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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 -
Biotechnology Advances 2020Harmonization of biomarkers is important for the comparability of laboratory results as it allows the definition of universal reference values and clinical decision... (Review)
Review
Harmonization of biomarkers is important for the comparability of laboratory results as it allows the definition of universal reference values and clinical decision limits. In diabetology, immunoassays are widely used to determine HbA1c, C-peptide, insulin, and autoantibodies to beta cell proteins, which are essential biomarkers for the diagnosis and classification of diabetes mellitus. Furthermore, as large clinical studies have identified HbA1c as a predictor for the development of diabetic complications, HbA1c has evolved as the general treatment target. For decades, the use of non-harmonized assays caused confusion. After the standardization of HbA1c, the worldwide comparability improved and increased the confidence in this laboratory biomarker. Insulin and C-peptide are not only valuable biomarkers to assess beta-cell function, but may also be used to evaluate insulin resistance, a metabolic feature of type 2 diabetes often occurring before its manifestation. Long-lasting efforts led to substantial improvements in the harmonization process of C-peptide assays, but harmonization of insulin assays is still ongoing. Therefore, C-peptide is now sometimes used as a surrogate biomarker for insulin. Furthermore, autoantibodies against beta cell components are important biomarkers for the accurate differentiation of type 1, type 2, and other special types of diabetes. Owing to the heterogeneity of these autoantibodies against beta cell proteins, harmonization is very difficult to achieve. International efforts are in progress to harmonize the current assays, as the presence of autoantibodies against beta cell proteins predicts the development of type 1 diabetes in early life. In conclusion, clinical studies linking diagnosis, classification, prediction, and treatment to laboratory values of the respective biomarkers need to be harmonized to avoid misdiagnosis and incorrect clinical decisions, thus improving patient care and safety.
Topics: Biomarkers; C-Peptide; Diabetes Mellitus; Humans; Immunoassay; Insulin
PubMed: 30802485
DOI: 10.1016/j.biotechadv.2019.02.015 -
Nature Metabolism Dec 2019The pancreatic islet is a complex mini organ composed of a variety of endocrine cells and their support cells, which together tightly control blood glucose homeostasis.... (Review)
Review
The pancreatic islet is a complex mini organ composed of a variety of endocrine cells and their support cells, which together tightly control blood glucose homeostasis. Changes in glucose concentration are commonly regarded as the chief signal controlling insulin-secreting beta cells, glucagon-secreting alpha cells and somatostatin-secreting delta cells. However, each of these cell types is highly responsive to a multitude of endocrine, paracrine, nutritional and neural inputs, which collectively shape the final endocrine output of the islet. Here, we review the principal inputs for each islet-cell type and the physiological circumstances in which these signals arise, through the prism of the insights generated by the transcriptomes of each of the major endocrine-cell types. A comprehensive integration of the factors that influence blood glucose homeostasis is essential to successfully improve therapeutic strategies for better diabetes management.
Topics: Animals; Blood Glucose; Homeostasis; Humans; Islets of Langerhans; Pancreatic Hormones
PubMed: 32694675
DOI: 10.1038/s42255-019-0148-2 -
Peptides May 2022Urocortin 3 (UCN3) is a peptide hormone expressed in pancreatic islets of Langerhans of both human alpha and human beta cells and solely in murine beta cells. UCN3... (Review)
Review
Urocortin 3 (UCN3) is a peptide hormone expressed in pancreatic islets of Langerhans of both human alpha and human beta cells and solely in murine beta cells. UCN3 signaling acts locally within the islet to activate its cognate receptor, corticotropin releasing hormone receptor 2 (CRHR2), which is expressed by delta cells, to potentiate somatostatin (SST) negative feedback to reduce islet cell hormone output. The functional importance of UCN3 signaling in the islet is to modulate the amount of SST tone allowing for finely tuned regulation of insulin and glucagon secretion. UCN3 signaling is a hallmark of functional beta cell maturation, increasing the beta cell glucose threshold for insulin secretion. In doing so, UCN3 plays a relevant functional role in accurately maintaining blood glucose homeostasis. Additionally, UCN3 acts as an indicator of beta cell maturation and health, as UCN3 is not expressed in immature beta cells and is downregulated in dedifferentiated and dysfunctional beta cell states. Here, we review the mechanistic underpinnings of UCN3 signaling, its net effect on islet cell hormone output, as well as its value as a marker for beta cell maturation and functional status.
Topics: Animals; Corticotropin-Releasing Hormone; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Somatostatin; Urocortins
PubMed: 35065098
DOI: 10.1016/j.peptides.2022.170748 -
Molecules (Basel, Switzerland) Jan 2018Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro-... (Review)
Review
Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro- and macro-complications like heart disease, stroke, dementia, cancer, kidney failure and blindness. All these complications rise primarily due to consistent high blood glucose levels. Insulin and glucagon help to maintain the homeostasis of glucose and lipids through signaling cascades. Pancreatic hormones stimulate translocation of the glucose transporter isoform 4 (GLUT4) from an intracellular location to the cell surface and facilitate the rapid insulin-dependent storage of glucose in muscle and fat cells. Malfunction in glucose uptake mechanisms, primarily contribute to insulin resistance in type 2 diabetes. Plant secondary metabolites, commonly known as phytochemicals, are reported to have great benefits in the management of type 2 diabetes. The role of phytochemicals and their action on insulin signaling pathways through stimulation of GLUT4 translocation is crucial to understand the pathogenesis of this disease in the management process. This review will summarize the effects of phytochemicals and their action on insulin signaling pathways accelerating GLUT4 translocation based on the current literature.
Topics: Animals; Diabetes Mellitus, Type 2; Glucose Transporter Type 4; Humans; Insulin; Insulin Resistance; Obesity; Phytochemicals; Protein Transport; Signal Transduction
PubMed: 29382104
DOI: 10.3390/molecules23020258 -
ELife Sep 2023Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of...
Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of human α-cells remains a challenge due to the lack of cost-effective purification methods to isolate high-quality α-cells from islets. Here, we use the reaction-based probe diacetylated Zinpyr1 (DA-ZP1) to introduce a novel and simple method for enriching live α-cells from dissociated human islet cells with ~95% purity. The α-cells, confirmed by sorting and immunostaining for glucagon, were cultured up to 10 days to form α-pseudoislets. The α-pseudoislets could be maintained in culture without significant loss of viability, and responded to glucose challenge by secreting appropriate levels of glucagon. RNA-sequencing analyses (RNA-seq) revealed that expression levels of key α-cell identity genes were sustained in culture while some of the genes such as , , were altered in α-pseudoislets in a time-dependent manner. In conclusion, we report a method to sort human primary α-cells with high purity that can be used for downstream analyses such as functional and transcriptional studies.
Topics: Humans; Glucagon; Transcriptome; Islets of Langerhans; Insulin; Glucagon-Secreting Cells; Glucose; Fluoresceins; Insulin-Secreting Cells
PubMed: 37732504
DOI: 10.7554/eLife.85056 -
Endokrynologia Polska 2022Not required for Clinical Vignette.
Not required for Clinical Vignette.
Topics: Gastrinoma; Humans; Pancreatic Neoplasms; Somatostatin
PubMed: 35381105
DOI: 10.5603/EP.a2021.0101 -
Life Science Alliance Aug 2022Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We...
Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (<i>GCG</i>, 56%), amylin (<i>IAPP</i>, 52%), insulin (<i>INS</i>, 44%), and somatostatin (<i>SST</i>, 24%). Inhibition of two DEGs, <i>UNC5D</i> and <i>SERPINE2</i>, impaired glucose-stimulated insulin secretion and impacted cell survival in a human β-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.
Topics: Diabetes Mellitus, Type 2; Glucagon; Humans; Insulin; Islets of Langerhans; Serpin E2
PubMed: 35948367
DOI: 10.26508/lsa.202201376 -
Annals of Surgical Oncology Sep 2022The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these...
BACKGROUND
The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these patients are limited and we therefore performed a nationwide analysis.
METHODS
Data from the prospective Dutch Pancreatic Cancer Audit were analyzed, including all patients undergoing pancreatic cancer resection between January 2014 and December 2016. Patients were classified into two age groups: <75 and ≥75 years. Major complications (Clavien-Dindo grade 3 or higher), 90-day mortality, rates of adjuvant chemotherapy, and survival were compared between age groups. Factors associated with start of adjuvant chemotherapy and survival were evaluated with logistic regression and multivariable Cox regression analysis.
RESULTS
Of 836 patients, 198 were aged ≥75 years (24%) and 638 were aged <75 years (76%). Median follow-up was 38 months (interquartile range [IQR] 31-47). Major complications (31% vs. 28%; p = 0.43) and 90-day mortality (8% vs. 5%; p = 0.18) did not differ. Adjuvant chemotherapy was started in 37% of patients aged ≥75 years versus 69% of patients aged <75 years (p < 0.001). Median overall survival (OS) was 15 months (95% confidence interval [CI] 14-18) versus 21 months (95% CI 19-24; p < 0.001). Age ≥75 years was not independently associated with OS (hazard ratio 0.96, 95% CI 0.79-1.17; p = 0.71), but was associated with a lower rate of adjuvant chemotherapy (odds ratio 0.27, 95% CI 0.18-0.40; p < 0.001).
CONCLUSIONS
The rate of major complications and 90-day mortality after pancreatic resection did not differ between elderly and younger patients; however, elderly patients were less often treated with adjuvant chemotherapy and their OS was shorter.
Topics: Aged; Chemotherapy, Adjuvant; Humans; Pancreatectomy; Pancreatic Hormones; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies
PubMed: 35653069
DOI: 10.1245/s10434-022-11831-7 -
Toxins Apr 2017In this study, the diabetogenic effects of long term Ochratoxin A (OTA) administration in rats were investigated, and its role in the etiology of diabetes mellitus (DM)...
In this study, the diabetogenic effects of long term Ochratoxin A (OTA) administration in rats were investigated, and its role in the etiology of diabetes mellitus (DM) was examined utilizing 42 female Wistar rats for these purposes. The rats were divided into three different study and control groups according to the duration of the OTA administration. The rats received 45 μg OTA daily in their feed for 6, 9 and 24 weeks, respectively. Three control groups were also used for the same time periods. Blood and pancreatic tissue samples were collected during the necropsy at the end of the 6, 9 and 24 weeks. The plasma values of insulin, glucagon and glucose were determined for the study and control groups. Pancreatic lesions were evaluated via histopathological examination and insulin and glucagon expression in these lesions was subsequently determined using immunohistochemical methods. Statistically significant decreases in insulin levels were observed, in contrast to increases in blood glucagon and glucose levels. Histopathological examinations revealed slight to moderate degeneration in Langerhans islet cells in all OTA-treated groups. Immunohistochemistry of pancreatic tissue revealed decreased insulin and increased glucagon expression. This study demonstrated that OTA may cause pancreatic damage in the Langerhans islet and predispose rats to DM.
Topics: Animals; Blood Glucose; Diabetes Mellitus; Female; Glucagon; Insulin; Ochratoxins; Pancreas; Rats, Wistar
PubMed: 28422066
DOI: 10.3390/toxins9040144