Stimulation Test With Intranasal Glucagon for Corticotroph, Somatotroph and Antidiuretic Axes

Study Overview
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Brief Summary
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The diagnosis of secondary hypoadrenalism and GH deficiency (GHD) often requires the performance of a dynamic test. The glucagon stimulation test (GST) is one of the options for evaluating hypothalamic-pituitary function, representing a stimulus for both the corticotropic and somatotropic axis, substantially safe and easily available. The standard procedure involves the intramuscular injection of 1-1.5 mg of glucagon based on the patient's weight. In addition to its antero-pituitary function, glucagon has also shown its ability to stimulate neurohypophyseal secretion. Using the copeptin dosage, it has been shown that after the administration of glucagon in healthy subjects there is a significant release of ADH. However, the available data are scarse and there is no standardized protocol for the use of the glucagon test in diabetes insipidus. At the moment, GST is not the most frequently chosen diagnostic option. In fact, despite having the advantage of being able to investigate different areas of anterohypophyseal and probably posterohypophyseal function at the same time, the test has some disadvantages: the prolonged duration makes the procedure challenging, the intramuscular injection can be unwelcome, and many variables can come into play in the definition of a normal response (age, BMI, glycemic status). The recent introduction of a single-dose nasal powder formulation (Baqsimi®) could overcome some of the limitations of classic GST and make the procedure less demanding. To date, no assessments are yet available regarding a purely diagnostic role in the context of hypopituitarism of this new formulation. Through the knowledge of the physiological response of the adrenocortical, somatotropic and ADH axis to the administration of intranasal glucagon in healthy subjects, it will be possible to evaluate its possible application in the diagnosis of GH deficiency, central adrenal insufficiency and possibly diabetes insipidus.

Official Title
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Stimulation Test With Intranasal Glucagon for Corticotroph, Somatotroph and Antidiuretic Axes

Conditions
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Hypopituitarism

Intervention / Treatment
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* Drug: Intranasal glugagon
* Drug: Intranasal placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Any adult healthy subject (age >= 18 years old) and not meeting the exclusion criteria listed below Exclusion Criteria: BMI < 18.5 kg/m2 or > 25 kg/m2 Any active pharmacological treatment Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intranasal Administration of Glucagon<br>Intranasal administration of glucagon in healthy subjects | Drug: Intranasal glugagon<br>* Intranasal glucagon is administered at the dose of 3 mg. This corresponds to the administration of a single dose of Baqsimi®.<br>* Other names: Baqsimi®;|
| Placebo Comparator: Intranasal Administration of Placebo<br>Intranasal administration of placebo (isotonic saline solution) in healthy subjects | Drug: Intranasal placebo<br>* Intranasal placebo (represented by isotonic saline solution) is administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum ACTH levels between baseline and 15 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 30 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 45 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 60 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 75 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 90 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 120 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 150 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum ACTH levels between baseline and 180 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum ACTH (ng/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 15 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 30 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 45 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 60 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 75 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 90 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 120 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 150 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum cortisol levels between baseline and 180 minutes after glucagon/placebo administration | The response of the corticotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum cortisol (µg/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 15 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 30 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 45 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 60 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 75 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 90 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 120 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 150 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum GH levels between baseline and 180 minutes after glucagon/placebo administration | The response of the somatotroph axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring serum GH (µg/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 15 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 30 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 45 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 60 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 75 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 90 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 120 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 150 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in plasma copeptin levels between baseline and 180 minutes after glucagon/placebo administration | The response of the antidiuretic axis to the administration of intranasal glucagon, compared to placebo, was evaluated by measuring plasma copeptin (pmol/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum sodium levels between baseline and 15 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 30 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 45 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 60 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 75 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 90 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 120 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 150 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum sodium levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum sodium (mmol/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 15 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 30 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 45 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 60 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 75 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 90 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 120 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 150 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum potassium levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum potassium (mmol/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 15 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 30 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 45 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 60 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 75 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 90 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 120 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 150 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in plasma osmolality between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma osmolality (mOsm/kg) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 15 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 30 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 45 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 60 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 75 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 90 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 120 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 150 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in serum glucose levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring serum glucose (mg/dl) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 15 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 15 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 15 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 30 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 30 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 30 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 45 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 45 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 45 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 60 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 60 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 60 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 75 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 75 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 75 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 90 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 90 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 90 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 120 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 120 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 120 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 150 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 150 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 150 minutes after glucagon/placebo administration | 
| Change in plasma insulin levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring plasma insulin (mU/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in urine sodium levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring urine sodium (mmol/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in urine potassium levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring urine potassium (mmol/L) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in urine creatinine levels between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring urine creatinine (mg/dl) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in urine osmolality between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of glycometabolic and hydro-electrolyte biochemical balance was evaluated by measuring urine osmolality (mOsm/kg) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in resistance at bioimpedance vector analysis between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of bioimpedance vector analysis (BIVA) was evaluated by measuring resistance (Ohm) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in reactance at bioimpedance vector analysis between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of bioimpedance vector analysis (BIVA) was evaluated by measuring reactance (Ohm) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration | 
| Change in phase angle at bioimpedance vector analysis between baseline and 180 minutes after glucagon/placebo administration | The response to the administration of intranasal glucagon, compared to placebo, in terms of bioimpedance vector analysis (BIVA) was evaluated by measuring phase angle (°) at baseline (0 minutes) and after 180 minutes from glucagon/placebo administration. | From baseline (0 minutes) to 180 minutes after glucagon/placebo administration |