Preinsulin Era Research Articles

History of Diabetes: Series 1 Diabetes Care in Antiquity and Beyond: The Preinsulin Era

Diabetes as a disease dates back to ancient times. Before the 1920s, treatment was rudimentary and largely ineffective, focusing primarily on dietary management, herbal remedies, and lifestyle modifications. Ancient civilizations, including the Egyptians, Greeks, Chinese, and Indians, recognized diabetes through symptoms such as excessive thirst and urination. They used “natural” treatments, such as dietary restrictions, physical exercise, and medicinal herbs such as fenugreek and bitter melon. Islamic scholars in the medieval period made significant advancements, recommending balanced diets and specific herbal treatments. In Europe, the preinsulin era saw the implementation of starvation diets in the early 20th century, aiming to control blood glucose by severely restricting caloric intake, though often at the cost of malnutrition. These historical approaches reflect the evolving understanding of diabetes and underscore the desperate need for effective treatments, setting the stage for the revolutionary discovery of insulin in the early 20th century.

Vascular complications of diabetes mellitus worldwide and in Russia: The path of 100 years. A review

With the discovery and introduction of insulin, the "palette" of life-threatening conditions for patients with diabetes mellitus has changed dramatically: from diabetic coma of the "pre-insulin era" to severe vascular complications in the modern period. The key risk factors for diabetic angiopathies in diabetes mellitus are poor glycemic control in combination with a long course of the disease. Over the past 30 years, there has been a downward trend in the incidence of late vascular complications of diabetes both worldwide and in Russia. In particular, the frequency of cardiovascular events (myocardial infarctions, strokes, amputations) decreased, and the incidence of several other complications, such as diabetic retinopathy and neuropathy, stabilized. However, the incidence of chronic kidney disease and chronic heart failure is still increasing. The Joslin Medal, awarded to patients over 50, 75 and even 80 years of life with diabetes, reflects success in the fight against this disease.

Mortality in childhood-onset type 1 diabetes

It is well-recognized that diabetes-related complications are the leading cause of the still increased morbidity and mortality from diabetes and exert a heavy economic burden on society. The discovery of insulin led to a dramatic change in life expectancy of patients with type 1 diabetes (T1D). Furthermore, it caused a major shift in the distribution of causes of death - from diabetic coma in the pre-insulin era, to long-term complications being the predominant causes of death nowadays. The aim of the present review is to assess the trends in the absolute and the relative mortality rates as well as the leading causes of death among patients with childhood-onset (< 18 years) T1D in populations from different latitudes. It is also observed how disease duration, age at diagnosis, and year of diagnosis affect these mortality trends. Eight population-based studies published in English in the last 14 years, as well as another one, published in 2001, with different duration of follow-up, are included in the review. However, it is hard to compare different populations due to the dissimilarities in the study methods and the characteristics of the examined cohorts.

The Discovery of Insulin: An Important Milestone in the History of Medicine.

The discovery of insulin represents an authentic breakthrough, characterized, at the same time, by contrasts, controversies and disputes among scholars, as well as by great disappointments, failures and hopes. It is the story of famous, almost famous and little known people, of serendipities, discoveries and re-discoveries. The discovery of insulin has been a milestone and has truly revolutionized both the therapy and the prognosis of the diabetes, one of the diseases most studied in the history of medicine, whose first mentions trace back to a collection of ancient Egyptian, Indian and Chinese textbooks. As stated by Colwell, the introduction of insulin has heralded the end of the so-called “pre-insulin era” or “frustration era”, paving the way for a new era and clinical advancements. The current review offers a broad, comprehensive overview of main steps culminating into insulin discovery, including recent advancements such as personalized and individualized insulin therapy.

Court of Last Appeal - The Early History of the High-fat Diet for Diabetes

The first low carbohydrate diets for diabetes, which were introduced in the 18th century, were not high fat diets so much as high protein diets. By the late nineteenth century a consensus had begun to appear in European studies that a higher fat and lower protein intake was more tolerable. Frederick Allen confirmed this in animal studies, but the diet he introduced into clinical practice in 1914 restricted fat, protein, and total calories, becoming in extreme cases a starvation diet with the deadly side effect of “inanition”. Interpreting Allen’s research in light of the studies in chemical metabolism of Rollin Woodyatt, Louis “Harry” Newburgh, with Phil Marsh, dared to increase fat in the diets of diabetic patients at the University of Michigan Hospital in 1918, with gratifying results which were published in 1920. A dispute followed between Newburgh and Allen’s disciple Elliott P Joslin; Woodyatt, Russell M Wilder, Karl Petren and others confirmed Newburgh’s results by experimentation and by 1924 Joslin too was reporting the higher fat diet’s ability to extend life in diabetics untreated with insulin. However, a dispute between Joslin and Newburgh about the long-term safety of the high fat diet continued long into the insulin era. Because the debate about the effect of the high-fat diet in the tabula rasa of the pre-insulin era only lasted a few years, and rigorous research into the question was largely limited to the state of Michigan, medical history has paid little attention to the fact that the question of what is the “optimum”, or default, diet for diabetes, based on physiological principles as well as clinical practice and experiment, was at one time almost settled. This historical review paper summarises the early clinical researches of Newburgh et al. into the effects of the high-fat diet in the treatment of diabetes, with a particular focus on events in Michigan between 1918 and 1930.

Results of the Epidemiology of Diabetes Interventions and Complications Trial.

Article A. Writing Team for the DCCT/EDIC Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 2003;290;2159–2167 Article B. Writing Team for the DCCT/EDIC Research Group. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313:45–53 The results of the Epidemiology of Diabetes Interventions and Complications (EDIC) study are in, and the results are very interesting. Historically, type 1 diabetes was associated with an increased risk of early or premature mortality compared with the general population. In the pre-insulin era, 50% of patients died within the first 20 months of diagnosis. After the discovery of insulin in 1922, patients with diabetes lived longer. However, they still had a 20-year reduction in life expectancy compared with the general population. In the second half of the 20th century and the beginning of the 21st century, advances have narrowed the survival gap to <4 years. EDIC, the long-term observational follow-up of the Diabetes Control and Complications Trial (DCCT) (1), has sought to help us understand the key factors that have contributed to narrowing this gap. ### Design and Methods The DCCT was …

Mortality in childhood-onset type 1 diabetes: Nationwide population based data from Norway

Type 1 diabetes with onset in childhood (0-14.9 years) represents one of the most frequent chronic diseases in children and young adults. Norway has one of the highest incidences of childhood onset type 1 diabetes in the world. Before introduction of insulin therapy in 1922, few children survived more than one to two years after clinical onset. When insulin came available, a major shift occurred in the distribution of causes of death in type 1 diabetic patients away from diabetic coma, which dominated the pre-insulin era, to renal and cardiac diseases. The disease is related to a significant burden to society and patients because most cases require lifelong treatment with insulin as well as day-to-day monitoring. Type 1 diabetes also confers increased risk of severe late complications such as renal failure, blindness, amputations, heart disease and stroke. Despite advances in diabetes treatment, type 1 diabetes is still associated with considerable premature mortality resulting from acute and chronic complications of diabetes and an increase in mortality at every age. Although the main cause of death in type 1 diabetes is long-term complications, an excess death rate has also been reported in subjects with short duration without signs of long-term complications.

The hypocaloric diet in type 2 diabetes - déjà vu

Dietary modification is considered a cornerstone in the management of diabetes superimposed upon which are pharmacological therapies as required. The value of hypocaloric diets in reducing and eliminating glycosuria was extolled in the pre-insulin era. A common feature of the nutrient balance of these diets was restriction in the availability of carbohydrate. Herein we review the use of diet as therapy in the past and discuss the rationale for hypocaloric dietary management of type 2 diabetes in the 21st century, drawing comparisons with bariatric surgery and considering why weight loss is particularly difficult for overweight and obese individuals with type 2 diabetes.

Elizabeth Lane Furdell, Fatal Thirst: Diabetes in Britain Until Insulin, History of Science and Medicine Library, Vol. 9 (Leiden: Brill, 2009), pp. xii + 195, €99.00/ $158.00, hardback, ISBN: 978-90-04-17250-0.

Elizabeth Lane Furdell, Fatal Thirst: Diabetes in Britain Until Insulin, History of Science and Medicine Library, Vol. 9 (Leiden: Brill, 2009), pp. xii + 195, €99.00/ $158.00, hardback, ISBN: 978-90-04-17250-0. - Volume 55 Issue 3

The Role of Genealogy and Clinical Family Histories in Documenting Possible Inheritance Patterns for Diabetes Mellitus in the Pre-Insulin Era

Part 2 presents detailed genealogic information on Josephine Imperato's paternal and maternal lineages extending from four to seven generations into the nineteenth and eighteenth centuries. Among these lineages are some where early adult death over successive generations is perhaps indicative of type 2 diabetes mellitus (type 2 DM). These lineages, all in the town of San Prisco in Italy, include both paternal and maternal ones with the following surnames: Casaccia, Casertano, Cipriano, de Angelis, de Paulis, Peccerillo, Foniciello, di Monaco, Vaccarella, Valenziano, Ventriglia, and Zibella. Genealogic studies of eighteenth and nineteenth century vital records in this area of Italy cannot definitively establish type 2 diabetes mellitus as either an immediate or contributory cause of death. This is because causes of death were not recorded and because disease diagnostic capabilities were largely absent. Genealogic studies of those who lived in Italy in the eighteenth and nineteenth centuries can at best provide data on approximate age at time of death. Early adult death in this era was not uncommon. However, its presence over several successive generations in a lineage raises the possibility of inherited diseases prominent among which is type 2 DM.

The Role of Genealogy and Clinical Family Histories in Documenting Possible Inheritance Patterns for Diabetes Mellitus in the Pre-Insulin Era: Part 1. The Clinical Case of Josephine Imperato

Establishing the role of heredity in type 2 diabetes mellitus (type 2 DM) is challenging. While type 2 DM frequently displays a pattern of familial aggregation, many other risk factors are responsible for the clinical expression of the disease. This paper reviews a number of the early twentieth-century studies of inheritance patterns for type 2 DM and presents in detail the history of Josephine Foniciello Imperato (Maria Giuseppa Foniciello) who died from the disease in New York City at the age of 52 years on 14 November 1921, ten months before commercial insulin became available.

Diet, delusion and diabetes

Diet is good for diabetes, as everyone agrees, but which diet? The word itself has acquired such negative associations that professionals now prefer to talk of medical nutrition therapy, abbreviated to MNT to avoid the negative connotations of the word ‘nutrition’. Shakespeare said that ‘a rose by any other name would smell as sweet’, but it will still have thorns, and we will continue to call a diet a diet. Three related health benefits might be expected from a diet for diabetes: improved metabolic control, weight loss, and reduced risk of vascular disease. From a patient’s point of view, you diet because you want to lose weight, a desire typically expressed in the future conditional, as in ‘I really must think about going on a diet’. Overweight cannot be divorced from emotion, and its consequences cannot be measured in kilograms, for its true costs to the individual must be paid in the currency of the soul. Let us therefore ask a much simpler question: weight loss apart, which diet is best for diabetes? The recent American Diabetes Association (ADA) guidelines, drafted in the light of 150 years of experience in the dietary management of diabetes, conclude that we lack the evidence needed to reach a conclusion [3]. Will we ever find the right answer? Or are we asking the wrong questions? From an historical perspective, it is easy to see that the investigators of diet have confused circular motion with progress. The very low carbohydrate diets of the pre-insulin era yielded to the high carbohydrate diets of the late 1920s and 1930s, and these gave way to the free diets of the 1930s through to the 1950s. The cycle then resumed with the low carbohydrate diet of the 1960s, the high carbohydrate/high fibre diet of the 1970s, the free diets of the latter part of the century and the reincarnation of the pre-insulin regimen in the form of the Atkins diet. The enthusiasts have come and gone, each claiming unique virtue and spectacular success for their own particular regimen, and it would be hard to imagine a diet that has not at some stage constituted an article of faith in diabetes management. Almost all these diets worked some of the time, but we may suspect that few were followed with any degree of rigour for most of the time. Diabetologia (2009) 52:1–7 DOI 10.1007/s00125-008-1203-9

Diabetes and Protein Metabolism

The celebrated Greek physician Aretaeus the Cappadocian some 1900 years ago described diabetes as a condition with “a melting down of the flesh and limbs into urine.” Remarkably, his observations are amazingly durable and accurate even by the standards of today with reference to type 1 diabetes. For example, insulin deprivation in type 1 diabetic patients causes a profound increase in catabolism, especially in skeletal muscle (1–4). Moreover, this net muscle protein catabolism is due to a net increase in protein breakdown rather than a decline in protein synthesis (1–4). In contrast, despite substantial alterations in glucose and lipid metabolism, the effect of type 2 diabetes on changes in protein metabolism is at best subtle, and results are inconsistent (5–8). A key difference is that in type 1 diabetic patients on insulin deprivation, muscle mass withers away (as demonstrated by profound cachexia in type 1 diabetic patients during the preinsulin era), whereas no such dramatic changes occur in type 2 diabetic patients with poor glycemic control. Withdrawal of treatment for 10 days in type 2 diabetic patients had little effect on amino acid levels or protein metabolism (8), although glucose metabolism is substantially altered; this may relate to differences in portal …

Private Practice: In the Early Twentieth-Century Medical Office of Dr. Richard Cabot (review)

Reviewed by: Private Practice: In the Early Twentieth-Century Medical Office of Dr. Richard Cabot Robert Aronowitz Christopher Crenner . Private Practice: In the Early Twentieth-Century Medical Office of Dr. Richard Cabot. Baltimore: Johns Hopkins University Press, 2005. xv + 303 pp. Ill. $48.00 (0-8018-8117-X). Most American physicians know about Richard Cabot (1868–1939) from the New England Journal of Medicine, which reminds its readers weekly that he started the Clinical Pathological Conference (CPC) in 1900. Chris Crenner's Private Practice does much more than fill in the details of Cabot's remarkable biography: it is an exemplary piece of scholarship, using Cabot's clinical records and patient correspondence to illuminate a much larger world of clinical medicine at a pivotal moment of change that he both catalyzed and exemplified. Cabot and his patients were suspended between home and hospital. Cabot combined private practice with (Harvard) medical teaching and writing on diverse medical issues. While he built his academic reputation as a technical expert in the meaning and use of diagnostic technologies, the arc of his career was toward medical ethics. He became well known for his blunt attacks on placebo use and lying about terminal diagnoses. Cabot's CPC made error in medicine too publicly visible for many of his medical contemporaries. His critics did not deny the reality of error so much as they feared that its public acknowledgment might undermine the authority of scientific medicine. Cabot believed that the more-technology-based medical practice that he promoted widened the gaps between doctor and patient; he argued that greater honesty in diagnosis and decision making were necessary to narrow these gaps and retain patient trust. Crenner uses Cabot's correspondence with patients and colleagues to question the accuracy and importance of many aspects of the received history of modern bioethics, which has emphasized the recent emergence of the active medical consumer and informed consent, the ascendancy of greater truthfulness in diagnosis and prognosis, and the pivotal role played by bioethicists in these developments. Crenner instead portrays a more complex and nuanced past: Cabot's patients were anything but passive, deploying multiple strategies in their decision making and self-understanding. They often shopped around for the best doctors and treatments, and they implicitly exchanged respect for physician competence and authority in return for physician steadfastness and commitment to maintain hope. Crenner uses the differences between Cabot's public pronouncements on truth telling and placebo use and his actual clinical practices to capture the complex mix of change and continuity in doctor-patient relations. Particularly revealing were two episodes in Cabot's life: his "mercy killing" of his brother, who was suffering from end-stage diabetes mellitus in the preinsulin era, and the management of his own wife's death. Cabot kept his role in his brother's death secret until nearly the end of his life. In one sense, this secrecy was conventional, for euthanasia was common but was not discussed publicly; on the other hand, Cabot found the experience extremely painful, at the time and decades later, and could not easily fit it into any explicit ethical system. Cabot's care for his wife during her terminal [End Page 381] illness was more shockingly at odds with his public statements: he had diagnosed her as suffering from lung cancer on clinical grounds, and he took great pains to conceal from her both this diagnosis and the reality of her imminent death. In both of these instances, the gap between private action and public pronouncement suggests how untidy and complex clinical decisions were and are, while evoking the historically contingent factors generally missing from bioethical analysis. For example, the gap becomes more understandable in light of the importance placed on familial rather than individual responsibility for decision making in Cabot's time. He and his contemporaries knew they were dealing with significant "collateral damage" from the new style of practice. Crenner devotes a chapter to Cabot's and others' changing strategies toward the great numbers of patients who could not be reliably diagnosed with objective disease. Another set of problems followed from the reality that these physicians promoted the technology-laden style of practice before there...

Dietary Treatment of Diabetes Mellitus in the Pre-Insulin Era (1914-1922)

Before the discovery of insulin, one of the most common dietary treatments of diabetes mellitus was a high-fat, low-carbohydrate diet. A review of Frederick M. Allen's case histories shows that a 70% fat, 8% carbohydrate diet could eliminate glycosuria among hospitalized patients. A reconsideration of the role of the high-fat, low-carbohydrate diet for the treatment of diabetes mellitus is in order.

New therapies for the pregnant patient with diabetes.

Gestational diabetes complicates 3-5% of pregnancies. Of diabetes seen during pregnancy, 10% is pregestational and the remaining 90% represents gestational diabetes. (1,2) Pregnancy in women with pregestational diabetes is especially high risk. Spontaneous abortion, preterm labor, congenital malformations, preeclampsia, macrosomia, birth injury, and cesarean section are all increased in these pregnancies. Deterioration of maternal health during pregnancy, especially in the setting of diabetes-induced end-organ disease, is a real concern. Vigilant surveillance and management of associated disorders such as retinopathy, nephropathy, and chronic hypertension are required. During the preinsulin era, maternal and perinatal mortality in pregnancies complicated by pregestational diabetes was approximately 50%. (1,2) Although modern obstetrical management and the appropriate use of insulin have dramatically improved maternal-fetal outcomes, pregnant patient with diabetes remains at increased risk for complications. There is no doubt that optimizing maternal glucose control is a key element in avoiding established perinatal risks. The most effective means to accomplish this control are topics of active research. Further, hormonal changes during pregnancy can make glycemic control difficult even for the most compliant and educated patient. This paper discusses several new approaches, either currently in practice or under consideration, to pregnancies complicated by diabetes, including oral hypoglycemic agents, lispro, the insulin pump, and transplantation.

Maturity-onset diabetes of the young: a clinical history.

A mild form of diabetes in young people was recognized in the pre-insulin era but was forgotten, probably because of Joslin's dictum that all young people with diabetes should have insulin as a safeguard against complications. After the introduction of sulphonylureas in the 1950s it was found, most notably by Fajans and Conn at the University of Michigan, that tolbutamide could improve or normalize carbohydrate tolerance in some young non-obese mildly diabetic patients. These experiments were not primarily of genetic interest because diabetes was regarded as homogeneous with young and old patients forming part of the same continuum. The question was whether treatment could prevent young subjects with mild diabetes progressing to a total loss of insulin reserve. By 1973, Fajans had shown that the carbohydrate intolerance of 45 patients diagnosed under age 25 had not progressed after up to 16 years on sulphonylureas. Nearly all (43 out of 45) these subjects had a first degree relative with diabetes. In 1974, under the title 'Mild familial diabetes with dominant inheritance' Tattersall described three families in which diabetes, although diagnosed in adolescence, could be treated with sulphonylureas over 40 years later and was dominantly inherited. Collaboration between Fajans and Tattersall established that 'chemical' diabetes in Michigan was also predominantly inherited and distinct from classical 'juvenile-onset' diabetes. In Paris in 1973 Lestradet also described a non-insulin-dependent form of childhood diabetes and later established that it was dominantly inherited. In 1974, Tattersall and Fajans coined the acronym MODY which was defined as 'fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years'.

Childhood diabetes, insulin, and Africa. DERI (Diabetes Epidemiology Research International) Study Group.

Mortality associated with Type 1 (insulin-dependent) diabetes has perceptually declined with the identification and widespread use of insulin. In the pre-insulin era, over 80% of all individuals developing diabetes died each year, now less than one in two hundred die. Sadly, this remarkable achievement has not reached the children who develop diabetes in sub-Saharan Africa where the onset of childhood diabetes is the equivalent of a death sentence. Two major issues of importance related to Type 1 diabetes in African and other developing countries are missed diagnosis and unavailability of insulin, issues which cannot be ignored.

Nutritional management of pregnancy complicated by diabetes: historical perspective.

The important role of diet in the management of pregnancies complicated by diabetes has been recognized since the nineteenth century. In this historical review we have traced the evolution of the diabetic diet from the pre-insulin era, when diabetic pregnancies were not only rare, but accompanied by high maternal mortality and fetal loss to 1981, when the nutritional management of carbohydrate intolerance during gestation is again raising provocative questions. Our recent understanding of diabetes as a heterogeneous syndrome, the 1979 dietary guidelines of the American Diabetes Association (ADA), and the 1980 revised Recommended Dietary Allowances (RDA) for pregnant and lactating women are summarized as representative of the current approach to the nutritional management of diabetic pregnancies. Many questions remain unanswered. These include the hundred-year-old debate concerning the optimal amount of carbohydrate in the diabetic diet, the possible beneficial role of large amounts of dietary fiber, and the nagging concern about total caloric intake in type I insulin-dependent diabetes mellitus (IDDM) versus type II non-insulin-dependent diabetes mellitus (NIDDM) pregnant diabetic women. We suggest that nutritional counseling during gestation in the future may need to be more highly individualized as metabolic distinctions between different types of patients with carbohydrate intolerance are more clearly delineated.

The intensive care of perinatal risk in pregnant diabetics (136 cases): A new therapeutic scheme for the best control of maternal disease.

k Fifty years have elapsed since the discovery of insulin; however, pregnancy is still far from being sufficiently safe in diabetic women. The most convincing proof is given by the high perinatal mortality ranging from 10 to 15% in specialized departments [16], which would be even higher if therapeutic abortion was not performed in numerous cases of severe maternal disease [3, 11, 23], On the other hand, as far as the mother is concerned, insulin therapy has deeply changed the prognosis of pregnant diabetic patients compared with the preinsulin era. However, severe complications such as toxemia, urinary tract infections, aggravation of vascular diseases and so forth contribute to maintain the death rate at about 1% [16, 23],