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Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu / Tam, Joseph


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

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2191-0286
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Volume 27, Issue 5

Issues

Non-diabetic clinical applications of insulin

Jyoti M. Benni
  • Corresponding author
  • Department of Pharmacology, JN Medical College, KLE University, Nehru nagar, Belgaum-590001, Karnataka, India
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Paragouda A. Patil
  • Department of Pharmacology, USM-KLE, International Medical Programme Belgaum, Karnataka, India
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-05-28 | DOI: https://doi.org/10.1515/jbcpp-2015-0101

Abstract

Background:

Introducing a new drug to the market is a time-consuming process, is complex, and involves consumption of a lot of resources. Therefore, discovering new uses for the old drugs (i.e. drug repurposing) benefits the patients by providing them time-tested drugs. With developments in insulin therapy still happening, it is worth keeping up to date on trends in the use of this powerful glucose-lowering agent. The aim of this article is to explore the potential non-diabetic clinical applications of insulin.

Methods:

Literature survey was carried out through the various scientific journals publishing experimental and clinical research papers regarding the diverse applications of insulin other than in diabetes mellitus. These applications include both therapeutic as well as diagnostic uses of insulin. The relevant information collected from these publications was paraphrased in the present paper.

Results:

On studying the literature, the non-diabetic uses of insulin include the following: wound healing, parenteral nutrition, antiaging, body building, cardioprotection in acute coronary syndromes, insulin tolerance test to test the hypothalamo-pituitary-adrenal axis functioning, cell culture, cancer treatment, organ preservation, and management of septic shock, calcium channel, β-blocker overdose and other critical illnesses in intensive care units.

Conclusions:

This review attempts to survey some interesting new applications of insulin other than in diabetes mellitus.

Keywords: antiaging; body building; insulin; insulin potentiation therapy; insulin tolerance test; non-diabetic uses; organ preservation; wound healing

Introduction

Insulin is a naturally occurring peptide hormone secreted by the β cells of the pancreatic islets of Langerhans and is a key regulator of glucose homeostasis by facilitating cellular glucose uptake in the liver, skeletal muscles, and fat tissue. The term “insulin” originated from the Latin word insula meaning islet/island. Insulin was discovered in 1921 by Frederick Banting and Charles Best who were awarded the Nobel Prize in Physiology or Medicine in 1923. In 1951 Frederick Sanger determined the primary structure of insulin. It has molecular weight of about 6000 Da and is made up of two polypeptide chains having 51 amino acids; A-chain has 21, while B-chain has 30 amino acids linked together by disulfide bonds. The pancreatic β cells secrete insulin at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, principally glucose.

Insulin exerts its action through the specialized receptors, so-called insulin receptors (IRs), located on the cell membrane of essentially every cell. An IR consists of two covalently linked heterotetrameric glycoproteins consisting of two extracellular α-subunits and two transmembrane β-subunits linked together by disulfide bonds. The α-subunit carries insulin binding sites, and the β-subunit has tyrosine kinase activity. On binding of insulin to the α-subunit there is activation of tyrosine kinase activity that initiates a series of events. The plasma half-life of insulin is 5–9 min. In 1939, the FDA first approved insulin for the management of diabetes mellitus (DM). The conventional insulin preparations are derived from beef and pork pancreas, and now currently recombinant (human) preparations are available. In 1982, the FDA approved the first recombinant human insulin [1]. Insulin remains fundamental to the management of DM patients [2]. Insulin therapy is essential and lifesaving in type 1 DM patients. For type 2 DM patients, insulin therapy is usually consigned to use during later stages of the disease. But the recent treatment paradigms approach is being reexamined, to encourage earlier use of insulin treatment algorithms for patients with type 2 DM [3].

Over the previous century, multiple pleiotropic effects [4] and actions of insulin have been demonstrated. The advances in biochemistry, physiology, and pharmacology of insulin have been published earlier, but no review has targeted the spectrum of non-diabetic uses of this hormone insulin. It has now been investigated for various activities other than maintaining euglycemia. Various other applications of insulin include the following: wound healing activity, for body building purpose in athletes, as an antiaging agent, as a diagnostic test to check hypothalamo-pituitary-adrenal (HPA) axis activity, in the management of septic shock and as one of the key constituents of parenteral nutrition solutions, cell culture media, organ preservation solutions, and glucose-insulin-potassium (GIK) infusions. Also recently, its role is extended for cancer treatment and calcium channel blocker and β-blocker overdose or poisoning. The role of insulin beyond management of DM is presented in this detailed review. With advances in insulin therapy still occurring, it is worth updating the trends in the use of this powerful glucose-lowering agent.

Various non-diabetic clinical applications are discussed below.

Insulin on wound healing

Wounds are commonly encountered in the clinical practice. If healing of the wound is disturbed, hospital stay is extended and cost escalates, which are also associated with comorbidities. Efforts have been continued to promote healing of wounds particularly in diabetic wounds which are reluctant to heal. The main aim for the treatment of wound is to achieve rapid wound closure with an appealingly acceptable scar. In 1960s, for the first time insulin was tried for topical application [5]; since then several experiments have documented the positive effects of exogenous insulin on wound healing activity in both animals and humans, without major systemic side effects [6], [7], [8]. Topical insulin application to cutaneous wounds accelerates wound healing in rats with or without diabetes [9] and so also in both diabetic and non-diabetic human wounds [5]. Similarly, zinc protamine insulin accelerated wound healing in open wounds, surgical incisions, and lacerations [10].

A study showed that application of the topical insulin prepared in moxifloxacin hydrochloride ophthalmic solution at the dose of 1, 2 or 5 U for 7 days [single drop (20 μL) from the commercial applicator bottle to the central cornea of the injured eye 4 times a day] promoted healing of the abraded corneas and also restored the hyposensitivity of the cornea by reepithelialization in the type I diabetic rats, compared to the healthy rats where no reepithelialization was seen [11]. Insulin did not affect corneal thickness, intraocular pressure or serum glucose level in the affected animals. Insulin, by increasing DNA synthesis in the peripheral cornea, limbus, and conjunctiva 48 h after abrasion in diabetic rats, accelerated reepithelization of the cornea [11]. The topical insulin for healing has several advantages including the cost-effectiveness, increased patient compliance, ease of delivery, and independence from systemic serum glucose levels and adverse effects. Previously, a study showed that insulin 100 U/mL in isotonic sodium chloride solution administered long-term for 8 weeks to the human eye was not toxic [12].

Similarly, a study done in humans with noninfected acute and chronic extremity wounds demonstrated that the twice daily topical application (spray) of 1 mL 0.9% saline with 10 units of insulin was safe and effective. No patients developed signs or symptoms of hypoglycemia, and glucose levels pre- and post-application did not differ significantly [13]. Inflammatory response plays an initial role during wound healing, which is characterized by increased endothelial permeability, infiltration of inflammatory cells, and secretion of numerous growth factors and chemokines. Insulin plays a vital role in regulating cellular proliferation and inducing repair process in the devitalized tissues. It regulates wound inflammatory response by stimulating proliferation and migration of macrophages and keratinocytes in the adjacent tissues [13], [14]. It stimulates the metabolism of adjacent layer and helps to regenerate and proliferate once the exudate and necrotic tissue has been removed. Insulin also lowers infection rate by arresting bacterial growth and enhancing phagocytosis [14]. In vitro studies have presented insulin-facilitated monocytes/macrophages chemotaxis, pinocytosis/phagocytosis, and also secretion of inflammatory mediators. Therefore, this study explained that insulin is a potent wound-healing accelerant by regulating the number and function of macrophages.

Diabetic keratopathy is seen in majority of diabetic patients as the disease progresses. The important clinical significance of topical insulin is that its direct application may serve as an important strategy for treating diabetic keratopathy. Previous studies suggest that the hyposensitivity observed in diabetic animals is not permanent and can be reversed at least in the early stages of the disease and does not influence serum glucose levels, denoting that insulin action is directly at the site of application rather than by systemic action [11]. Other therapeutic utilities of topical insulin need to be explored in patients with corneal transplantation, vitrectomy, cataract surgery, and procedures such as laser photocoagulation and refractive surgery which are risk factors for abnormal corneal epithelial healing where the conventional therapies such as artificial tears and bandage contact lenses have failed.

Insulin in parenteral nutrition solutions

Parenteral nutrition (PN), also known as intravenous feeding, is feeding a person intravenously, bypassing the normal process of eating and digestion. PN formulations are balanced mixes of essential and non-essential amino acids, glucose, fat emulsions, electrolytes, micronutrients, water, vitamins, insulin, and other required vital medications [15]. PN has become one of the imperative primary and adjuvant therapies over the past few years for the treatment of patients with significant disruption in gastrointestinal function like in diseases such as Crohn’s disease, cancer, short bowel syndrome, and ischemic bowel disease, etc. PN is administered via a central venous catheter or through a peripheral limb vein. PN therapy in acute care institutions is on an average 10–14 days duration [16]. The duration of feeding depends on the degree of malnutrition. PN is expensive and also carries higher risk of complications. The major complication is hyperglycemia, which sets the patient at risk for infection. Therefore, insulin is frequently required in PN solutions to control hyperglycemia [17].

Literature review shows that insulin availability in PN solutions ranges from 10% to 95% [17], [18]. Only regular human insulin is added to the admixtures, as insulin analogs such as insulin lispro or insulin aspart are not compatible with PN formulations [19]. During infusion the blood glucose level is maintained between 80 and 130 mg/dL [20]. Routine insulin dosage practiced is 0.1 unit/g of dextrose in the PN infusion and in hyperglycemic patients (>150 mg/dL), 0.15 unit/g of dextrose [15], [21]. If the blood glucose level is ≥300 mg/dL, PN is halted until the glucose level recedes to <200 mg/dL. Capillary glucose levels are checked every 6 h and supplemented with additional subcutaneous insulin appropriately dosed by sliding-scale insulin coverage to maintain the desired glucose range. A separate insulin infusion is started if hyperglycemia persists even when 0.3 unit/g of PN dextrose is surpassed, to achieve more appropriate glycemic control [15]. At times, PN is withdrawn in the refractory hyperglycemic patients, till euglycemia is achieved [22]. Other approaches for glycemic control during PN infusion include just adequate feed to the patient, limited dextrose in PN to 150 g/day, increase insulin units according to sliding scale coverage, monitoring glucose levels frequently, and discontinuation of TPN for 24 h [19].

Insulin plays a key role in protein anabolism in addition to its regulatory functions in glucose homeostasis. Insulin enhances the rate of amino acid uptake and protein synthesis in muscles and also inhibits the extent of protein degradation [23], [24]. Deficiency of insulin results in muscle wasting and increased nitrogen balance as seen in patients with DM and in bed-ridden patients. A study showed that addition of insulin to PN solutions accelerates restoration of a depleted body cell mass, i.e. the correction of the malnourished state [24]. Acute complications of PN include hyperglycemia [17], catheter- related infections, electrolyte imbalances, etc. Long-term complications of PN include fatty liver, cholestasis, cholelithiasis, metabolic bone disease, and electrolyte/vitamin/mineral depletion or toxicity [25]. However, PN may include many other drugs like heparin, type-2 histamine receptor antagonists, albumin, digoxin, dopamine, erythropoietin, furosemide, hydrocortisone, methylprednisolone, metoclopramide, octreotide, and ondansetron to correct the underlying conditions [26].

PN is a valuable and necessary medical treatment for several patients providing both nutritional maintenance and life extension at a time when it is not possible to sustain them any other way. Appropriate use of this complex nutrition therapy maximizes clinical benefits while minimizing the potential risk for adverse events.

Insulin for body building

Athletes use performance-enhancing drugs for muscle-building purposes so as to improve their endurance. Commonly used performance-enhancing drugs in athletes include anabolic androgenic steroids, clenbutarol, erythropoietin, diuretics, growth hormone (GH), and, recently, insulin; all of these have potential health consequences [27].

Doping is the use of prohibited substances unlawfully to improve their sporting performance (body building) and is detrimental to the overall impact of sporting spirit. Doping in sports has been ongoing since the original Olympic Games, with the desire to win at all cost. The International Olympic Committee Medical Commission and sub-commission ‘Doping and Biochemistry in Sport’ announce annually a list of ‘banned substances’ and have developed a sophisticated system for detecting drug abuse. Recent evidences suggest that insulin and GH have now become a significant threat in the sports arena [28].

GH, due to its anabolic and lipolytic properties, which leads to an increase in lean body mass and reduction in fat mass, has been used in sports since the early 1980s [29]. Insulin was used as a doping agent frequently in the Olympic Games, as in Nagano in 1998 [28], [30]. Insulin with GH is being used by many athletes and body builders for increasing their muscle mass.

The primary source of carbohydrate during exercise is muscle glycogen stores. Performance in many events is known to be a function of muscle glycogen stores; ‘bulking up’ these stores will most probably enhance performance, i.e. the greater the muscle glycogen stores, the longer the exercise time to exhaustion [31]. Insulin increases protein synthesis in the muscle by increase in amino acid transport and ribosomal protein synthesis. It also increases glycogen synthesis by increasing transport of glucose and inducing glycogen synthase enzyme [32]. Physiological hyperinsulinemia reportedly stimulates amino acid transport in human skeletal muscles [33]. It is remarkably difficult to detect insulin abuse using laboratory tests because of its short half-life [34].

Most of the abusers inject 10 IU regular insulin and then consume sugar-containing foods and drinks so as to avoid hypoglycemic events [27]. Insulin abuse in body builders is an increasing problem and can lead to potentially serious consequences like hypoglycemia for prolonged periods away from possible medical assistance, potentially resulting in coma and death. The athletes are risking long-term harm by using these drugs. The medical exception to the rule is athletes with DM requiring insulin treatment [34].

Insulin as antiaging agent

Aging is an inevitable extremely complex multifactorial process. Aging is defined as the process that progressively converts a physiologically and cognitively fit healthy individual into a less fit individual with increased vulnerability to injury, illness, and death. It includes progressive accumulation of random molecular defects that build up within tissues and cells and, regardless of multiple repair mechanisms, result in age-related functional impairment of tissues and organs [35]. Aging is associated with a metabolic decline characterized by the development of changes in fat distribution, obesity, and insulin resistance. The human aging is characterized by reduced insulin secretion from β cell and increased insulin resistance in the peripheral tissues [36]. Insulin resistance leads to compensatory increase in insulin release, while hyperinsulinemia promotes insulin resistance via depletion of IRs, and earlier studies have revealed that hyperinsulinemia and insulin resistance accelerate aging [37]. This is likely to result in hyperglycemic state.

Caloric restriction due to euglycemia is broadly used to study aging processes, as it is known to increase life span and retard occurrence of age-related diseases, including cancer and diabetes [38]. Hyperglycemia is an important aging factor involved in generation of advanced glycosylation end products (AGE) and glycation of proteins [39]. Hyperglycemia can promote age-related disease by a variety of mechanisms including abnormal enhancement of the sensitivity of vascular smooth muscle to IGF-1 and generation of atherosclerotic lesions, impaired wound healing, cataracts, and microvascular damage. The accumulation of pentosidine, an AGE, is accelerated in diabetic patients and has been recognized to be a reliable biomarker of aging [40].

Klotho is a recently discovered antiaging (aging suppressor) gene, and it is expressed in mouse pancreatic islets and insulinoma β cells (MIN6 cells) [41]. Klotho gene is named after a Greek goddess Klotho, who spins the thread of life [42]. Klotho protein is predominantly expressed in the pancreas, kidney, and the brain choroid plexus [42]. In humans, the klotho levels decrease gradually with advanced age [43]. Insulin hormone increases significantly the levels of secreted klotho. Previous studies led to the observation that secretion of Klotho is regulated by insulin [44]. Klotho inhibits aging by interfering with the actions of insulin and insulin growth factor 1, an evolutionarily conserved mechanism for extending life span [45]. Klotho protein activates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, thereby inducing expression of manganese superoxide dismutase. This in turn facilitates removal of reactive oxygen species and confers oxidative stress resistance. Thus, Klotho-induced inhibition of insulin/IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the anti-aging properties of klotho [44].

Another study disclosed that Klotho protein enhances glucose-induced insulin secretion via regulation of transient receptor potential V2 (TRPV2). TRPV2 is a membrane calcium channel that determines calcium entry in β cells. It was noted that calcium entry and glucose-induced insulin secretion were increased by overexpression of the klotho gene and were abolished by tranilast, a TRPV2 channel inhibitor [41]. Overexpression of klotho protein extended the life span in mice [46]. A previous study demonstrated that a defect in klotho gene expression in mice leads to a syndrome closely approximating human aging, including shortened life span, infertility, growth arrest, hypoactivity, skin atrophy, premature thymic involution, arteriosclerosis, osteoporosis, and pulmonary emphysema [42], [46]. Genetic Klotho deficiency leads to hypoinsulimia and pancreatic β-cell dysfunction in mice [47].

In humans, enhanced insulin sensitivity and reduced insulin levels reduce risk of age-related diseases and are associated with improved survival. Therefore, conserving physiological health in an aging population is of vital significance and also from a social perspective helps to reduce the liability on health care services [48]. Loss of these functional reserves may compromise an individual’s ability to survive with external challenges such as surgery or trauma.

Insulin for cell culture and organ preservation

Cell culture, one of the major techniques in life science research, is a complex process by which cells are grown under controlled conditions, in a favorable artificial environment. Insulin is required for the growth and development of cells [49] and also stimulates the proliferation of certain cells in culture [50]. Numerous hormones including insulin are used as an essential component of synthetic growth media for cell culture [51]. Insulin has been found to be stimulatory in serum-free medium for the growth of virtually every cell type including mammalian cells [52]. It is used for the manufacture of monoclonal antibodies, virus vaccines, gene therapy products, and other biological drugs [53].

Insulin, by increasing the permeability of cell membranes to glucose and making nutrients available to the cells, promotes the growth of mammalian cells [51]. The action of insulin in mammalian cell culture is primarily through the binding and activation of IGF-1R [54]. Mammary tumor cell lines, like the MCF-7 cell line, respond to low levels of insulin, suggesting that the growth-promoting effect is mediated by the IR [55], [56]. Insulin through the IR also inhibits apoptosis induced by serum withdrawal in a variety of cell types [57], [58].

The recommended concentration of insulin in cell culture media is 1–10 mg/L, depending on cell type and specific application [53]. In mammalian cell cultures, recombinant insulin is added at approximately 100 times the physiological concentration. Insulin at this high concentration acts as a growth factor, with anti-apoptotic and mitogenic effects [59]. Also at higher concentrations insulin maintains anabolic effect on cells required for optimal cell growth [60].

In an earlier study, the effects of three concentrations of insulin (100, 1000, and 10,000/U/mL) added to tissue culture medium containing 1% serum were compared with the effects of the 1% serum medium alone and medium containing 5% serum. Higher concentrations of insulin lead to successively greater stimulation of aortic smooth muscle cell proliferation and weakened response to serum when insulin has been extracted from it, indicating that insulin has growth-promoting properties [61].

Organ preservation is the supply line for organ transplantation. Transplantation of organs continues to be a primary therapeutic modality for treatment of end-stage organ disease. University of Wisconsin (UW) cold storage solution was the first solution designed for use in organ transplantation and is often called the gold standard for organ preservation [62]. Currently, the liver, pancreas, and kidney can be successfully preserved for up to 2 days by flushing the organs with the UW solution and storing them at hypothermia (0–5 °C) [62]. The UW solution contains a number of cell impermeant agents (lactobionic acid, raffinose, hydroxyethyl starch), to prevent the cells from swelling during cold ischemic storage, and regular insulin 40 U/L [63]. It has increased the safe time of preservation for the liver, kidney, and pancreas and helped to increase the quality and number of organs available for transplantation [64]. But in one previous study, insulin in UW preservation solution was shown to exacerbate the hepatic ischemic/reperfusion injury by energy depletion in rat liver transplantation and decrease the graft survival rate [65].

Hyperglycemia is common in organ donor individuals, due to stress response to injury and catecholamine-induced insulin resistance or rapid infusion of large volumes of glucose-containing fluids. Mainly to prevent osmotic diuresis and electrolyte imbalances, IV regular insulin is administered when blood glucose level is more than 200 mg/dL [66].

Diagnostic use of insulin

It is well known that the HPA axis is a major part of the neuroendocrine system that controls reactions to stress and regulates many of the body processes. The core function of HPA axis is to enable sufficient cortisol release under regular and stressful situations. Cortisol produced in the adrenal cortex has negative feedback to inhibit both the hypothalamus and the pituitary gland. Insulin tolerance test (ITT) is accepted as the gold standard test for the evaluation of both HPA and GH-IGF-1 axis [67], [68]. The principle of the test is that hypoglycemia induces a severe stress, which stimulates the HPA axis maximally and releases adrenocorticotropic hormone (ACTH) and GH [68]. Thus, ITT may help in patients who require GH replacement therapy [69].

The test is conducted in overnight fasted patients with normal electrocardiogram (ECG). After the side effects are explained, patients in recumbent position are administered soluble insulin 0.15 U/kg body weight to produce adequate hypoglycemia. Blood samples are drawn at 0, 30, 45, 60, 90, and 120 min for blood glucose, plasma cortisol, and GH estimation. The test cannot be interpreted unless adequate hypoglycemia (tachycardia and sweating with blood glucose <40 mg/dL) is achieved. Patients with impaired cortisol responses, i.e. <550 but >400 nmol/L may only need steroid cover for major illnesses or stresses. In Cushing’s syndrome, there will be a rise of >170 nmol/L above the fluctuations of basal levels of cortisol [70], [71]. Severe GH deficiency is defined by a GH peak lower than 3 μg/L. Other alternative tests to check HPA axis include the low-dose ACTH stimulation test, corticotropin-releasing hormone test, metyrapone test, and glucagon stimulation test [67], [70].

ITT is also used to differentiate Cushing’s syndrome from pseudo-Cushing’s syndrome associated with depression, alcohol excess, etc. [71]. Occasionally, ITT is performed to assess the peak adrenal capacity, in stressful events like acute illness or major surgery where appropriate cortisol rise is observed [72]. Side effects of the test include sweating, palpitations, loss of consciousness, and, rarely, convulsions due to severe hypoglycemia, and Addisonian crisis may be precipitated in subjects with poor adrenal reserve [71]. It is contraindicated in the elderly, in patients with cardiovascular or cerebrovascular diseases, history of seizures, an abnormal electroencephalogram, recent brain surgery, and severe hypopituitarism [71], [73].

Glucose-insulin-potassium infusion

In 1962, the electrocardiographer Sodi-Pallares pioneered the use of GIK as an adjuvant treatment for ST segment elevation myocardial infarction (STEMI) [74], and GIK infusion was one of the first agents to be studied for protection of the ischemic myocardium that will reduce myocardial infarct size and improve clinical outcomes [75]. Several pharmacological agents and approaches have been studied over the years with variable results in both animal models and humans. The GIK infusion was formerly designed to restore potassium flux into the ischemic myocardium and to normalize the ECG abnormalities. It encompassed a high-dose insulin (HDI) infusion constituent (up to 2 units/kg/24 h) and an adjuvant glucose infusion to avoid hypoglycemia and to allow hyperglycemia [76]. GIK infusion showed favorable effects on a number of intermediate biomarkers: complete resolution of ST segment elevation [77], fewer arrhythmias [78], smaller infarct size [79], and lowering of circulating free fatty acids [80].

GIK infusion is relatively harmless and free from major side effects. It is cardioprotective by the following mechanisms: firstly, it suppresses plasma levels of free fatty acids (i.e. suppress lipolysis) that are elevated during acute cardiovascular stress, as a consequence of the release of counter-regulatory hormones and cytokines [81]. Under aerobic conditions free fatty acids are the dominant substrates for myocardial cells, but during ischemic conditions, a shift occurs toward anaerobic glycolysis, and long-chain free fatty acids produced have deleterious effects. GIK solution promotes glycolysis and thereby reduces ischemic damage [82]. In ischemic conditions there is accumulation of toxic intermediates of free fatty acid metabolism, which can lead to inhibition of glucose utilization and higher production of lactate and hydrogen ions, which can decrease cardiac contractility, cause diastolic dysfunction and can precipitate arrhythmias [83].

Secondly, recent evidence suggests that insulin itself, as a component of GIK, when administered by restoring normoglycemia, could be a cardioprotective, because it has anti-inflammatory, antiapoptotic and provasodilatory properties through the release of nitric oxide and increased expression of endothelial nitric oxide synthase [84]. Thirdly, GIK infusion in acute STEMI patients reduced levels of C-reactive protein and serum amyloid A and attenuated an increase in plasminogen activator-1, which suggests that GIK has an anti-inflammatory and profibrinolytic effect [83]. Fourthly, glucose and insulin infusion causes potassium to move intracellularly, so the addition of exogenous potassium helps prevent hypokalemia and helps to electrically stabilize the myocardial cell membrane to avoid arrhythmias [84].

The antiapoptotic [83] effect of insulin in ischemia/reperfusion is mediated via phosphatidylinositol-3-kinase-AKT-endothelial nitric oxide synthase signaling pathway, the subsequent phosphorylation of endothelial nitric oxide synthase, and the generated nitric oxide protects the myocardium. Previous studies have shown that when insulin is administered at the time of myocardial reperfusion in animal models, it reduced the myocardial ischemia/reperfusion injury [85], [86].

The GIK regimen is also shown to be beneficial in the management of cardiac diseases like acute myocardial infarction, congestive heart failure, and cardiogenic shock. It preserves myocardial integrity and function and warrants quick recovery. It acts as cardioprotection by the above said mechanisms and also by suppressing the production of pro-inflammatory cytokines like tumor necrosis factor (TNF), interleukin-6, macrophage migration inhibitory factor, and free radicals, besides increasing synthesis of anti-inflammatory cytokines interleukin-4 and interleukin-10 [87]. Its use is extended in the management of diabetic ketoacidosis, septicemia, septic shock, and inflammatory conditions such as ulcerative colitis, Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, and cancer [88].

The most important adverse effects accompanying GIK infusion include hyperglycemia [89], [90], hyperkalemia [91], [92], volume overload [89], [90], and rise in cardiac markers [91]. Prerequisites for GIK infusion include the following: check for the metabolic status of the patient including insulin resistance syndrome or type 1 or type 2 DM, where myocardial response may vary in these conditions [93]. An earlier trial, The immediate myocardial metabolic enhancement during initial assessment and treatment in emergency care (IMMEDIATE trial) [94], evaluated the impact of GIK on acute coronary syndromes in prehospital emergency medical service settings in the ambulance by the paramedics. The trial showed that progression to infarction (by biomarkers and ECGs), the primary endpoint, was not prevented, but infarct size was significantly diminished, and there was significant reduction of free fatty acid levels and acute mortality rate [94].

As known since >45 years, GIK regimen is a simple, cheap, and intriguing therapeutic strategy to optimize myocardial protection. The precise role of GIK in cardiovascular medicine and its mechanism needs to be further elucidated in detail, and also the intermediate and long-term effects of GIK need to be considered.

Insulin for septic shock

Sepsis is a clinical syndrome characterized by systemic inflammation due to infection, which can progress in severity ranging from sepsis to severe sepsis and septic shock. Septic shock being a major complication of infectious diseases triggers systemic inflammatory response and has high mortality rate within a short period [95], [96]. Septic shock is due to inappropriate increase in innate immune response by neutrophils, macrophages, and natural killer cells [97]. Hyperglycemia and insulin resistance are common in critically ill patients, independent of a history of DM [21], [96], [98]. Insulin resistance is due to elevated concentrations of TNF-α, IL-1, IL-2, and/or IL-6 [97]. Other reasons for hyperglycemia during critical illness include enhanced hepatic gluconeogenesis, impaired insulin secretion, and decreased insulin sensitivity due to anti-insulin effects of stress hormones, and proinflammatory cytokines have been revealed [99]. Insulin resistance seen in sepsis can be restored to normalcy by infusing insulin continuously [97].

Short-term hyperglycemia in critically ill patients markedly impairs cardiovascular function [100]. Previous studies have shown that hyperglycemia increased the size of myocardial necrosis, reduced coronary collateral blood flow, exaggerated ischemia reperfusion cellular injury, and impaired ischemic preconditioning [101]. Other studies showed hyperglycemia favoring thrombosis by causing abnormalities in hemostasis and inducing endothelial dysfunction [102]. Numerous different glucose management protocols are followed for tight glycemic control in critically ill patients, as maintaining euglycemia in intensive care units (ICU) is accepted as one of the basic approaches in ICUs [103], [104].

The “Leuven study” [105], which was performed on critically ill patients, majority with 63% cardiac surgery, demonstrated that intensive insulin therapy aimed to maintain euglycemia (80–110 mg/dL) reduced mortality by 42% and also markedly decreased the complications rate associated with critical illness in comparison to conventional treatment with insulin infusion only hyperglycemia exceeding 215 mg/dL so as to maintain blood glucose levels between 180 and 200 mg/dL [105]. The Leuven algorithm or protocol has become the gold standard protocol for glucose management of critically ill patients in ICUs. According to this protocol, an insulin infusion is started if the blood glucose level >110 mg/dL, and the infusion was adjusted to maintain normoglycemia (80 to 110 mg/dL). The maximal recommended dose of insulin was randomly set at 50 IU/h. When the patient was shifted from the ICU, a conventional approach was implemented, i.e. maintenance of blood glucose level between 180 and 200 mg/dL. Regardless of history of diabetes or hyperglycemia, intensive insulin treatment reduced the number of deaths from multiple-organ failure associated with sepsis [106]. Intensive insulin treatment also reduced the use of intensive care resources in ICU, prevented acute renal failure, and reduced the risk of cholestasis and polyneuropathy due to either hyperglycemia or insulin deficiency or both [105], [107].

Apart from its use in routine treatment of DM, negative effects of hyperglycemia are well known in patients with diabetes and now reported to be the same for critically ill patients. The use of insulin must be to maintain blood glucose and reduce morbidity and mortality among critically ill patients in the ICUs, regardless of the history of diabetes [106].

Role of insulin in cancer treatment

Insulin potentiation therapy (IPT) is a treatment regimen using insulin as an adjunct to conventional chemotherapy, which was invented by Dr. Donato Perez Garcia in 1932 [108]. It is claimed that insulin potentiates the effects of chemotherapy, which enables 75%–90% reduction of the estimated doses of anticancer drugs thus reducing the risk of their adverse effects [108]. Therefore, insulin is used as an adjunct to low-dose chemotherapy.

The mechanism of potentiation of chemotherapy is unclear. The following mechanisms were put forward. Firstly, insulin increases the permeability of the cell membrane for cytotoxic drugs, resulting in higher intracellular drug concentrations. On the other hand, with the influence of insulin on cell cycle kinetics, insulin would increase the S-phase fraction of tumor cells, i.e. increase the number of cells with active DNA replication, hence making the tumor more vulnerable for the action of cytotoxic drugs, in particular cell-cycle-phase-specific agents. Additionally, IPT would differentiate between cancerous and normal cells based on the higher levels of insulin receptors on cancerous cells [109].

In previous IPT clinical trials [110], [111], cancer patients were administered insulin 0.3 to 0.4 U per kg body weight intravenously, followed by chemotherapy at lower doses than usual, starting 20 min after insulin administration or sooner if symptoms of hypoglycemia were observed. In another case study [112], a woman with breast cancer was treated with IPT. Treatment (insulin+chemotherapy) was repeated twice weekly for 3 weeks and then weekly for 5 weeks. After 8 weeks, the breast mass was no longer palpable, and no evidence of tumor was found on a xeromammogram at 3 months.

Still, clinical trials need to prove whether such low doses of chemotherapy in combination with insulin can produce the same anticancer effect as the recommended doses, and whether the use of lower doses of chemotherapeutic drugs may promote drug resistance needs to be evaluated.

Insulin for calcium channel blockers and β-blocker overdoses

The overdoses of β-blockers and calcium channel blockers (due to unintentional or suicidal ingestions, medication errors, or drug interactions) may be associated with significant morbidity and mortality [113]. General goals of therapy are aimed at improving inotropy and chronotropy. Important interventions to manage their overdose include intravenous fluids, atropine, glucagon, calcium, and vasopressors. Unfortunately, in severe overdoses, these agents do not consistently improve hemodynamic parameters [114].

From recent clinical and experimental evidence, HDI therapy has emerged as an effective antidote to calcium channel blocker and β-blocker overdose [115], [114]. In the previous literature reports of calcium channel blocker and combined calcium channel blocker and β-blocker ingestions, the majority of patients have received between 0.5 and 2 units/kg/h insulin infusions [116].

In a case report [117], a young woman presented to the emergency department with history of β-blocker overdosage. Normal saline boluses of a total 4 L was infused, but her systolic blood pressure was 50 mm Hg, and also patient’s hypotension was refractory to epinephrine requiring additional norepinephrine and dobutamine, as well as a glucagon infusion, started at 0.5 mg/h. HDI therapy was then initiated. One insulin bolus (0.25 units/kg) was administered, followed by a regular insulin infusion, initiated at 0.3 units/kg/h and increased to 0.5 units/kg/h. Blood glucose levels were checked every 10 min, and dextrose infusion was titrated to maintain glucose concentrations above 100 mg/dL. The patient’s hemodynamics began to stabilize (93/59 mm Hg), and her condition improved within 2 h of HDI initiation. Vasopressors were titrated down slowly and were all discontinued [117].

The benefit of insulin in β-blocker and calcium channel blocker overdose is anticipated to be related to three primary mechanisms: increased inotropy, increased intracellular glucose transport, and vascular dilatation. Exogenous insulin is believed to improve cardiac function by increasing myocardial carbohydrate metabolism, which in turn expedites myocardial oxygen delivery and cardiac contractility [117]. HDI appears to enhance cardiac contractility without increasing myocardial work, unlike cathecholamines.

General recommendations for HDI dosing include an initial bolus of 1 unit/kg followed by a 0.5–1 unit/kg/h continuous infusion, although doses of up to 10 units/kg/h have been used in refractory cases. HDI’s accessibility, economical cost, and minimal adverse event profile further support its use widely. Adverse events of insulin are predictable and can be effectively managed with glucose and potassium supplementation [118].

Conclusions

This review explores the diverse newer applications of insulin, which conventionally has been associated with the management of DM, and suggests that it is a potential remedial for many more diseases, importantly in ICUs to treat septic shock, β-blocker and calcium channel blocker toxicity, and myocardial infarction and to significantly reduce doses of chemotherapeutic drugs in the management of cancer. With developments in insulin therapy still happening, it is worth keeping up to date on some interesting innovative applications of insulin other than in DM.

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About the article

Corresponding author: Dr. Jyoti M. Benni, Assistant Professor, Department of Pharmacology, JN Medical College, KLE University, Nehru nagar, Belgaum-590001, Karnataka, India, Phone: 09739462128


Received: 2015-08-22

Accepted: 2016-04-12

Published Online: 2016-05-28

Published in Print: 2016-09-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, Volume 27, Issue 5, Pages 445–456, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2015-0101.

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