysis and gluconeogenesis in the conscious dog.

The evanescence of glucagon's effect on glucose production (GP) is well documented, but it is unclear (1) whether this response involves both glycogenolysis and gluconeogenesis and (2) whether the liver becomes dependent on the increased glucagon level for the maintenance of a basal supply of glucose. To answer these questions, conscious overnight-fasted dogs were given somatostatin (0.8 microgram/kg . min) plus basal intraportal replacement amounts of insulin (273 microU/kg . min) and glucagon (0.65 ng/kg . min) for 2 h, after which the rate of glucagon infusion was increased fourfold for 3 h and then returned to basal for 1.5 h. GP was determined using a primed infusion of [3-3H]glucose, and gluconeogenesis (GNG) was estimated by determining the conversion rate of alanine and lactate to glucose. An increase in the plasma glucagon level from 55 to 206 pg/ml resulted in an initial 180% increase in GP, followed by a decline such that after 3 h of hyperglucagonemia GP was increased by only 41%. Contrary to overall GP, gluconeogenesis increased progressively throughout the hyperglucagonemic period, eventually reaching a rate 3 times basal. Restoration of the basal glucagon level (63 pg/ml) caused a marked decline in GP and GNG. In fact, GP fell to a level 29% below the initial control rate and consequently the plasma glucose level fell rapidly. The data suggest that (1) the downregulation of glucagon-stimulated GP is attributable to a decline in glycogenolysis and not gluconeogenesis, and (2) following adaptation to the hormone, the liver becomes dependent on the elevated glucagon concentration for the maintenance of basal glucose production.

The effects of fasting on glucagon binding and action in isolated rat hepatocytes

The effect of fasting on the basal and glucagon-stimulated uptake of α-aminoisobutyric acid (AIB) and the binding of glucagon was studied in isolated hepatocytes from fed and 72 hr-fasted rats. The basal rate and the absolute amount of glucagon-stimulated AIB transport was significantly increased in hepatocytes from fasted rats as compared to controls when measured at 0.1 m M AIB. In both groups of animals the minimal effective hormone concentration, half maximal stimulation, and maximal stimulation of AIB transport was achieved at a similar glucagon concentration. In contrast, hepatocytes from fasted rats bound from 37% to 50% less glucagon than those from fed rats. This decrease of glucagon binding appears to be the result of a decrease in the number of binding sites rather than a consequence of a change in binding affinity or increased glucagon degradation. In conclusion, our data are supportive of the hypothesis that there exists in fasting an increased efficiency of amino acid extraction by the liver at low ambient amino acid levels. The absolute uptake of AIB in response to glucagon is similarly increased which, in conjunction with the increased glucagon levels in fasting, results in further augmentation of amino acid extraction. This alteration in glucagon action appears to be a reflection of the enhanced basal rates of AIB uptake and is unrelated to the observed alterations in glucagon binding.

Increased ATP inhibition of liver phosphofructokinase from genetically diabetic mice.

Phosphofructokinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) was partially purified from the livers of genetically diabetic mice (C57BL/KsJ-db) and their lean littermates (C57BL/KsJ). These genetically diabetic mice have been shown to be hyperglucagonemic and to exhibit symptoms resembling those of maturity-onset diabetes in humans. Two isoenzymes of phosphofructokinase were obtained after DEAE-Sephadex chromatography of extracts of livers from either normal or diabetic animals. One of these isozymes, peak II, from the genetically diabetic mice was shown to be more sensitive to ATP inhibition at physiological pH than the peak II isozyme from the normal animals. In addition, the peak II isozyme from the diabetic mice exhibited decreased affinity for fructose 6-phosphate. The altered kinetic properties of phosphofructokinase from diabetic animals are markedly similar to those recently reported for liver phosphofructokinase isolated from normal animals after glucagon treatment. Our results suggest that increased glucagon levels in diabetes may lead to altered regulation of phosphofructokinase in this disease.