Technology is increasingly proving beneficial in helping patients with diabetes achieve better glycemic control with less hypoglycemia. However, there are little data during pregnancy. Old randomized trials using insulin pump during pregnancy have not shown improvements in glycemic control, while more recent cohort studies obtained variable results with either similar or worse glycemic control and neonatal outcomes. Considering these still unsatisfactory results, many expectations have been raised by the introduction of continuous glucose monitoring (CGM). "Professional" CGM has proved valuable as an investigational tool, giving deeper insight into glucose pathophysiology and effects of diabetes in perinatal outcomes, but its routine clinical application was predominantly disappointing on pregnancy outcome. More recently, real-time CGM (RTCGM) seems to offer the most interesting prospects. While an earlier trial using intermittent RTCGM was not very encouraging, the CONCEPTT study, a multicenter, randomized trial of continuous use of CGM showed improved glycemic control and neonatal outcomes. Preliminary data from closed-loop studies in pregnancy show improved nocturnal time in target and less hypoglycemia. Daytime time in target with postprandial highs remain a challenge. Further large randomized trials in pregnancy with hybrid closed-loop systems are needed to show safety and efficacy in the broader pregnant population. (c) 2020 S. Karger AG, Basel
The relationships between psyche and glycemic disorders can be divided into three historical periods: the first one before Thomas Willis's discovery of "sweet urine" in 1670, the second between this event and the discovery of insulin, and the third one following the introduction of insulin into clinical practice. These relationships can be categorized as: (1) influence of psycho-emotional factors at the onset of diabetes, (2) influence of psycho-emotional factors on the course of diabetes, and (3) influence of diabetes on psychological conditions. Since it was first thought of, the fundamental importance of continual psychological support in achieving complete control of diabetes has been obvious, and progress made thanks to the willpower of diabetologists. This was achieved by such varied means as: summer camps, teaching programs, patient education, development of standards for employment and insurance, proposing diabetic celebrities as models, the organization of public open days, and dedicated newsletters and magazines. Finally came the opening of diabetes centers and setup of patient associations at national and, subsequently, international level, culminating in the first International Congress of Diabetic Associations in 1949 and of the International Diabetes Federation in 1952. All these instruments helped to strengthen and guide patients away from passivity and resignation and towards a philosophy of hope and proactive self-management. (c) 2020 S. Karger AG, Basel
Insulin was discovered in 1921, and was first used to treat diabetes in humans in January 1922 in Toronto, Canada. However, there was little regulation at that time concerning how to share the knowledge of new medications and how to legally produce them in foreign countries. In Europe insulin was first used in August 1922, and its commercial production started in 1923. There was, however, no single strategy to implement insulin manufacturing across recently war-torn Europe, and each country had to find its own way to make insulin available for its people. Three European countries were among the first to produce their own insulin: Great Britain, Denmark, and newly independent Poland. The reason for the variety of pathways to insulin production may be the fact that there was a personal story behind the arrival of insulin to each of these countries. Moreover, people who played the main roles in these processes had shown little interest in diabetes before - just like Banting. Here we present the tormented history of the early days of insulin production and use in those three countries, with focus on how individual initiatives eventually made insulin available across Europe by 1924. (c) 2020 S. Karger AG, Basel
The development of antidiabetic agents prior to 2000 was largely the result of fortuitous discovery coupled with insightful clinical acumen. Many years intervened between the chance discovery and the development of marketable clinically important products. The first hint that biguanides might be useful in managing diabetes was noted in the early 1900s; however, metformin did not achieve worldwide use and recognition as the first-line treatment for type 2 diabetes until the late 1990s. The hypoglycemic potency of sulfa drugs was first noted in 1942, but the introduction of sulfonylurea drugs to treat patients with type 2 diabetes occurred in 1956. Defining their mechanisms of action did not occur until the 1990s. The elucidation of the profound effects of thiazolidinediones through their activation of the transcription factor PPAR. (peroxisome proliferator-activated receptor gamma) came many years after the discovery of ciglitazone. It is of note that in the development of each of these classes of antidiabetic drugs, regulatory agencies struggled with controversial data and made decisions which had profound effects on their clinical use. (c) 2020 S. Karger AG, Basel
The discovery of insulin in Toronto in 1921/1922 was rapidly recognized by a Nobel Prize shared by Dr. Frederick Banting and Prof. John Macleod. However, in the popular imagination it is attributed to "Banting and Best." Here we review the important individual and collective contributions of the four main players in Toronto at that time: Banting, Macleod, Best, and Collip. Drawing on the work of the late Canadian historian Michael Bliss, we reflect on some of the enduring myths that surround the tale. We question the romantic notion that Banting's inspirational "idea" led directly to the discovery, and argue that it can instead be attributed to a fortunate collision of opportunity, ability, experience, and drive. We go on to recount the clashes of personality that detracted from the celebration that should have marked the delivery of insulin to the world. Finally, we set out evidence that Banting consistently overestimated his own contribution, conducting a successful and enduring campaign to downplay the roles of his colleagues. In the hope of redressing the historical balance, we focus on the neglected role of John Macleod, an established international expert on carbohydrate metabolism at the time of the discovery, who directly supervised the work. (c) 2020 S. Karger AG, Basel
Offspring of women with pregravid diabetes face a 3- to 5-fold increased risk for congenital malformations and growth disturbances. The mechanisms behind this increased risk are likely to be multifactorial and, at present, not fully understood. Glucose is identified as an important teratogen in diabetic pregnancy; however, there are other teratogenic agents involved. The findings from clinical and preclinical studies point to profound alterations in embryonic intracellular development, exerted by the diabetic condition. One such early effect is the induction of intracellular oxidative stress in embryonic tissues, followed by, and/or associated with, endoplasmic reticulum stress, nitrosative stress, hexosamine stress, as well as a state of diminished autophagy and enhanced apoptosis. There are also several epigenetic changes in the offspring, some of which are likely to affect the embryo-fetal development and to follow the offspring throughout life. Many studies have investigated these detrimental pathways and support the notion that preconceptional care and preconceptional dietary supplement decrease the enhanced risk factors involved in the outcome of pregestational women. (c) 2020 S. Karger AG, Basel
Diabetic pregnancy represents the most important challenge of insulin therapy, requiring a continuous effort to maintain euglycemia and avoid severe hypoglycemic episodes. Hypoglycemia becomes a charge nearly inevitable to pay. Pregnancy itself may be associated with impaired counter-regulation system and hypoglycemia unawareness. The risk of hypoglycemia in diabetic pregnancy is mainly due to the pharmacokinetics of current therapies that produces inappropriately high insulin concentrations and a failure in the physiological protective mechanism that limits falls in blood glucose concentrations. Around 45-71% of type 1 diabetic women experienced severe hypoglycemia during pregnancy; severe hypoglycemia can occur during pregnancy 3-5 times more frequently in the first trimester and at a lower rate in the third trimester. Risk factors include a history of severe hypoglycemia in the preceding years, long duration of diabetes, low hemoglobin A1c in early pregnancy, fluctuating plasma glucose levels, and excessive use of supplementary insulin between meals and impaired hypoglycemia awareness. The effects of hypoglycemia on the fetus is controversial, in particular its possible role in teratogenicity is still debated. Low levels of maternal glucose during pregnancy may cause fetal growth retardation and small for gestational age infants. In addition, maternal hypoglycemia may also determine impaired fetal beta cell function. (c) 2020 S. Karger AG, Basel
Up to 16.2% of pregnant women have some form of hyperglycemia, and an estimated 85% of them are due to gestational diabetes mellitus (GDM). Usually, the impairment of glucose tolerance in GDM is the result of relative insulin deficiency not due to autoimmune mechanisms. But autoimmune mechanisms similar to those in classical type 1 diabetes mellitus (DM-1A) and latent autoimmune diabetes in adults also play a pathophysiological role in a subset of GDM patients. Women with autoimmune GDM are those with glucose intolerance in pregnancy depicting in their sera diabetes-related autoantibodies (DRAs). The prevalence varies depending upon study population, methodology, and type of antibody. Women with GDM who display DRA positivity have higher rates of insulin requirement and a higher risk of abnormal glucose tolerance after pregnancy, including DM-1A. (c) 2020 S. Karger AG, Basel
The American Diabetes Association (ADA) was founded in 1940, and the European Association for the Study of Diabetes (EASD) was founded in 1965. In a little more than half a century, the EASD has evolved from a small association of academics into an effective medical society whose voice has relevance not only in Europe, but throughout the world. The EASD and ADA started a successful collaboration 2 decades ago - the joint EASD-ADA statements represent an outstanding example of an effective transatlantic collaboration and academic friendship. The annual meetings of both associations have provided the forum for major discoveries in diabetes research, such as the presentations of Diabetes Control and Complications Trial and UK Prospective Diabetes Study. (c) 2020 S. Karger AG, Basel
During pregnancy, maternal insulin resistance develops, primarily during the second and third trimesters. Placental hormones and adipocytokines contribute to this phenomenon. Insulin resistance allows glucose and amino acid sparing for fetal construction, while the mother utilizes lipolysis for her nutritional needs during fasting. (c) 2020 S. Karger AG, Basel
The incidence of gestational diabetes mellitus (GDM) is on the increase and, if not diagnosed, managed and treated adequately, can have unfavorable maternal and fetal outcomes. Several studies have shown that glycemic values considered as adequate in the past when monitoring GDM failed to contain these adverse outcomes and randomized trials are needed to ascertain whether these targets should be lowered. Dietary restrictions remain the mainstay of GDM management and suitable physical exercise can help too. The use of rapid-acting insulin analogues (lispro and aspart) are novel treatments for improving metabolic control by reducing postprandial glycemia, while long-acting insulin analogues need to be evaluated by further studies for safety in clinical use before they can be prescribed. Numerous studies have found glyburide and metformin safe in women with GDM but more randomized controlled trials are needed, with a long-term follow-up of mother and child, to confirm these results.
Apollinaire Bouchardat was the leading clinical diabetologist of the 19th century. He invented patient education for people with type 2 diabetes. He told patients to lose weight until the urine tests for glucose they performed at home became negative. Today's treatment of obese people with type 2 diabetes does not differ very much from Bouchardat's approach. He summarized his observations in the monography De la glucosurie ou diabete sucre. Bouchardat also wrote a very popular textbook on hygiene, over 1,000 pages long, in which he summarized all his views on a healthy life, from nutrition to the frequency of sexual intercourse, garnished with many amusing remarks based on his political, very socially oriented, and anticlerical opinions. (c) 2020 S. Karger AG, Basel
The evolution of gestational diabetes mellitus (GDM) diagnosis starts at the 1960s. Since then it has been the focus of ongoing debate, regarding questions such as - when, how and who to screen? What is the most appropriate diagnostic procedure? What cutoffs to diagnose GDM? By far, the hyperglycemia and adverse pregnancy outcome (HAPO) study provided the best evidence base to support answers to some of these questions - yet, some remain unsolved and others are still a matter of debate. Translating clinical evidence to practice guidelines is not a pure matter of science, but other considerations come into play, especially when the associations between the diagnostic variables to the selected outcomes are linear. Here, we shall provide an overview of the pathway which has led to HAPO and the path taken since its publication, striding toward a consensus for GDM diagnosis. (c) 2020 S. Karger AG, Basel
Shortly before the discovery of insulin, the prominent American physicians Frederick Allen and Elliott Joslin advocated severe fasting and undernutrition to prolong the lives of their youthful diabetic patients. Detractors called this "starvation dieting," and indeed, some patients did starve to death. The public record contains only the briefest account of relevant animal experiments, and clinical experience at the time provided little indication that severe undernutrition had better outcomes than low carbohydrate diets then in use. (c) 2020 S. Karger AG, Basel
R.D. Lawrence was diagnosed as having diabetes in 1920, at the age of 28 years. He received his first injection of insulin on May 31, 1923. Thereafter, he devoted his life to the understanding of the disease. This chapter describes the outstanding contributions made by Dr. R.D. Lawrence to the clinical management of diabetes and research. He was the founder of the diabetes unit at King's College in London and together with H.G. Wells he founded the British Diabetic Association. He was one of the leading figures to set up the International Diabetes Federation (IDF) and served the IDF as its first President. When he stepped down from the presidency of IDF, grateful friends and patients had written on his gift: "Thank you for teaching us to live in joy and happiness." (c) 2020 S. Karger AG, Basel
Among noncommunicable diseases spreading worldwide, maternal obesity and hyperglycemia in pregnancy (HIP) represent a major public health concern. Not only are these anomalies progressing with increasing prevalence but recent research demonstrated that HIP is associated with susceptibility to fetal defects, neonatal adverse events and metabolic disorders in later life. HIP represents a model of environmental determinant of developmental programming. If adequately screened and managed during pregnancy, the consequences of HIP might be significantly improved. Early dietary counseling to pregnant mothers seems a low-cost easy-to- implement program to reduce dramatic aftermath of HIP at a global scale especially in low-income developing countries. (c) 2020 S. Karger AG, Basel
In 1976 no treatment of diabetic nephropathy was available, and the median survival time was 5-7 years. In 1982-1983, two Danish investigators independently demonstrated the beneficial renoprotective effect of blood pressure lowering. Ten years later the superior renoprotective effect of ACE inhibition in type 1 diabetes was documented. The estimated median survival time from the onset of diabetic nephropathy increased to more than 21 years. A paradigm shift took place in mid-1990s since the topic for kidney research changed towards type 2 diabetic patients. in 2001 two large randomized controlled trials with angiotensin II receptor blockades demonstrated a beneficial effect on a combined renal endpoint including death. Finally, a breakthrough in cardiorenal protection was described in 2019 with the publication of the SONAR and CREDENCE trials. SONAR used a selective endothelin A receptor antagonist, while a sodium glucose co-transporter 2 inhibitor was used in CREDENCE. In 1969, Keen and colleagues detected elevated urinary albumin excretion (microalbuminuria) applying a sensitive radioimmunoassay in diabetes. Later studies demonstrated that microalbuminuria heralds end-stage kidney disease and fatal and non-fatal cardiovascular events in diabetes. It marks the need for intensified treatment with multifactorial intervention targeting glycemic control, blood pressure including blockade of the renin-angiotensin system, and dyslipidemia. This intervention has been demonstrated to reduce complications and improve prognosis significantly. Thus, screening for and treatment of microalbuminuria has changed diabetes care and patient outcomes. (c) 2020 S. Karger AG, Basel
Metabolomics is one of the newest "omics" sciences that provides a picture of the metabolism of an individual in both physiological and pathological conditions and during treatment administration. This is achieved through the analysis of metabolites present in biological fluids and tissue samples. This technology may help elucidate the yet-unknown pathophysiological mechanism of diseases and would allow improving diagnosis, treatment, and quality of life of patients. In the past years, there was an increase in the application of metabolomics in gynecology, neonatology, and pregnancy-induced complications such as gestational diabetes mellitus. In this paragraph, the authors reviewed the literature concerning the application of metabolomics in the investigation of gestational diabetes, summarized the most relevant findings, and hypothesized possible future utilizations of these discoveries in clinical practice. (c) 2020 S. Karger AG, Basel
Diabetes education has a long and rich history. The first to recognize the importance of patient education was Apollinaire Bouchardat in his book Le Diabete Sucre in 1875. Another early promoter of patient education was Prof. Karl Stolte, who invented "insulin dose adjustment for normal eating." Structured education, provided in groups, was first popularized by J.P. Assal in the late 1970s and was implemented and evaluated in numerous locations. Our group in Dusseldorf was at the forefront of developing such education programs and Germany became the first country to introduce an adequate compensation for diabetes education in the healthcare system. In the following decades, several structured programs were developed in a number of countries, such as ROMEO in Italy, and DAFNE and DESMOND in the UK. Today, NICE and many other guidelines recommend group education for people with diabetes. (c) 2020 S. Karger AG, Basel
