The discovery of insulin revisited: lessons for the modern era

Lewis, Gary F.; Brubaker, Patricia L.

doi:10.1172/jci142239

Cited by 56 publications

(42 citation statements)

References 38 publications

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“…It should be pointed out, however, that much of what we know about insulin action comes from studies that used the dog model, with the most noteworthy being the work of Banting and Macleod, whose discovery of insulin led to the Nobel Prize in Physiology or Medicine in 1923 (for a review, see ref. 67 ). Since that time, use of the dog model has continued to provide a portal into how HGP is regulated by the pancreatic hormones because of the remarkable similarity of this interaction to that seen in humans ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Moore¹,

Warner²,

Dai³

et al. 2021

JCI Insight

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Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5m/4f). After a 2 hr basal period, an IV-infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hrs. At the same time, an IVinfusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hrs, but the glucose was allowed to fall to ~50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL, but remained unchanged from basal in CPEP. During hypoglycemia, glucagon secretion in CPEP was two times higher than SAL, which increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia, and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Moore¹,

Warner²,

Dai³

et al. 2021

JCI Insight

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“…Insulin, the first protein with a known sequence [ 44 ] (for review, see [ 45 , 46 ]), also played a distinguished role in the history of protein crystallography. J.J. Abel's crystallization of zinc-free insulin in 1926 (the second protein to be crystallized after urease [ 47 ]), extended by Scott in 1934 to include zinc ions [ 48 ], set the stage for large-scale use of insulin crystallization in the pharmaceutical purification of animal insulins [ 49 ]. Additionally, x-ray diffraction studies of insulin crystals were undertaken by D. Crowfoot Hodgkin [ 50 ], who began in 1935 as a doctoral student at Cambridge University U.K. under the guidance of Prof. J.D.…”

Section: Insulin Hexamer and Mode Of Assemblymentioning

confidence: 99%

Structural principles of insulin formulation and analog design: A century of innovation

Jarosinski

Dhayalan

Chen

et al. 2021

Molecular Metabolism

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Background The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Scope of review Pioneering crystallographic analyses—beginning with Hodgkin's solving of the 2-Zn insulin hexamer—elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. Major conclusions Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.

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“…Frederick G. Banting made a breakthrough and landmark achievement in the discovery of insulin ( Fig. 2 ) [ 11 , 12 ]. Returning from World War 1 and after working at the Toronto Military Orthopaedic Hospital, Banting established his private clinic in London, ON, Canada.…”

Section: The History Of Insulin Discoverymentioning

confidence: 99%

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

Lee

Yoon

2021

Diabetes Metab J

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The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances in medical science. A rapid bench-to-bedside application of the lifesaving pancreatic extract and its immediate commercialization was the result of a promising idea, positive drive, perseverance, and collaboration of Banting and colleagues. As one of the very few proteins isolated in a pure form at that time, insulin also played a key role in the development of important methodologies and in the beginning of various fields of modern science. Since its discovery, insulin has evolved continuously to optimize the care of people with diabetes. Since the 1980s, recombinant DNA technology has been employed to engineer insulin analogs by modifying their amino acid sequence, which has resulted in the production of insulins with various profiles that are currently used. However, unmet needs in insulin treatment still exist, and several forms of future insulins are under development. In this review, we discuss the past, present, and future of insulin, including a history of ceaseless innovations and collective intelligence. We believe that this story will be a solid foundation and an unerring guide for the future.

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The discovery of insulin revisited: lessons for the modern era

Cited by 56 publications

References 38 publications

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Structural principles of insulin formulation and analog design: A century of innovation

A Century of Progress in Diabetes Care with Insulin: A History of Innovations and Foundation for the Future

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