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Journal of Diabetes Mar 2024
Topics: Humans; Insulin Resistance; Insulin; Diabetes Mellitus, Type 2
PubMed: 38516866
DOI: 10.1111/1753-0407.13552 -
Physical Chemistry Chemical Physics :... Sep 2023Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling... (Review)
Review
Given the significance of protein aggregation in proteinopathies and the development of therapeutic protein pharmaceuticals, revamped interest in assessing and modelling the aggregation kinetics has been observed. Quantitative analysis of aggregation includes data of gradual monomeric depletion followed by the formation of subvisible particles. Kinetic and thermodynamic studies are essential to gain key insights into the aggregation process. Despite being the medical marvel in the world of diabetes, insulin suffers from the challenge of aggregation. Physicochemical stresses are experienced by insulin during industrial formulation, storage, delivery, and transport, considerably impacting product quality, efficacy, and effectiveness. The present review briefly describes the pathways, mathematical kinetic models, and thermodynamics of protein misfolding and aggregation. With a specific focus on insulin, further discussions include the structural heterogeneity and modifications of the intermediates incurred during insulin fibrillation. Finally, different model equations to fit the kinetic data of insulin fibrillation are discussed. We believe that this review will shed light on the conditions that induce structural changes in insulin during the lag phase of fibrillation and will motivate scientists to devise strategies to block the initialization of the aggregation cascade. Subsequent abrogation of insulin fibrillation during bioprocessing will ensure stable and globally accessible insulin for efficient management of diabetes.
Topics: Humans; Insulin; Kinetics; Thermodynamics; Protein Aggregates; Proteostasis Deficiencies
PubMed: 37674360
DOI: 10.1039/d3cp03103a -
Diabetes Sep 2023Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE...
UNLABELLED
Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of Cpe in pancreatic β-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic β-cell-specific Cpe knockout mice (βCpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in βCpeKO islets remained intact. High-fat diet-fed βCpeKO mice showed weight gain and glucose tolerance comparable with those of Wt littermates. Notably, β-cell area was increased in chow-fed βCpeKO mice and β-cell replication was elevated in βCpeKO islets. Transcriptomic analysis of βCpeKO β-cells revealed elevated glycolysis and Hif1α-target gene expression. On high glucose challenge, β-cells from βCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin injections, βCpeKO mice had accelerated development of hyperglycemia with reduced β-cell insulin and Glut2 expression. These findings suggest that Cpe and proper proinsulin processing are critical in maintaining β-cell function during the development of hyperglycemia.
ARTICLE HIGHLIGHTS
Carboxypeptidase E (Cpe) is an enzyme that removes the carboxy-terminal arginine and lysine residues from peptide precursors. Mutations in CPE lead to obesity and type 2 diabetes in humans, and whole-body Cpe knockout or mutant mice are obese and hyperglycemic and fail to convert proinsulin to insulin. We show that β-cell-specific Cpe deletion in mice (βCpeKO) does not lead to the development of obesity or hyperglycemia, even after prolonged high-fat diet treatment. However, β-cell proliferation rate and β-cell area are increased, and the development of hyperglycemia induced by multiple low-dose streptozotocin injections is accelerated in βCpeKO mice.
Topics: Animals; Mice; Carboxypeptidase H; Diabetes Mellitus, Type 2; Glucose; Hyperglycemia; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice, Knockout; Obesity; Proinsulin; Streptozocin
PubMed: 37364047
DOI: 10.2337/db22-0945 -
Journal of Pediatric Endocrinology &... Mar 2024Artificial intelligence (AI) in medicine is transforming healthcare by automating system tasks, assisting in diagnostics, predicting patient outcomes and personalising... (Review)
Review
Artificial intelligence (AI) in medicine is transforming healthcare by automating system tasks, assisting in diagnostics, predicting patient outcomes and personalising patient care, founded on the ability to analyse vast datasets. In paediatric endocrinology, AI has been developed for diabetes, for insulin dose adjustment, detection of hypoglycaemia and retinopathy screening; bone age assessment and thyroid nodule screening; the identification of growth disorders; the diagnosis of precocious puberty; and the use of facial recognition algorithms in conditions such as Cushing syndrome, acromegaly, congenital adrenal hyperplasia and Turner syndrome. AI can also predict those most at risk from childhood obesity by stratifying future interventions to modify lifestyle. AI will facilitate personalised healthcare by integrating data from 'omics' analysis, lifestyle tracking, medical history, laboratory and imaging, therapy response and treatment adherence from multiple sources. As data acquisition and processing becomes fundamental, data privacy and protecting children's health data is crucial. Minimising algorithmic bias generated by AI analysis for rare conditions seen in paediatric endocrinology is an important determinant of AI validity in clinical practice. AI cannot create the patient-doctor relationship or assess the wider holistic determinants of care. Children have individual needs and vulnerabilities and are considered in the context of family relationships and dynamics. Importantly, whilst AI provides value through augmenting efficiency and accuracy, it must not be used to replace clinical skills.
Topics: Child; Humans; Artificial Intelligence; Pediatric Obesity; Algorithms; Endocrinology; Insulin
PubMed: 38183676
DOI: 10.1515/jpem-2023-0554 -
Journal of Diabetes Science and... Nov 2023A wave of expiring patents for first-generation insulin analogues has created opportunities in the global insulin market for highly similar versions of these products,... (Review)
Review
BACKGROUND
A wave of expiring patents for first-generation insulin analogues has created opportunities in the global insulin market for highly similar versions of these products, biosimilar insulins. Biologics are generally large, complex molecules produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell. Since manufacturing processes of biologics vary, biosimilars cannot be exact copies of their reference product but must exhibit a high degree of functional and structural similarity. Biosimilarity is proven by analytical approaches in comparative assessments, preclinical cell-based and animal studies, as well as clinical studies in humans facilitating the accumulation of evidence across all assessments. The approval of biosimilars follows detailed regulatory pathways derived from those of their reference products and established by agencies such as the European Medicines Agency and the US Food and Drug Administration. Regulatory authorities impose requirements to ensure that biosimilars meet high standards of quality, safety, and efficacy and are highly similar to their reference product.
PURPOSE
This review aims to aid clinical understanding of the high standards of development, manufacturing, and regulation of biosimilar insulins.
METHODS
Recent relevant studies indexed by PubMed and regulatory documents were included.
CONCLUSIONS
Driven by price competition, the emergence of biosimilar insulins may help expand global access to current insulin analogues. To maximize the impact of the advantage for falling retail costs of biosimilar insulins compared with that of reference insulins, healthcare professionals and insulin users must gain further awareness and confidence.
Topics: Animals; United States; Humans; Biosimilar Pharmaceuticals; Insulin; Insulins; Insulin, Regular, Human; United States Food and Drug Administration; Drug Approval
PubMed: 35818669
DOI: 10.1177/19322968221105864 -
Journal of Diabetes and Its... Oct 2023One of the greatest barriers to the treatment of T2DM is nonadherence which particularly applies to insulin therapy. There is a need for a comprehensive overview of all... (Review)
Review
BACKGROUND AND AIM
One of the greatest barriers to the treatment of T2DM is nonadherence which particularly applies to insulin therapy. There is a need for a comprehensive overview of all factors associated with nonadherence to insulin therapy. The aim of this study was to identify factors associated with adherence or nonadherence to insulin therapy among adults with T2DM.
METHODS
A scoping review was conducted in accordance with the PRISMA 2020 statement. A systematic search was performed in PubMed, Cinahl, and Web of Science (January 2013 to March 2023).
RESULTS
A final sample of 48 studies was included in the scoping review. The synthesis revealed 30 factors associated with adherence or nonadherence. The factors were grouped into 6 themes: demographics, attitude and perceptions, management of diabetes, impact on daily living, disease and medication, and healthcare system.
CONCLUSION
The most prominent factors identified were age, cost of healthcare, personal beliefs towards insulin therapy, social stigma, patient education, complexity of diabetes treatment, impact of insulin therapy on daily life, and fear of side effects. The results indicate a need for further research to determine threshold values for the factors associated with adherence or nonadherence.
Topics: Humans; Adult; Diabetes Mellitus, Type 2; Insulin; Medication Adherence; Insulin, Regular, Human; Drug-Related Side Effects and Adverse Reactions
PubMed: 37651772
DOI: 10.1016/j.jdiacomp.2023.108596 -
Annals of Internal Medicine Sep 2023
Topics: Humans; Prescription Drugs; Insulin; Insulins
PubMed: 37665994
DOI: 10.7326/M23-1105 -
International Journal of Molecular... Jan 2024Drugs based on peptides and proteins (PPs) have been widely used in medicine, beginning with insulin therapy in patients with diabetes mellitus over a century ago.... (Review)
Review
Drugs based on peptides and proteins (PPs) have been widely used in medicine, beginning with insulin therapy in patients with diabetes mellitus over a century ago. Although the oral route of drug administration is the preferred one by the vast majority of patients and improves compliance, medications of this kind due to their specific chemical structure are typically delivered parenterally, which ensures optimal bioavailability. In order to overcome issues connected with oral absorption of PPs such as their instability depending on digestive enzymes and pH changes in the gastrointestinal (GI) system on the one hand, but also their limited permeability across physiological barriers (mucus and epithelium) on the other hand, scientists have been strenuously searching for novel delivery methods enabling peptide and protein drugs (PPDs) to be administered enterally. These include utilization of different nanoparticles, transport channels, substances enhancing permeation, chemical modifications, hydrogels, microneedles, microemulsion, proteolytic enzyme inhibitors, and cell-penetrating peptides, all of which are extensively discussed in this review. Furthermore, this article highlights oral PP therapeutics both previously used in therapy and currently available on the medical market.
Topics: Humans; Gastrointestinal Agents; Insulin; Cell-Penetrating Peptides; Biological Availability; Hydrogels
PubMed: 38255888
DOI: 10.3390/ijms25020815 -
Diabetes, Obesity & Metabolism Sep 2023To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing... (Randomized Controlled Trial)
Randomized Controlled Trial
First-in-human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations.
AIMS
To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively.
MATERIALS AND METHODS
A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones.
RESULTS
No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8).
CONCLUSIONS
GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin; Bile Acids and Salts; Blood Glucose; Insulin, Regular, Human; Glucose; Obesity; Double-Blind Method
PubMed: 37380614
DOI: 10.1111/dom.15066 -
Home Healthcare Now
Topics: Humans; Hypoglycemia; Hypoglycemic Agents; Blood Glucose; Insulin
PubMed: 37922137
DOI: 10.1097/NHH.0000000000001219