One hundred years after the discovery of insulin and glucagon: the history of tumors and hyperplasias that hypersecrete these hormones

in Endocrine-Related Cancer
Authors:
Wouter W de Herder Department of Internal Medicine, Sector of Endocrinology, Erasmus MC & Erasmus MC Cancer Institute, ENETS Center of Excellence, Rotterdam, the Netherlands

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Günter Klöppel Department of Pathology, Technical University Munich, Munich, Germany

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Correspondence should be addressed to W W de Herder: w.w.deherder@erasmusmc.nl

This paper is part of a themed collection celebrating the Discovery of Insulin and Glucagon. The Guest Editors for this collection were Günter Klöppel and Wouter de Herder.

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One century ago, in 1922, Frederick G Banting, Charles H Best, James B Collip and John J R Macleod first published their experiments resulting in the isolation of a hypoglycemic factor, named insulin, from a solution extract from a dog’s pancreas. One year later, in 1923, a hyperglycemic factor named glucagon was isolated by Charles P Kimball and John R Murlin. In the following years, it could be demonstrated that pancreatic islet alpha- and beta-cell neoplasms and hyperplasias could inappropriately secrete excessive amounts of these two hormones. This review is a sequel to the discovery of insulin and glucagon and introduces the history of this fascinating group of neuroendocrine neoplasms and hyperplasias of the pancreas.

Abstract

One century ago, in 1922, Frederick G Banting, Charles H Best, James B Collip and John J R Macleod first published their experiments resulting in the isolation of a hypoglycemic factor, named insulin, from a solution extract from a dog’s pancreas. One year later, in 1923, a hyperglycemic factor named glucagon was isolated by Charles P Kimball and John R Murlin. In the following years, it could be demonstrated that pancreatic islet alpha- and beta-cell neoplasms and hyperplasias could inappropriately secrete excessive amounts of these two hormones. This review is a sequel to the discovery of insulin and glucagon and introduces the history of this fascinating group of neuroendocrine neoplasms and hyperplasias of the pancreas.

Introduction

One century ago, in 1922, Frederick G Banting, Charles H Best, James B Collip and John J R Macleod first published their experiments resulting in the isolation of a hypoglycemic factor, named insulin, from a solution extract from a dog’s pancreas (Banting et al. 1922, 1923, Banting & Best 1922, Bliss, 1993, 2021). One year later, in 1923, a hyperglycemic factor named glucagon was isolated by Charles P Kimball and John R Murlin (Kimball & Murlin 1923, Piper et al. 1923, Foa et al. 1957, Unger 1971, Müller et al. 2017). In the following years, it could be demonstrated that pancreatic islet alpha- and beta-cell neoplasms and hyperplasias could inappropriately secrete excessive amounts of these two hormones. This review is a sequel to the discovery of insulin and glucagon and introduces the history of this fascinating group of neuroendocrine neoplasms and hyperplasias of the pancreas.

Pancreatic islets

Pancreatic islet cells were first described in the rabbit by the German medical student Paul Langerhans (1847–1888) in his doctoral thesis in 1869 (Langerhans 1869, Kloppe 1969, Hausen 1987a , Baskin 2015). He worked in the laboratory of the eminent Berlin pathologist Rudolf Virchow (1821–1902), who was also a close friend of the Langerhans family and who could probably be considered as a godfather of Paul Langerhans (Hausen 1987a ). Virchow, whose scientific curiosity was unlimited, was also interested in the pancreas. In 1854, he published a small account on the biochemistry of the pancreas, which he concluded with the presumption ‘... that this gland also secretes not only outwards, but also inwards into the blood’ (Virchow 1854). What facts were these prophetic words by the godfather of cellular pathology based on? The exocrine function of the pancreas was already established in 1848, when the French physiologist Claude Bernard (1813–1878), the godfather of experimental medicine, had shown that pancreatic juice is required for fat digestion (Bernard 1848). These findings were further supported in 1876 by a former assistant of Rudolf Virchow, the German physiologist Wilhelm F Kühne (1837–1900), who succeeded in isolating a protein-splitting pancreatic enzyme, later named ‘trypsin’ (Kühne 1876, 1877). The possibility that the pancreas could also have an endocrine function was based on clinical and pathological observations, suggesting that the diseased pancreas might be responsible for the development of diabetes mellitus. However, this dialogue about the existence of a pancreatogenous diabetes mellitus became muted after Claude Bernard’s numerous attempts to induce diabetes mellitus through pancreatic resections failed (Grmek 1967). This was the situation when Paul Langerhans began his histological studies. Very little was known about the detailed microscopic structure of the pancreas. For his study, he chose the rabbit's pancreas because of its translucent structure allowing a quick native examination under the microscope. However, he obtained the best results when he macerated the tissue with Müller’s solution. He finally was able to distinguish several cell types, including acinar, centroacinar, ductal, stromal, hematogenous and neural cells. The ninth cell type which he described as homogeneous, with no granules and often grouped in small clusters, represented the pancreatic islet cells. No illustration highlighted these cells and no functional explanation was offered other than the suggestion that these cells may have something to do with nerval structures. He was dissatisfied with the meagre results of his study and expressed this at the beginning of his doctoral thesis: ‘Unfortunately, I have to begin my communications by stating that I am in no way able to present the completed results of a successful investigation. The purpose of these lines, at the very best, can be only to help to direct somewhat greater attention to the pancreas than has been given to it by anatomists until present‘ (Langerhans 1869, Kloppe 1969, Hausen 1987a,b,c,d). This dissatisfaction was probably the reason why he interrupted his work for almost a year to devote his energy to a histological investigation of tactile corpuscles of the skin. He stained cut sections of the dermis with gold chloride, a method invented by the German pathologist Julius F Cohnheim (1839–1884), who also worked in Virchow’s institute at that time. Using this technique, Langerhans discovered dermal cells with long tentacles, which he captured in a beautiful drawing and which he regarded as intraepidermal receptors for extracutaneous signals of the nervous system of the skin. However, these cells, which nowadays also bear his name, were not found to be of neural nature but instead were identified as antigen-presenting immune cells of the dermis and called ‘dendritic cells’ almost 100 years later (Hausen 1987a,b,c,d). In 1868, Paul Langerhans received for this work the Berlin University Faculty prize. After this interlude, he resumed his work on the pancreatic islet cells and submitted it as his doctoral thesis in 1869 (Langerhans 1869, Kloppe 1969, Sakula 1988). Thereafter, he never studied the pancreas again. Paul Langerhans died in 1888 of tuberculosis and never knew the significance and function of ‘his’ islet cells (Hausen 1987a,b,c,d). In line with Langerhans, Rudolf Virchow also never dealt with this topic again.

From 1869 to 1889, not much happened in the field of the pathophysiology of diabetes mellitus (Schäfer 1895, Diamare 1899, Baskin 2015), but in 1889, the next epochal discovery was made. The German physicians Joseph von Mering (1849–1908) and Oskar Minkowski (1858–1931) met by chance in the library of the University Hospital of Strasbourg/Strassburg (pre-First World War – Germany) where both worked in different departments. They got into a dispute about whether pancreatic juice is necessary for the breakdown of fatty acids. To answer this question, Minkowski proposed to remove the pancreas and, although they were aware of Claude Bernard’s statement that the removal of the pancreas would result in no adverse effect on the body, they operated a dog that same afternoon (Houssay 1952). The success of the operation was mainly due to Oskar Minkowski’s manual dexterity which had given him the reputation of being an excellent experimental surgeon. The dog survived, although he had hyperglycemia and severe diabetes mellitus the very next day. Oskar Minkowski repeated the operation in other dogs and all animals developed diabetes mellitus within hours after the removal of the pancreas. Joseph von Mering and Oskar Minkowski reported their groundbreaking observation in a communication on the 8th of June 1889, which was no longer than a single page, and from that time on diabetes mellitus was linked closely to the pancreas (von Mering & Minkowski 1890, Minkowski 1893, de Leiva-Hidalgo & de Leiva-Pérez 2022).

The next decisive step, confirming the suggestion that the pancreatic islet cells as described by Langerhans some 24 years earlier are the morphological source of the postulated internal secretion of the pancreas, was taken by the French pathologist G-Édouard Laguesse (1861–1927 in 1894). He translated Langerhans’ expression ‘Zellhäufchen’ (a lump of cells) into ‘islands/islets of Langerhans,’ a term that is universally accepted since that time (Laguesse 1894, 1896). The term ‘internal secretion’ was already introduced by Claude Bernard in 1855, when he, for the first time, could demonstrate that the liver secretes bile into the duodenum (‘external secretion’) and glucose into the blood (‘internal secretion’) (Bernard 1865, Renan et al. 1881). In 1905, the British physiologist Ernest H Starling (1866–1927) introduced the term ‘hormone’ (Starling 1905) and defined ‘hormones’ as chemical messengers, which are ‘carried from the organ where they are produced to the organ which they affect by means of the blood stream and the continually recurring physiological needs of the organism must determine their repeated production and circulation from the body’ (Starling 1905). Édouard Laguesse’s internal secretion hypothesis of mediated glucose regulation by the islets of Langerhans was further supported by successive studies. In 1877, the French physician Étienne Lancereaux (1829–1910) coined the term ‘diabète pancréatique’ (pancreatic diabetes) based on clinical and autopsy studies. He classified diabetes mellitus either as ‘diabète maigre‘ (thin diabetes), which he believed to be pancreatic in origin and which he claimed had a poor prognosis, or ‘diabète gras’ (fat diabetes), which he believed had a much better prognosis and was not pancreatic in origin (Lancereaux 1877, 1880a,b).

In 1901, Eugene Opie (1873–1971) (Opie 1901a,b) and, in his wake, a whole group of pathologists including the German pathologist Walter Schulze in 1900, the Russian pathologist Leonid V Ssobolev (1876–1919) in 1902, the Austrian pathologists Anton Weichselbaum (1845–1920) and E Stangl in 1902, the US resident-pathologist/physician Russel L Cecil (1881–1965) in 1909, the Danish pathologist K Heiberg in 191, and the US–Russian pathologist Moses Barron (1883–1974) in 1920 noted hyaline degeneration, sclerosis and lymphocytic infiltration of the islets of Langerhans and/or reduced islet numbers in pancreases, which were removed at autopsy from patients who were afflicted with diabetes mellitus. The same researchers, however, also noticed that there were also pancreases of diabetic patients without any changes of the islets of Langerhans. They drew two conclusions from these observations: first, that there is a suspected link between diabetes mellitus and islet abnormalities and second, that diabetes mellitus is obviously a heterogeneous disease (Schulze 1900, Ssobolew 1902, Weichselbaum & Stangl 1902, Cecil 1909, Heiberg 1916, Barron 1920, Opie 1901a,b).

At the same time as the histopathology of the islets was described, their cellular diversity was also recognized (Schadewaldt 1989). Using stains such as safranin and methyl green, the Italian histologist Vincenzo Diamare (1971–1966) in 1899, S Tschassownikow from Poland in 1900, Walter Schulze in 1900, Leonid V Ssobolev in 1902 and the US pathologist and anatomist Lydia M Adams DeWitt (1859–1928) in 1906 suggested the existence of more than one cell type in the islets of Langerhans (Diamare 1899, Schulze 1900, Tschassownikow 1900, 1905, Ssobolew 1902, DeWitt 1906). In 1911, the US pathologist Michael A. Lane in 1907 and the Canadian physiologist Robert R Bensley (1867–1956) differentiated two populations of islet cells in guinea pigs, naming them A cells and beta cells (with Bensley changing the term beta cell to B cell) (Lane 1907, Bensley 1914, Baskin 2015). Several decades after these studies, it became evident that the A cells were in fact two cell populations: the A1 cells and A2 cells (later named alpha cells). In 1957, the US pathologists Paul E Lacy (1924–2005) and Jack Davies, using a fluorescein-labeled anti-insulin immune serum that was produced in guinea pigs and using small pieces of mouse and beef pancreas, showed that the hormone produced by the beta cells in the islets of Langerhans is insulin (Lacy & Davies 1957). In 1962, using immunofluorescence, John Baum and colleagues were able to show that the alpha cells in the islets of Langerhans expressed glucagon (Baum et al. 1962, Baskin 2015). In the same year, the Japanese anatomists Shin-ichi Mikami and Kazuyuki Ono could confirm the findings of the group of Baum by demonstrating that deprivation of the alpha cell part of the pancreas caused severe hypoglycemia in birds, which was not caused by hypersecretion of insulin (Mikami & Ono 1962).

Next to the alpha and beta cells, at least three other cell types were found in the islets of Langerhans of humans: delta cells (D cells) that produce somatostatin, PP cells (F cells) that produce pancreatic polypeptide (PP) and ghrelin cells (E-cells) that excrete acylated ghrelin (Wierup et al. 2002, Wierup et al. 2014, Baskin 2015). Further two types of pancreatic islet cells have been described in specific animal species containing serotonin (enterochromaffin (EC) cells) and gastrin (G cells) (Wierup et al. 2014).

In 1902, the Canadian–British pathologist Albert G Nicholls (1870–1946) was the first to describe a tumor which he named ‘simple adenoma’ originating from the pancreatic islets and which he had discovered incidentally by autopsy (Nicholls 1902). It is not reported whether the deceased person suffered from signs or symptoms of hormonal excess. The name simple adenoma was later replaced by ‘islet cell tumor’. Between 1960 and 2000, the islet cell tumors were often given the acronym ‘APUDoma‘ (APUD, amine precursor uptake and decarboxylation; after Anthony Pearse (1916–2003)), a term that referred to characterizing histochemical properties of the tumor cells and was also used for all neoplasms of the neuroendocrine cell system (Pearse 1974, de Herder et al. 2016). Since 2000, the islet cell tumors are referred to by the world health organization (WHO) as pancreatic neuroendocrine neoplasms (PanNENs) (Rindi et al. 2022, Capella et al. 1995). In 2006, the European Neuroendocrine Tumor Society (ENETS) proposed a separate grading and TNM staging system for PanNENs (Rindi et al. 2006) that soon was adopted by the WHO (Konukiewitz et al. 2022).

Insulin

In the years after Joseph von Mering’s and Oskar Minowski’s successful pancreatectomy experiments in dogs, which resulted in severe and fatal diabetes mellitus, several other groups subsequently experimented with injections and infusions of pancreatic extracts and emulsions in healthy and depancreatized animals demonstrating blood glucose-lowering properties of these substances (Forschbach 1909, Scott 1912, Murlin & Kramer 1913, Kleiner & Meltzer 1915, Kleiner 1919, Gibbs et al. 1922, Murlin et al. 1922, Sutter & Murlin 1922). Most of these attempts failed because of the ineffectivity of the extracts or their unclear composition which caused severe side effects or, in some cases, probably hypoglycemic effects, which were not yet known in their symptomatology. Most notable were the studies by Eugène Gley, Georg Zülzer and Nicolae Paulescu, which are of importance in the priority dispute of the discovery of insulin and which preceded the work of Frederick Banting, Charles Best and James Collip in the laboratory of John Macleod (see later).

The French physician M Eugène É Gley (1857–1930) was the first to demonstrate the presence of an ‘antidiabetic principle’ in extracts from ‘sclerosed’ pancreases (Gley 1900, de Leiva-Hidalgo & de Leiva-Pérez 2022). In 1900, he showed that destruction of the exocrine pancreas after the injection of foreign materials into the pancreatic ducts does not induce diabetes mellitus. He stated, as already indicated by the work of Édouard Laguesse, that following this procedure the islets of Langerhans remain unharmed. Gley, therefore, prepared aqueous extracts from sclerosed remains of pancreases and showed that intraperitoneal administration to completely depancreatized dogs resulted in a decrease of glycosuria and alleviated diabetic symptoms (Gley 1900). A written report summarizing the experiments he started in 1890 with ‘extracts of degenerated pancreas’ titled ‘Sur la sécrétion interne du pancréas et son utilisation thérapeutique’ was deposited in February 1905 in a sealed package with the ‘Société de Biologie’ in Paris, France. It was only until the assembly of this society on December 23, 1922, that Eugène Gley requested that this envelope be opened and read (Gley 1922). In 1926, John Macleod credited Eugène Gley for his scientific efforts in relation to the antidiabetic hormone from the pancreas (Macleod 1926).

In 1908, the German physician Georg L Zülzer (1870–1949) treated a patient in diabetic coma after amputation of a gangrenous leg with an alcoholic extract of the pancreas with the idea to counteract the effects of adrenaline, because he believed in antagonism between adrenaline and insulin as a cause of diabetes. The treatment led to a 5-day improvement, but the patient died because the extract (which he called ‘Acomatol, das deutsche Insulin’) was no longer available (Zuelzer 1908, 1923, Zuelzer et al. 1908). Georg Zülzer repeated these treatments in other diabetic patients with success but saw such severe side effects (of possibly hypoglycemic nature) that he discontinued his studies in 1909 (Mellinghoff 1972). In June 1921, the Rumanian physiologist Nicolae C Paulescu (1869–1931) reported that he had succeeded in obtaining an extract from dog and beef pancreas containing a blood glucose-lowering substance with which he successfully treated diabetic dogs and which he named ‘pancreine’ (Paulescu 1921a,b). Paulescu therefore discovered pancreine earlier than the Toronto group discovered isletin (insulin), but as his product was not used in humans, Nicolae Paulescu was never fully credited for his discovery.

In May 1921, the joint efforts of the Canadians Frederick G Banting (1891–1941) and Charles H Best (1899–1978) together with James B Collip (1892–1965) led to the discovery of insulin on the 11th of January 1922, ‘isletin’ (before it was renamed ‘insulin’) was successfully administered to the 14-year-old diabetic boy Leonard Thompson (1908–1935) (Banting et al. 1922, 1923, Banting & Best 1922, Bliss 1993, 2021). The British physiologist Sir Edward A Sharpey-Schafer (1850–1935) described in 1916 that the pancreatic islands are able to secrete a substance capable of controlling glucose metabolism, which he termed ‘insulin,’ from the Latin term ‘insula’ (‘island’), with reference to the íslets of Langerhans (Sharpey-Schäfer 1916). However, already in 1909, the Belgian physiologist Jean de Meyer (1878–1934) introduced the name ‘insulin’ (De Meyer 1909). Frederick Banting was originally a surgeon who, however, had settled as an orthopedist and also worked as a lecturer to medical students at the London University of Ontario, Canada. Charles Best was a research student invited to study with Banting, who worked in a laboratory of the Physiological Department of the University of Toronto, Canada. The laboratory was provided by the department’s director John J R Macleod (1876–1935) after Banting had approached him with the idea to ‘Ligate pancreas ducts of dogs. Keep dogs alive till acini degenerate leaving islets. Try to isolate the internal secretion of these to relieve glycosuria’ (Friesen 1993). This idea had struck Banting the night before, sleepless after preparing for a lecture on carbohydrate metabolism, when he read the article by Moses Barron on ‘The relation of the islets of Langerhans to diabetes ...’ in which the preservation of the pancreatic islets despite acinar degeneration by the ligation of the ducts is described (Barron 1920, 1966). Frederick Banting later stated: ‘It was not until 2 o’clock in the morning that I was able to crystallize the idea into a form that would lend itself to experimentation’. This was the starting point for the experiments which were successful in the end but turned out to be extremely difficult at the beginning, particularly in refining the pancreatic extracts. The problem was only solved with the help of the young biochemist James Collip from Edmonton, who succeeded to clean the extracts by precipitating out contaminating proteins and lipids with increasing concentrations of alcohol. James Collip was only a few, but decisive months in Toronto, and was asked by John Macleod to help Frederick Banting and Charles Best. The Nobel Prize in Physiology or Medicine 1923 was awarded to Frederick G Banting and John J R Macleod ‘for the discovery of insulin’ (de Herder 2014). Frederick Banting divided his share with Charles Best, which led John MacLeod to provide half of his share to James Collip. While Collip’s role in the purification process of insulin was decisive for the clinical application of the hormone, the role that Macleod played in the discovery process of insulin is still regarded as ambiguous (Bliss 2021).

In 1960, the US nuclear physician Rosalyn (Sussman) Yallow (1921–2011) and the internist Salomon A Berson (1918–1972) developed a (radio)immunoassay (RIA) for measuring endogenous insulin in human plasma. Plasma insulin concentrations during glucose tolerance tests in nondiabetic and in early diabetic subjects and plasma insulin concentrations in subjects with ‘functioning islet cell tumors’ or ‘leucine-sensitive hypoglycemia’ (see later) could now be measured (Yalow & Berson 1960). The Nobel Prize in Physiology or Medicine 1977 was divided between Rosalyn Yalow ‘for the development of RIAs of peptide hormones’ and the other half jointly to Roger Guillemin and Andrew Victor Schally ‘for their discoveries concerning the peptide hormone production of the brain’ (de Herder 2014).

Insulinoma

After having served the U.S. Army Medical Corps during the First World War, the US surgeon Seale Harris (1870–1957) went to Toronto to join the group of Frederick G Banting and Charles H Best. Harris recalled that some of his nondiabetic patients exhibited the clinical effects of insulin overdosing (‘insulin shock’) several hours after meals and discussed with Banting on the theoretical possibility of endogenous excessive insulin secretion. After moving back to Birmingham, AL, USA, he obtained the files of his patients with these symptoms from the archives and studied these patients further. At the meeting of the American Medical Association in 1924, Harris reported on five patients in whom the above-described symptoms were associated with a blood glucose level lower than 70 mg/dL (3.9 mmol/L) and suggested that this was caused by an excessive endogenous secretion of insulin/hyperinsulinism. Harris developed a theory that sugar-rich foods may cause the pancreas to oversecrete insulin and started experimenting with diets in the management of functional hyperinsulinism. In 1920, he opened the Seale Harris Clinic and shortly thereafter founded the Gorgas Hospital (currently: Trinity Medical Center) in Birmingham (AL, USA) (Harris 1924, 1933, Smelo 1957). ‘Harris' syndrome’ is a historical eponym for ‘hyperinsulinemic hypoglycemia’ (Smelo 1957). Harris remained a great admirer of Sir Frederick G Banting and published his biography in 1946 (Harris 1946).

In 1926, the US surgeon William J Mayo (1861–1939) performed an exploratory laparotomy on a male patient suffering from recurrent severe hypoglycemias and found an unresectable pancreatic tumor with multiple liver, lymph node and mesenteric metastases (van Heerden & Churchward 1999). The patient, a 41-year-old orthopedic surgeon, remained poor after the surgery and required constant oral candy and i.v. glucose. He died (without leaving the hospital) 1 month later because of ‘exhaustion’. According to the reports, the patient was ‘conscious and entirely rational to within a few minutes of death’ (van Heerden & Churchward 1999). In 1927, the US internist Russel M Wilder Sr (1885–1959) and colleagues reported on the autopsy of this patient (Wilder et al. 1927). When extracts of liver metastasis were injected into rabbits, this was followed by a marked lowering of the blood glucose levels. Since Mayo’s and Wilder’s patient also had renal stones and his cousin had had similar symptoms and died 6years earlier, it seems likely that he might have had multiple endocrine neoplasia type 1 (MEN-1, Mendelian inheritance in man (MIM) numbering # 131100 (https://www.omim.org/)) (Wilder et al. 1927, van Heerden & Churchward 1999). Twenty-seven years later, in 1954, the US internist Paul Wermer (1898–1975) reported disorders of one or more endocrine glands in five members of one family (Wermer 1954). This familial syndrome was once called Wermer syndrome but is nowadays better known as MEN-1.

The first cure of hyperinsulinism following the removal of an insulinoma by the Canadian surgeon Roscoe R Graham (1890–1948) was reported in 1929 by the occupational therapist Goldwin Howland (1875–1950) and colleagues (Howland et al. 1929b, Howland et al. 1929a). Ten years later in 1939, this patient was still disease free (Campbell et al. 1939). The US surgeon Allen O Whipple (1881–1963) and pathologist Virginia K Frantz (1896–1967) defined the diagnostic hallmark of insulinoma which is at present still known as Whipple’s triad: (1) symptoms known or likely to be caused by hypoglycemia, (2) low plasma glucose measured at the time of the symptoms and (3) relief of symptoms when the glucose is raised to normal (Whipple & Frantz 1935). Frantz collected 43 published cases of endogenous hyperinsulinism (including 15 from their own series) in which a pancreatic tumor was found either at operation or necropsy. These cases were further categorized into 24 ‘benign’ and 19 ‘suspected of being malignant’ tumors on the basis of their pathology. In five cases, there was ‘no dispute about the malignancy,’ since metastases were found. All these five malignant cases were the most severe ones, and patients’ survival was generally short (Frantz 1940). In 1947, the pathologists R Lopez-Kruger and Malcolm B Dockerty (1909–1987) from the Mayo Clinics, Rochester, USA, classified islet-cell tumors as follows: (1) adenomas of islet cells without hypoglycemia, (2) adenomas of islet cells with hyperinsulinism, (3) metastasizing carcinomas of islet cells without hypoglycemia, (4) metastasizing carcinomas of islet cells with hyperinsulinism and (5) borderline malignant islet-cell tumors with or without hyperinsulinism (Lopez-Kruger & Dockerty 1947). In 2006, a grading and TNM staging system for panNENs including insulinomas was proposed for the first time by the ENETS TNM (Rindi et al. 2006). Since then, this grading and staging system has been regularly updated (Rindi et al. 2006, Rindi et al. 2022, Konukiewitz et al. 2022). Only very recently, it became more clear that so-called ‘indolent’ (insulinoma without metastasis) and ‘aggressive’ insulinoma (insulinoma with metastasis) are different entities. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor alpha-thalassemia/mental retardation, X-linked (ATRX) and death domain associated protein (DAXX) mutations, the alternative lengthening of telomeres phenotype (ALT) and chromosomal instability (CIN). Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal pancreatic islet alpha cells and nonfunctional panNENs, while indolent insulinomas remain closely related to normal pancreatic islet betacells (Hackeng et al. 2023, Hackeng et al. 2020).

Congenital hyperinsulinism in infancy

In 1933, the US surgeons Evarts A Graham (1883–1957) and Nathan A Womack (1901–1975) performed the first curative spleen-preserving subtotal pancreatectomy for idiopathic hyperinsulinemic hypoglycemia in a child (Graham & Womack 1933). In 1938, the US pathologist George F Laidlaw (1871–1958) suggested the term ‘nesidioblastoma’ for islet cell tumor and coined the term ‘nesidioblastosis’ based on a ‘diffuse or disseminated proliferation of islet cells as a possible cause of hypoglycemia’ (Laidlaw 1938, Sempoux & Kloppel 2023). Persistent hyperinsulinemic hypoglycemia, currently summarized under the term ‘congenital hyperinsulinism,’ was first described in detail in 1954 by the US pediatrician Irvine McQuarrie (1891–1961) and, although it is a rare disease, it is the most common cause among the non-neoplastic hypoglycemic disorders in neonates, infants and adults (McQuarrie 1954, Sempoux & Kloppel 2023). McQuarrie considered it unlikely that hyperinsulinism was the cause of this ‘idiopathic hypoglycemia of infancy’ because of the lack of evidence of a pancreatic tumor or islet hyperplasia, but this was subsequently proven to be wrong (McQuarrie 1954). McQuarrie was concerned because of the unrepairable brain damage he had observed in young children caused by either insulin ‘misuse’ or severe spontaneous hypoglycemia, and he was also concerned about the limited treatment options for these infants (McQuarrie 1954). Ten years later, in 1964, the US pediatric endocrinologist Alan Drash (1931–2009) and pharmacologist Frederick Wolff published the first account on the use of diazoxide to treat children with ‘leucine-sensitive hypoglycemia’ (Drash & Wolff 1964). William A Cochrane (1926–2017) and colleagues described in 1956 three cases of hypoglycemia occurring in one family and one unrelated case in which protein feeding, particularly leucine, induced hypoglycemia and convulsions and thus the term ‘leucine-sensitive hypoglycemia’ was born (Cochrane et al. 1956). Leucine-sensitive hypoglycemia refers to the hyperinsulinism/hyperammonemia (HI/HA) syndrome, which is the second most common cause of congenital hyperinsulinism. The HI/HA syndrome (familial hyperinsulinemic hypoglycemia-6 – HHF6 – MIM numbering 606762) is caused by dominant gain-of-function mutations in GLUD1, encoding the mitochondrial enzyme glutamate dehydrogenase (GDH) and resulting in an increased GDH activity (Casertano et al. 2021).

The term ‘congenital hyperinsulinism’ was proposed in 1976 by the US pediatricians Charles A Stanley and Lester Baker (1930–2000), who outlined the diagnostic criteria for HI: (1) hyperinsulinemia, (2) hypoketonemia, (3) hypofatty acedemia, and (4) hyperglycemic response to glucagon (Stanley & Baker 1976). Alternatively, the term ‘persistent hyperinsulinemic hypoglycemia in infancy’ is used (Glaser et al. 1989, Sempoux & Kloppel 2023). This condition represents a group of clinically, genetically and histologically heterogeneous disorders, characterized by inappropriate insulin secretion from the pancreatic beta cells in the presence of low blood glucose levels. Histologically, two major subgroups, namely a diffuse and a focal form, have been identified. A third atypical form related to morphological mosaicism has also been described. Genetically, these disorders are linked to ABCC8 (familial hyperinsulinemic hypoglycemia-1 (HHF1) – MIM numbering 256450), KCNJ11 (HHF2 – MIM numbering 601820, GCK (Glucokinase gene – HHF3 – MIM numbering 602485), HADH (HHF4 – MIM numbering 609975), INSR (HHF5 Insulin receptor gene – MIM numbering 609968, GLUD1 (HHF6 – MIM numbering 606762) or SLC16A1 (HHF7 – MIM numbering 610021) mutations (Shah et al. 2017).

Insulinomatosis

Starting in 2006, a disorder was described, which was characterized by the synchronous and metachronous occurrence of multiple insulinomas which was different from solitary sporadic and MEN-1-associated insulinomas. Metastases have not been reported so far (Anlauf et al. 2009, Anlauf et al. 2006). This condition was named ‘insulinomatosis’ by the German pathologist Martin Anlauf and colleagues (Anlauf et al. 2009, Christ et al. 2023). An autosomal-dominant inheritance associated with a MAFA (MAF BZIP Transcription Factor A mutation (MIM numbering # 147630)) and causing familial insulinomatosis or diabetes mellitus was first described by the clinical research fellow Donato Iacovazzo and his colleagues from London, UK, in 2018 (Iacovazzo et al. 2018, Christ et al. 2023, Fottner et al. 2022).

Glucagon

In 1923, a hyperglycemic factor named ‘glucagon’ was isolated from beef pancreas in Rochester (NY, USA), by the biochemistry student Charles P Kimball (b 1897) and his mentor John R Murlin (1874–1960) (Kimball & Murlin 1923, Unger 1971, Müller et al. 2017). Subsequently, the German physician Max T F Bürger (1885–1966) and colleagues showed that the hyperglycemic effect of glucagon is due to a direct glycogenolytic effect in the liver (Bürger & Kramer 1929, Bürger & Brandt 1935, Seige 1986). The US physician Roger Unger (1924–2020) and colleagues made seminal contributions to the research on the multiple physiologic effects of glucagon (Unger 1971, Unger et al. 1970, Gromada et al. 2007).

Glucagonoma

In 1942, the US dermatologist S William Becker (1894–1964) and colleagues described a patient with skin eruptions in their paper on ‘cutaneous manifestations of internal malignant tumors,’ who was found at autopsy to have a metastasizing islet cell tumor of the body and tail of the pancreas (Becker et al. 1942). The patient was a woman of 45 years old with an 8 months' history of sore tongue and an exudative papulo-vesicular erythema which appeared on the legs and then spread to the groin, vulva and trunk. She had lost 17 pounds in weight. A normochromic anemia persisted despite iron therapy and two transfusions. There was glycosuria and a dextrose tolerance test showed a diabetic curve. She died 6 weeks after admission. The case description can be considered typical of the glucagonoma syndrome with glossitis, weight loss, diabetes mellitus, anemia and the typical necrolytic migratory erythema (NME) (Alexandraki et al. 2023). In their paper, Becker and colleagues already claimed that ‘the disappearance of the cutaneous manifestations after removal of the tumor and their recurrence with the reappearance of the tumor, as observed in single cases, seemed to prove the causal connection between tumor and eruption’ (Becker et al. 1942). In 1963, Roger Unger and colleagues succeeded in recovering ‘physiologically significant quantities’ of glucagon from extracts of ‘non-beta-cell islet tumors’ found either at operation in three patients with diabetes mellitus and metastatic disease or as an incidental finding at necropsy in one patient with diabetes mellitus. The three patients with metastatic disease also had elevated total body glucagon levels (Unger et al. 1963). This report for the first time provided evidence of glucagon-secreting metastatic and localized panNENs (Unger et al. 1963). In 1966, the US pathologist Malcolm H McGavran (1923–1999) together with Roger Unger and colleagues published a case report on a 42-year-old woman presented with diabetes mellitus, anemia, a peculiar skin eruption and a metastatic pancreatic alpha-cell tumor (McGavran et al. 1966). Later in the course of the disease, elevated plasma glucagon levels were found (McGavran et al. 1966). The tumor was biopsied and operated by the US surgeon Hiram C Polk Jr (McGavran et al. 1966). The case report is considered the first evidence of a glucagon-secreting panNEN in combination with manifestations of the glucagonoma syndrome. The British dermatologist Darrell S Wilkinson (1919–2009) named characteristic cutaneous eruption which occurs in association with the glucagonoma syndrome )NME in 1971 (Wilkinson 1971). In 1974, the British gastroenterologist Christopher N Mallinson in collaboration with Stephen R Bloom and colleagues described four glucagonoma patients with the glucagonoma syndrome and NME with increased plasma glucagon levels and very low plasma amino acid concentrations (Mallinson et al. 1974). One patient fully recovered after resection of the glucagonoma, hereby confirming the claim by S. William Becker already made in 1942 (Mallinson et al. 1974, Becker et al. 1942). In the same year, a similar complete response of the glucagonoma syndrome and NME after surgical resection was described by the British dermatologist R Douglas Sweet (1917–2001) (Sweet 1974). In 2006, a grading and TNM staging system for panNENs including glucagonomas was proposed for the first time by the ENETS TNM (Rindi et al. 2006).

Glucagonomatosis

In 1977, the US diabetologists Guenther Boden (1935–2015) and Oliver E Owen (1934–2010) first reported on a family with autosomal dominant hyperglucagonemia with no significant clinical abnormalities (Boden & Owen 1977). Subsequently, more (familial) cases of this syndrome of hyperglucagonemia and glucagon cell hyperplasia, multiple glucagon-producing PanNETs and micro NETs, but without glucagonoma syndrome were reported (Yu et al. 2008, Henopp et al. 2009). These patients exhibited no stigmata or family history of MEN-1 (Henopp et al. 2009, Yu et al. 2008). This new genetic disorder is also named Mahvash disease (MIM numbering # 619290) (after the first name of the first patient) and was shown to be caused by inactivating mutations in the glucagon receptor (GCGR) gene (Zhou et al. 2009, Yu 2014, Sipos et al. 2015, Sipos & Klöppel 2023). Patients with glucagon cell hyperplasia and neoplasia (GCHN) of the endocrine pancreas show that loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis. Loss of function of the glucagon receptor causes increased glucagon levels, increased amino acid levels and pancreatic islet alpha-cell hyperplasia. A hepatico–pancreatic feedback regulation of the alpha cells, possibly involving amino acids, may exist in humans (Sipos & Klöppel 2023, Larger et al. 2016).

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

Both authors contributed equally to the manuscript.

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