An introduction to the special issue of the Canadian Journal of Health History/Revue canadienne d\'histoire de la santé on J.J.R. Macleod, a co-discoverer of insulin.
Résumé. Introduction au numéro spécial du Canadian Journal of Health History/Revue canadienne d’histoire de la santé sur J.J.R. Macleod, codécouvreur de l’insuline.

John James Rickard Macleod provided the facilities and support that enabled Frederick Banting and Charles Best to perform the experimental work that resulted in the discovery of insulin. This review considers Macleod\'s intellectual contribution to the initial discovery in light of his previously expressed opinions on glucose metabolism. He acknowledged the likely existence of an internal secretion from the pancreas and was aware of previous work in the area; however, seeking it was not among his research priorities. His advice in the immediate aftermath of the discovery does not appear to have made any essential contribution to the project, although he made its ultimate success possible. Instead, he gave Banting the chance he needed, gave him full credit for what he achieved, and promoted insulin tirelessly as a gift to the world.
Résumé. John James Rickard Macleod fournit les installations et le soutien qui ont permirent à Frederick Banting et Charles Best de découvrir l’insuline. Il contribua aussi intellectuellement au projet. Ce texte étudie cette contribution en analysant les idées de Macleod sur le métabolisme des glucides. Bien au fait des travaux antérieurs, le chercheur admettait l’existence probable d’une sécrétion interne du pancréas, mais l’étudier ne faisait pas partie de ses priorités de recherche. Si les conseils qu’il prodigua immédiatement après cette découverte ne semblent pas avoir été essentiels, ils contribuèrent néanmoins au succès du projet. En fait, Macleod offrit à Banting l’opportunité dont il avait besoin, lui attribua pleinement le mérite de la découverte et fit ensuite sans relâche la promotion des bienfaits de l’insuline.

On 7 November 1923, when J.J.R. Macleod announced that he would split his half of the Nobel Prize with J.B. Collip, following F.G. Banting splitting his half of the prize with C.H. Best, a reporter asked Macleod to assess his share in the discovery of insulin. \"Oh, I was only the impresario - the managing director,\" he replied. Whether Macleod deserved the recognition with Banting of the Nobel Committee for the discovery of insulin, it is certainly clear that the discovery, and especially its efficient development into a remarkably effective diabetes treatment, would not have happened without Macleod\'s knowledge and laboratory research experience. Nor would it have happened without his leadership and, especially, without his acumen as the managing director, or impresario, of the insulin enterprise.
Résumé. Le 7 novembre 1923, lorsque J.J.R. Macleod annonça qu’il allait partager sa part du Prix Nobel avec J.B. Collip – imitant ainsi F.G. Banting, qui avait partagé la sienne avec C.H. Best –, un journaliste demanda à Macleod d’évaluer sa contribution à la découverte de l’insuline. « Oh, je n’étais que l’impresario, le directeur général », répondit-il. Que Macleod mérite ou non la récompense que le Comité du prix Nobel lui décerna conjointement avec Banting, il est certain que la découverte de l’insuline, qui déboucha sur un traitement remarquablement efficace du diabète, n’aurait pas eu lieu sans les connaissances et l’expérience de Macleod en matière de recherche en laboratoire. Elle n’aurait pas non plus eu lieu sans son leadership et, surtout, sans sa perspicacité en tant que directeur général ou impresario.

After the discovery of insulin at the University of Toronto in 1921-22, Frederick Banting and Charles Best downplayed the contributions of physiology professor John James Rickard Macleod, the director of the laboratory where the discovery was made. Banting and Best, their allies, and to a lesser extent the university promoted a \"fairy tale\" version in which the two young investigators made the discovery on their own, creating the so-called \"Banting and Best myth.\" Over the next 60 years, the myth prevailed and Macleod\'s reputation became increasingly tarnished, with both Banting and Best actively maligning their former mentor. While the publication of Michael Bliss\' The Discovery of Insulin in 1982 placed Macleod\'s reputation on the road to recovery, there are still many lingering issues that have been raised, and Macleod remains misunderstood, misinterpreted, and maligned. This paper, using primary and secondary historical sources, addresses topics that have been repetitively raised by Macleod\'s detractors over the past century.
Résumé. Après la découverte de l’insuline à l’Université de Toronto en 1921–1922, Frederick Banting et Charles Best ont minimisé les contributions du professeur de physiologie John James Rickard Macleod, directeur du laboratoire où la découverte a été faite. En compagnie de leurs alliés et dans une certaine mesure de l’Université, Banting et Best ont propagé un conte de fée dans lequel les deux jeunes chercheurs auraient fait cette découverte par eux-mêmes, donnant ainsi naissance au « mythe Banting et Best ». Au cours des 60 années suivantes, ce mythe a prévalu et la réputation de Macleod a été ternie, Banting et Best s’employant à calomnier leur ancien mentor. Si la publication de The Discovery of Insulin (1982) par Michael Bliss a quelque peu rétabli la réputation de Macleod, celui-ci est encore largement incompris, mal interprété et dénigré. En s’appuyant sur des sources historiques premières et secondaires, cet article aborde les enjeux qui ont été soulevés de manière répétée par les détracteurs de Macleod au cours du XXe siècle.

OBJECTIVE: Evidence suggests that glucose levels in menstruating females with type 1 diabetes change throughout the menstrual cycle, reaching a peak during the luteal phase. The Type 1 Diabetes Exercise Initiative (T1DEXI) study provided the opportunity to assess glycemic metrics between early and late phases of the menstrual cycle, and whether differences could be explained by exercise, insulin, and carbohydrate intake.
METHODS: One hundred seventy-nine women were included in our analysis. Glycemic metrics, carbohydrate intake, insulin requirements, and exercise habits during the early vs late phases of their menstrual cycles (i.e. 2 to 4 days after vs 2 to 4 days before reported menstruation start date) were compared.
RESULTS: Mean glucose increased from 8.2±1.5 mmol/L (148±27 mg/dL) during the early follicular phase to 8.6±1.6 mmol/L (155±29 mg/dL) during the late luteal phase (p<0.001). Mean percent time-in-range (3.9 to 10.0 mmol/L [70 to 180 mg/dL]) decreased from 73±17% to 70±18% (p=0.002), and median percent time >10.0 mmol/L (>180 mg/dL) increased from 21% to 23% (p<0.001). Median total daily insulin requirements increased from 37.4 units during the early follicular phase to 38.5 units during the late luteal phase (p=0.02) and mean daily carbohydrate consumption increased slightly from 127±47 g to 133±47 g (p=0.05); however, the difference in mean glucose during early follicular vs late luteal phase was not explained by differences in exercise duration, total daily insulin units, or reported carbohydrate intake.
CONCLUSIONS: Glucose levels during the late luteal phase were higher than those of the early follicular phase of the menstrual cycle. These glycemic changes suggest that glucose management for women with type 1 diabetes may need to be fine-tuned within the context of their menstrual cycles.

Diabetes is very common in people over 75. A broad arsenal of treatments is now available. It is important, however, to choose the right treatment regimen to suit the patient\'s specific glycemic targets.

In this study, we wanted to verify whether the effect of insulin on calcium homeostasis depends on the heart\'s development stage. Using a quantitative 3D confocal microscopy, we tested the effect of a high insulin concentration (100 µU) in freshly cultured ventricular cardiomyocytes from newborn and adult rats. Our results showed that the cytosolic basal level of calcium was higher in newborn cardiomyocytes with no change in the nuclear basal calcium level compared with the adult cardiomyocytes; in addition, insulin induced a slow increase of cytosolic and nuclear calcium in newborn ventricular cardiomyocytes, followed by two phases. However, the first phase of slow cytosolic and nuclear calcium increase was absent in adult rat ventricular cardiomyocytes. Furthermore, the time to the onset of increase of cytosolic and nuclear calcium was longer in newborn cardiomyocytes compared with adults. Moreover, the time to peak of the calcium transient was shorter in newborns than in adult cardiomyocytes. These results demonstrate that insulin differently regulates calcium homeostasis in newborns than in adult cardiomyocytes. Thus, newborn rat cardiomyocytes, commonly used in research as a model for adult cardiomyocytes, should be used with caution when dealing with insulin in normal and disease conditions.

OBJECTIVE: Depression in patients with diabetes mellitus is common and associated with poorer outcomes. This study aims to identify demographic, socioeconomic and medical factors associated with the initiation of antidepressant medication after a diagnosis of diabetes in adult patients without a previous prescription for antidepressants. We also examined frequency of primary care visits in the year after antidepressant initiation compared with the year before treatment began.
METHODS: This was a retrospective cohort study using routinely collected electronic medical record data spanning January 2011 to December 2019 from the University of Toronto Practice-based Research Network (UTOPIAN) Data Safe Haven. Our primary outcome was a first prescription for an antidepressant in patients with diabetes. We used a mixed-effects logistic regression model to identify sociodemographic and medical factors associated with this event.
RESULTS: Among 22,750 patients with diabetes mellitus, 3,055 patients (13.4%) began taking an antidepressant medication. Increased odds of antidepressant initiation were observed in younger patients (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.39 to 2.26), females (OR, 1.60; 95% CI, 1.46 to 1.7), those receiving insulin treatment (OR, 1.59; 95% CI, 1.43 to 1.78) and cases of polypharmacy (OR, 3.67; 95% CI, 3.29 to 4.11). There was an increase in the mean number of primary care visits from 4.6 to 5.9 per year after antidepressant initiation.
CONCLUSIONS: In patients with diabetes, age, sex and medical characteristics were associated with the initiation of antidepressants. These patients accessed primary care more frequently. Screening and prevention of depression, particularly in these subgroups, could reduce its personal and systemic burdens.

Discovery of insulin. If the symptoms of diabetes have been known since Antiquity, it is at the end of the 19th century that several investigators searched for the active substance of the pancreas and endeavoured to produce extracts that lowered blood and urine glucose and decreased polyuria in pancreatectomized dogs. The breakthrough came 100 years ago when the team of Frederick Banting, Charles Best and James Collip, working in the Department of Physiology, headed by John MacLeod at the University of Toronto, managed to obtain pancreatic extracts that could be used to treat patients and rescue them from the edge of death by starvation, the only treatment then available. This achievement was quickly recognized by the Nobel Prize in Physiology or Medicine to Banting and MacLeod in 1923. The discovery has had important scientific, industrial and clinical developments still efficient nowadays.
UNASSIGNED: La découverte de l’insuline 1921–1922 : un saut dans la recherche biomédicale.
UNASSIGNED: Si les symptômes du diabète ont été décrits depuis l’Antiquité et caractérisés par la présence de sucre dans les urines et une soif intense, ce n’est qu’à la fin du xixe siècle que les travaux de plusieurs équipes aboutissent à rechercher la substance active de la sécrétion interne du pancréas dans des extraits susceptibles de diminuer le glucose dans le sang et les urines chez le chien diabétique. C’est à l’Université de Toronto, au Canada, il y a 100 ans, entre 1921 et 1922, que Frederick Banting, Charles Best et James Collip, travaillant dans le département de physiologie dirigé par John MacLeod, obtiennent des extraits pancréatiques suffisamment purifiés qui permettent de traiter de jeunes patients diabétiques. Cette découverte de l’insuline est très vite reconnue et saluée par l’attribution du Prix Nobel de Physiologie ou Médecine en 1923 à Frederick Banting et John MacLeod. Cette découverte a eu d’importantes retombées scientifiques, industrielles et cliniques, toujours d’actualité.

OBJECTIVE: The objective of this study was to compare initiation of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) vs insulin glargine U100 (iGlar) along with gliclazide, exclusively in people of South Asian origin with type 2 diabetes (T2D).
METHODS: The Variability of glucose Assessed in a Randomized trial comparing the Initiation of A Treatment approach with biosimilar basal Insulin analog Or a titratable iGlarLixi combinatioN in type 2 diabetes among South Asian participants (VARIATION 2 SA) trial (ClinicalTrials.gov identifier: NCT03819790) randomized insulin-naïve adults with T2D having glycated hemoglobin (A1C) 7.1% to 11% to initiate either iGlarLixi or iGlar + gliclazide. Insulin doses were titrated similarly to a prebreakfast glucose target of 4.0 to 5.5 mmol/L. Average time in range (TIR) on a masked continuous glucose monitor (CGM), A1C, fasting plasma glucose (FPG) and weight were assessed at the end of the 12-week treatment period.
RESULTS: Mean baseline characteristics for the 104 randomized participants were similar between treatment groups, including the following: age, 59±11 years; diabetes duration, 13.7±7.3 years; and A1C, 8.5%±1.2%. Coprimary outcomes of average TIRs within 24- and 12-h (6 am to 6 pm) periods at the end of trial were 70.5%±16.8% and 72.9%±17.6% for iGlarLixi, whereas these TIRs were 65.6%±21.6% and 67.3%±20.7% for the iGlar + gliclazide regimen, respectively, with no significant differences between groups (p=0.35 for 24-h TIR and p=0.14 for 12-h TIR). No significant difference in secondary outcomes was observed between treatment groups. Self-reported hypoglycemic events throughout the trial period and CGM-reported hypoglycemia (<4 and <3 mmol/L) were similar between randomized treatments.
CONCLUSIONS: Initiation of iGlarLixi resulted in similar TIR, A1C, FPG, weight and hypoglycemia compared with the more affordable option of starting iGlar + gliclazide in adults of South Asian origin with T2D.