The Evolution of Insulin Glargine and its Continuing Contribution to Diabetes Care
- First Online:
- 2.1k Downloads
The epoch-making discovery of insulin heralded a new dawn in the management of diabetes. However, the earliest, unmodified soluble insulin preparations were limited by their short duration of action, necessitating multiple daily injections. Initial attempts to protract the duration of action of insulin involved the use of various additives, including vasoconstrictor substances, which met with limited success. The subsequent elucidation of the chemical and three-dimensional structure of insulin and its chemical synthesis and biosynthesis allowed modification of the insulin molecule itself, resulting in insulin analogs that are designed to mimic normal endogenous insulin secretion during both fasting and prandial conditions. Insulin glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice more than 10 years ago and is specifically designed to provide basal insulin requirements. It has a prolonged duration of action and no distinct insulin peak, making it suitable for once-daily administration and reducing the risk of nocturnal hypoglycemia that is seen with intermediate-acting insulins. Insulin glargine can be used in combination with prandial insulin preparations and non-insulin anti-diabetic agents according to individual requirements.
1.1 The Pre-Insulin Era
Prior to the 1920s, the prognosis for people with insulin-requiring diabetes mellitus was very poor, with limited treatment options being available and high resultant morbidity and mortality, particularly in children and young adults . Generally, confirmation of the diagnosis of diabetes in this ‘pre-insulin’ era meant eventual coma and subsequent death, often within 2 years of diagnosis . At this time, physicians had to manage the disease through dietary modification alone, with some affected individuals being restricted to a diet with an almost negligible carbohydrate intake in a bid to control blood glucose levels [3, 4, 5]. In such circumstances, the benefit of such ‘starvation’ diets, involving repeated fasting and prolonged undernourishment, was relatively short-lived, providing only a modest extension of life . Furthermore, there was little or no evidence to support longer-term efficacy benefits of undernourishment therapy, which was accompanied by a risk of infection, inanition, and poor quality of life . However, such an approach would have improved the metabolic status of those with ‘non-insulin-dependent’ diabetes, which was not recognized as a separate entity until the mid-1930s and so this differentiation between diabetes types could not be used in treatment decisions at the time . Indeed, dietary intake continues to be a mainstay of the management of type 2 diabetes mellitus (T2DM), taking on increased importance as obesity has become an increasing problem worldwide.
1.2 The Discovery of Insulin
Diabetes has been known about for millennia, with the first known description of symptoms allied to diabetes and suggested treatment written circa 1500 BC in the Ebers papyrus from ancient Egypt [1, 7]. Circa 230 BC, Apollonius of Memphis first used the term ‘diabetes’; however, its cause and the organ responsible for this condition were not elucidated until more than two millennia later (in the late nineteenth century) [1, 7].
In 1889, in the laboratory of Oscar Minkowski and Joseph von Mering, it was observed that a dog developed diabetes, with all of the characteristic symptoms of the disease, after total pancreatectomy . This finally confirmed the central role of the pancreas in the etiopathogenesis of diabetes. Later in 1893, Eduoard Hédon further demonstrated that, in animals, complete removal of the pancreas was required for the development of diabetes . Hédon observed that grafting a small piece of pancreatic tissue under the skin after total pancreatectomy alleviated diabetes, but it promptly returned on removal of the tissue. This was also demonstrated independently by Minkowski and, in 1893, led Gustave-Eduoard Laguesse to suggest that the small clusters of ductless cells within the pancreas—that had been described by Paul Langerhans in his doctoral thesis, and that he named the Islets of Langerhans—could be the source of the substance involved in glucose control [5, 10]. This association between the islet cells and diabetes was confirmed in 1901 by Eugene Opie who connected the degeneration of the islet cells to the appearance of diabetes [1, 11, 12]. Subsequently, numerous attempts were made to isolate the glucose-lowering substance, with varying success, by a number of investigators, including Georg Ludwig Züzler (alcohol and saline extraction) , Nicolas Paulesco (ice-cold water) , Ernest Lyman Scott (acid and ethanol extraction) , Israel Kleiner and Samuel James Meltzer (water and saline dilution) , John Rennie and Thomas Fraser (boiling water and weak acetic acid) , and CP Kimball and John Murlin (acid and alcohol extraction) , among others [1, 5, 19, 20].
In 1907, Züzler removed the pancreas from a dog, extracted the pancreas with alcohol and injected the same dog with this extract, which he called ‘acomatol’. He observed that it reduced the amount of glycosuria and raised the pH of the blood . Soon after, in 1908, he used the extract to revive a subject who was in diabetic coma. However, the treatment produced severe complications, which were ascribed to toxic impurities in the extract. The person later died when the supply of the extract ran out; nevertheless, Züzler continued his attempts to produce a pure extract for a further few years and, in 1911, Hoffman-La Roche assisted Züzler’s creation of an experimental laboratory [5, 13, 19, 21]. On 28 May 1912, acomatol was granted a patent (Patent 1027790) .
In 1916, Paulesco injected a diabetic dog with a pancreatic extract, extracted with ice-cold water, and observed that this led to the death of the dog from hypoglycemia, with its blood glucose levels falling from 140 to 26 mg% [1, 5, 14]. In 1921, Paulesco presented papers at meetings of the Romanian Society of Biology on his experiments in dogs (21 April, 19 May, and 23 June), and these results were published in France on 23 July 1921 [14, 21]. These demonstrated that his pancreatic extract, ‘pancreine’, reduced blood sugar, ketones, urea, and urine in both normal and depancreatized dogs [22, 23, 24, 25]. Further details of this work were published in France on 31 August 1921 and, on 10 April 1922, he filed a patent application with the Romanian Government for pancreine [21, 23]. The publication of these results was delayed owing to the First World War, and this also meant that there was a hiatus during which his research was effectively put on hold, delaying his progress. In 1919, Kleiner reported on his work, whereby he extracted freshly ground dog pancreas with salted distilled water; in all 16 reported experiments, the extract caused a temporary decrease in the blood sugar levels of depancreatized dogs [16, 20]. However, these decreases in blood sugar levels were accompanied by mild toxic symptoms—most commonly, elevated temperature.
1.3 The Successful Extraction and Use of Insulin to Treat Human Diabetes
On 17 May 1921, Banting and Best began working together in Professor JR Macleod’s laboratory at the University of Toronto and, within 6 months, had succeeded in both extracting insulin and demonstrating that their crude extract reduced blood glucose in pancreatectomized dogs . Over the course of the next 2 years (1921–1922), Frederick Banting, Charles Best, and John James Rickard Macleod, with the invaluable assistance of the chemist James Collip, achieved an improved extract of insulin from animal pancreata and successfully administered the extract to individuals with diabetes mellitus [26, 27]. Their original process involved ligating the pancreatic duct, therefore destroying the exocrine pancreas, and isolating the endocrine-producing islet of Langerhans from whole pancreas followed by acid-ethanol extraction . This approach was adopted as Banting thought that this would yield a purer extract, free from trypsin, which would degrade the active principle. However, owing to the labor-intensive surgery needed to ligate the pancreas, production of the extract was slow and other approaches were attempted. Initially, they used secretin-exhausted glands for the extraction, which had been produced by slow injection of secretin over 4 h until the flow of pancreatic fluid through a cannula placed in the pancreatic duct stopped . This was also extremely labor intensive and, on 6 December 1921, they extracted fetal-calf pancreas with slightly acidic 95 % alcohol, and the extract successfully lowered blood glucose levels. Finally, on 11 December 1921, they performed the extraction on whole adult cow pancreas, and this extract reduced a depancreatized dog’s blood sugar from 0.460 to 0.180 % in 3 h [20, 29]. This discovery that insulin could be extracted from whole pancreas was a major step towards its successful use in treating diabetes, as the extract was available from a cheap and readily available source material.
Having demonstrated that their extract reduced blood glucose levels in dogs, they moved on to human trials. The first administration to a person with diabetes, 14-year-old Leonard Thompson, occurred in January 1922 [20, 27, 30]. This resulted in a reduction of blood sugar levels from 0.440 to 0.320 %, as well as a drop in the 24-h excretion of glucose from 91.5 to 84 g [20, 27]. However, no clinical benefit was observed and severe local reactions, including abscesses, were observed. This extract was described as a murky, light-brown liquid, and Collip subsequently provided an improved extract of greater purity, which was tested on 23 January 1922 on Leonard Thompson [20, 27]. Frequent injections over the first 24 h of treatment resulted in immediate improvement, with blood sugar levels dropping from 0.520 to 0.120, and glucose excretion from 71.1 to 8.7 g, and the elimination of ketonuria, accompanied by an associated symptomatic improvement [1, 20, 27, 30]. This purer and more consistent extract did not result in such severe injection-site reactions, highlighting the importance of obtaining as pure an extract as possible. Subsequently, the patent for the production of insulin was given to the University of Toronto by Banting, Best, and Collip.
The discovery of insulin represented a significant moment in medical history, with Banting and Macleod being awarded the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin. Banting shared his prize money with Best, and Macleod shared his with Collip; however, there is still controversy over the awarding of this Nobel Prize [20, 21]. The availability of insulin meant that people with insulin-requiring diabetes could now survive and successfully manage their disease.
2 Large-Scale Production of Insulin
The life-giving properties of insulin led to great demand worldwide, and therefore a need for improved production and purification techniques. Connaught Laboratories, a predecessor company of Sanofi, initiated large-scale production of insulin, which enabled additional but limited clinical testing . However, there were difficulties in scaling up the production of insulin, including a period when they were unable to produce an extract with a similar potency to that originally investigated, as well as obtaining reduced yields. This reduced yield and potency was related to the use of heating to evaporate the alcohol following extraction, which destroyed some of the insulin present. By modifying this step to an evaporation technique involving a milder warm air current, insulin production could continue . Nonetheless, Connaught Laboratories were unable to produce enough insulin to meet clinical demand and so they entered into collaboration with Eli Lilly to develop larger-scale production techniques; this enabled them to escalate production to meet global demand .
The insulin being produced at this time was inconsistent, with wide batch-to-batch variation in potency . This meant that people being treated had to be closely monitored and, between October and December 1922, George Walden, Eli Lilly’s chief chemist, developed a purification technique that enabled the production of insulin at a higher purity and with reduced batch-to-batch variation (10 % compared with 25 % with the previous technique) . He found that insulin precipitated from the extract under mildly acidic conditions. By adjusting the solution to insulin’s isoelectric point, insulin of much greater purity could be obtained . Another group, led by Phillip Shaffer, discovered the isoelectric precipitation method of purification at a similar time independently of Eli Lilly, which resulted in Eli Lilly Company accepting a non-exclusive licensing contract for the production of insulin from the University of Toronto. This important step meant that other companies could also produce insulin, enabling rapid, widespread, large-scale production of insulin . By 1925, there were 12 different pharmaceutical companies producing insulin, which emphasized the enormous global demand that existed for insulin to treat diabetes .
3 Development of Synthetic Human Insulin
The first insulin preparations were porcine- and/or bovine-based. It was not until the 1980s that semi-synthetic human insulin became clinically available [32, 33, 34]. Human insulin had been available in small quantities since the 1960s; it was extracted from human cadaveric pancreases [1, 35, 36, 37, 38, 39, 40] and was used as reference material in insulin radioimmunoassay or physicochemical identity tests [1, 41]. This human insulin was also used clinically in a limited manner for skin-testing of insulin-allergic individuals , pharmacokinetic studies [43, 44, 45], and short-term clinical studies [1, 46]. Owing to the limited availability, efforts were undertaken to produce a synthetic version of human insulin in the belief that human insulin was preferable to animal insulin. The first total chemical synthesis of human insulin was performed in 1974 by Sieber and his co-workers , and this was shown to be biologically equivalent to the natural hormone . However, this method comprised several hundred reactions and was too costly for widespread use. Therefore, alternative approaches for the synthesis of insulin were examined, with many groups focusing on the conversion of porcine to human insulin . The first successful semi-synthesis was carried out by Obermeier and Geiger in 1976, but the overall yield was very low (~6 to 10 %) . The breakthrough that enabled the large-scale production of human insulin was the discovery that the hydrolytic reaction normally performed by proteases could be reversed by carrying out the reaction in a mixture of water and organic solvent, thus enabling the formation of peptide bonds . Several methods were developed involving enzymatic transformations, including the direct conversion of porcine insulin to human insulin ester via transpeptidation, as discussed by Markussen et al. . This process produced the ester in a yield of 97 % and this mixture was purified to meet the specifications of mono-component insulin [1, 33].
The introduction of recombinant DNA technology meant that, by the end of the 1980s, most human insulin was produced biosynthetically . These recombinant insulins were produced using either Escherichia coli or yeast (Saccharomyces cerevisiae). In the first recombinant human insulins, the A and B chains were produced separately and then combined to produce insulin . Subsequently, it has also been prepared by the biosynthetic production of human proinsulin, either within the expressing cell or excreted from it, which is then converted enzymatically to human insulin [1, 17, 51].
3.1 Insulin Modification
Pharmacokinetics of currently available insulin preparations 
Insulin lispro (Humalog)
Insulin aspart (NovoLog)
Insulin glulisine (Apidra)
Insulin glargine (Lantus)
Insulin detemir (Levemir)
Up to 24
Insulin degludec (Tresiba)
Insulin protamine aspart/aspart 70/30 (NovoLog mix)
Insulin protamine lispro/lispro 75/25 (Humalog mix)
Early protracted animal insulins developed by Hallas-Møller and Schlichtkrull capitalized on the varying solubilities of their components (i.e. porcine and/or bovine insulins) at physiological pH. The lente family of insulins (semilente, lente, and ultralente) were created by complexing neutral insulin suspensions with small amounts of zinc ions, in the absence of any added foreign proteins or synthetic compounds [54, 66]. This provided a spectrum of time–action characteristics. The original lente insulin, which had an intermediate timing of action similar to that of NPH insulin, comprised a 30:70 mixture of amorphous porcine insulin and crystalline bovine insulin particles [67, 68]. Bovine ultralente insulin formed fairly large crystals (30 μm) that remained in a subcutaneous depot for a number of days, resulting in a duration of action similar to that of protamine zinc insulin, enabling once-daily administration .
The remainder of this review discusses insulin analog preparations that are designed to possess a protracted action, with a focus on insulin glargine, which was the first ‘long-acting’ insulin and was approved for clinical use in 2000.
3.2 Long-Acting Insulin Preparations: Mimicking Basal Insulin Physiology
The main role of basal insulin secretion is to limit hepatic glucose production and lipolysis in the fasting state, particularly overnight, without impairing glucose availability for brain function . However, older basal insulin preparations, e.g. NPH and lente insulins, are acknowledged to be associated with a number of limitations, such as variable absorption with notable inter- and intra-individual variation, and discernible peak plasma concentrations after subcutaneous injection, thus increasing the risk of hypoglycemia (in particular, nocturnal hypoglycemia). Therefore, individuals treated with NPH insulin before the evening meal or before bed may be at an increased risk of fasting hyperglycemia. In addition, due its activity of less than 24 h duration, a second dose in the morning is often required. For example, even the longest-acting preparation, human ultralente, with a peak insulin level at 10–14 h post-injection, did not always provide adequate basal coverage with once-daily administration at the lower dose levels [51, 58].
Therefore, in an attempt to avoid the shortcomings of conventional basal insulin therapies, long-acting basal insulin analogs were developed. To date, there have been two main protraction strategies used: (1) modification of the insulin molecule to achieve a low solubility at physiological pH, e.g. insulin glargine; (2) the addition of a fatty-acid chain of variable length to the insulin molecule, which can bind to albumin, forming a circulating depot from which the insulin analog is slowly released, e.g. the insulins detemir and degludec. More recently, a third strategy is being explored that involves the pegylation of insulin, e.g. LY2605541 (insulin peglispro), which is currently undergoing extensive clinical evaluation [70, 71].
3.3 Early Analogs: Modified Chemical Structures
During the 1980s, initial attempts at creating long-acting insulin analogs involved the addition of positive charges to the insulin molecule, either by removing carboxylates (Glu, Asp), or by the introduction of lysine or arginine using single-chain insulin precursors [54, 77, 78, 79, 80]. Early efforts by Novo Nordisk involved changing GluB27 to arginine and replacing the terminal carboxylate of the B chain by an amide (ThrB30–NH2) [77, 78, 79]; further structural modifications created NovoSol Basal, a GlyA21ArgB27ThrB30 insulin amide . Although NovoSol Basal achieved prolonged absorption compared with ultralente, it required double the dose for comparable glycemic control. NovoSol Basal also had low intra-individual variability, but high inter-individual variability. This agent failed in clinical testing in 1989, and this was thought to be due to subcutaneous crystal formation and degradation of the drug in the subcutaneous depot by significant macrophage infiltration, leading to reduced bioavailability .
Subsequent investigation, in animal models, of subcutaneous injection of acidic solutions with varying zinc concentrations revealed that the lowest total potency of 20 µg/mL was the ideal concentration for ArgB31ArgB32 insulin crystallization in vitro, and may indicate a change in the morphology of the subcutaneous precipitate from amorphous to crystalline (Fig. 5b).
Findings from studies of long-acting insulin analogs demonstrate that, even in cases such as NovoSol Basal and ArgB31ArgB32 insulin, which have similar solubility profiles, variations in chemical structure can produce markedly different pharmacokinetic profiles and pharmacodynamic outcomes in vivo. This is highlighted by a study of NovoSol Basal in dogs, which reported lower total blood glucose-lowering properties than for insulin glargine (Fig. 5c). In addition, the failure of analogs such as ArgB0 to exhibit prolonged glucose-lowering activity in spite of an increased isoelectric point suggested that merely increasing the isoelectric point was too simple a concept to achieve prolonged activity; rather, the impact of the three-dimensional structure seemed to play a major role.
Packing density and inter-hexamer contacts in monoclinic crystals of insulin and insulin analogs
Crystal packing density (Da/Å3)
Water content (%)
Hydrogen bonds (n)
Salt bridges (n)
GlyA21ArgB31ArgB32 (Insulin glargine)
4 Development of Insulin Glargine (Lantus®)
As a result of its chemical structure, this insulin analog is less soluble at neutral pH than human insulin and precipitates in the subcutaneous tissue post-injection, slowing its absorption and extending its duration of action . The structural properties of insulin glargine mean that it is soluble in acidic solutions (pH 4) and does not require re-suspension prior to injection, unlike NPH insulin. This need for resuspension was the predominant cause of the increased variability in the time–action characteristics of NPH insulin . Furthermore, insulin glargine functions essentially as a ‘prodrug’ in the subcutaneous tissue, with the majority of activity from its metabolites.
Following subcutaneous injection, insulin glargine is rapidly metabolized into its two main active metabolites: M1 (GlyA21) and M2 (GlyA21, des-ThrB30) , with little or no glargine molecule being detected in the systemic circulation. The M1 metabolite accounts for approximately 90 % of the available daily plasma insulin , and its release from the poorly soluble parent compound is the primary mechanism, resulting in the pharmacokinetic characteristics and consequent pharmacodynamic effect with the long-acting time–action profile observed with insulin glargine treatment [98, 99, 100]. Steady state is attained within a few days . Importantly, adverse events, injection-site reactions, and antibody formation with insulin glargine were found to be comparable with NPH .
A patent for the GlyA21ArgB31ArgB32 insulin analog, i.e. insulin glargine (Fig. 4c), was filed in 1988, and a New Drug Application was made in the USA and Europe in April 1999. Following an extensive clinical trial program, insulin glargine was approved by the US FDA and the European Medicines Agency for once-daily subcutaneous administration for the treatment of type 1 diabetes mellitus (T1DM) and T2DM in the year 2000.
5 Clinical Experience with Insulin Glargine
The recent joint recommendations from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) highlight the importance of basal insulin therapy in people with T2DM. These guidelines recommend the individualization of care and the progressive intensification of therapy until glycemic targets (glycated hemoglobin [HbA1c] <7.0 %) are met . NPH insulin is still an effective and valuable intermediate-acting insulin. However, the clinical need for an effective long-acting agent to reduce the number of injections required and lower the risk of hypoglycemia, whilst striving to achieve near normoglycemia led to the rapid adoption of long-acting insulin analogs.
Clinical studies have demonstrated that, compared with NPH, glargine has a more prolonged duration of action of up to 24 h due to a slower and more delayed absorption from the subcutaneous tissue, reduced variability, and a relatively consistent, peakless concentration–time profile, thus reducing the risk of hypoglycemia [58, 103, 104, 105]. Glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice, and it has now been in clinical use for more than 10 years .
It has been suggested that insulin analogs may be associated with an increased risk of cancer compared with human insulin, owing to enhanced affinities for the insulin receptor or the insulin-like growth factor receptor . However, the di-arginyl molecules in insulin glargine, which increase binding to the insulin-like growth factor receptor in vitro, are not present in the glargine M1 metabolite, and the metabolic and mitogenic characteristics of both the M1 and M2 metabolites have been shown to be essentially similar to those of human insulin [97, 106]. Indeed, large epidemiological studies indicate that insulin glargine does not have any independent carcinogenic effects at therapeutic doses [107, 108, 109]. This is strongly supported by the ORIGIN (Outcome Reduction with Initial Glargine INtervention) study of 12,537 people with early T2DM or pre-diabetes, which included cancer incidence as a secondary outcome . This represents the longest randomized controlled study of insulin therapy, extending over a median period of 6.2 years, with no increase seen in the incidence of all cancers combined, any organ-specific cancer (including breast, lung, colon, prostate, and melanoma), or cancer in the glargine group compared with the standard care group.
In people with T1DM, glargine offers improved convenience, with only once-daily administration, and flexibility as to timing of injection (morning, pre-dinner, or pre-bedtime) . In people with T2DM, glargine offers both increased safety (reduced risk of nocturnal hypoglycemia) and convenience (once-daily administration) when attempting to reach the target HbA1c level of 7.0 % and below, which is achieved in more than 50 % of subjects .
The efficacy and safety of insulin glargine in both people with T1DM and those with T2DM have been demonstrated in a number of key randomized controlled clinical studies. An overview of some of the key trials is presented in Supplementary Table 1. Importantly, insulin glargine can be used successfully with other oral and parenteral agents in the treatment of T2DM; for example, in combination with prandial insulin or prandial glucagon-like peptide (GLP)-1 receptor agonists as part of a basal-bolus therapy [54, 113, 114]. This offers a new option for the intensification of treatment of people with T2DM who are not reaching glycemic targets despite receiving basal insulin therapy. Currently, treatment is usually intensified by the addition of prandial insulin, either as premixed insulin or as separate injections. However, this increases the risk of hypoglycemia and weight gain, side effects not observed with GLP-1 receptor agonists, which have a low risk of hypoglycemia and either a neutral effect on weight or cause weight loss [115, 116, 117, 118].
Insulin analogs tend to be associated with higher initial medication costs than NPH and for this reason there is debate as to whether they offer value for money in clinical practice . Cost-effectiveness analyses have demonstrated that the initial expenditure associated with insulin analogs is offset by reductions in the incidences of hypoglycemia associated with their use [120, 121, 122]. Other studies indicate that there may be no such cost reductions . While cost may be a consideration, it is only one of several important factors that need to be considered when deciding the most appropriate treatment regimen for patients with diabetes. Blood glucose control, tolerability, adverse events, patient adherence to treatment, and quality of life are all essential considerations. Lower incidences of nocturnal and severe hypoglycemia  and improvements in patient adherence and quality of life have been reported with use of insulin analogs due to the need for fewer injections .
The discovery of insulin heralded a new dawn for people with diabetes, with significant gains in both life expectancy and quality of life. The ultimate goal of insulin therapy is to mimic the physiological secretion of insulin to accommodate both fasting and prandial requirements, and advances in protein engineering have enabled the development of insulin analogs that mimic both basal and prandial requirements.
The structural characteristics underlying the physiological properties of insulin glargine define its clinical effectiveness. Data indicate that low solubility at physiological pH is a prerequisite, but this alone is not sufficient for a basal insulin analog. Instead, factors determining successful prolonged and continuous delivery of the analog are likely to include a balanced number of inter-hexamer interactions and moderate crystal stability.
Insulin glargine has demonstrated efficacy and consistent safety in numerous large randomized clinical studies, supporting its use as basal insulin therapy for the treatment of diabetes, in line with ADA/EASD recommendations. Insulin glargine continues to achieve real success in the clinical setting, providing important benefits to people with diabetes. Importantly, as glargine can be used in combination with other insulin and non-insulin antidiabetic agents, it has a central role to play in the tailoring of treatment on an individual basis, which is recognized as the most appropriate approach to the effective management of diabetes.
In conclusion, the development and introduction of long-acting insulin analogs represented a dramatic step forward in diabetes care, fulfilling the clinical need for a basal insulin analog (which was hinted at by NPH insulin almost half a century previously). Insulin glargine now represents a reference basal insulin against which future developments in long-acting insulin analogs are measured [70, 126, 127].
The authors are grateful to all members of the “New Insulins” team of former Hoechst AG. They thank Dr. Naoki Sakai (University of Lübeck) for help with Fig. 3. RH acknowledges support by the Chinese Academy of Sciences through a Visiting Professorship for Senior International Scientists (Grant no. 2010T1S6). Editorial support for this article was provided by Alexander Jones, Ph.D., from Medicus International, London, and funded by Sanofi.
Conflict of interest
DO has received lecture fees and honoraria from Sanofi and Roche Diagnostics. GS and HB are employees of Sanofi. RH declares no conflict of interest.
The authors would like to dedicate this manuscript to the late Professor Geiger and the late Dr. Obermeier who were pioneers in the development of human insulin and insulin pumps.
The contents of this article and opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. The authors conceived and critically reviewed the manuscript, including input into every stage of the development of the manuscript, and approved the final version for submission.
- 1.Owens DR. Human insulin. UK, Europe, USA: MTP Press; 1986.Google Scholar
- 5.Zajac J, Shrestha A, Patel P, Poretsky L. The main events in the history of diabetes mellitus. In: Poretsky L, editor. Principles of diabetes mellitus. New York: Springer Science + Business Media; 2010. p. 3–16.Google Scholar
- 6.Himsworth HP. Diabetes mellitus: Its differentiation into insulin-sensitive and insulin-insensitive types. Lancet. 1936;227(5864):127–30.Google Scholar
- 7.Papaspyros NS. Introduction. In: Verlag GT, editor. The history of diabetes mellitus. Stuttgart: Thieme; 1964. p. 1–10.Google Scholar
- 8.von Mering J, Minkowski O. Diabetes mellitus nach Pankreasexstirpation. Arch Exp Path Pharmakol. 1890;26:371–87.Google Scholar
- 9.Hédon E. Sur la consommation du sucre chez la chien après l’extirpation du pancreas. Arch Physiol Normal Pathol Vth Series. 1893;5:154–63.Google Scholar
- 13.Zülzer G. Ueber Versuche einer specifischen Fermenttherapie des Diabetes. Zeitschrift für die experimentelle Pathologie und Therapie. 1908;5(2):307–18.Google Scholar
- 14.Paulesco NC. Action de l’extrait pancréatique injecté dans le sang, chez un animal diabétique. CR Seanc Soc Biol (Paris). 1921;85:555–9.Google Scholar
- 15.Scott EL. On the influence of intravenous injections of an extract of the pancreas on experimental pancreatic diabetes. Am J Physiol. 1912;29:306–10.Google Scholar
- 16.Kleiner IS. The action of intravenous injections of pancreas emulsions in experimental diabetes. J Biol Chem. 1919;40:153–70.Google Scholar
- 18.Kimball CP, Murlin JR. Aqueous extracts of pancreas: III. Some precipitation reactions of insulin. J Biol Chem. 1923;58:337–46.Google Scholar
- 19.Lasker SP, McLachlan CS, Wang L, Ali SMK, Jelinek HF. Discovery, treatment and management of diabetes. J Diabetol. 2010;1(1).Google Scholar
- 22.Paulesco NC. Traitement du diabete. La Presse Medicale; 1924.Google Scholar
- 23.Paulesco NC. Recherches sur le role du pancreas dans l’assimilation nutritive. Arch Int Physiol. 1921;17:85–109.Google Scholar
- 24.Paulesco NC. Quelques reactions chimiques et physiques appliquees a l’extrait aqueux du pancreas pour le debarrasser des substances proteiques en exces. Arch Int Physiol. 1923;21:71–85.Google Scholar
- 25.Paulesco NC. Divers procedes pour entroduire l’extrait pamcreatique dans l’organisme d’un animal diabetique. Arch Int Physiol. 1923;21:215–38.Google Scholar
- 26.Banting FG, Best CH. The internal secretion of the pancreas. J Lab Clin Med. 1922;7:251–66.Google Scholar
- 28.Barron M. The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. Surg Gynecol Obstet. 1920;31:437–48.Google Scholar
- 29.Banting FG, Best CH. Pancreatic extracts. J Lab Clin Med. 1922;7:464–72.Google Scholar
- 30.Chamoun D, Choi D, Tavares AB, Udoff LC, Levitas E, Resnick CE, et al. Regulation of granulosa cell-derived insulin-like growth factor binding proteins (IGFBPs): role for protein kinase-C in the pre- and posttranslational modulation of IGFBP-4 and IGFBP-5. Biol Reprod. 2002;67(3):1003–12.PubMedGoogle Scholar
- 31.von Horn H, Hwa V, Rosenfeld RG, Hall K, Teh BT, Tally M, et al. Altered expression of low affinity insulin-like growth factor binding protein related proteins in hepatoblastoma. Int J Mol Med. 2002;9(6):645–9.Google Scholar
- 33.Markussen J, Damgaard U, Jorgensen KH, Sorensen E, Thim L. Human monocomponent insulin. Chemistry and characteristics. Acta medica Scandinavica Supplementum. 1983;671:99–105.Google Scholar
- 41.World Health Organization. WHO Technical Report Series 565. Geneva1975.Google Scholar
- 42.Kreines K. The use of various insulins in insulin allergy. Arch Intern Med (Chicago). 1965;116:167–71.Google Scholar
- 47.Sieber P, Kamber B, Hartmann A, Jöhl A, Riniker B, Rittel W. Totalsynthese von Humaninsulin unter gezielter Bildung der Disulfidbindungen. Vorläufige Mitteilung. Helvetica Chimica Acta. 1974;57(8):2617–21.Google Scholar
- 51.Owens DR, Vora JP, Heding LG, Luzio S, Ryder RE, Atiea J, et al. Human, porcine and bovine ultralente insulin: subcutaneous administration in normal man. Diabetic Med: J Br Diabet Assoc. 1986;3(4):326–9.Google Scholar
- 52.Best CH. Prolongation of insulin action. Ohio J Sci. 1937;37(6):362–77.Google Scholar
- 53.Schlichtkrull J, Pingel M, Heding LG. Insulin preparations with prolonged effect. In: Hasselblatt A, Bruchhausen FV, editors. Handbook of experimental pharmacology. Berlin, Heidelberg, New York: Springer; 1975. p. 729–77.Google Scholar
- 55.Bauman L. Clinical experience with globin insulin. Am J Med Sci. 1939;198(4):475–81.Google Scholar
- 56.Reiner L, Searle DS, Lang EH. On the hypoglycemic activity of globin insulin. J Pharmacol Exp Ther. 1939;67:330–40.Google Scholar
- 57.Umber F, Stoerring FK, Foellmer W. Erfolge mit einem neuartigen Depot Insulin ohne Protaminzusatz (Surfen-Insulin). Klin Woch. 1938;17:443–6.Google Scholar
- 58.Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49(12):2142–8.PubMedGoogle Scholar
- 59.Chikama T, Nakamura M, Nishida T. Up-regulation of integrin alpha5 by a C-terminus four-amino-acid sequence of substance P (phenylalanine-glycine-leucine-methionine- amide) synergistically with insulin-like growth factor-1 in SV-40 transformed human corneal epithelial cells. Biochem Biophys Res Commun. 1999;255(3):692–7.PubMedGoogle Scholar
- 64.Krayenbuhl C, Rosenberg T. Crystalline protamine insulin. Rep Steno Mem Hosp Nord Insulinlab. 1946;1:60–73.Google Scholar
- 69.White JR Jr., Campbell RK, Hirsch I. Insulin analogues: new agents for improving glycemic control. Postgrad Med. 1997;101(2):58–60, 3–5, 70.Google Scholar
- 70.Bergenstal RM, Rosenstock J, Arakaki RF, Prince MJ, Qu Y, Sinha VP, et al. A randomized, controlled study of once-daily LY2605541, a novel long-acting basal insulin, versus insulin glargine in basal insulin-treated patients with type 2 diabetes. Diabetes Care. 2012;35(11):2140–7. doi:10.2337/dc12-0060.PubMedCentralPubMedGoogle Scholar
- 71.Rosenstock J, Bergenstal RM, Blevins TC, Morrow LA, Prince MJ, Qu Y, et al. Better glycemic control and weight loss with the novel long-acting basal insulin LY2605541 compared with insulin glargine in type 1 diabetes: a randomized, crossover study. Diabetes Care. 2013;36(3):522–8. doi:10.2337/dc12-0067.PubMedCentralPubMedGoogle Scholar
- 74.Adams MJ, Blundell TL, Dodson EJ, Dodson GG, Vijayan M, Bakar EN, et al. Structure of rhombohedral 2 zinc insulin crystals. Nature. 1969;224(5218):491–5.Google Scholar
- 78.Markussen J, Diers I, Hougaard P, Langkjaer L, Norris K, Snel L, et al. Soluble, prolonged-acting insulin derivatives. III. Degree of protraction, crystallizability and chemical stability of insulins substituted in positions A21, B13, B23, B27 and B30. Protein Eng. 1988;2(2):157–66.PubMedGoogle Scholar
- 80.Geiger R. Chemie des Insulins. Chemiker Zeitung. 1976;100:111–29.Google Scholar
- 83.Monti LD, Poma R, Caumo A, Stefani I, Picardi A, Sandoli EP, et al. Intravenous infusion of diarginylinsulin, an insulin analogue: effects on glucose turnover and lipid levels in insulin-treated type II diabetic patients. Metab: Clin Exp. 1992;41(5):540–4.Google Scholar
- 85.Grau U. Inventor Hoechst Aktiengesellschaft, assignee. Pharmaceutical agent for the treatment of diabetes mellitus United States1984.Google Scholar
- 86.Rhodes CJ. Processing of the insulin molecule. In: LeRoith D, Taylor SI, Olefsky JM, editors. Diabetes mellitus: a fundamental and clinical text. 3rd ed. London: Lippincott Williams & Wilkins; 2004.Google Scholar
- 87.Berchtold H, Hilgenfeld R. Binding of phenol to R6 insulin hexamers. Biopolymers. 1999;51(2):165–72. doi:10.1002/(SICI)1097-0282(1999)51:2<165:AID-BIP6>3.0.CO;2-X.PubMedGoogle Scholar
- 89.Brange J, Skelbaek-Pedersen B, Lankjaer L, Damgaar U, Ego H, Havelund S, et al. Galenics of insulin preparations. In: Berger M, editor. Subcutaneous insulin therapy. Berlin, Heidelberg: Springer; 1985.Google Scholar
- 90.Seipke G, Geisen K, Neubauer H-P, Pittius C, Rosskamp R, Schwabe D. New insulin preparations with prolonged action profiles: A21-modified arginine insulins [abstract]. Diabetologia. 1992;35(Suppl. 1):A4.Google Scholar
- 91.Seipke G, Berchtold H, Geisen K, Hilgenfeld R, Rosskamp R. HOE 901: a new insulin with prolonged action [abstract]. Eur J Endocrinol. 1995;132(Suppl. 1):25.Google Scholar
- 92.Hilgenfeld R, Sicker T, Dörschug M, Obermeier R, Geisen K, Seipke G, et al. Controlling insulin bioavailability by crystal contact engineering. Diabetologia. 1992;35(Supplement):A193.Google Scholar
- 94.HOE 901/2004 Study Investigators Group. Safety and efficacy of insulin glargine (HOE 901) versus NPH insulin in combination with oral treatment in Type 2 diabetic patients. Diabet Med: J Br Diabet Assoc. 2003;20(7):545–51.Google Scholar
- 97.Owens DR. Optimizing treatment strategies with insulin glargine in Type 2 diabetes. Expert Rev Endocrinol Metab. 2012;7(4):377–93.Google Scholar
- 98.Bolli GB, Frick A, Schmidt R, Eisenblaetter T, Becker R. Plasma concentrations of insulin glargine and its metabolites after SC injection of glargine in subjects with type 1 diabetes. ADA 71st Scientific Sessions; June 24–28, 2011; San Diego, CA. Abstract 71-OR2011.Google Scholar
- 99.Lucidi P, Portcellati F, Rossetti P, Candeloro P, Andreoli AM, Frick A et al. Metabolism of insulin glargine after subcutaneous injection of therapeutic dose in type 2 diabetes mellitus. ADA 71st Scientific Sessions; June 24–28, 2011; San Diego, CA. Abstract 1092-P2011.Google Scholar
- 100.Werner U, Schmidt R, Blair E, Renna SM, Tennagels N. The molecular mechanism of insulin glargine metabolism in vivo. ADA 72nd Scientific Sessions; June 8–12, 2012; Philadelphia, PA. Abstract 1645-P2012.Google Scholar
- 101.Porcellati F, Rossetti P, Ricci NB, Pampanelli S, Torlone E, Campos SH, et al. Pharmacokinetics and pharmacodynamics of the long-acting insulin analog glargine after 1 week of use compared with its first administration in subjects with type 1 diabetes. Diabetes Care. 2007;30(5):1261–3. doi:10.2337/dc06-2208.PubMedGoogle Scholar
- 102.Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–79. doi:10.2337/dc12-0413.PubMedCentralPubMedGoogle Scholar
- 113.Owens DR, Luzio SD, Sert-Langeron C, Riddle MC. Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6-month ‘proof-of-concept’ study. Diabetes, Obes Metab. 2011;13(11):1020–7. doi:10.1111/j.1463-1326.2011.01459.x.Google Scholar
- 114.Hollander P, Cooper J, Bregnhoj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther. 2008;30(11):1976–87. doi:10.1016/j.clinthera.2008.11.001.PubMedGoogle Scholar
- 116.Riddle M, Home P, Marre M, Niemoeller E, Ping L, Rosenstock J. Efficacy and safety of once-daily lixisenatide in Type 2 diabetes insufficiently controlled with basal insulin ± metformin: GetGoal-L study. Diabetes. 2012;61(Supplement 1):983-P (A251).Google Scholar
- 117.Rosenstock J, Forst T, Aronson R, Sau-que-reyna L, Souhami E, Ping L et al. Efficacy and safety of once-daily lixisenatide added on to titrated glargine plus oral agents in Type 2 diabetes: GetGoal-Duo 1 Study. Diabetes. 2012;61(Supplement 1):62-OR (A18).Google Scholar
- 118.Seino Y, Min KW, Niemoeller E, Takami A, Investigators EG-LAS. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes, Obes Metab. 2012;14(10):910–7. doi:10.1111/j.1463-1326.2012.01618.x.Google Scholar
- 120.Brandle M, Azoulay M, Greiner RA. Cost-effectiveness and cost-utility of insulin glargine compares with NPH insulin nased on a 10-year simulation of long-term complications with the Diabetes Mellitus Model in patients with type 2 diabetes in Switzerland. Int J Clin Pharmacol Ther. 2007;45:203–20.PubMedGoogle Scholar
- 124.Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis. Diab Obes Metab. 2009;11:372–8.Google Scholar
- 126.Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498–507. doi:10.1016/S0140-6736(12)60205-0.PubMedGoogle Scholar
- 127.Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489–97. doi:10.1016/S0140-6736(12)60204-9.PubMedGoogle Scholar
- 128.Yang Y, Hua QX, Liu J, Shimizu EH, Choquette MH, Mackin RB, et al. Solution structure of proinsulin: connecting domain flexibility and prohormone processing. J Biol Chem. 2010;285(11):7847–51. doi:10.1074/jbc.C109.084921
- 129.Smith GD, Pangborn WA, Blessing RH. The structure of T6 human insulin at 1.0 A resolution. Acta Crystallogr D Biol Crystallogr. 2003;59:474–82.Google Scholar
- 130.Takiya L, Dougherty T. Pharmacist’s guide to insulin preparations: a comprehensive review. Last accessed August 2012. https://secure.pharmacytimes.com/lessons/200510-03.asp.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.