A systematic review and meta-analysis of the child-level effects of family-based interventions for the prevention of type 2 diabetes mellitus.

AIMS: The purpose of this systematic review and meta-analysis was to investigate the effects of family-based health promotion interventions on child-level risk factors for type 2 diabetes in vulnerable families. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for systematic reviews formed the methodological framework. CINAHL, Embase, MEDLINE, PsycINFO, and Web of Science were searched on January 12, 2024. The NTP-OHAT Risk of Bias Assessment Tool was used to assess the risk of bias in the individual studies, and meta-analyses were performed. RESULTS: The 4723 studies were identified, and 55 studies met the inclusion criteria. Results showed significant effects on children's body mass index (mean difference [MD], -0.18, 95% CI [-0.33 to -0.03], p = 0.02), body fat percentage (MD, -2.00, 95% CI [-3.31 to -0.69], p = 0.003), daily activity (standardized mean difference [SMD], 0.23, 95% CI [0.01; 0.44], p = 0.04), physical activity self-efficacy (SMD, 0.73, 95% CI [0.36 to 1.10], p < 0.01), intake of snacks (MD, -0.10, 95% CI [-0.17 to -0.04], p = 0.002), and sugar-sweetened beverages (SMD, -0.21, 95% CI [-0.42 to -0.01], p = 0.04). Subgroup analyses suggested that interventions aiming to change child and parent behavior simultaneously have larger effect on fasting glucose and nutrition consumption, and that interventions longer than 26 weeks have larger effects on body composition and physical activity behavior than shorter interventions.

Molecular engineering of insulin for recombinant expression in yeast.

Since the first administration of insulin to a person with diabetes in 1922, scientific contributions from academia and industry have improved insulin therapy and access. The pharmaceutical need for insulin is now more than 40 tons annually, half of which is produced by recombinant secretory expression in Saccharomyces cerevisiae. We discuss how, in this yeast species, adaptation of insulin precursors by removable structural elements is pivotal for efficient secretory expression. The technologies reviewed have been implemented at industrial scale and are seminal for the supply of human insulin and insulin analogues to people with diabetes now and in the future. Engineering of a target protein with removable structural elements may provide a general approach to yield optimisation.

The role of weight control in the management of type 2 diabetes mellitus: Perspectives on semaglutide.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used to address multiple aspects of type 2 diabetes mellitus (T2DM) management, including glycaemic control, weight loss, and cardiovascular risk reduction. Semaglutide, a well-established GLP-1 RA approved for T2DM treatment and weight management, demonstrates marked efficacy in achieving these clinically important goals. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus report emphasizes the importance of a holistic approach to T2DM treatment, with weight control as a key component for improving patient outcomes. Notably, semaglutide is mentioned in the consensus report as having 'very high' efficacy for both glucose lowering and weight loss in T2DM treatment. Nevertheless, as has been observed with other weight-lowering drugs, weight loss observed with semaglutide appears less profound in individuals with T2DM than in those with obesity without T2DM, a phenomenon requiring further investigation. The semaglutide safety and tolerability profiles are well established, and it is approved in some countries to reduce cardiovascular risk in certain populations with T2DM. Thus, semaglutide offers a well-established therapeutic option that aligns well with guideline recommendations for T2DM management, emphasizing the high importance of weight control and amelioration of other cardiometabolic risk factors.

Glucagon-like peptide-1 receptor agonists to expand the healthy lifespan: Current and future potentials.

To help ensure an expanded healthy lifespan for as many people as possible worldwide, there is a need to prevent or manage a number of prevalent chronic diseases directly and indirectly closely related to aging, including diabetes and obesity. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have proven beneficial in type 2 diabetes, are amongst the few medicines approved for weight management, and are also licensed for focused cardiovascular risk reduction. In addition, strong evidence suggests several other beneficial effects of the pleiotropic peptide hormone, including anti-inflammation. Consequently, GLP-1 RAs are now in advanced clinical development for the treatment of chronic kidney disease, broader cardiovascular risk reduction, metabolic liver disease and Alzheimer's disease. In sum, GLP-1 RAs are positioned as one of the pharmacotherapeutic options that can contribute to addressing the high unmet medical need characterising several prevalent aging-related diseases, potentially helping more people enjoy a prolonged healthy lifespan.

Derivatization with fatty acids in peptide and protein drug discovery.

Peptides and proteins are widely used to treat a range of medical conditions; however, they often have to be injected and their effects are short-lived. These shortcomings of the native structure can be addressed by molecular engineering, but this is a complex undertaking. A molecular engineering technology initially applied to insulin - and which has now been successfully applied to several biopharmaceuticals - entails the derivatization of peptides and proteins with fatty acids. Various protraction mechanisms are enabled by the specific characteristics and positions of the attached fatty acid. Furthermore, the technology can ensure a long half-life following oral administration of peptide drugs, can alter the distribution of peptides and may hold potential for tissue targeting. Due to the inherent safety and well-defined chemical nature of the fatty acids, this technology provides a versatile approach to peptide and protein drug discovery.

Commemorating insulin's centennial: engineering insulin pharmacology towards physiology.

The life-saving discovery of insulin in Toronto in 1921 is one of the most impactful achievements in medical history, at the time being hailed as a miracle treatment for diabetes. The insulin molecule itself, however, is poorly amenable as a pharmacological intervention, and the formidable challenge of optimizing insulin therapy has been ongoing for a century. We review early academic insights into insulin structure and its relation to self-association and receptor binding, as well as recombinant biotechnology, which have all been seminal for drug design. Recent developments have focused on combining genetic and chemical engineering with pharmaceutical optimization to generate ultra-rapid and ultra-long-acting, tissue-selective, or orally delivered insulin analogs. We further discuss these developments and propose that future scientific efforts in molecular engineering include realizing the dream of glucose-responsive insulin delivery.

Insulin at 100: still central in protein-based therapy for chronic disease.

The discovery of insulin has inspired several pivotal medical and scientific developments during the past 100 years. Here, we describe how insulin as a model protein will drive future advances in peptide- and protein-based therapies for chronic diseases.

Pharmacology of insulin detemir.

Insulin detemir (Levemir [Novo Nordisk A/S, Bagsvaerd, Denmark]) is a soluble, long-acting basal insulin analog. It differs from human insulin in that the amino acid threonine in position B30 has been removed and a 14-carbon fatty acid (myristic acid) has been acylated to lysine at B29. This modification increases self-association and enables albumin binding of insulin detemir. In this manuscript, the unique molecular properties and the resulting pharmacodynamics of insulin detemir are reviewed. The protracted duration of action, smooth activity profile, and low intrapatient variability of insulin detemir are presented as properties that may potentially help patients maximize glycemic control and minimize the long-term complications of diabetes.

Insulin's 85th anniversary--An enduring medical miracle.

In 1922, the discovery of insulin led to a revolution in diabetes management. Since then, many improvements have been made to insulin preparations: early preparations of bovine and porcine insulins were purified and their duration of action prolonged, giving rise to the introduction of Neutral Protamine Hagedorn (NPH) insulin and monocomponent insulins. Then, with the advances in genetic engineering in the 1980s, it became possible to produce recombinant human insulin. Nowadays, modern molecular biology techniques enable the production of insulin analogues, which have several advantages over human insulin preparations including a reduced risk of hypoglycaemia. Insulin delivery is still predominantly via subcutaneous injections, but alternative routes of insulin administration are being investigated. Pulmonary delivery has emerged as the most feasible option thus far but oral delivery is an ultimate goal, although basic problems of insulin stability in the gut and absorption from the gastrointestinal tract still need to be resolved. The availability of a true artificial pancreas by means of a closed-loop system, linking continuous glucose monitoring with insulin-pump technology, would also constitute a significant advance, but major technological problems still need to be overcome.

Insulin detemir: from concept to clinical experience.

Insulin detemir (Levemir, Novo Nordisk) is a novel, biologically engineered analogue of human insulin that has been successfully developed for clinical use in diabetes as a basal insulin. Its unique mechanism of prolongation of action, achieved through acylation to give reversible albumin binding and additional self-association, goes some way to addressing one of the fundamental limitations of previously available, subcutaneously administered basal insulins, a high level of within-person variability in time-action profile from one injection to another. The pharmacological profile of insulin detemir, characterised in a series of studies, suggested it had the potential to offer efficacy and tolerability advantages in the clinical setting. Such advantages, in comparison to NPH (neutral protamine Hagedorn) insulin, have subsequently been illustrated in trials. Despite glucose control targets that are identical to comparators, insulin detemir achieved levels of glycaemic control that, overall, were at least as good as NPH insulin in the Phase III development programme, with lower variability being a consistent finding. This was associated with consistent risk reductions in nocturnal hypoglycaemic events, which are closely linked with the basal component of insulin therapy. Another consistent finding has been a significantly reduced propensity for weight gain. An all-analogue regimen combining insulin detemir with the rapid-acting insulin aspart illustrated the potential benefits achievable when insulins that are designed to achieve defined pharmacokinetic profiles are employed clinically; blood glucose control, including hypoglycaemia, was significantly superior to a human insulin-based mealtime plus basal regimen. Insulin detemir is, therefore, a valuable addition to the range of exogenous insulins, as it should enable treatment regimens to be constructed that offer good outcomes of efficacy and tolerability.

The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin.

PURPOSE: Insulin detemir has been found in clinical trials to be absorbed with very low variability. A series of experiments were performed to elucidate the underlying mechanisms. METHODS: The disappearance from an injected subcutaneous depot and elimination studies in plasma were carried out in pigs. Size-exclusion chromatography was used to assess the self-association and albumin binding states of insulin detemir and analogs. RESULTS: Disappearance T50% from the injection depot was 10.2+/-1.2 h for insulin detemir and 2.0+/-0.1 h for a monomeric acylated insulin analog. Self-association of acylated insulin analogs with same albumin affinity in saline correlated with disappearance rate and addition of albumin to saline showed a combination of insulin detemir self association and albumin binding. Intravenous kinetic studies showed that the clearance and volume of distribution decreased with increasing albumin binding affinity of different acylated insulin analogs. CONCLUSIONS: The protracted action of detemir is primarily achieved through slow absorption into blood. Dihexamerization and albumin binding of hexameric and dimeric detemir prolongs residence time at the injection depot. Some further retention of detemir occurs in the circulation where albumin binding causes buffering of insulin concentration. Insulin detemir provides a novel principle of protraction, enabling increased predictability of basal insulin.

Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. A new class of selective GSK-3 inhibitors.

A novel class of GSK-3 inhibitors with favorable water solubility was identified in a HTS screen. SAR studies identified bioisosteric structural moieties in this class of compounds. The compounds were tested in a GSK-3 inhibition assay at 100 microM ATP giving IC(50)'s in the range from 0.1 to 10 microM. The compounds are ATP competitive inhibitors. They modulate glycogen metabolism and stimulate the accumulation of intracellular beta-catenin in whole cell assays with EC(50)'s in the range from 2 to 18 microM and 4.5-44 microM, respectively. For selected compounds, only a 10-fold lower potency was obtained in cellular assays compared to the potency obtained for inhibition of the isolated enzyme, reflecting a good cell permeability of this compound class. At 10 microM of test compound a 3-fold stimulation of the glycogen synthesis in rat soleus muscle was obtained compared to the level of glycogen synthesis observed at 0.2 nM insulin. This stimulation of glycogen synthesis is comparable to the maximal stimulation by insulin itself.

Insulin aspart: promising early results borne out in clinical practice.

The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.