Glucagon As a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin?
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biomolecules Review Glucagon as a Therapeutic Approach to Severe Hypoglycemia: After 100 Years, Is It Still the Antidote of Insulin? Francesca Porcellati 1, Stefania Di Mauro 2, Alessio Mazzieri 1, Alessandra Scamporrino 2 , Agnese Filippello 2 , Michelantonio De Fano 1, Carmine Giuseppe Fanelli 1 , Francesco Purrello 2 , Roberta Malaguarnera 3,* and Salvatore Piro 2 1 Department of Medicine and Surgery, Perugia University School of Medicine, Via Gambuli 1, 06126 Perugia, Italy; [email protected] (F.P.); [email protected] (A.M.); [email protected] (M.D.F.); [email protected] (C.G.F.) 2 Department of Clinical and Experimental Medicine, Internal Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122 Catania, Italy; [email protected] (S.D.M.); [email protected] (A.S.); agnese.fi[email protected] (A.F.); [email protected] (F.P.); [email protected] (S.P.) 3 Faculty of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy * Correspondence: [email protected]; Tel.: +39-0935-536577 Abstract: Hypoglycemia represents a dark and tormented side of diabetes mellitus therapy. Patients treated with insulin or drug inducing hypoglycemia, consider hypoglycemia as a harmful element, which leads to their resistance and lack of acceptance of the pathology and relative therapies. Severe hypoglycemia, in itself, is a risk for patients and relatives. The possibility to have novel strategies Citation: Porcellati, F.; Di Mauro, S.; and scientific knowledge concerning hypoglycemia could represent an enormous benefit. Novel Mazzieri, A.; Scamporrino, A.; Filippello, A.; De Fano, M.; Fanelli, available glucagon formulations, even now, allow clinicians to deal with hypoglycemia differently C.G.; Purrello, F.; Malaguarnera, R.; with respect to past years. Novel scientific evidence leads to advances concerning physiopathological Piro, S. Glucagon as a Therapeutic mechanisms that regulated glycemic homeostasis. In this review, we will try to show some of the Approach to Severe Hypoglycemia: important aspects of this field. After 100 Years, Is It Still the Antidote of Insulin?. Biomolecules 2021, 11, 1281. Keywords: diabetes; glucagon; hypoglycemia; therapy https://doi.org/10.3390/ biom11091281 Academic Editor: Vladimir 1. Introduction N. Uversky When insulin was introduced to the scientific world of diabetes in 1922, it immediately became clear that it was one of medicine’s most significant breakthroughs. Nevertheless, Received: 3 August 2021 shortly after the discovery, Elliot Joslin wrote, “insulin is not a cure for diabetes, but a potent Accepted: 26 August 2021 Published: 27 August 2021 preparation ... for evil and for good”. It might have seemed unusual for Joslin to describe insulin in this way, yet clearly, he was referring to the most common and feared side-effect Publisher’s Note: MDPI stays neutral of insulin therapy, hypoglycemia [1]. with regard to jurisdictional claims in Moreover, in 1922 James Collip, while working with Frederick Banting on purifying published maps and institutional affil- insulin, in an attempt to measure insulin activity, identified one unit of insulin as the iations. amount necessary to induce hypoglycemic seizures in a rabbit. After 100 years, despite all the major advances in insulin therapy and blood glucose monitoring, hypoglycemia still remains the dark side of insulin, the major barrier preventing the full realization of its promise in diabetes management [2]. Hypoglycemia has severe clinical consequences. It is a risk factor for morbidity Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. and mortality and heavily impacts the quality of life of people with diabetes and their This article is an open access article caregivers. distributed under the terms and Moreover, hypoglycemia may contribute greatly to increased health costs. Therefore, conditions of the Creative Commons prevention and minimization of the risk and burden of hypoglycemia must be one of the Attribution (CC BY) license (https:// main objectives in the treatment of diabetes. Hypoglycemia in people with diabetes is the creativecommons.org/licenses/by/ consequence of treatment necessary to control hyperglycemia and prevent its long-term 4.0/). complications. However, pharmacological treatments for Type 2 Diabetes (T2DM) available Biomolecules 2021, 11, 1281. https://doi.org/10.3390/biom11091281 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 1281 2 of 19 on the market today, include a number of options. Some of these agents have a low risk of hypoglycemia and for this reason they are strongly recommended for patients for whom avoiding hypoglycemia is a clinical priority [3]. In such conditions, preferred pharmaco- logical strategies include DPP-4 (Dipeptidyl Peptidase 4) inhibitors, GLP-1 (Glucagon-Like Peptide 1) receptor agonists, SGLT2 (Sodium-Glucose Cotransporter-2) inhibitors, and TZDs (Thiazolidinediones), while sulfonylureas and glinides should be avoided [3]. With regards to injectable treatments whenever possible, GLP-1 receptor agonists should be preferred to insulin. In Type 1 Diabetes (TD1M), insulin analogues, both short-acting and long-acting, should always be offered as an option, which more closely reproduce the physiological needs and translate into a lower risk of hypoglycemia given the specific pharmacokinetics and pharmacodynamics of both preparations [4–8]. Sensor technology is providing evidence of improving patients’ lives not only by attaining glycaemic control but also by reducing hypoglycemia. Therefore, the actual scenario in terms of therapeutic options, that may limit the risk of hypoglycemia in diabetes care, is doubtless far better than that of a few decades ago. However, mild hypoglycemia is still “a fact of life” for people with T1DM [9]. Severe episodes still represent a burden in terms of quality of life for people with diabetes, a diabetes management’s issue for healthcare providers, and a high cost for national healthcare systems. This review first describes the epidemiological context of hypoglycemia and in par- ticular severe hypoglycemia both in T1DM and T2DM, subsequently, it briefly focuses on its pathophysiology. The review further aims to illustrate ways and options to limit hypo- glycemia in clinical practice, and the striking power of structured education programs. Last but not least, it shows the available treatments for severe hypoglycemia with a particular focus on the novel formulation of nasal glucagon. 2. The “Numbers” of Hypoglycemia In people with diabetes, hypoglycemia is defined as a condition in which blood glucose level is lower than normal, thereby exposing the individual to potential harm [10,11]. Hypoglycemia in diabetes is usually defined by clinical criteria based on the severity of hypoglycemic events [12]. Non-severe hypoglycemia episodes (Level 1), are defined by plasma glucose concentrations between 54 and 70 mg/dL [3.0 and 3.9 mmol/L]. These non- severe events are generally characterized by a series of behavioral responses (symptoms), including the ingestion of carbohydrates, aimed at correcting of hypoglycemia and at preventing the further decrease in plasma glucose level and, as consequence, the risk of cognitive impairment. When glucose continues to decrease (Level 2), reaching levels that are less than 54 mg/dL [less of 3.0 mmol/L], or when patients need assistance from third parties (Level 3), we are in a condition of severe hypoglycemia (SH). When this situation occurs, assistance from another person to actively administer carbohydrates, glucagon, or to take other corrective measures is required to recover the clinical status, especially the functional brain failure of the affected individual [3]. Plasma glucose measurements may not be available during the hypoglycemic crisis, but the prompt neurological recovery after raising plasma glucose level is considered sufficient evidence that severe hypoglycemic episode took place. In T1DM, the frequency of non-severe (mild) hypoglycemia is believed to be approxi- mately 0.7–2 episodes/patient-week [13,14]. This estimate is most likely under-reported because main mild hypoglycemic episodes are often ignored, especially when occurring at night, or are treated by patients themselves. Therefore, detailed information on most of non-severe hypoglycemic events are not likely provided to doctors and healthcare visitors. However, mild hypoglycemia has relevant clinical implications and may result in serious acute consequences. In fact, recurrent episodes of mild/moderate hypoglycemia over a short time, may induce unawareness of hypoglycemia and counter-regulatory response, thereby predisposing to the risk of SH [1]. In contrast, much information is available on SH, as most episodes require the help of another person or hospital admission so that these hypoglycemic events are easily Biomolecules 2021, 11, 1281 3 of 19 recognized by patients or their relatives/caregivers. Several scientific evidences indicate that rates of SH are higher in unselected populations than in those recruited in clinical trials where, almost always, people with risk factors for SH (i.e., hypoglycemia unaware- ness, previous episodes of SH, long duration of insulin therapy) are excluded [15]. In- deed, in an observational study in the UK, the rate of severe hypoglycemia ranged from 1.1 to 3.2 episodes/patient-year according to insulin treatment duration (<15 years and >15 years, respectively) [13]. This rate was substantially higher compared