Glucagon Administration Research Articles

Rapid Ca2+ influx induced by the action of dibutylhydroquinone and glucagon in the perfused rat liver

Glucagon induces a slight Ca2+ efflux when administered to the perfused rat liver. However, the hormone promotes rapid and significant Ca2+ influx after the prior administration of 2, 5-di(t-butyl)-1,4-hydroquinone (BHQ), an agent that promotes Ca2+ release from the endoplasmic reticulum (ER). The concentrations of glucagon that promote Ca2+ influx are similar to those that promote glycogenolysis and gluconeogenesis in isolated hepatocytes. The permeable analogue of cAMP, but not that of cGMP, is able to duplicate the Ca2+-mobilizing effects of glucagon. The influx of Ca2+ into liver is blocked by Ni2+. Administration of sodium azide, an inhibitor of mitochondrial electron transport, also blocks the BHQ plus glucagon-induced Ca2+ influx and this is reversed when azide administration is terminated. The actions of azide are evident within 60 s after administration or withdrawal, and also occur when either oligomycin or fructose is co-administered; this provides evidence for an effect of azide independent of cellular ATP depletion. Measurement of total calcium in mitochondria that were isolated rapidly from perfused livers after the combined administration of glucagon and BHQ confirmed that large quantities of extracellular Ca2+ had entered these organelles. These experiments provide evidence that in the perfused rat liver the artificial emptying of the ER Ca2+ pool allows glucagon to promote rapid and sustained Ca2+ influx that seems to terminate in mitochondria.

EVALUATION OF PROGNOSTIC FACTORS IN AMANTTA PHALLOIDES POISONING IN CHILDREN. A STUDY BASED ON 281 CASES.

The majority of Amanita mushroom poisonings is caused by the green death cap Amanita phalloides. In the 1980ies the mortality rate of Amanita poisonings was stated between 20-30%. Nowadays mortality has been reduced to a value between 10-15%. The aim of the study was to evaluate potential prognostic parameters such age and sex of patients, hospitalisation time, presence of Amanita phalloides spores, the concentration of amanitin in urine, various laboratory parameters (prothrombin index, SGPT, bilirubin, serum creatinine and glucose) and different methods of treatment. The study was carried out in 281 children aged 1-17 years treated for Amanita poisoning at the Child Health Centre in Warsaw in the years 1983-1991. 69 (25%) pts were assigned to the group of severe poisoning (based on values of SGPT, prothrombin, bilirubin and grade of consciousness) and 39 (13%) died. Therapy contains: 1/ removal of amatoxin by immediate stomach and intestine washingduodenal suction during 4 days, plasmapheresis (in 146 pts) before 48 hrs after the onset of intoxication, 2/ in order to reduce the amatoxin uptake by live penicillin, silibin, glucocorticoids were used, 3/ balancing of metabolic disturbances, 4/ induction of liver regeneration by i.v. administration of insulin and glucagon or insulin and human growth hormone/ hGH/. Spores of A. phalloides were found in 205 (73%) of the patients, but detection of Amanita spores did not allow the unambiguous identification of Amanita poisoning. In 137 patients the concentration of amanitin in urine was determined by radioimmunoassay, but again no significant correlation was found with grade of intoxication or number of casualties. Among the laboratory parameters, factors of poor prognosis are: prothrombin index below 30% - in 57pts / 37 died /, SGPT activity over 2000 - in 80 pts /34 died/, bilirubin over 3 mg/dl - in 71 pts /38 died /. Significant prognostic factors which indicates a poor prognosis are too: the late onset of gastrointestinal phase and simultaneous occurrence of abdominal pain, vomiting, diarrhoea; the time from intoxication to admission to a specialised hospital above 48 hours from intoxication, especially in children aged below 10 years / age itself hasn't have a prognostic value but a tendency to higher mortality in small children below 10 years was noticed /. Better treatment result have been obtained after therapy considering acceleration/induction of liver regeneration (synchronous administration of insulin and glucagon or insulin and hGH - it refers to children with severe liver injury). It cannot be univocally stated whether or not plasmapheresis affected decrease of the mortality rate.

A syndrome of congenital hyperinsulinism and hyperammonemia

This report describes two patients from unrelated families with an unusual syndrome of hyperinsulinism plus hyperammonemia. The diagnosis of hyperinsulinism was based on the demonstration of fasting hypoglycemia with inappropriately elevated insulin levels, inappropriately low β-hydroxybutyrate and free fatty acid levels, and inappropriately large glycemic response to the administration of glucagon. In both patients, plasma ammonium levels were persistently elevated and unaffected by protein feeding, protein restriction, or benzoate therapy. Plasma and urinary amino acids, urinary organic acids, and urinary orotic acid levels were not consistent with any of the urea cycle enzyme defects or other hyperammonemic disorders. These two patients appear to represent a unique form of congenital hyperinsulinism distinct from the previously described autosomal dominant and autosomal recessive variants. We speculate that the underlying defect involves a site that is common to the amino acid regulation of both insulin secretion in pancreatic β-cells and urea synthesis in the liver. (J Pediatr 1997;130:661-4)

IDDM patients' opinions on the use of glucagon emergency kit in severe episodes of hypoglycaemia

AbstractThis study investigated the coping strategies of IDDM patients with mild and severe episodes of hypoglycaemia. One hundred and two IDDM patients, aged 4–62 years old, 59% male and 41% female, were interviewed by telephone using a structured questionnaire.Most of the patients recognised the symptoms of hypoglycaemia and accordingly treated their mild episodes with either Coca Cola or fruit juice (61%), sweets (32%), milk (26%), or a slice of bread (23%). Forty two per cent of the patients treated themselves with additional chocolate, fruit or honey. While 83% of the patients reported that they had received an explanation regarding the use of the glucagon emergency kit, only 60% actually owned it. In only 19% of the patients who had ever experienced a severe episode of hypoglycaemia had this mode of treatment actually been used. Most of the patients (67%) said they would prefer the intranasal route if available and 82% assumed that the people surrounding them would prefer to administer an intranasal spray or drops in emergency hypoglycaemic situations.We conclude that only in a small percentage of patients is subcutaneous or intramuscular glucagon used in an emergency situation, and speculate that other modes of glucagon administration such as the intranasal route would increase the use of glucagon and prevent some of the IDDM patients from waiting for the emergency paramedic teams or from being referred to hospitals.

Effect of glucagon on the xylitol-induced increase in the plasma concentration and urinary excretion of purine bases

To investigate whether glucagon affects the xylitol-induced increase in the production of purine bases (hypoxanthine, xanthine, and uric acid), the present study was performed with five healthy subjects. Intravenous administration of 300 mL 10% xylitol increased the plasma concentration and urinary excretion of purine bases, erythrocyte concentrations of adenosine monophosphate (AMP) and adenosine diphosphate (ADP), and blood concentrations of glyceraldehyde-3-phosphate (GA3P) + dihydroxyacetone phosphate (DHAP), fructose-1,6-bisphosphate (FBP), and lactic acid; it decreased the blood concentration of pyruvic acid and the plasma concentration and urinary excretion of inorganic phosphate. However, intravenous administration of 1 mg glucagon together with xylitol reduced the xylitol-induced changes in oxypurines, pyruvic acid, GABP + DHAP, and FBP, whereas it promoted the xylitol-induced increase in the urinary excretion of total purine bases and did not affect the xylitol-induced increase in the plasma concentration of total purine bases. In addition, in vitro study demonstrated that sodium pyruvate prevented the xylitol-induced degradation of adenine nucleotides in erythrocytes. These results suggested that gluconeogenesis due to glucagon increased the production of pyruvic acid, accelerated the conversion of NADH to NAD, and thereby prevented both the xylitol-induced degradation of adenine nucleotides in organs similar to erythrocytes and the inhibition of xanthine dehydrogenase in the liver and small intestine, resulting in decreases in the plasma concentration and urinary excretion of oxypurines. However, it was also suggested that in the liver storing glycogen, glucagon-induced glycogenolysis accumulated sugar phosphates, resulting in purine degradation, since the xylitol-induced increase in the NADH NAD ratio partially blocked glycolysis at the level of GABP dehydrogenase. Therefore, administration of glucagon together with xylitol may synergistically increase purine degradation more than xylitol alone, despite decreases in the plasma concentration and urinary excretion of oxypurines.

Molecular motor mechanics in the contracting heart. V1 versus V3 myosin heavy chain.

The amount of iron in the low molecular weight pool (LMW) increases during no-flow ischemia and is thought to be essential to oxygen radical-derived damage upon reperfusion. Applying three short ischemic periods (5 min) preconditioning before 15 min ischemia results in an improved contractility compared to a direct 15 min ischemic insult. This raises the question whether preconditioning leads to a decrease in hte LMW iron pool. We therefore investigated the change in in hte LMW iron pool during ischemic insult after applying preconditioning. It is assumed that an increase in LMW iron is dependent on the accumulation of reduction equivalents derived from the anaerobic glycolysis. Therefore the glycogen content was also reduced by administration by anoxia and glucagon administration to study the effect on the LMW iron pool.

Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment.

1. This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP levels were determined in the effluate and bile by radio immunoassay methods. 2. After endotoxin treatment, infusion of enoximone at three concentrations (1 microM, 10 microM) resulted in an increased glucose output from -1.4 +/- 0.9 to 7.8 +/- 2.5 mumol l-1 20 min-1. Bile acid-independent bile flow increased also, in a dose-dependent manner. 3. In untreated livers, cyclic AMP release increased in the effluate from 1000 +/- 73 fmol g-1 min-1 to 1710 +/- 143 fmol g-1 min-1 when enoximone (10 microM) was administered. In bile from untreated livers, the level of cyclic AMP was also significantly increased by enoximone. After endotoxin treatment, the enoximone (10 microM) effect on cyclic AMP levels in effluate and bile was greatly reduced. Levels of cyclic GMP in the effluate and bile appeared unchanged in the presence of enoximone. 4. During co-infusion of glucagon (1 nM) and enoximone (10 microM), cyclic nucleotide levels in the effluate and bile of livers after endotoxin treatment were determined. In the effluate, cyclic AMP release increased from 827 +/- 144 fmol g-1 min-1 to 17802 +/- 2821 fmol g-1 min-1 when glucagon was administered. The presence of enoximone enhanced cyclic AMP further to 41696 +/- 920 fmol g-1 min-1. The same changes in cyclic AMP release were found in bile. Levels of cyclic GMP in the effluate and bile were not significantly affected by the administration of glucagon and the PDI. 5. Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to glucagon increased glucose release by 8.2 +/- 2.8 mumol g-1 20 min-1, without alteration of lactate balance. The PDI enhanced the glycogenolytic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production. 6. Enoximone significantly enhanced the bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was unaffected by the PDI. The vasoconstrictor effect of nerve stimulation was reduced by the PDI. 7. We conclude that endotoxin treatment reduces the ability of the PDI, enoximone, to increase cyclic AMP release in the perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 is involved in the degradation of cyclic AMP in the liver after exposure to endotoxin. Additionally, the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.

Basal and glucagon-stimulated plasma C-peptide concentrations in healthy dogs, dogs with diabetes mellitus, and dogs with hyperadrenocorticism.

Serum glucose and plasma C-peptide response to i.v. glucagon administration was evaluated in 24 healthy dogs, 12 dogs with untreated diabetes mellitus, 30 dogs with insulin-treated diabetes mellitus, and 8 dogs with naturally acquired hyperadrenocorticism. Serum insulin response also was evaluated in all dogs, except 20 insulin-treated diabetic dogs. Blood samples for serum glucose, serum insulin, and plasma C-peptide determinations were collected immediately before and 5, 10, 20, 30, and (for healthy dogs) 60 minutes after i.v. administration of 1 mg glucagon per dog. In healthy dogs, the patterns of glucagon-stimulated changes in plasma C-peptide and serum insulin concentrations were identical, with single peaks in plasma C-peptide and serum insulin concentrations observed approximately 15 minutes after i.v. glucagon administration. Mean plasma C-peptide and serum insulin concentrations in untreated diabetic dogs, and mean plasma C-peptide concentration in insulin-treated diabetic dogs did not increase significantly after i.v. glucagon administration. The validity of serum insulin concentration results was questionable in 10 insulin-treated diabetic dogs, possibly because of anti-insulin antibody interference with the insulin radioimmunoassay. Plasma C-peptide and serum insulin concentrations were significantly increased (P < .001) at all blood sampling times after glucagon administration in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Five-minute C-peptide increment, C-peptide peak response, total C-peptide secretion, and, for untreated diabetic dogs, insulin peak response and total insulin secretion were significantly lower (P < .00l) in diabetic dogs, compared with healthy dogs, whereas these same parameters were significantly increased (P < .01) in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Although not statistically significant, there was a trend for higher plasma C-peptide concentrations in untreated diabetic dogs compared with insulin-treated diabetic dogs during the glucagon stimulation test. Baseline C-peptide concentrations also were significantly higher (P < .05) in diabetic dogs treated with insulin for less than 6 months, compared with diabetic dogs treated for longer than 1 year. Finally, 7 of 42 diabetic dogs had baseline plasma C-peptide concentrations greater than 2 SD (ie, > 0.29 pmol/mL) above the normal mean plasma C-peptide concentration; values that were significantly higher, compared with the results in healthy dogs (P < .001) and with the other 35 diabetic dogs (P < .001). In summary, measurement of plasma C-peptide concentration during glucagon stimulation testing allowed differentiation among healthy dogs, dogs with impaired beta-cell function (ie, diabetes mellitus), and dogs with increased beta-cell responsiveness to glucagon (ie, insulin resistance). Plasma C-peptide concentrations during glucagon stimulation testing were variable in diabetic dogs and may represent dogs with type-1 and type-2 diabetes or, more likely, differences in severity of beta-cell loss in dogs with type-1 diabetes.

Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects

Increased endogenous glucose production (EGP) and gluconeogenesis contribute to the pathogenesis of hyperglycaemia in non-insulin-dependent diabetes mellitus (NIDDM). In healthy subjects, however, EGP remains constant during administration of gluconeogenic precursors. This study was performed in order to determine whether administration of fructose increases EGP in obese NIDDM patients and obese non-diabetic subjects. Eight young healthy lean subjects, eight middle-aged obese NIDDM patients and seven middle-aged obese non-diabetic subjects were studied during hourly ingestion of 13C fructose (0.3 g.kg fat free mass-1.h-1) for 3 h. Fructose failed to increase EGP (measured with 6,6 2H glucose) in NIDDM (17.7 +/- 1.9 mumol.kg fat free mass-1.min-1 basal vs 15.9 +/- 0.9 after fructose), in obese non-diabetic subjects (12.1 +/- 0.5 basal vs 13.1 +/- 0.5 after fructose) and in lean healthy subjects (13.3 +/- 0.5 basal vs 13.8 +/- 0.6 after fructose) although 13C glucose synthesis contributed 73.2% of EGP in lean subjects, 62.6% in obese non-diabetic subjects, and 52.8% in obese NIDDM patients. Since glucagon may play an important role in the development of hyperglycaemia in NIDDM, healthy subjects were also studied during 13C fructose ingestion + hyperglucagonaemia (232 +/- 9 ng/l) and during hyperglucagonaemia alone. EGP increased by 19.8% with ingestion of fructose + glucagon (p < 0.05) but remained unchanged during administration of fructose or glucagon alone. The plasma 13C glucose enrichment was identical after fructose ingestion both with and without glucagon, indicating that the contribution of fructose gluconeogenesis to the glucose 6-phosphate pool was identical in these two conditions. We concluded that during fructose administration: 1) gluconeogenesis is increased, but EGP remains constant in NIDDM, obese non-diabetic, and lean individuals; 2) in lean individuals, both an increased glucagonaemia and an enhanced supply of gluconeogenic precursors are required to increase EGP; this increase in EGP occurs without changes in the relative proportion of glucose 6-phosphate production from fructose and from other sources (i.e. glycogenolysis + gluconeogenesis from non-fructose precursors).

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.

Percutaneous gastrostomy without gastropexy : O'Donovan NA, Heelan JA (Department of Diagnostic Radiology, McMaster University Medical Centre, 1200 Main Street W. Hamilton, Ontario L8N 3Z5, Canada). Can Assoc Radiol J 1995;46:194–195

To describe in detail the technique for percutaneous gastrostomy without gastropexy, to determine the overall success rate for this technique in providing access to the gastrointestinal tract for feeding and to determine if routine gastropexy is necessary.The authors reviewed all cases of percutaneous gastrostomy performed over a 14-month period. In total, 24 patients (12 males and 12 females) underwent insertion of gastrostomy tubes in the radiology department during this period. Eighteen of the patients had ear, nose and throat tumours and the other 6 had feeding difficulties as a result of neurologic disorders. All gastrostomy tubes were inserted under fluoroscopic guidance without sedation or administration of glucagon. Gastric fixation was not employed.All of the procedures were successful. No major complications occurred. One minor episode of chemical peritonitis did not require treatment.Percutaneous gastrostomy, performed in the radiology department, is safe and effective. On the basis of these findings and a literature review, the authors suggest that routine gastric fixation is not required. However, gastropexy may be appropriate in some circumstances, and its role in these situations has still to be confirmed.

In vivo brain glucose measurements: differential normal pulse voltammetry with enzyme-modified carbon fiber microelectrodes.

The enzyme glucose oxidase was immobilized on the surface of carbon fiber microelectrodes (CFMEs) either by cross-linking in glutaraldehyde vapor or by enzyme entrapment in electropolymerized films of m-phenylenediamine or resorcinol. The cross-linked enzymatic layer was, in the given conditions, covered with an additional membrane of Nafion or cellulose acetate. The prepared glucose sensors were tested using differential normal pulse voltammetry (DNPV, in which the scan comprises successive double pulses ("prepulse and pulse"), the prepulses are of increasing amplitude, and the current measured is the differential of the current existing between each prepulse and pulse). With properly chosen DNPV parameters, the response to glucose presented a peak at a potential of about 1 V versus an Ag/AgC1-reference, owing to the oxidation of enzymatically produced hydrogen peroxide. The calibration curves obtained (peak height/glucose concentration) were linear from 0.3-0.5 up to 1.5-6.5 mM and showed a sensitivity ranging from 1.4 up to 34.5 mA M-1 cm-2, depending on the sensor type. The DNPV response to glucose exhibited an essential insensitivity toward easily oxidizable interfering substances such as ascorbic acid and acetaminophen present at physiological concentrations. Peptides, the interfering species typical of the cerebral medium, were effectively retained by the above additional membranes. Concentration values of glucose in plasma and cerebrospinal fluid, determined in vitro from the DNPV peak height, agreed well with those measured by standard procedures. In the anesthetized rat, extracellular brain concentration of glucose was also monitored during administration of either insulin or glucagon. Under such pharmacological conditions, the changes observed in the peak height were in perfect agreement with the known effects induced by both substances.

Superoxide anion (O 2-) production and bactericidal capacity of polymorphonuclear neutrophils obtained from patients subjected to glucagon test

Superoxide anion (O 2 -) production and bactericidal capacity of morphologically mature bone marrow polymorphonuclear neutrophils (PMN) were evaluated in 30 haematologically normal individuals. These same parameters of peripheral PMNs were estimated in 15 healthy volunteers before and after glucagon-induced marrow granulocyte reserve mobilization. Bone marrow PMN in comparison with cells obtained from peripheral blood manifested impaired superoxide anion production and diminished bactericidal capacity. The admixture of bone marrow PMN released into the circulation by the use of glucagon administration significantly lowered both estimated PMN functions.

Hepatic contrast enhancement at CT: influence of intravenous glucagon in a canine model.

To investigate the effect of glucagon on the timing and degree of hepatic enhancement at computed tomography. Each of 11 dogs underwent injection of contrast material at two uniphasic rates (0.5 mL/sec and 1.5 mL/sec) with without previous intravenous administration of 0.5 mg of glucagon. Scans were obtained at a single intrahepatic level every 3.5 seconds for 120-160 seconds. Attenuation values in the liver, aorta, portal vein, and inferior vena cava (IVC) were measured. Glucagon administration was associated with greater hepatic enhancement throughout the study: Peak hepatic enhancement was greater at contrast injection rates of 0.5 mL/sec (P = .021) and 1.5 mL/sec (P = .0001). Peak hepatic enhancement also occurred earlier during the glucagon runs. Portal vein enhancement was greater during the glucagon runs at an injection rate of 1.5 mL/sec (P = .032). IVC enhancement was greater during the nonglucagon runs at 0.5 mL/sec (P = .013) and at 1.5 mL/sec (P = .005). Intravenous administration of glucagon before contrast material injection produces greater and more rapid hepatic enhancement in a canine model.

Impaired TSH Secretion during Sustained Hyperglucagonemia in Anesthetized Dogs

We previously demonstrated that hyperglucagonemia may be responsible for thyroid hormone alterations noted in some nonthyroidal illnesses. Since TSH secretion is also known to be altered in many subjects with several nonthyroidal illnesses, we assessed the influence of sustained hyperglucagonemia on TSH secretory pattern in 5 anesthetized dogs. Serum TSH concentrations were determined after a 16-h fast and again at intervals of 15 min during sustained hyperglucagonemia (515-645 pg/mL) induced by iv bolus administration of glucagon 0.1 mg followed by a continuous glucagon infusion 3 ng/kg/min for 3 h. TRH (200 micrograms) was administered iv at 60 min to assess the influence of sustained hyperglucagonemia on the hypothalamic pituitary thyrotroph axis during the study. A control study was also conducted using normal saline instead of glucagon, and both studies were performed in a randomized sequence. Basal TSH levels were not significantly different during both studies. However, serum TSH declined significantly during sustained hyperglucagonemia prior to TRH administration (delta TSH, pre-TRH, -0.86 +/- 0.24 vs 0.02 +/- 0.07 ng/mL for normal saline, p < 0.01). Furthermore, TSH response to iv TRH administration was significantly blunted during glucagon infusion alone as expressed by both the absolute rise (delta TSH, post-TRH, 1.1 +/- 0.5 vs 5.9 +/- 1.7 ng/ml for normal saline, p < 0.01) as well as an integrated response over a 2-h period (sigma TSH, post-TRH, 4.0 +/- 1.1 vs 11.7 +/- 3.5 ng/min/mL, p < 0.001). Therefore, this study demonstrates that sustained hyperglucagonemia inhibits basal TSH secretion as well as TSH response to iv TRH administration, a TSH secretory pattern similar to that noted at the peak of many nonthyroidal illnesses.

Does routine intravenous glucagon administration facilitate colonoscopy? A randomized trial

Background: Previous studies on the routine use of glucagon in colonoscopy have produced conflicting results.Methods: Two separate studies were performed. In one study (Study 1), 80 consecutive patients were randomized after cecal intubation to receive 1 mg glucagon ( n = 41) or placebo ( n = 39), intravenously, in double-blind fashion. In a second study (Study 2) 90 sedated patients undergoing colonoscopy were randomized to receive 1 mg glucagon ( n = 46) or placebo ( n = 44), intravenously, just before colonoscope insertion. In each study, colonoscope insertion and withdrawal time, therapeutic intervention time, the presence and severity of colonic spasm, colonoscopy yield, and side effects were recorded.Results: Mean withdrawal time in Study 1 was similar in those receiving glucagon (6.85 min) and in those receiving placebo (6.92 min). Mean insertion time in Study 2 (5.07 min) was identical between groups. Spasm scores and colonoscopy yield did not differ between glucagon and placebo in either study. There was a trend toward more side effects (nausea and vomiting) with glucagon in Study 1. Glucagon did not facilitate insertion or withdrawal in the subset of patients with diverticulosis.Conclusions: Routine use of intravenous glucagon in a dosage of 1 mg does not facilitate colonoscopy by experienced examiners. (Gastrointest Endosc 1995;42:346-50.)

Effects of glucagon with or without insulin administration on liver glycogen metabolism.

Rats fed ad libitum were given insulin alone (4 U/kg), glucagon alone (25 micrograms/kg), or insulin and glucagon sequentially. Phosphorylase a and synthase R activities, hepatic glycogen, uridine diphosphoglucose, inorganic phosphate (Pi), and plasma glucose, lactate, glucagon, and insulin concentrations were determined over the subsequent 40 min. In separate animals, muscle extraction of 2-deoxy-D-[3H]glucose also was determined. After glucagon administration, glycogen phosphorylase a and plasma glucose were increased within 5 min. However, the glycogen concentration did not decrease for 20 min. Glucagon administration to rats pretreated with insulin stimulated a similar increase in phosphorylase a activity. Again, glycogen was not degraded for 20 min. After insulin only, glycogen concentration remained unchanged. Plasma glucose decreased as expected. In each group, muscle extraction of 2-deoxy-D-[3H]glucose increased compared with the controls (P < 0.05). In summary, glucagon and/or insulin administration did not stimulate significant glycogen degradation for 20 min, even though phosphorylase was activated. The mechanism remains to be determined.

Increased muscle sympathetic nerve activity after glucagon administration in man

Muscle sympathetic nerve activity (MSNA) after glucagon administration was quantitatively measured in five healthy male volunteers (age: 20–28 years old). After an overnight fasting, 1 mg glucagon dissolved in a 1-ml vehicle was injected i.v. as a bolus. MSNA, ECG and blood pressure were simultaneously recorded 15 min before and after the injection. MSNA (bursts/min), heart rate (HR), and systolic and diastolic blood pressures (dBP and sBP) were significantly increased at 2–3 min after glucagon injection. Their means and standard deviations of control for 15 min vs. 3 min after the injection were in the five subjects; MSNA, 10 ± 6 vs. 30 ± 10 bursts/min, HR, 61 ± 10 vs. 76 ± 8 beats/min, dBP, 66 ± 9 vs. 91 ± 9 mmHg and sBP, 122 ± 12 vs. 152 ± 11 mmHg. These results suggest that glucagon has a direct facilitatory effect on the central sympathetic nervous system.

Diabetic ketoacidosis in obese African-Americans.

Our preliminary data indicate that 15% of African-American patients presenting with diabetic ketoacidosis (DKA) are obese. To determine underlying mechanisms, we analyzed the clinical characteristics and indexes of insulin secretion and insulin sensitivity in 35 obese patients with DKA, 22 obese patients with hyperglycemia, 10 lean patients with DKA, and 10 obese nondiabetic subjects. Studies were performed 1 day after resolution of DKA and after 12 weeks of follow-up. At presentation, both obese DKA and obese hyperglycemic patients had no detectable insulin response to intravenous glucose, but they did respond to glucagon administration. The acute insulin response (AIR) to glucagon in obese DKA patients (0.9 +/- 0.1 ng/ml, P < 0.01), but significantly greater than in lean patients with DKA (0.1 +/- 0.1 ng/ml, P < 0.01). After 12 weeks of follow-up, the AIR to glucose improved in both groups of obese diabetic patients but remained significantly lower than in nondiabetic control subjects (both P < 0.01). In contrast, the AIR to glucagon was not significantly different from that in obese control subjects. Insulin sensitivity was decreased in both groups of obese diabetic patients at presentation and improved after follow-up to levels similar to those in obese nondiabetic control subjects. Reactivity with islet cell antibodies was not detected in any of the patients. During follow-up, 25 of 35 obese DKA and 16 of 22 hyperglycemic patients were able to discontinue insulin therapy, with continued good metabolic control. Our results indicate that in African-Americans, obese patients with DKA represent a subset of type II diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucagon effect on intracellular proteolysis and pericanalicular location of hepatocyte lysosomes in isolated perfused guinea pig livers

In guinea pigs, glucagon choleresis is accompanied by a significant, but transient, stimulation of biliary protein secretion, which can be accounted for mainly by biliary discharge of lysosomal enzymes. To clarify whether intracellular proteolysis-a process regulated by glucagon and taking place predominantly in the lysosomes-may interact with biliary protein secretion, we determined hepatic proteolytic activity and bile secretory function during substrate deprivation, amino acid supplementation, and glucagon administration in isolated perfused guinea pig livers. To further elucidate the nature of transient lysosomal enzyme release into bile during glucagon infusion, we analyzed pericanalicular distribution of lysosomes by quantitative electron microscopy. The results demonstrate that intracellular proteolysis is accompanied by biliary excretion of lysosomal enzymes. Glucagon-induced secretion of these enzymes as well as labeled proteins into bile occurs independent of protein breakdown and cannot be modulated by addition of amino acids as potent inhibitors of intracellular proteolysis. During glucagon administration, bile canalicular area and pericanalicular distribution of secondary lysosomes show a rapid increase, which persists during the entire infusion period and thus does not explain the transient biliary release of lysosomal enzymes. We therefore postulate that regulation of this process must be located beyond the lysosomal compartment, either involving transport processes or intracellular kinetics of lysosome formation or altered fusion kinetics at the bile canalicular membrane compartment. Metabolic and biliary effects of glucagon seem to occur independent of each other and to underly different regulatory mechanisms.