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BioDrugs : Clinical Immunotherapeutics,... Aug 2020The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin... (Review)
Review
The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin glargine) and Admelog (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.
Topics: Biosimilar Pharmaceuticals; Drug Approval; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulins; United States
PubMed: 32681425
DOI: 10.1007/s40259-020-00431-0 -
Endocrinology and Metabolism (Seoul,... Feb 2023To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells... (Review)
Review
To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic β-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic β-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic β-cell sensitivity to glucose and incretin hormones.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Blood Glucose; Glucagon-Like Peptide 1; Insulin; Gastric Inhibitory Polypeptide; Glucose
PubMed: 36781163
DOI: 10.3803/EnM.2023.103 -
Diabetes, Obesity & Metabolism Jun 2022The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion,...
AIMS
The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post-bariatric hypoglycaemia (PBH).
MATERIALS AND METHODS
Participants with PBH following gastric bypass were recruited from outpatient clinics at the Joslin Diabetes Center, Boston, Massachusetts for an open-label study of pramlintide efficacy over 8 weeks. Twenty-three participants were assessed for eligibility, 20 participants had at least one pramlintide dose, and 14 completed the study. A mixed-meal tolerance test (MMTT) was performed at baseline and after 8 weeks of subcutaneous pramlintide with a sequential dose increase to a maximum of 120 micrograms (mean 69 ± 32 mcg) three times daily. The primary endpoint was change in glucose excursions during the MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose (SG) <3.9 mM, and number of days with minimum SG <3 mM, during masked continuous glucose monitoring.
RESULTS
There were no differences in MMTT glucose, glucagon or insulin between baseline and post treatment. We observed no significant change in satiety or dumping scores. The overall frequency of low SG values did not change, although there was substantial inter-individual variability.
CONCLUSIONS
In PBH, pramlintide does not modulate glycaemic or insulin responses, satiety, or dumping scores during an MMTT and does not impact glycaemic excursions or decrease low SG levels in the outpatient setting.
Topics: Bariatric Surgery; Blood Glucose; Blood Glucose Self-Monitoring; Glucagon; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Islet Amyloid Polypeptide
PubMed: 35137513
DOI: 10.1111/dom.14665 -
Islets Dec 2023The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different...
The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.
Topics: Animals; Humans; Endocannabinoids; Glucagon; Metabolic Syndrome; Islets of Langerhans; Insulin; Diabetes Mellitus; Receptors, Cannabinoid
PubMed: 36598083
DOI: 10.1080/19382014.2022.2163826 -
Islets Dec 2023Pancreatic islets are mini-organs composed of hundreds or thousands of ɑ, β and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones... (Review)
Review
Pancreatic islets are mini-organs composed of hundreds or thousands of ɑ, β and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones for the regulation of blood glucose. In pancreatic islets, hormone secretion is tightly regulated by both internal and external mechanisms, including electrical communication and paracrine signaling between islet cells. Given its complexity, the experimental study of pancreatic islets has been complemented with computational modeling as a tool to gain a better understanding about how all the mechanisms involved at different levels of organization interact. In this review, we describe how multicellular models of pancreatic cells have evolved from the early models of electrically coupled β-cells to models in which experimentally derived architectures and both electrical and paracrine signals have been considered.
Topics: Islets of Langerhans; Insulin-Secreting Cells; Insulin; Glucagon; Pancreatic Hormones
PubMed: 37415423
DOI: 10.1080/19382014.2023.2231609 -
Science Translational Medicine Jan 2021Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately... (Review)
Review
Insulin was first isolated almost a century ago, yet commercial formulations of insulin and its analogs for hormone replacement therapy still fall short of appropriately mimicking endogenous glycemic control. Moreover, the controlled delivery of complementary hormones (such as amylin or glucagon) is complicated by instability of the pharmacologic agents and complexity of maintaining multiple infusions. In this review, we highlight the advantages and limitations of recent advances in drug formulation that improve protein stability and pharmacokinetics, prolong drug delivery, or enable alternative dosage forms for the management of diabetes. With controlled delivery, these formulations could improve closed-loop glycemic control.
Topics: Biological Products; Blood Glucose; Diabetes Mellitus, Type 1; Drug Compounding; Glucagon; Humans; Hypoglycemic Agents; Insulin
PubMed: 33504649
DOI: 10.1126/scitranslmed.abd6726 -
Surgical Oncology Clinics of North... Apr 2020The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are... (Review)
Review
The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Disease Management; Humans; Intestinal Neoplasms; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms
PubMed: 32151362
DOI: 10.1016/j.soc.2019.11.004 -
Current Opinion in Pharmacology Apr 2022Diabetes is the result of dysregulation of both insulin and glucagon. Still, insulin has attracted much more attention than glucagon. Glucagon is released from alpha... (Review)
Review
Diabetes is the result of dysregulation of both insulin and glucagon. Still, insulin has attracted much more attention than glucagon. Glucagon is released from alpha cells in the islets of Langerhans in response to low glucose and certain amino acids. Drugs with the primary aim of targeting glucagon signalling are scarce. However, glucagon is often administered to counteract severe hypoglycaemia, and commonly used diabetes medications such as GLP-1 analogues, sulfonylureas and SGLT2-inhibitors also affect alpha cells. Indeed, there are physiological and developmental similarities between the alpha cell and the insulin-secreting beta cell and new data confirm that alpha cells can be converted into insulin-secreting cells. These aspects and attributes, the need to find novel therapies targeting the alpha cell and more are considered in this review.
Topics: Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Homeostasis; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans
PubMed: 35245797
DOI: 10.1016/j.coph.2022.102199 -
The Journal of Endocrinology Jul 2023In commemoration of 100 years since the discovery of glucagon, we review current knowledge about the human α cell. Alpha cells make up 30-40% of human islet endocrine... (Review)
Review
In commemoration of 100 years since the discovery of glucagon, we review current knowledge about the human α cell. Alpha cells make up 30-40% of human islet endocrine cells and play a major role in regulating whole-body glucose homeostasis, largely through the direct actions of their main secretory product - glucagon - on peripheral organs. Additionally, glucagon and other secretory products of α cells, namely acetylcholine, glutamate, and glucagon-like peptide-1, have been shown to play an indirect role in the modulation of glucose homeostasis through autocrine and paracrine interactions within the islet. Studies of glucagon's role as a counterregulatory hormone have revealed additional important functions of the α cell, including the regulation of multiple aspects of energy metabolism outside that of glucose. At the molecular level, human α cells are defined by the expression of conserved islet-enriched transcription factors and various enriched signature genes, many of which have currently unknown cellular functions. Despite these common threads, notable heterogeneity exists amongst human α cell gene expression and function. Even greater differences are noted at the inter-species level, underscoring the importance of further study of α cell physiology in the human context. Finally, studies on α cell morphology and function in type 1 and type 2 diabetes, as well as other forms of metabolic stress, reveal a key contribution of α cell dysfunction to dysregulated glucose homeostasis in disease pathogenesis, making targeting the α cell an important focus for improving treatment.
Topics: Humans; Glucagon; Diabetes Mellitus, Type 2; Glucagon-Secreting Cells; Islets of Langerhans; Glucose; Insulin; Insulin-Secreting Cells
PubMed: 37114672
DOI: 10.1530/JOE-22-0298 -
International Journal of Molecular... Jan 2023Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical... (Review)
Review
Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.
Topics: Humans; Prognosis; Biomarkers, Tumor; Extracellular Vesicles; Pancreatic Neoplasms; Pancreatic Hormones
PubMed: 36614326
DOI: 10.3390/ijms24010885