Intranasal glucagon for hypoglycaemia in diabetic patients. An old dream is becoming reality?

In 1983 it was shown that glucagon administered intranasally (IN) was absorbed through the nasal mucosa and increased blood glucose in healthy subjects. Shortly thereafter, it was shown that IN glucagon counteracts with hypoglycaemia in insulin-treated diabetic patients. In spite of this evidence, IN glucagon was not developed by any pharmaceutical company before 2010, when renewed interest led to intensive evaluation of a possible remedy for hypoglycaemia in insulin-treated diabetic adults and children. IN glucagon is now being developed as a needle-free device that delivers glucagon powder for treatment of severe hypoglycaemia; the ease of using this device stands in stark contrast to the difficulties encountered in use of the current intramuscular glucagon emergency kits. Studies have demonstrated the efficacy, safety and ease-of-use of this IN glucagon preparation, and suggest IN glucagon as a promising alternative to injectable glucagon for treating severe hypoglycaemia in children and adults who use insulin. This would meet the unmet medical need for an easily administered glucagon preparation.

Two-channel gastric pacing with a novel implantable gastric pacemaker accelerates glucagon-induced delayed gastric emptying in dogs.

BACKGROUND: The aim of the current study was to investigate the efficacy of 2-channel gastric electrical stimulation (GES) with a custom-made implantable pacemaker on delayed gastric emptying and gastric dysrhythmia induced by glucagon in dogs. METHODS: Six dogs were studied in 4 randomized session (saline, glucagon, glucagon with single-channel or 2-channel GES). GES was applied via the first pair of electrodes for single-channel GES or the first and third pairs of electrodes for 2-channel GES. Gastric emptying was assessed for 90 minutes and gastric slow waves were recorded at the same time. RESULTS: Both single-channel and 2-channel GES improved gastric dysrhythmia (P < .05 vs glucagon session). Two-channel GES but not single-channel GES improved glucagon-induced delayed gastric emptying at 30 minutes, 45 minutes, 60 minutes, 75 minutes, and 90 minutes. CONCLUSION: Two-channel GES with a novel implantable pacemaker is more efficient and effective than single-channel GES in improving delayed gastric emptying induced by glucagon. This implantable multipoint pacemaker may provide a new option for treatment of gastric motility disorders.

Delayed hypersensitivity reaction after intravenous glucagon administered for a barium enema: a case report.

INTRODUCTION: Few reports have documented allergic hypersensitivity reactions after barium gastrointestinal studies. Of these, the barium suspension, its additives or intravenous glucagon given for bowel relaxation has been implicated as possible allergens. We report a patient with delayed hypersensitivity reaction after barium enema and discuss the reasons supporting glucagon as the possible allergen. CLINICAL PICTURE: A 74-year-old Chinese woman presented with pruritic rashes, 1 day after a barium enema. Intravenous glucagon (GlucaGen, Novo Nordisk, Denmark) was administered during the barium enema. Physical examination revealed palpable purpuric rashes on the legs with erythematous papules and plaques on the arms and trunk. Skin biopsy demonstrated superficial perivascular infiltrates of lymphocytes and eosinophils, consistent with a drug eruption. TREATMENT AND OUTCOME: The rashes resolved with antihistamines and topical corticosteroids. CONCLUSION: This report highlights the potential of glucagon to cause hypersensitivity reactions. Awareness of this entity is important for the prevention and recognition of complications during barium gastrointestinal studies.

Impact of portacaval anastomosis on plasma fatty acid profile in cirrhosis: a randomized 24-month follow-up study.

BACKGROUND: Portacaval anastomosis has an hypolipemic effect in familial hypercholesterolemia and in healthy animals. In cirrhosis, it raises serum cholesterol, but there is no information on its effect upon plasma fatty acids. However, indirect data suggest that portacaval shunting might contribute to the polyunsaturated fatty acid deficit of these patients. We assessed the effect of portacaval anastomosis on plasma fatty acid profile in cirrhosis. METHODS: Forty-four Child-Pugh class A/B bleeding cirrhotics were randomized to be treated with portacaval anastomosis (n = 20) or nonsurgical therapy (n = 24). Fatty acid profile in plasma total lipids, alcohol intake, anthropometry, Child-Pugh score, serum cholesterol, triglycerides, and antioxidant micronutrients were assessed before and 3, 6, 12, 18, and 24 months after surgery or the start of nonsurgical therapy. Time course of plasma fatty acids was assessed using unbalanced repeated measures models with the above mentioned variables acting as covariates. RESULTS: No changes in the time course of percent plasma saturated, monounsaturated, and essential fatty acids were found between groups. Percent long-chain omega-6 and omega-3 polyunsaturated fatty acids decreased during follow-up in shunted patients compared with controls (p = .007 and p < .0005). However, this was not due to a true decrease in polyunsaturated fatty acid levels but to greater increases in saturated and monounsaturated fatty acid concentrations in shunted patients compared with control patients (p = .047 and p = .006). CONCLUSIONS: Portacaval anastomosis does not worsen plasma polyunsaturated fatty acid deficiency in cirrhosis. However, by increasing saturated and monounsaturated fatty acids, it further decreases plasma lipid unsaturation.

Use of antispasmodic drugs in double contrast barium enema examination: glucagon or buscopan?

PURPOSE: To compare the spasmolytic effect of glucagon and buscopan in double contrast barium enema examination. PATIENTS AND METHODS: Three hundred and twenty-four consecutive patients referred for double contrast barium enema examination were randomly allocated to receive an intravenous injection of either 1 mg of glucagon, 20 mg of buscopan or physiological saline. The transit of the barium column from rectum to caecum, the quality of the radiographs and side effects were assessed blindly without knowledge of the injected drug. RESULTS: Antispasmodic drugs (glucagon or buscopan) resulted in better transit of the barium column to the caecum compared to placebo (Mann-Whitney: P < 0.05), but no differences occurred between glucagon and buscopan (Mann-Whitney: P > 0.05). Buscopan produced better distension of the rectosigmoid than glucagon or placebo (P < 0.05). Of 109 patients who received buscopan five complained of blurred vision afterwards. CONCLUSION: Because buscopan is less expensive and more effective in distending the colon than glucagon, it is preferred for the routine double contrast examination. However, patients should be warned about the possibility of temporary visual impairment.

Glucagon potentiates intestinal reperfusion injury.

Vasoactive agents, including glucagon, have been used in treatment of mesenteric ischemia. Such drugs change both intestinal blood flow and metabolism. Since reperfusion injury reflects the metabolic state of an organ as well as the duration and severity of ischemia, we investigated the effect of glucagon in a standard model of intestinal ischemia. Data were generated from denervated isoperfused rat small intestinal preparations (n = 39). Arterial and venous pressures, intestinal blood flow, and oxygen consumption were monitored. Animals were subjected to 15, 30, or 45 minutes of ischemia followed by 1 hour reperfusion. Experiments were performed without drug infusion or during intravenous glucagon administration (0.1, 0.2, or 0.4 micrograms/kg/min). After the rats were killed, histologic sections of intestine were graded 1 through 5 in a blinded fashion with 1 = normal villi and 5 = severe injury. Results (mean +/- SD) were analyzed by analysis of variance (*p less than 0.05). Glucagon at all concentrations increased intestinal blood flow and oxygen consumption before ischemia. For example, with 0.2 micrograms/kg/min glucagon, intestinal blood flow increased from 80.78 +/- 13.5 to 114.79 +/- 21.02 ml/min.100 gm* and oxygen consumption increased from 3.65 +/- 0.73 to 5.73 +/- 1.37 ml/min.100 gm.* Mucosal injury after ischemia reflected duration of ischemia and glucagon infusion rate. At all ischemic intervals, increased glucagon concentrations were associated with greater mucosal injury. In fact the histologic injury with 15 minutes of ischemia + 0.2 microgram/kg/min glucagon (3.04 +/- 0.49) exceeded that of 30 minutes of ischemia (2.87 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of the effects of growth hormone release inhibiting factor enhances plasma growth hormone response to GHRH.

Responses of serum growth hormone (hGH) to glucagon (G), growth hormone releasing hormone (GHRH) and G/GHRH were measured in 8 normal adults and 6 patients with growth hormone deficiency (GHD). In normal adults, serum hGH reached its peak value (12.7 +/- 1.6 ng/ml) at 150 +/- 10 min, as blood glucose declined to its minimum after a transitory hyperglycemia in G test. The normal adults were responsive to GHRH test (GH peak 14.7 +/- 2.3 ng/ml at 30 +/- 0 min). In GHD, the responders to both G and GHRH tests showed a strongly positive response in G/GHRH test, with a serum hGH peak value of 34.6 +/- 4.1 ng/ml at 131 +/- 8 min being much higher than that of either single G or GHRH test (P less than 0.01), but without significant difference to the sum of the two single tests (P greater than 0.10). Among GHD patients, only 2 responded to GHRH and G/GHRH tests with hGH peak values 6.8 +/- 0.7 and 6.9 +/- 0.7 ng/ml at 45 +/- 15 and 90 +/- 0 min, respectively, both peak values being essentially similar (P greater than 0.10). We suggest that the mechanism of stimulation of pituitary hGH secretion in G test might involve inhibition of release of hypothalamic GH release inhibiting factor (GHRIF) caused by hypoglycemia after a transitory hyperglycemia following G injection. These results may further confirm our previous postulation (1986) that insulin hypoglycemia may increase hGH release by inhibiting hypothalamic cell secretion of GH release inhibiting factor.

Cardiopulmonary arrest following barium enema examination with glucagon.

This is a case report of a patient who presented to the hospital's ambulatory radiology suites for a barium enema to evaluate guaiac-positive stools. The patient, after receiving glucagon 0.5 mg iv and a small amount of rectally administered barium sulfate, experienced an "itchy tingling" feeling, vomited, became diaphoretic, and had a cardiopulmonary arrest. Despite a prompt response by the cardiac arrest team, the patient could not be resuscitated. This case demonstrates the potential for serious reactions during this procedure.

Anaphylactic and allergic reactions during double-contrast studies: is glucagon or barium suspension the allergen?

The authors report three anaphylactic reactions and one allergic reaction during double-contrast studies using glucagon. Symptoms included hives, periorbital edema, and breathing difficulties. Studies performed were three double-contrast barium enemas and one double-contrast upper gastrointestinal series. Glucagon injection and/or an additive in barium suspension are suspected as the likely causes. The allergic potential of glucagon injection, which is not generally appreciated, is reviewed.

Glucagon and barium enema examinations: a controlled clinical trial.

In a double-blind crossover clinical trial, 10 healthy volunteers received placebo and 2 mg glucagon intramuscularly preceding barium enema examination on separate days. In addition, 50 patients were given either placebo or 2 mg glucagon prior to barium enema examination in a double-blind study. The results of 38 variables determined on each study population were similar. When glucagon was given, both the patients and examiners noted significantly less discomfort and more bowel relaxation. There were no significant changes in pulse, blood pressure, or electrocardiogram. Adverse reactions did not occur frequently enough to allow confident comparison of placebo and glucagon. It is concluded that the use of glucagon can provide a more comfortable barium examination with acceptable safety.

Hypotonic examination of the colon with glucagon.

The authors report their experience with glucagon in the barium enema examination. Two milligrams of glucagon given intramuscularly was found to be safe and effective in overcoming functional spasm, permitting more detailed evaluation of organic narrowing. The relatively infrequent side effects and few contraindications seen with glucagon make it the drug of choice when reduction in intestinal tone is indicated.