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Nature Medicine Jul 2021The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment... (Review)
Review
The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
Topics: Blood Glucose; Diabetes Mellitus, Type 1; Humans; Insulin
PubMed: 34267380
DOI: 10.1038/s41591-021-01418-2 -
The Journal of Cell Biology Jul 2018Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated... (Review)
Review
Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms in different organs or "stations" of its bodily journey. In this review, we focus on these five stages of the journey of insulin through the body and the captivating cell biology that underlies the interaction of insulin with each organ. We first analyze insulin's biosynthesis in and export from the β-cells of the pancreas. Next, we focus on its first pass and partial clearance in the liver with its temporality and periodicity linked to secretion. Continuing the journey, we briefly describe insulin's action on the blood vasculature and its still-debated mechanisms of exit from the capillary beds. Once in the parenchymal interstitium of muscle and adipose tissue, insulin promotes glucose uptake into myofibers and adipocytes, and we elaborate on the intricate signaling and vesicle traffic mechanisms that underlie this fundamental function. Finally, we touch upon the renal degradation of insulin to end its action. Cellular discernment of insulin's availability and action should prove critical to understanding its pivotal physiological functions and how their failure leads to diabetes.
Topics: Adipocytes; Adipose Tissue; Diabetes Mellitus; Glucose; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Muscle, Skeletal; Testosterone Congeners
PubMed: 29622564
DOI: 10.1083/jcb.201802095 -
Canadian Journal of Diabetes Feb 2017Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently... (Review)
Review
Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently autophosphorylated and activated to tyrosine phosphorylate key cellular substrates that are essential for entraining the insulin response. Although IRK activation begins at the cell surface, it is maintained and augmented following internalization into the endosomal system (ENS). The peroxovanadium compounds (pVs) were discovered to activate the IRK in the absence of insulin and lead to a full insulin response. Thus, IRK activation is both necessary and sufficient for insulin signalling. Furthermore, this could be shown to occur with activation of only the endosomal IRK. The mechanism of pV action was shown to be the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs). Our studies showed that the duration and intensity of insulin signalling are modulated within ENS by the recruitment of cellular substrates to ENS; intra-endosomal acidification, which promotes dissociation of insulin from the IRK; an endosomal acidic insulinase, which degrades intra-endosomal insulin; and IRK-associated PTPs, which dephosphorylate and, hence, deactivate the IRK. Therefore, the internalization of IRKs is central to insulin signalling and its regulation.
Topics: Animals; Diabetes Mellitus; Endothelium, Vascular; Humans; Insulin; Receptor, Insulin; Signal Transduction
PubMed: 27614806
DOI: 10.1016/j.jcjd.2016.07.002 -
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 -
Molecular Metabolism Oct 2021Insulin's discovery 100 years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor.... (Review)
Review
BACKGROUND
Insulin's discovery 100 years ago and its ongoing use since that time to treat diabetes belies the molecular complexity of its structure and that of its receptor. Advances in single-particle cryo-electron microscopy have over the past three years revolutionized our understanding of the atomic detail of insulin-receptor interactions.
SCOPE OF REVIEW
This review describes the three-dimensional structure of insulin and its receptor and details on how they interact. This review also highlights the current gaps in our structural understanding of the system.
MAJOR CONCLUSIONS
A near-complete picture has been obtained of the hormone receptor interactions, providing new insights into the kinetics of the interactions and necessitating a revision of the extant two-site cross-linking model of hormone receptor engagement. How insulin initially engages the receptor and the receptor's traversed trajectory as it undergoes conformational changes associated with activation remain areas for future investigation.
Topics: Amino Acid Sequence; Animals; Cryoelectron Microscopy; Crystallography, X-Ray; Humans; Insulin; Protein Multimerization; Protein Structure, Tertiary; Receptor, Insulin
PubMed: 33992784
DOI: 10.1016/j.molmet.2021.101255 -
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 -
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 -
Journal of Traditional Chinese Medicine... Apr 2014Insulin is involved in regulation of glucose utilization in the body. Inability of the body to synthesize insulin of human cells resistance to insulin leads to a... (Review)
Review
Insulin is involved in regulation of glucose utilization in the body. Inability of the body to synthesize insulin of human cells resistance to insulin leads to a condition called Diabetes mellitus which is characterized by chronic hyperglycaemia. There are two types of diabetes; type 1 and type 2. Exogenous supply of insulin is needed consistently for type 1 diabetes treatment and type 2 diabetes also needs to be cured by the exogenous supply of insulin in advance stages of the disease. These sources have been proved very useful to meet the needs of the patients. However, these insulin types are expensive for the large population of patients in the developing countries. Furthermore, the incidence of diabetes is advancing at an alarming rate. Hence production systems with even higher capabilities of production are desired. Therefore, currently plants are being investigated as alternative production systems. Based on the mode of action of insulin various formulations of insulin have been developed that have different onset of action, peak effect and duration of action according to the needs of the patients.
Topics: Animals; Biotechnology; Diabetes Mellitus; Gene Expression; Humans; Insulin; Plants
PubMed: 24783939
DOI: 10.1016/s0254-6272(14)60084-4 -
Cellular and Molecular Gastroenterology... 2019Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally... (Review)
Review
Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin's control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway.
Topics: Animals; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Liver; Models, Biological; Signal Transduction
PubMed: 30739869
DOI: 10.1016/j.jcmgh.2018.10.016 -
The Journal of Clinical Endocrinology... Mar 2022Design of "first-generation" insulin analogues over the past 3 decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic... (Review)
Review
Design of "first-generation" insulin analogues over the past 3 decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool kit-integrating protein sequence, chemical modification, and formulation-has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultrarapid and ultrabasal analogue formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogues seek to exploit therapeutic mechanisms: glucose-responsive ("smart") analogues, pathway-specific ("biased") analogues, and organ-targeted analogues. Smart insulin analogues and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogues may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will affect use and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale, and potential clinical applications.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Goals; Humans; Hypoglycemic Agents; Insulin; Insulins
PubMed: 34850005
DOI: 10.1210/clinem/dgab849