History Of Insulin Research Articles

Exploring the “New World”: weekly basal insulins

therapeutic option today, especially in specific clinical conditions, even in type 2 diabetes. Our country is approaching a new era in the history of insulin. We are indeed close to the availability of the first weekly basal insulin formulations. The AMD annals present a unique chance to evaluate the evolution of pharmacological therapies for diabetes in recent years. The AMD annals confirm that in 2023 still more than 32% of the population with type 2 diabetes in Italy was treated with insulin, and more than 97% of subjects were treated with basal insulin. The appropriate prescription of insulin is hindered by numerous obstacles, resulting in therapeutic inertia. Among these, the non-acceptance of daily injection therapy and the difficulty in adherence justify the rationale for developing weekly basal insulin Among the weekly basal insulins in development, icodec and efsitora are the closest to being introduced into our clinical practice. The development of new biotechnological approaches has resulted in the development of insulins with a half-life of 8 and 17 days for icodec and efsitora, respectively. Icodec and efsitora, in the QWINT and ONWARDS phase 3 programs, have been shown to be effective in achieving primary and secondary efficacy endpoints. The two weekly basal insulins have shown that in the context of an oral basal regimen for people with type 2 diabetes, the risk of hypoglycemia is not different from that of daily basal insulins In studies in type 1 diabetes and in people with type 2 diabetes on basal bolus insulin therapy, the risk of hypoglycemia was found to be higher for new weekly basal insulins than for daily basal insulins, bringing up the need for more research and possibly a different prescribing approach for basal weekly insulins in this population. The reduction in the number of injections results in patients being more satisfied with the treatment, this could result in a significant improvement in quality of life and an increase in acceptance and adherence to prescribed treatment, and finally, it responds to the urgent need to counter therapeutic inertia in the care of people with diabetes.

Metformin-Associated Lactic Acidosis Precipitated by an Acute Obstructing Ureteral Stone in a Patient with a Single Functioning Kidney

A 35-year-old male with type-2 diabetes mellitus and a history of insulin and metformin (2,000 mg/day) use presented to the emergency department (ED) with generalized weakness. Abdominal computed tomography (CT) performed 3 months prior to presentation showed a severely atrophic right kidney and a few tiny stones in the left kidney, with a serum level of creatinine of 1.14 mg/dL. At the ED, the patient’s blood pressure was 153/89 mmHg. Workup revealed acute kidney injury (creatinine, 11.97 mg/dL), high-anion-gap metabolic acidosis (pH, 6.93), and a blood lactic acid level > 15 mmol/L. Based on the medication history, the patient was diagnosed with metformin-associated lactic acidosis. CT showed a left distal ureteral stone, measuring 6 mm in size, which resulted in hydroureteronephrosis. The patient was initially treated with continuous renal replacement therapy. Subsequently, left percutaneous nephrostomy was performed, which led to the return of the creatinine level to baseline, with complete resolution of lactic acidosis.

“It Works! Now What?” Insulin Development, Production, and Distribution at Connaught Laboratories, University of Toronto, 1922–24

The first successful human use of a pancreatic extract on Leonard Thompson, a 13-year-old severe diabetic at Toronto General Hospital, on 23 January 1922, is generally seen as the climax of the discovery-of-insulin story. However, this seminal event in the history of medicine begs the question: “It works! Now what?” The story may well have ended abruptly if not for the foresight and leadership of Dr. John G. FitzGerald, director of the University of Toronto’s Connaught Antitoxin Laboratories, based in the basement of the same Medical Building where F.G. Banting and C.H. Best, under the direction of J.J.R. Macleod, conducted the research that led to the first tests on Thompson. Significantly, it was the addition to the team of biochemist J.B. Collip and his purification of the extract that enabled the successful 23 January test. Within a day, however, tensions within the group, especially between Banting and Collip, and Collip’s threat to leave and take out his own patent, prompted FitzGerald to act. On 25 January, FitzGerald finalized a seminal agreement between Connaught and Banting, Best, Collip, and Macleod that secured the further development of methods to prepare the extract on a larger scale to enable further clinical testing. From this point, Connaught would play a fundamental role in the insulin story, although its historical significance has been minimized and often misunderstood, overshadowed by the weight of the primary discovery, as well as by the critical contributions of Eli Lilly and Co. This article focuses on Connaught’s intimate involvement in the history of insulin from January 1922 through the summer of 1924, tracing the challenges and innovations of developing larger-scale production methods, the establishment and expansion of Canadian insulin production capacity, and the key role the labs played in spearheading the global distribution of insulin.

Insulin Centennial: Milestones influencing the development of insulin preparations since 1922.

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life-giving properties, giving rise to the birth of insulin therapy. In the early years (1922-1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost.

A history of insulin: initial discovery to first use in the treatment of T1D

A history of insulin: initial discovery to first use in the treatment of T1D

Race/ethnicity and challenges for optimal insulin therapy

AimsWe aimed to review insulin dosing recommendations, insulin regulation and its determinants, glycaemic response to carbohydrates, and the efficacy and safety of insulin therapy in different races/ethnicities. MethodsWe searched for articles in PubMed and Google Scholar databases up to 31 March 2021, with the following keywords: “ethnicity”, “diabetes”, “insulin”, “history of insulin”, “insulin therapy”, “food/rice”, “carbohydrate intake”, “insulin resistance”, “BMI”, “insulin dosing”, “insulin sensitivity”, “insulin response”, “glycaemic index”, “glycaemic response”, “efficacy and safety”, with interposition of the Boolean operator “AND”.In addition, we reviewed the reference lists of the articles found. ResultsThe differential effect of race/ethnicity has not yet been considered in current insulin therapy guidelines. Nevertheless, body size and composition, body mass index, fat distribution, diet, storage, and energy expenditure vary significantly across populations. Further, insulin sensitivity, insulin response, and glycaemicresponse to carbohydrates differ by ethnicity. These disparities may lead to different insulin requirements, adversely impacting the efficacy and safety of insulin therapy among ethnic groups. ConclusionsRace/ethnicity affects glucose metabolism and insulin regulation.Until now, international guidelines addressing racial/ethnic-specific clinical recommendations are limited. Comprehensive updated insulin therapy guidelines by ethnicity are urgently needed.

17-LB: Prognostic Value of Gamma-Glutamyl Transferase Variability in Individuals with Diabetes: A Nationwide Population-Based Study

Objective: We investigated whether gamma-glutamyltransferase (GGT) variability can predict the risk of stroke, myocardial infarction (MI), and all-cause mortality in individuals with diabetes. Methods: The study subjects were Koreans with diabetes who had undergone health examinations provided by the Korean National Health Insurance Corporation more than once during 2009-2012 (baseline). After excluding subjects aged <40 years and those with histories of stroke, MI, chronic liver disease, or drinking ≥30g/day of alcohol, a total 698937 individuals were included. As a parameter of variability, we calculated the average successive variability (ASV) of GGT values measured during the five years before the baseline exam. We estimated the risk of stroke, MI, all-cause mortality according to GGT ASV quartiles using multivariate-adjusted Cox analyses, until December 31, 2016. Stroke and MI was defined using ICD-10 codes (I63-I64 and I21-I22) and admission record. Results: During follow-up period, 26119 cases of stroke, 15103 cases of MI, and 39982 cases of death were identified. GGT ASV quartile showed significantly higher risk of stroke and all-cause mortality compared with quartile 1, even after adjustment for age, sex, renal function, obesity, drinking, smoking, exercise, presence of hypertension and dyslipidemia, hemoglobin, income status, glucose and GGT level, duration of diabetes, the number of histories of oral antidiabetic medication, prescription history of insulin, presence of diabetic retinopathy and peripheral artery disease. The fully adjusted HRs (95% CIs) of GGT ASV quartiles 4 were 1.06 (1.03-1.10) and 1.23 (1.20-1.27), respectively. This significance was maintained regardless of baseline GGT quartile in all-cause mortality. Conclusions: GGT variability was associated with the risk of all-cause mortality and stroke. This tendency is most pronounced in all-cause mortality, regardless of baseline GGT levels. Disclosure D. Lee: None. J. Yu: None. K. Han: None. J. Seo: None. N. Kim: None. Funding National Research Foundation of Korea

PULMONARY HYPERTENSION CAUSED BY ARTERIOVENOUS FISTULA

The creation of an arteriovenous fistula (AVF) has been implicated in the development of pulmonary hypertension (PH). A specific finding on right heart catheterization (RHC) could identify patients who would benefit most from surgical closure of AVF. A 57 year old man with history of insulin-

Insulin in America: A Right or a Privilege?

Even as a medical student, I was interested in the history of insulin. As an endocrine fellow, I read The Discovery of Insulin by Michael Bliss (1). It is a book anyone interested in diabetes should read, as life before insulin is difficult to appreciate by today’s standard of care, at least in the United States. Amazing stories of what people did to obtain insulin are plentiful, perhaps none more dramatic than Eva Saxl’s story, with her husband making insulin in Shanghai, China, for the more than 200 Jews who escaped Nazi persecution during World War II (2). But in the United States, access to insulin had never been a problem. As a medication required for survival by 10% of those with diabetes, it was always available, although for decades quite crude by today’s standards. The insulin patent from the University of Toronto was sold for $1 with the understanding that cheap insulin would become available (3). Through the years, insulin remained affordable. Even with the introduction of human insulin in 1982 ($14 per vial) and then insulin analogs in 1996 ($24 per vial), the increases in insulin pricing did not seem to be a concern. At least in the United States, the vast majority of patients requiring insulin had access to all of the insulin analogs as they were developed. As the years passed, the cost of insulin continued to increase. In 2004, I was asked to write a review of insulin analogs, which was published in early 2005 (4). Just before publication, one of the reviewers asked me to publish the costs of the insulin products. In those days, we used the Web site drugstore.com to compare prices, and, in general, vials of insulin analogs cost ∼$60 each. Although this represented a substantial price increase since the …

Industrial Production of Insulin by Genetically Modified Organism

Insulin is a hormone secreted from the β cells of the islets of Langerhans, a specific group of cells in the pancreas. Life would not exist without insulin. In order to utilize the glucose (energy) found within the carbohydrate-laden foods we consume, insulin must be present to facilitate its (glucose) absorption. The rapid increase in the number of diabetic patients globally and exploration of alternate insulin delivery methods such as inhalation or oral route that rely on higher doses, is bound to escalate the demand for recombinant insulin in near future. Recombinant human insulin has been produced predominantly using E. coli (Escherichia coli)and Saccharomyces cerevisiae (a species of yeast) for therapeutic use in human. Current manufacturing technologies would be unable to meet the growing demand of affordable insulin due to limitation in production capacity and high production cost. Insulin is one of the most important drugs in medical science therefore it is important to have a basic knowledge about it. In this review we take a brief look on the history of insulin, its properties and function. We also focus on its industrial production concept and technique along with its purification process. We conclude with the current delivery system for insulin and future prospects.

История создания инсулина. Взгляд в прошлое

История создания инсулина. Взгляд в прошлое

Is there any correlation between vitamin D insufficiency and diabetic retinopathy?

To determine a relation between vitamin D level, which is an inhibitor of angiogenesis, and diabetic retinopathy and its risk factors. In a clinic-based cross sectional study two hundred and thirty-five type 2 diabetic patients older than 20y were selected. Patients were classified according to ophthalmologic examination as following: no diabetic retinopathy (NDR) (n=153), non-proliferative diabetic retinopathy (NPDR) (n=64) and proliferative diabetic retinopathy (PDR) (n=18). Study subjects were tested for fasting blood glucose, glycated hemoglobin A1C (HbA1C), lipid profile, microalbuminuria, HsCRP, IGF1, insulin (in patients without history of insulin taking) and 25 hydroxy vitamin D [25 (OH) D] levels. Vitamin D insufficiency was defined according to 25 (OH) D level less than 30 ng/mL. The relationship between diabetic retinopathy and serum 25 (OH) D insufficiency was evaluated. The prevalence of diabetic retinopathy was 34.8% in our patients. Long duration of diabetes, hypertension, poor glycemic control, diabetic nephropathy, hyperinsulinemia and insulin resistance were risk factors for diabetic retinopathy but 25 (OH) D level was not significant different between NDR, NPDR and PDR groups. Correlation between 25 (OH) D level and other known risk factors of diabetic retinopathy was not significant. This study did not find any association between diabetic retinopathy and its severity and vitamin D insufficiency. Vitamin D insufficiency is not related to risk factors of diabetic retinopathy.

Recurring Rare Liver Tumor Presenting With Hypoglycemia

Question: A 55-year-old woman presented to the hospital with drowsiness, lethargy, and several months of abdominal pain and weight loss. Bloodwork performed in the emergency department detected a very low blood glucose level (2-3 mmol/L), but was otherwise unremarkable, except for mildly elevated liver enzymes. There was no history of insulin or antihyperglycemic use. CT of the abdomen and pelvis with intravenous contrast detected a large (15.3 15.5 15.4 cm) mass arising within the left hepatic lobe, which demonstrated hypervascularity on arterial phase imaging (Figure A), heterogeneity on the venous and delayed phases (Figure B, C), and mild biliary duct dilatation owing to mass effect (Figure D, white arrow). No other intra-abdominal or pelvic mass lesions, nor evidence of metastases, were detected. The patient experienced multiple additional episodes of hypoglycemia controlled with glucose tablets until she underwent a left extended hepatectomy. Pathology showed a tumor composed of small cells individually separated by thin bands of collagen fibers, with positive staining for CD34 and bcl-2 protein (Figure E, bottom). The patient’s presenting symptoms resolved entirely after the tumor resection, with normal periodic follow-up CT imaging, until she presented to the hospital again 5 years later with confusion, lethargy, and similar symptoms to the initial presentation. A right upper quadrant mass was palpable 10-12 cm below the costal margin. Blood glucose measured 1.6 mmol/L and liver enzymes were normal with the exception of mildly elevated g-glutamyl transpeptidase. CT imaging of the abdomen and pelvis demonstrated a large (11 17 15 cm), well-defined mass lesion adjacent to the resection site with imaging features similar to the previously detected mass lesion—markedly heterogeneous parenchyma. MRI of the liver demonstrated a mass lesion with heterogeneous low-to-isointense signal intensity on T1-weighted imaging (Figure F) and heterogeneous hyperintensity on T2-weighted imaging (Figure G), restricted diffusion on diffusion-weighted imaging, and heterogeneous progressive enhancement on postcontrast dynamic acquisition sequences without evidence of retention of hepatocyte-specific gadolinium. The patient underwent a hepatectomy involving segments V-VIII. Her presenting symptoms again resolved following surgery and she was discharged with a plan for clinical and radiological follow-up.

Tooth Loss and Atherosclerosis

Several epidemiologic studies have suggested that oral disease is a risk factor for cardiovascular disease (CVD). However, whether a clinically significant association exists between the 2 disorders remains controversial. Here, we investigated the association between tooth loss, as an indicator of oral disease, and arterial stiffness, as a marker of atherosclerosis, in Japanese adults. Cross-sectional data were collected for 8,124 persons aged 30 to 75 y with no history of tooth loss for noninflammatory reasons, such as orthodontic treatment, malposition, and trauma. Participants received a comprehensive dental examination and extensive in-person measurements of CVD risk factors, and arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI). We examined the association between CAVI and tooth loss using general linear models with adjustment for age, sex, body mass index, smoking status, hemoglobin A1c, and a history of insulin or hypoglycemic medication depending on the model. In addition, we performed an analysis that included interaction terms of the centered variables tooth loss, sex, and age. The results of the multiple regression analysis that included the interaction terms detected that the relationship between CAVI and tooth loss was dependent on sex, with only men showing a positive correlation (β for interaction = 0.04; 95% confidence interval, 0.02–0.06). The findings from this study suggest that a linear relationship exists between tooth loss and degree of arterial stiffness and that the association differed depending on sex.

The history of insulin: the mystery of diabetes

The history of insulin: the mystery of diabetes

History of insulin

The advancement of diabetes treatment has gone from crude extracts of insulin and accidental discovery of sulfa-like drugs in antibiotics to the development of drugs based on improved understanding of the pathophysiology of diabetes mellitus. This article will review the history of the discovery and development of insulin. A companion focusing on non-insulin diabetes agents will follow in the next issue of JCHIMP.

268: Early treatment without rescreening among women with a history of insulin requiring gestational diabetes (GDM) reduces the incidence of macrosomia

268: Early treatment without rescreening among women with a history of insulin requiring gestational diabetes (GDM) reduces the incidence of macrosomia

Diabetes: classification and strategies for integrated care.

This article is the third in a series of three in-depth literature reviews on diabetes. The first article (Vol 12(18): 1091-5) detailed the history of diabetes from the first recorded mention of the disease in the Ebers papyrus through to the discovery of insulin. The second (Vol 12(19): 1137-41) dealt with the history of insulin over the past 80 years and the development of possible alternatives. This final article in the series details the new classifications for diabetes and addresses the aetiology, pathophysiology and complications of the disease. While discussing both type 1 and type 2 diabetes, the article concentrates on the newly defined type 1 diabetes mellitus. An examination of the recently released National Service Framework for Diabetes: Delivery Strategy (DoH, 2003) is included, healthcare provision is discussed, as is the role of the diabetes specialist nurse. An insight is given into the challenges and opportunities available for healthcare practitioners to work in partnership to reform the way in which diabetes services are managed.

A history of insulin: from discovery to modern alternatives.

Following on from the first article in this series (Vol 12(18): 1091-5), which described the history of diabetes, this article, the second of three literature reviews, explores the early production and development of insulin, from its initial production in a university laboratory to becoming a major pharmaceutical product. Also discussed are the various forms of insulin developed over the last 80 years and their means of delivery to the patient. The future is considered and the development of insulin analogues (substances that mimic the effect of human insulin) is described. The article also looks at the introduction of DAFNE (dose adjustment for normal eating) - an intensive programme of education aimed at teaching individuals the necessary skills to adjust their own insulin injection dosage to reflect their individual eating patterns.

Development and Evaluation of Criteria Allowing Paramedics to Treat and Release Patients Presenting with Hypoglycemia: A Retrospective Study

AbstractIntroduction:A retrospective study of patients transported by paramedics to a community teaching hospital was conducted to: 1) determine the response of hypoglycemic patients to prehospital treatments, 2) develop criteria to identify patients who safely could be released without transport to a hospital, and 3) evaluate the prehospital release criteria.Methods:Patients presenting to EMT-paramedics with an altered level of consciousness were identified retrospectively. Pre- and post-treatment blood glucose levels were measured and response to treatment noted (Phase 1). Criteria were established using these data and a second sample was evaluated using these criteria (Phase 2).Results:During a 12-month period, 60 patients with an altered level of consciousness (ALOC) were encountered. Of the 60 patients, 27 (45%) were documented to be hypoglycemic (blood glucose [BG] <80 mg/dl, mean 27±13 mg/dl). Of the 27 hypoglycemic patients, 24 (89%) were discharged from the emergency department (ED) and three patients (11%) were admitted. Criteria were developed to identify patients who could be treated and released safely without transport to a hospital: 1) history of insulin (IDDM) or non-insulin (NIDDM) dependent diabetes mellitus; 2) pre-treatment BG <80 mg/dl; 3) post-treatment BG >80 mg/dl; 4) return to normal mental status within 10 minutes of treatment; and 5) absence of complicating factors (renal dialysis, chest pain, arrhythmia, dyspnea, seizures, alcohol intoxication, focal neurological signs/symptoms). The criteria were applied retrospectively to 27 hypoglycemic (mean BG=28±14 mg/dl) patients during a different 10-month period. Of the 27 hypoglycemic patients, 23 (85%) were discharged from the ED, and prehospital release criteria correctly identified 19 of 23 (83%). The prehospital release criteria did not select for release any patient who required an additional, major intervention or who was admitted.Conclusion:This study demonstrates that there is a group of hypoglycemic patients who respond favorably to paramedic interventions. Retrospectively, the prehospital release criteria were successful in selecting patients who did not require additional interventions. A larger prospective study must be conducted before prehospital treatment and release can be recommended for general practice.