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Pharmacological Reviews Jul 2015Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin... (Review)
Review
Amylin is a pancreatic β-cell hormone that produces effects in several different organ systems. Here, we review the literature in rodents and in humans on amylin research since its discovery as a hormone about 25 years ago. Amylin is a 37-amino-acid peptide that activates its specific receptors, which are multisubunit G protein-coupled receptors resulting from the coexpression of a core receptor protein with receptor activity-modifying proteins, resulting in multiple receptor subtypes. Amylin's major role is as a glucoregulatory hormone, and it is an important regulator of energy metabolism in health and disease. Other amylin actions have also been reported, such as on the cardiovascular system or on bone. Amylin acts principally in the circumventricular organs of the central nervous system and functionally interacts with other metabolically active hormones such as cholecystokinin, leptin, and estradiol. The amylin-based peptide, pramlintide, is used clinically to treat type 1 and type 2 diabetes. Clinical studies in obesity have shown that amylin agonists could also be useful for weight loss, especially in combination with other agents.
Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Weight Loss
PubMed: 26071095
DOI: 10.1124/pr.115.010629 -
The Journal of Clinical Investigation Jan 20212021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1... (Review)
Review
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin's discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin's role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry's role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Topics: Animals; Drug Industry; History, 20th Century; History, 21st Century; Humans; Insulin; Pancreas
PubMed: 33393501
DOI: 10.1172/JCI142239 -
Diabetes Technology & Therapeutics Dec 2020Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many... (Review)
Review
Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many additional insulin formulations are in development. This review outlines recent advances in insulin therapy and novel therapies in development.
Topics: Humans; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Insulin, Regular, Human
PubMed: 32310681
DOI: 10.1089/dia.2020.0065 -
Journal of Diabetes Investigation Apr 2016Glucagon-like peptide-1 (GLP-1) is a product of proglucagon cleavage synthesized in L cells in the intestinal mucosa, α-cells in the pancreatic islet, and neurons in... (Review)
Review
Glucagon-like peptide-1 (GLP-1) is a product of proglucagon cleavage synthesized in L cells in the intestinal mucosa, α-cells in the pancreatic islet, and neurons in the nucleus of the solitary tract. GLP-1 is essential for normal glucose tolerance and acts through a specific GLP-1 receptor that is expressed by islet β-cells as well as other cell types. Because plasma concentrations of GLP-1 increase following meal ingestion it has been generally presumed that GLP-1 acts as a hormone, communicating information from the intestine to the endocrine pancreas through the circulation. However, there are a number of problems with this model including low circulating concentrations of GLP-1 in plasma, limited changes after meal ingestion and rapid metabolism in the plasma. Moreover, antagonism of systemic GLP-1 action impairs insulin secretion in the fasting state, suggesting that the GLP-1r is active even when plasma GLP-1 levels are low and unchanging. Consistent with these observations, deletion of the GLP-1r from islet β-cells causes intolerance after IP or IV glucose, challenges that do not induce GLP-1 secretion. Taken together, these data support a model whereby GLP-1 acts through neural or paracrine mechanisms to regulate physiologic insulin secretion. In contrast, bariatric surgery seems to be a condition in which circulating GLP-1 could have an endocrine effect. Both gastric bypass and sleeve gastrectomy are associated with substantial increases in postprandial GLP-1 release and in these conditions interference with GLP-1r signaling has a significant impact on glucose regulation after eating. Thus, with either bariatric surgery or treatment with long-acting GLP-1r agonists, circulating peptide mediates insulinotropic activity. Overall, a case can be made that physiologic actions of GLP-1 are not hormonal, but that an endocrine mechanism of GLP-1r activation can be co-opted for therapeutics.
Topics: Animals; Fasting; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Humans; Incretins; Insulin; Insulin Secretion; Proglucagon
PubMed: 27186356
DOI: 10.1111/jdi.12466 -
Nature Metabolism Feb 2022Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. The aetiology of this complex disease is dependent on the...
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. The aetiology of this complex disease is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment. Here, we provide a single-cell atlas of pancreatic islets of 24 T1D, autoantibody-positive and nondiabetic organ donors across multiple quantitative modalities including ~80,000 cells using single-cell transcriptomics, ~7,000,000 cells using cytometry by time of flight and ~1,000,000 cells using in situ imaging mass cytometry. We develop an advanced integrative analytical strategy to assess pancreatic islets and identify canonical cell types. We show that a subset of exocrine ductal cells acquires a signature of tolerogenic dendritic cells in an apparent attempt at immune suppression in T1D donors. Our multimodal analyses delineate cell types and processes that may contribute to T1D immunopathogenesis and provide an integrative procedure for exploration and discovery of human pancreatic function.
Topics: Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Pancreatic Hormones
PubMed: 35228745
DOI: 10.1038/s42255-022-00531-x -
Physiological Reviews Apr 2017In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis.... (Review)
Review
In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network. Paradoxically, the pancreatic peptide glucagon has reemerged in this period among a plethora of newly identified metabolic macromolecules, and new data complement and challenge its historical position as a gut hormone involved in metabolic control. The synthesis of glucagon analogs that are biophysically stable and soluble in aqueous solutions has promoted biological study that has enriched our understanding of glucagon biology and ironically recruited glucagon agonism as a central element to lower body weight in the treatment of metabolic disease. This review summarizes the extensive historical record and the more recent provocative direction that integrates the prominent role of glucagon in glucose elevation with its under-acknowledged effects on lipids, body weight, and vascular health that have implications for the pathophysiology of metabolic diseases, and the emergence of precision medicines to treat metabolic diseases.
Topics: Animals; Brain; Gastrointestinal Tract; Glucagon; Homeostasis; Humans; Liver; Metabolic Diseases; Pancreas
PubMed: 28275047
DOI: 10.1152/physrev.00025.2016 -
BMJ Open Diabetes Research & Care Aug 2021Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties of insulin icodec.
RESEARCH DESIGN AND METHODS
A number of in vitro assays measuring receptor binding, intracellular signaling as well as cellular metabolic and mitogenic responses were used to characterize the biological properties of insulin icodec. To evaluate the pharmacological properties of insulin icodec in individuals with type 2 diabetes, a randomized, double-blind, double-dummy, active-controlled, multiple-dose, dose escalation trial was conducted.
RESULTS
The long half-life of insulin icodec was achieved by introducing modifications to the insulin molecule aiming to obtain a safe, albumin-bound circulating depot of insulin icodec, providing protracted insulin action and clearance. Addition of a C20 fatty diacid-containing side chain imparts strong, reversible albumin binding, while three amino acid substitutions (A14E, B16H and B25H) provide molecular stability and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro cell-based studies showed that insulin icodec activates the same dose-dependent IR-mediated signaling and metabolic responses as native human insulin (HI). The affinity of insulin icodec for the insulin-like growth factor-1 receptor was proportionately lower than its binding to the IR, and the in vitro mitogenic effect of insulin icodec in various human cells was low relative to HI. The clinical pharmacology trial in people with type 2 diabetes showed that insulin icodec was well tolerated and has pharmacokinetic/pharmacodynamic properties that are suited for once-weekly dosing, with a mean half-life of 196 hours and close to even distribution of glucose-lowering effect over the entire dosing interval of 1 week.
CONCLUSIONS
The molecular modifications introduced into insulin icodec provide a novel basal insulin with biological and pharmacokinetic/pharmacodynamic properties suitable for once-weekly dosing.
TRIAL REGISTRATION NUMBER
NCT02964104.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Insulin, Regular, Human
PubMed: 34413118
DOI: 10.1136/bmjdrc-2021-002301 -
Comprehensive Physiology Apr 2021Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose....
Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon's biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease. © 2021 American Physiological Society. Compr Physiol 11:1759-1783, 2021.
Topics: Blood Glucose; Glucagon; Glucose; Humans; Insulin; Liver
PubMed: 33792899
DOI: 10.1002/cphy.c200013 -
Diabetes Care Oct 2023In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1...
OBJECTIVE
In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10.
RESEARCH DESIGN AND METHODS
To provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted.
RESULTS
The primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted.
CONCLUSIONS
These data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment.
Topics: Adult; Child; Humans; Diabetes Mellitus, Type 1; C-Peptide; Insulin, Regular, Human; Antibodies, Monoclonal, Humanized; Insulin
PubMed: 37607392
DOI: 10.2337/dc23-0675 -
Expert Opinion on Pharmacotherapy Apr 2021: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult...
: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin
PubMed: 33131345
DOI: 10.1080/14656566.2020.1845651