Insulin discovery: A pivotal point in medical history.

The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with diabetes.

100 years of physiology, discrimination and wonder.

There has been 100 years of research detailing the role of insulin in glucose, protein and free fatty acid metabolism. We explore the learnings though evolution and changes in management with an understanding of how it has impacted the care of people with diabetes. The discrimination endured is described and recent advances to empower and counter this are highlighted.

Insulin action at a molecular level - 100 years of progress.

The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.

Scientometric Evaluation of Research Productivity on Diabetes from the Kingdom of Saudi Arabia over the Last Two Decades (2000-2019).

MATERIALS AND METHODS: Data was extracted from the Web of Science (WoS) platform and later bibliometric analysis performed using the "R-Bibliometrix" package. A wide range of indicators was explored to measure the quantity and quality of the publications related to diabetes from KSA. RESULTS: Saudi Arabia was 28th in rank with 2600 documents (0.83% of global share). Articles were the main document type (76%). The total number of authors was 9715 from 104 countries. Three authors showed >50 publications and >100 total citations while 2 authors showed an H-index of ≥20. The USA, UK, and Egypt were other leading contributive countries in terms of corresponding authors and total citations per country. King Saud University was the major contributing affiliation followed by King Abdulaziz University. Among 865 sources, Saudi Medical Journal was the leading and consistent source over the years. Diabetes, Diabetes Mellitus, and Type 2 Diabetes were the most frequently used keywords. CONCLUSION: This study provides a macroscopic overview of diabetes-related research output from KSA. Overall, similar identifications and trends of top authors were observed in terms of productivity, impact, international collaborations, and organizational affiliations. Generally, an increasing productivity trend was observed with the majority published in the last 5 to 10 years. Study findings can benefit relevant stakeholders to better understand the trends and performance of diabetes-related regional research.

[Obesity as a global challenge of the 21st century: clinical medical nutrition, prevention and therapy].

The article presents modern data on the prevalence of overweight and obesity, provides updated information on personalized programs for managing body weight, individual recommendations for a healthy diet, adequate physical activity and long-term lifestyle changes. It is shown that dietary therapy is the basic treatment method in weight loss programs and is aimed at long-term maintenance of a negative energy balance in the patient's organism by limiting the calorie intake. A significant place in the article is devoted to the use of diets modified by calorie value and macronutrient content which are recommended for obese patients. A strategy for the prevention of obesity and its associated diseases is presented.

Prevalence, incidence and outcomes of diabetes in Ontario First Nations children: a longitudinal population-based cohort study.

BACKGROUND: First Nations people are known to have a higher risk of childhood-onset type 2 diabetes, yet population-level data about diabetes in First Nations children are unavailable. In a partnership between Chiefs of Ontario and academic researchers, we describe the epidemiologic features and outcomes of diabetes in First Nations children in Ontario. METHODS: We created annual cohorts from 1995/96 to 2014/15 using data from the Registered Persons Database linked with the federal Indian Register. We used the Ontario Diabetes Database to identify children with all types of diabetes and calculated the prevalence and incidence for First Nations children and other children in Ontario. We describe glycemic control in First Nations children and other children in 2014. RESULTS: In 2014/15, there were 254 First Nations children and 10 144 other children with diagnosed diabetes in Ontario. From 1995/96 to 2014/15, the prevalence increased from 0.17 to 0.57 per 100 children, and the annual incidence increased from 37 to 94 per 100 000 per year among First Nations children. In 2014/15, the prevalence of diabetes was 0.62/100 among First Nations girls and 0.36/100 among other girls. The mean glycosylated hemoglobin level among First Nations children was 9.1% (standard deviation 2.7%) and for other children, 8.5% (standard deviation 2.1%). INTERPRETATION: First Nations children have substantially higher rates of diabetes than non-Aboriginal children in Ontario; this is likely driven by an increased incidence of type 2 diabetes and increased risk for diabetes among First Nations girls. There is an urgent need for strategies to address modifiable factors associated with the risk of diabetes, improve access to culturally sensitive diabetes care and improve outcomes for First Nations children.

Exploring the geography of serious mental illness and type 2 diabetes comorbidity in Illawarra-Shoalhaven, Australia (2010 -2017).

OBJECTIVES: The primary aim of this study was to describe the geography of serious mental illness (SMI)-type 2 diabetes comorbidity (T2D) in the Illawarra-Shoalhaven region of NSW, Australia. The Secondary objective was to determine the geographic concordance if any, between the comorbidity and the single diagnosis of SMI and diabetes. METHODS: Spatial analytical techniques were applied to clinical data to explore the above objectives. The geographic variation in comorbidity was determined by Moran's I at the global level and the local clusters of significance were determined by Local Moran's I and spatial scan statistic. Choropleth hotspot maps and spatial scan statistics were generated to assess the geographic convergence of SMI, diabetes and their comorbidity. Additionally, we used bivariate LISA (Local Indicators of Spatial Association) and multivariate spatial scan to identify coincident areas with higher rates of both SMI and T2D. RESULTS: The study identified significant geographic variation in the distribution of SMI-T2D comorbidity in Illawarra Shoalhaven. Consistently higher burden of comorbidity was observed in some urban suburbs surrounding the major metropolitan city. Comparison of comorbidity hotspots with the hotspots of single diagnosis SMI and T2D further revealed a geographic concordance of high-risk areas again in the urban areas outside the major metropolitan city. CONCLUSION: The identified comorbidity hotspots in our study may serve as a basis for future prioritisation and targeted interventions. Further investigation is required to determine whether contextual environmental factors, such as neighbourhood socioeconomic disadvantage, may be explanatory. IMPLICATIONS FOR PUBLIC HEALTH: Ours is the first study to explore the geographic variations in the distribution of SMI and T2D comorbidity. Findings highlight the importance of considering the role of neighbourhood environments in influencing the T2D risk in people with SMI.

Pueraria lobata for Diabetes Mellitus: Past, Present and Future.

Gegen (Radix Puerariae Lobatae), the root of Pueraria lobata, is an edible and medicinal herb which has been used in treating diabetic symptoms in the orient for thousands of years. We present an evidence map of the efficacy and safety of Gegen and Gegen formulas (GGFs) that use Gegen as an essential herb for diabetes, and also its mechanism of actions. We comprehensively searched the ancient medical records to identify empirical evidence; conducted a systematic review (SR) based on moderate- to high-quality randomized controlled trials (RCTs) to synthesize the clinical evidence; and reviewed the possible mechanisms of its antidiabetic effects. Empirical application of Gegen in treating diabetic symptoms dated back to more than 2000 years ago. Common herbs used in RCTs that accompany with Gegen included Radix et Rhizoma Glycyrrhizae, Radix et Rhizoma Ginseng, Rhizoma Dioscoreae, Poria, and Radix Ophiopogonis. The combinations used today are consistent with their usage in ancient times. Results of the SR showed that GGFs could benefit patients with type 2 diabetes for blood glucose control. When in combination with hypoglycemic agents or insulin, GGFs enhanced the glucose-lowering effect as well as the lipid-lowering effects. Also, the incidence and the risk of adverse events (AE), especially the hypoglycemic episodes, were lower in the combination group. No serious or life-threatening AE was reported. The experimental evidence presented that Gegen and GGFs might exert and enhance the anti-diabetic effects through activation of multiple mechanisms, such as reducing insulin resistance, increasing insulin release, inhibiting glucose absorption and reabsorption, and improving insulin sensitivity, glucose uptake, and metabolism.

Sodium-Glucose Cotransporter-2 Inhibitors: Lack of a Complete History Delays Diagnosis.

On 15 May 2015, the U.S. Food and Drug Administration (FDA) warned that administration of sodium-glucose cotransporter-2 (SGLT2) inhibitors could lead to ketoacidosis in patients with diabetes mellitus. This announcement came more than 2 years after the FDA's first approval of an SGLT2 inhibitor, although the phenomenon had been known for more than 125 years. Luminaries of diabetes research (including Josef von Mering, Frederick Allen, I. Arthur Mirsky, and George Cahill) had described ketosis and ketoacidosis induced by administration of the phytochemical phlorizin, the prototypical SGLT inhibitor, as well as in patients with familial renal glucosuria, a condition that is considered a natural model of SGLT2 inhibition. Neither government regulators nor manufacturers of SGLT2 inhibitors evinced an awareness of this extensive historical record. The absence of historical inquiry delayed notice of ketoacidosis as an adverse reaction, which could have reduced the burden of illness from these drugs.

Ancient origins of low lean mass among South Asians and implications for modern type 2 diabetes susceptibility.

Living South Asians have low lean tissue mass relative to height, which contributes to their elevated type 2 diabetes susceptibility, particularly when accompanied by obesity. While ongoing lifestyle transitions account for rising obesity, the origins of low lean mass remain unclear. We analysed proxies for lean mass and stature among South Asian skeletons spanning the last 11,000 years (n = 197) to investigate the origins of South Asian low lean mass. Compared with a worldwide sample (n = 2,003), South Asian skeletons indicate low lean mass. Stature-adjusted lean mass increased significantly over time in South Asia, but to a very minor extent (0.04 z-score units per 1,000 years, adjusted R2 = 0.01). In contrast stature decreased sharply when agriculture was adopted. Our results indicate that low lean mass has characterised South Asians since at least the early Holocene and may represent long-term climatic adaptation or neutral variation. This phenotype is therefore unlikely to change extensively in the short term, so other strategies to address increasing non-communicable disease rates must be pursued.

The re-emerging association between tuberculosis and diabetes: Lessons from past centuries.

The association between tuberculosis (TB) and diabetes mellitus (DM) had a common place in the literature up to the first half of the 20th century, but virtually disappeared with the discovery of insulin to treat DM and antibiotics to cure TB. In the late 1990s the literature began to re-emerge with the worldwide increase in type 2 DM, particularly in TB-endemic countries. Today, type 2 DM is the most prevalent comorbidity among TB patients and the World Health Organization considers it a threat to TB control. We summarize the literature on TB and DM up to the 1960s. Then we evaluate unique aspects of this comorbidity in older times, such as the frequent diabetic comas that suggest challenges for proper DM management as insulin was being implemented, or the absence of antibiotics to cure TB. Despite the unique aspects of each study period, the literature across times is consistent in key aspects of the association. Namely, a higher TB prevalence among DM (versus non-DM patients), the importance of glucose control and chronic DM on TB susceptibility and the higher risk of death among patients with the co-morbidity. From the older literature, we can infer the likely contribution of type 1 DM to TB (in addition to type 2), regardless of their differing autoimmune or metabolic pathophysiology, respectively. Furthermore, in the older literature there was a notable reporting of DM development among TB patients, even though DM usually preceded TB. This observation deserves further epidemiological and basic studies to elucidate this intriguing aspect of the relationship between TB and DM.

The past decade in type 2 diabetes and future challenges.

There is today an exponential increase in prevalence of type 2 diabetes mellitus (T2DM), especially in young people. This downward shift in age of onset of T2DM has been shown by abundant evidence to be due to an increase in obesity among the young, the latter mainly attributable to unhealthy dietary habits and a sedentary lifestyle. It is therefore obvious that the prevention of diabetes rather its treatment is of is paramount importance. In the past decade, because concerns about the safety of antidiabetic agents took precedence over the issue of efficacy, almost all studies have been diabetes CVOTs and not traditional CVOTs. Until 2015, the evidence showed that antidiabetic agents are effective in terms of reduction of microvascular, as opposed to macrovascular, complications. However, following publication of the results of some new studies, it became clear that the new class of antidiabetic drugs, e.g., SGLT 2 inhibitors and GLP-1 agonists, are also effective in reducing cardiovascular disease (CVD). In the coming decade, numerous health challenges are expected to arise, the most important being the greater expansion of the therapeutic armamentarium for T2DM and the adoption of strategies for prevention of CVDs. In parallel, the new generation of antidiabetic agents will target the recently investigated pathophysiologic disorders of diabetes, while, ideally, treatments should include smart drugs without side effects.

ANNIVERSARY REVIEW: 50 years since the discovery of bromocriptine.

Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus Claviceps purpurea and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony's fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by Claviceps purpurea This was the cultural background and scientific foundation on which bromocriptine was discovered.

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade.

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.