Modern Insulin Research Articles

Factors Influencing Insulin Absorption Around Exercise in Type 1 Diabetes.

International charities and health care organizations advocate regular physical activity for health benefit in people with type 1 diabetes. Clinical expert and international diabetes organizations’ position statements support the management of good glycemia during acute physical exercise by adjusting exogenous insulin and/or carbohydrate intake. Yet research has detailed, and patients frequently report, variable blood glucose responses following both the same physical exercise session and insulin to carbohydrate alteration. One important source of this variability is insulin delivery to the circulation. With modern insulin analogs, it is important to understand how different insulins, their delivery methods, and inherent physiological factors, influence the reproducibility of insulin absorption from the injection site into circulation. Furthermore, contrary to the adaptive pancreatic response to exercise in the person without diabetes, the physiological and metabolic shifts with exercise may increase circulating insulin concentrations that may contribute to exercise-related hyperinsulinemia and consequent hypoglycemia. Thus, a furthered understanding of factors underpinning insulin delivery may offer more confidence for healthcare professionals and patients when looking to improve management of glycemia around exercise.

Transplantation technologies for treatment of carbohydrate metabolism disorders

The review includes results of retrospective and prospective clinical studies (foreign and national) and guidelines on the use of transplantation technologies for treatment of type 1 diabetes and pancreatogenic diabetes in chronic pancreatitis and pancreatic conditions. Modern data on prevalence of diabetes and modern insulin delivery methods are presented. Results of transplantation of pancreas and islets of Langerhans in primary insulin-dependent conditions are considered. Analysis of the technology for isolation and autotransplantation of islets after pancreatectomy in chronic pancreatitis and benign tumor diseases are given.

Blood Glucose Prediction with Variance Estimation Using Recurrent Neural Networks

Many factors affect blood glucose levels in type 1 diabetics, several of which vary largely both in magnitude and delay of the effect. Modern rapid-acting insulins generally have a peak time after 60–90 min, while carbohydrate intake can affect blood glucose levels more rapidly for high glycemic index foods, or slower for other carbohydrate sources. It is important to have good estimates of the development of glucose levels in the near future both for diabetic patients managing their insulin distribution manually, as well as for closed-loop systems making decisions about the distribution. Modern continuous glucose monitoring systems provide excellent sources of data to train machine learning models to predict future glucose levels. In this paper, we present an approach for predicting blood glucose levels for diabetics up to 1 h into the future. The approach is based on recurrent neural networks trained in an end-to-end fashion, requiring nothing but the glucose level history for the patient. Our approach obtains results that are comparable to the state of the art on the Ohio T1DM dataset for blood glucose level prediction. In addition to predicting the future glucose value, our model provides an estimate of its certainty, helping users to interpret the predicted levels. This is realized by training the recurrent neural network to parameterize a univariate Gaussian distribution over the output. The approach needs no feature engineering or data preprocessing and is computationally inexpensive. We evaluate our method using the standard root-mean-squared error (RMSE) metric, along with a blood glucose-specific metric called the surveillance error grid (SEG). We further study the properties of the distribution that is learned by the model, using experiments that determine the nature of the certainty estimate that the model is able to capture.

Current Challenges in Non-Invasive Insulin Drug Delivery System: A Review

The Frederick Banting and Charles Best extracted insulin from bovine pancreas in 1922, who received the Nobel prize for their contribution in the medical field with Johan McLeod, The gastrointestinal tract (GIT) is the route of choice for the administration of most drugs, regardless of their molecular structure or weight and administration of insulin exogenously via subcutaneous route which mimic the pancreatic insulin secretion, for In todays era, insulin delivery by noninvasive route is an area of current interest in diabetes mellitus treatment by parenteral route for type-I and type-II diabetes mellitus , while noninvasive therapy through oral delivery is greatly desired, there are challenges that include the low bioavailability due to the rapid enzymatic degradation in the stomach. This review article patent that provides the novel approaches for noninvasive insulin drug delivery system to the bloodstream through the go tract. Keywords: Diabetes mellitus, insulin, non-invasive insulin drug delivery, modern insulin drug delivery, absorption enhancer, insulin pump.

The Predictive Low Glucose Management System in Prevention of Clinically Significant Hypoglycemia in Type 1 Diabetes. A Preliminary Study Identifying the Most Common Events Leading Up to Hypoglycemia During Insulin Pump Therapy.

Prevention of hypoglycemia remains a major challenge in diabetic management, despite the introduction of modern insulin pumps in daily clinical practice. The Low Glucose Suspend (LGS) and the newer Predictive Low Glucose Management (PLGM) systems incorporated in the Medtronic insulin pumps have shown promising results in prevention of hypoglycemia. Our aim was to evaluate the effect of the 2 systems relative to the frequency of clinically significant hypoglycemia in Type 1 diabetes (T1DM). In addition, we investigated the events preceding clinically significant hypoglycemia episodes. A cross-sectional study was conducted in 30 T1DM patients using the MiniMed 640G vs. 30 using the MiniMed Veo sensor-augmented insulin pump. All data was recorded during patients' normal daily activity and living conditions. The patients were matched for age and duration of diabetes. PLGM use was associated with lower incidence of clinically significant hypoglycemia (1.9±1.4 vs. 3.6±1.9 episodes per week), along with reduced exposure to hypoglycemia. The data indicated that both pump systems are effective in preventing severe hypoglycemic episodes. In both groups the most common events preceding hypoglycemic episodes included adjustment of hyperglycemia, basal rate increase and miscalculation of carbohydrates. The results indicated that the use of the Minimed 640G pump system can help reduce the frequency of clinically significant hypoglycemia. Management of hyperglycemia must be addressed in diabetes education programs in order to encourage proper adjustment of high blood glucose levels. Future studies would be useful in exploring the details of the events preceding hypoglycemia episodes in insulin pump users.

Earlier puberty in boys with type 1 diabetes mellitus compared to a simultaneously recruited group of control adolescents.

Recent studies have suggested that there is an earlier age of onset of puberty in healthy boys. However, no study has determined the age of pubertal development in boys with type 1 diabetes (T1D) and compared the results with a simultaneously recruited group of healthy children. The aim of this study was to evaluate the age of pubertal events in boys with TD1 and determine whether the duration of diabetes, metabolic control or insulin dose are associated with the age of puberty in boys with T1D. Boys aged 7 to 19 years with T1D (n = 148, age 12.9 ± 3.0 years) and healthy boys recruited from schools (n = 388 controls, age 12.8 ± 2.2 years) were studied. A pediatric endocrinologist evaluated pubertal development. Boys at genital Tanner stage 2 and the final stages of puberty (genital Tanner 4 and 5) were younger than the control group (P = 0.005, P = 0.003, and P = 0.015, respectively). Both groups of boys had a similar age of pubic Tanner stage development. There were no cases of pubertal delay observed in the T1D cohort. There was no association observed between metabolic control with pubertal timing. T1D adolescents had lower height-SDS than the C group at the final stages of puberty. Boys with T1D who are treated with modern insulin therapy appear to have an earlier age of onset and an earlier age of final pubertal events than a simultaneously studied group of healthy children. These data suggest that pubertal delay is not a frequent problem for male T1D patients.

The impact of cardiovascular outcome trials on the choice of insulins in the management of type 2 diabetes mellitus: An expert review

Introduction. This expert review aims to address the epidemiology and pathophysiology of cardiovascular disease (CVD) in persons with type 2 diabetes mellitus (T2DM), help understand the various statistical considerations and interpretational nuances of cardiovascular outcome trials (CVOTs) in general, and discuss in particular, the CVOTs with insulins, and their impact on the choice of insulins in day-to-day clinical practice. Material and methods. The expert panel critically analysed published data from observational studies, randomized clinical trials, meta-analyses and CVOTs regarding cardiovascular (CV) safety of insulin preparations, and agreed on a series of consensus statements supported by available scientific evidence and the collective clinical judgement of the experts. Results. A proportion of persons with T2DM have a high risk of CVD and CV mortality, which is partly contributed by insulin resistance-related, and hyperglycaemiarelated, risk factors. Over the past decade, CVOTs have become an integral part of the drug approval process of anti-diabetic therapies by the United States Food and Drug Administration (FDA). Most insulin preparations in use today, barring a few modern insulins, were introduced much before this regulatory requirement was put in place, and hence, have not undergone rigorous CVOTs. There is a large body of observational data concerning the CV safety of insulin preparations, which are often confusing and, at times, contradictory. In this background, it is reassuring to note that CVOTs of two basal insulin analogues, namely insulin glargine, studied in the Basal Insulin and Cardiovascular and Other Outcomes in Dysglycaemia Trial (ORIGIN), and insulin degludec, studied in the Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes Trial (DEVOTE), established their long-term CV safety. The DEVOTE trial provided additional safety data reporting fewer severe hypoglycaemic events with insulin degludec in comparison to insulin glargine. Conclusions. This review critically analyses the two CVOTs of basal insulin analogues, in tandem with a general review of the methodological and interpretational aspects of CVOTs in general. The long-term CV safety of analogue basal insulins is discussed. The lack of CVOTs with prandial and pre-mixed insulins, either human or analogue, was identified as the main research gap in this area.

John A. Galloway, MD, FACP: A Pharmaceutical Physician and Leader in Diabetes Therapy.

John A. Galloway, MD, FACP. There have been extraordinary individuals active in patient care, clinical research, professional and patient organizations, and pharmaceutical science who devoted their careers to constantly focusing on and campaigning for “what is best for the patient.” Dr. John A. Galloway has been that leader, whose clinical curiosity, insights, dedication, and commitment to others brought insulin therapy from the impurified, low-potency animal insulins to the modern insulins of today. Born in Omaha, Nebraska, in 1928, Galloway moved to Washington, DC, and graduated from St. Albans School in 1946 and then from the University of Pennsylvania in Philadelphia in 1950 with a B.A. in English and Pre-Med. After 2 years in the U.S. Army and serving in combat in Korea, 1st Lt. Galloway was released to start medical school at the University of Nebraska College of Medicine in Omaha, where he gained his MD in 1956. Upon completion of his internship, he began his residency in internal medicine at Temple University Hospital in Philadelphia, serving as Chief Medical Resident from 1959–1960. This was followed by a Fellowship in Diabetes, Endocrinology and Nuclear Medicine with Charles R. Shuman, MD, at Temple, where Galloway and Shuman published the first report in the medical literature on the use of computers to analyze large volumes of clinical data in a study of surgery in patients with diabetes (1). After a report in the Journal of Clinical Investigation by Solomon A. Berson, MD, and Rosalyn S. Yalow, PhD, a physicist, on a method they had developed for measuring insulin in the blood using immunologic techniques (the radioimmunoassay or RIA) (2), Shuman arranged for Galloway to attend the first workshop that Berson and Yalow gave on how to perform their assay. Also selected to attend were Lisa G. Heding from Novo Laboratory (now …

Breastfeeding at Night Is Rarely Followed by Hypoglycemia in Puerperal Women with Type 1 Diabetes Using Carbohydrate Counting and Modern Insulin Treatment

Aim: Hypoglycemia in association with breastfeeding is a feared condition in women with type 1 diabetes. Thus, routine carbohydrate intake at each night-time breastfeeding is often recommended despite lack of evidence. We evaluated glucose levels during breastfeeding with focus on whether night-time breastfeeding induced hypoglycemia in women with type 1 diabetes. Methods: Prospective study of 25 consecutive breastfeeding women (mean age 30.8 (SD ±5.9) years, 64% nulliparous, singleton pregnancy) with type 1 diabetes for 18.8 (±10.5) years. All were experienced in carbohydrate counting with 44% on insulin pump and 56% on multiple daily injections. At 33 (±7.2) and 66 (±14.2) days postpartum blinded continuous glucose monitoring (CGM) was applied for six days and the women recorded breastfeedings and carbohydrate intake. Results: At both CGM periods mean glucose levels were similar at night (11 pm to 7 am) (8.3 (±1.7) and 8.7 (±2.5) mmol/l, p=0.56) and over 24 hours (8.4 (±1.5) and 8.7 (±2.1) mmol/l, p=0.56). The percentage of time <4.0 mmol/l was similar at night (median 5.8% (range 0-20.8) and 3.1% (0-36.1), p=0.24) and over 24 hours (5.0% (0-19.8) and 3.9% (0-22.8), p=0.75). At 33 days postpartum maternal weight was close to the pre-pregnancy weight (79.1 (±15.0) vs. 75.6 (±14.2) kg, p=0.50) while insulin dose was 18% lower than before pregnancy (p=0.04). A total of 340 night-time breastfeedings were recorded with 2 (0-4) breastfeedings per night. Carbohydrate was ingested at 42 (12%) of the breastfeedings. CGM <4.0 mmol/l within three hours after night-time breastfeeding occurred after 5% of breastfeedings. Conclusion: Despite almost 300 night-time breastfeedings without carbohydrate intake, hypoglycemia within 3 hours after breastfeeding was rare. The recommendation of routine carbohydrate intake at night-time breastfeeding in women with type 1 diabetes on modern insulin treatment who count carbohydrate may be obsolete. Disclosure L. Ringholm: None. A.B. Roskjær: None. S. Engberg: None. H.U. Andersen: Advisory Panel; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Advisory Panel; Self; AstraZeneca. E. Hommel: None. A.L. Secher: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. E.R. Mathiesen: Speaker's Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S, Novo Nordisk Foundation, Novo Nordisk A/S.

Lessons for modern insulin development.

There have been many advances in insulin with a realistic possibility of mimicking nature to improve insulin replacement, with a view to achieving improved metabolic control. Lessons can be learnt from the evolution of insulin, insulin development, and new advances in technology. This may lead to fewer side effects of therapy resulting in a lower risk of hypoglycaemia and less weight gain, which could in turn could reduce long-term complications for people with diabetes.

Type 1 Diabetes at High Altitude: Performance of Personal Insulin Pumps and Patient Metabolic Control.

High-altitude trekking can expose people to extreme environmental conditions, like low temperatures and hypobaric hypoxia. Such extreme conditions make it more difficult for people with type 1 diabetes mellitus (T1DM) to maintain glycemic control. Intensive blood glucose monitoring using either glucose meters or continuous systems is imperative in these cases. In this observational study, we report metabolic control of T1DM patients and the performance of various insulin pumps at high altitude. All 19 patients with T1DM included in this study participated in the final step of the "5000 meters above sugar level" initiative, which involved trekking Damavand Mountain to an altitude of 5670 meters above sea level. We found that all pump models worked well without any disruption and no cases of diabetes decompensation or severe hypoglycemia occurred. Therefore, healthy, physically fit, and experienced individuals with T1DM should not be discouraged from participating in mountain trekking activities, as modern personal insulin pumps work well at high altitudes.

Insulin-From its Discovery to the Industrial Synthesis of Modern Insulin Analogues.

After the discovery of insulin as a drug for diabetes, the pharmaceutical companies were faced with the challenge to meet the demand for insulin with the highest possible degree of purity in the required quantities from animal sources. The observation of an immune reaction of patients to insulin from animal pancreatic extracts made the availability of human insulin of highest priority. Only the enzyme-catalyzed semisynthesis at the C-terminus of the insulin B-chain led to a commercial process, but it depended on porcine insulin and was aggravated by supply concerns. The advent of rDNA technology allowed the commercial preparation of human insulin by biosynthesis in virtually unlimited quantities. An increased chemical diversity was only envisaged through chemical synthesis, which was simplified by advances in solid-phase peptide synthesis and chemical ligation. Single-chain insulin precursors are now being synthesized that should enable fast screening of insulin analogues for improved biophysical, biological, and thus promising new therapeutic properties, as well as for the industrial manufacture of insulin analogues not accessible by biosynthesis.

Perioperative management of endocrine insufficiency after total pancreatectomy for neoplasia.

Indications for total pancreatectomy (TP) have increased, including for diffuse main duct intrapapillary mucinous neoplasms of the pancreas and malignancy; therefore, the need persists for surgeons to develop appropriate endocrine post-operative management strategies. The brittle diabetes after TP differs from type 1/2 diabetes in that patients have absolute deficiency of insulin and functional glucagon. This makes glucose management challenging, complicates recovery, and predisposes to hospital readmissions. This article aims to define the disease, describe the cause for its occurrence, review the anatomy of the endocrine pancreas, and explain how this condition differs from diabetes mellitus in the setting of post-operative management. The morbidity and mortality of post-TP endocrine insufficiency and practical treatment strategies are systematically reviewed from the literature. Finally, an evidence-based treatment algorithm is created for the practicing pancreatic surgeon and their care team of endocrinologists to aid in managing these complex patients. A PubMed, Science Citation Index/Social sciences Citation Index, and Cochrane Evidence-Based Medicine database search was undertaken along with extensive backward search of the references of published articles to identify studies evaluating endocrine morbidity and treatment after TP and to establish an evidence-based treatment strategy. Indications for TP and the etiology of pancreatogenic diabetes are reviewed. After TP, ~80% patients develop hypoglycemic episodes and 40% experience severe hypoglycemia, resulting in 0-8% mortality and 25-45% morbidity. Referral to a nutritionist and endocrinologist for patient education before surgery followed by surgical reevaluation to determine if the patient has the appropriate understanding, support, and resources preoperatively has significantly reduced morbidity and mortality. The use of modern recombinant long-acting insulin analogues, continuous subcutaneous insulin infusion, and glucagon rescue therapy has greatly improved management in the modern era and constitute the current standard of care. A simple immediate post-operative algorithm was constructed. Successful perioperative surgical management of total pancreatectomy and resulting pancreatogenic diabetes is critical to achieve acceptable post-operative outcomes, and we review the pertinent literature and provide a simple, evidence-based algorithm for immediate post-resection glycemic control.

Introduction of biosimilar insulins in Europe.

Regulatory approval of the first biosimilar insulin in Europe, LY2963016 insulin glargine (Abasaglar®), in 2014 expanded the treatment options available to people with diabetes. As biosimilar insulin products come to market, it is important to recognize that insulin products are biologicals manufactured through complex biotechnology processes, and thus biosimilar insulins cannot be considered identical to their reference products. Strict regulatory guidelines adopted by authorities in Europe, the USA and some other countries help to ensure that efficacy and safety profiles of biosimilar insulins are not meaningfully different from those of the reference products, preventing entry of biological compounds not meeting quality standards and potentially affecting people's glycaemic outcomes. This review explains the concept of biosimilar medicines and outlines regulatory requirements for registration of biosimilar insulins in Europe, which is illustrated by the successful development of LY2963016 insulin glargine and MK‐1293 insulin glargine (Lusduna®). Preclinical and clinical comparative studies of the biosimilar insulin glargine programmes include in vitro bioassays for insulin and insulin‐like growth factor 1 receptor binding, assessment of in vitro biological activity, evaluation of pharmacokinetic/pharmacodynamic profiles in phase I studies and assessment of long‐term safety and efficacy in phase III studies. The emergence of biosimilar insulins may help broaden access to modern insulins, increase individualized treatment options and reduce costs of insulin therapy.

МАРКЕРЫ ВОСПАЛЕНИЯ, ПОКАЗАТЕЛИ ГЕМОСТАЗА И СОСТОЯНИЕ ОРГАНОВ-МИШЕНЕЙ У МОЛОДЫХ ПАЦИЕНТОВ С РАЗЛИЧНЫМИ КОМПОНЕНТАМИ МЕТАБОЛИЧЕСКОГО СИНДРОМА

Введение. Согласно современным представлениям, инициирующим фактором для запуска каскада метаболических нарушений при артериальной гипертензии (АГ) и абдоминальном ожирении (АО) является инсулинорезистентность. Активация локального и системного воспалительного ответа, а также протромботические изменения при АГ и АО являются основой для органных поражений, прогрессирования атеросклеротического процесса и развития осложнений. Цель исследования. Изучение взаимосвязи между маркерами воспалительного ответа, показателями гемостаза и состоянием органов-мишеней у молодых пациентов с различными компонентами метаболического синдрома. Материалы и методы. Проведена комплексная оценка взаимосвязи уровней адипокинов, цитокинов и показателей гемостаза с состоянием органов-мишеней у 251 пациента в возрасте 18–44 лет: 1 группа — 35 пациентов с изолированной АГ; 2 группа — 76 пациентов с изолированным АО; 3 группа — 60 пациентов с сочетанием АГ и АО; 4 группа — 80 практически здоровых волонтеров. Результаты. У больных с комбинацией АГ и АО выявлено повышение лептина и интерлейкина-6, снижение адипонектина и протромботические изменения гемостаза по сравнению с пациентами с изолированными АГ, АО и практически здоровыми. В группе больных с комбинацией АГ и АО с бóльшей частотой обнаруживались гипертрофия левого желудочка и увеличение комплекса интима-медиа сонных артерий по сравнению с пациентами, имевшими только АГ и только АО. Обнаружены положительные линейные корреляции индекса массы миокарда левого желудочка с концентрацией интерлейкина-6 и толщины комплекса интима-медиа с уровнем интерлейкина-1β, отрицательная связь этих показателей с уровнями адипонектина и ингибитора активатора плазминогена 1 типа. Заключение. При сочетании АГ с АО в молодом возрасте чаще выявляется субклиническое поражение органов-мишеней; установлено более высокое содержание глюкозы, общего холестерина, холестерина липопротеинов низкой плотности, триглицеридов, лептина, интерлейкина-6, фибриногена, ингибитора активатора плазминогена 1 типа и ингибитора пути тканевого фактора по сравнению с пациентами с изолированной АГ и изолированным АО. Introduction. According to modern concepts insulin resistance is the initiating factor for triggering a cascade of metabolic disorders in hypertension (AH) and abdominal obesity (AO). Activation of local and systemic infl ammatory response as well as prothrombotic changes at AH and AO are the basis for organ’s lesions, progression of atherosclerotic process and complications development. The aim: to study the relationship between the markers of infl ammatory response, hemostatic parameters and target organs in young patients with diff erent components of metabolic syndrome. Materials and methods. Complex assessment of relationships between adipokines, cytokines, hemostatic parameters and status of target organs was done in 251 patients (18–44 years old): group 1–35 patients with isolated AH; group 2–76 patients with isolated AO; group 3–60 patients with combination of AH and AO; group 4–80 practically healthy volunteers. Results. In patients with combination of AH and AO we revealed increased values of leptin and interleukin-6, decreased values of adipokine and prothrombotic changes as compared to patients with isolated AH, isolated AO and with healthy people. Left ventricular hypertrophy and thickening of intima-media of carotid arteries were revealed more frequently in patients with combination of AH and AO. We found positive correlations between the left ventricular mass index and interleukin-6 content, thickening of intima-media complex and interleukin-1β concentration, negative correlation of these parameters with adiponectin level and plasminogen activator inhibitor type 1 content. Conclusion. The subclinical lesion of target organs is more often detected in young people with AH in combination with AO; higher levels of glucose, total cholesterol, low-density lipoprotein cholesterol, triglycerides, leptin, interleukin-6, fibrinogen, inhibitor of plasminogen activator type 1 and inhibitor of tissue factor were revealed as compared to patients with isolated AH and with isolated AO.

Insulins NPH, glargine, and detemir, and risk of severe hypoglycemia among working-age adults*

Introduction: The longer acting basal insulin analogs glargine and detemir have shown a lower incidence of hypoglycemia compared to insulin NPH in clinical studies. We evaluated the real-life risk of severe hypoglycemia among new users of insulins in the working-age population in Finland.Methods: All persons aged 18–65 years with diabetes mellitus who were newly prescribed with insulins NPH, glargine, or detemir during 2006–2009, were identified from national registers. Risk of severe hypoglycemia requiring hospital care was compared between insulin types.Results: A total of 16,985 persons initiated basal insulin treatment (5586, 7499, and 3900 patients started NPH, glargine, and detemir, respectively) during follow-up. Five hundred and thirty-six persons were hospitalized because of severe hypoglycemia. Absolute rate (per 1000 patient-years) was 20.6 (95% CI 17.9, 23.8), 17.8 (15.6, 20.3), and 12.4 (9.9, 15.5) for NPH, glargine, and detemir initiators, respectively. With NPH as reference, the adjusted hazard ratio (HR) was 0.92 (95% CI 0.74, 1.15, p = 0.47) for glargine, and 0.70 (0.51, 0.94, p= 0.018) for detemir. The HR for detemir compared to glargine was 0.76 (0.58, 0.99, p = 0.040).Conclusions: Initiating insulin treatment with detemir, but not with glargine, was associated with a significantly lower risk of severe hypoglycemia compared to NPH, among working-age adults.KEY MESSAGESThe comparative safety of modern basal insulins regarding hypoglycemia among the working-age population is unclear.Large reductions in the incidence of severe hypoglycemia were seen among real-life patients who started insulin detemir, as compared to patients who initiated glargine or especially NPH insulin.Given the large amount of patients using insulin, these findings may have considerable clinical consequences at the population level.

Striving for control: lessons learned from a successful international Type 1 Diabetes Youth Challenge.

To demonstrate whether young people with T1D using modern insulin treatment and CGM could successfully participate in extreme sport activity while maintaining good glycemic control. The challenge took place in Crete/Greece over 4days combining a long-distance trek of different levels of severity with final destination the summit of the White Mountains at 2080m. Eleven participants (5/6 female/male, age 18.2±1.3years, T1D duration 7.9±3.5years, HbA1c 7.3±.7% (56±16mmol/mol); mean±SD) from 11 SWEET centers in Belgium, Brazil, Canada, Germany, Greece, France, India, Italy, Portugal, Slovenia and Sweden participated to the challenge. Five participants were on CSII, six on MDI; all were wearing a continuous glucose monitoring system. The glycemic targets during trekking were defined as 80-180mg/dl (4.4-10mmol/l). All participants completed the challenge. In total, the group walked 54.5km under varying climate conditions (temperature 14-35°C). During the challenge, insulin requirements decreased significantly compared to baseline: total daily insulin by 31.1±16.7% (p<.001), basal by 30.8±14.9% (p<.001), and prandial by 32.5±28.0% (p=.023), with no differences between participants with CSII or MDI.No episode of severe hypoglycemia or DKA occurred. Mean glucose levels were 170.7±60.1mg/dl with 61.5±18.7% of CGM values in the target range, 5.4±5.4% under 80mg/dl and 32.8±16.6% above 180mg/dl. The results of this SWEET Initiative activity demonstrated that well-educated adolescents and young adults with T1D using modern insulin treatments are able to perform successfully even extraordinary physical challenges while maintaining good glycemic control without diabetes-related acute complications.

Insulin Formulation Characterization-the Thioflavin T Assays.

The insulin molecule was discovered in 1921. Shortly thereafter, its propensity towards amyloid fibril formation, fibrillation, was observed and described in the literature as a "precipitate." In the past decades, the increased incidence of type 2 diabetes has reached global epidemic proportions. This has emphasized the demands for both insulin production and the development of modern insulin products for unmet medical needs. Bringing such new insulin drug products to the market for the benefit of patients requires that many CMC-related processes are understood, described, and controlled. One potential undesired process is insulin fibril formation. The compound thioflavin T (ThT) is known as a fluorescent probe for amyloid fibrils. As such, ThT is utilized in a versatile research assay in microtiter plate format, the ThT assay. This review will describe an experimental set-up using not only a ThT microtiter plate assay but also two orthogonal methods. The use of the ThT assay in research and characterization of insulin analogues, as well as formulations of insulin, is described by cases drawn from the scientific literature and patents. The ThT assay is compared to other physical stability tests and in conclusion the advantages and limitations of the assay are compared.

Clinical use of the co-formulation of insulin degludec and insulin aspart.

To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting their individual pharmacodynamic profiles. Clinical evidence in phase 2/3 trials of IDegAsp efficacy and safety in type 1 and type 2 diabetes mellitus (T1DM and T2DM) have been assessed and summarised. In people with T2DM, once- and twice-daily dosing provides similar overall glycaemic control (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice-daily, based on individual need. People switching from more than once-daily basal or premix insulin therapy can be converted unit-to-unit to once-daily IDegAsp, although this strategy should be assessed by the physician on an individual basis. IDegAsp offers physicians and people with T2DM a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins.

Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism.

Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein?