International Journal of Molecular Sciences Review Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks Melanie Leroux, Martial Boutchueng-Djidjou and Robert Faure * Centre de Recherche du CHU de Québec and Département de Pédiatrie, Faculté de Médecine, Université Laval, Québec, QC G1V4G2, Canada; [email protected] (M.L.); [email protected] (M.B.-D.) * Correspondence: [email protected] Abstract: In 2021, the 100th anniversary of the isolation of insulin and the rescue of a child with type 1 diabetes from death will be marked. In this review, we highlight advances since the ingenious work of the four discoverers, Frederick Grant Banting, John James Rickard Macleod, James Bertram Collip and Charles Herbert Best. Macleoad closed his Nobel Lecture speech by raising the question of the mechanism of insulin action in the body. This challenge attracted many investigators, and the question remained unanswered until the third part of the 20th century. We summarize what has been learned, from the discovery of cell surface receptors, insulin action, and clearance, to network and precision medicine. Keywords: insulin; hundredth anniversary Citation: Leroux, M.; Boutchueng-Djidjou, M.; Faure, R. Insulin’s Discovery: New Insights on 1. Introduction Its Hundredth Birthday: From Insulin The purification of insulin by the Toronto “Fab Four”, leading to the rescue of hu- Action and Clearance to Sweet mans dying from diabetes, is one of the most dramatic examples of translational research, Networks. Int. J. Mol. Sci. 2021, 22, providing inspiration for us all. Banting, a practicing surgeon in Toronto, was inspired in 1030. https://doi.org/10.3390/ October 1920 by reading an article related to pancreatic lithiasis, the islets of Langerhans ijms22031030 and diabetes [1], and he explained his idea to Macleod in November 1920. After reviewing the experimental protocol and bypassing the pancreatic duct ligation step to preserve the Academic Editor: Sonia islets, they started experiments with a student, Charles Best, in Macleod’s lab in May 1921. Michael Najjar, Amalia Gastaldelli, After several wrong turns, they invited Collip, a young professor from the University of Hilda E. Ghadieh Alberta on sabbatical leave in the laboratory of Macleod, who brought with him a new Received: 5 January 2021 technique called chromatography, to join the group. Within weeks, Collip and Best devel- Accepted: 19 January 2021 oped a robust purification protocol to purify insulin from crude extracts. They successfully Published: 21 January 2021 delivered purified insulin to the first patient, Leonard Thompson, on 23 January 1922, 15 months after the initial idea and 8 months from the onset of experiments [2–5]. They Publisher’s Note: MDPI stays neutral were awarded the Nobel Prize in October 1923 (Figure1). In medical research, the ultimate with regard to jurisdictional claims in published maps and institutional affil- goal is to have a practical application introduced rapidly after the relevant basic science iations. discovery. Albeit unachievable now—that was translation! One hundred years later, we have learned that insulin is not fully restorative [6]; many patients on insulin suffer complications, and strict attention to a dietary program is essential. Normalized insulin remains the mainstay for treating type 1 diabetes (T1D) [7]. It was discovered that diabetes is a leading cause of morbidity and mortality, with type Copyright: © 2021 by the authors. 2 diabetes (T2D) accounting for more than 90% of cases [8]. Insulin is also prescribed for Licensee MDPI, Basel, Switzerland. patients with T2D who are not achieving adequate control of hyperglycemia with drugs, This article is an open access article distributed under the terms and such as Metformin and other interventions [9]. Insulin is used for the control of gestational conditions of the Creative Commons diabetes [10]. It is used to reduce transient hyperglycemia, which in nondiabetic patients Attribution (CC BY) license (https:// can accompany acute medical situations [7]. The idea of a strong hereditary component creativecommons.org/licenses/by/ in both T1D and T2D became well established. Approximately 40% of the variance in 4.0/). T2D is due to genetics [11,12], with an association between parental history deriving Int. J. Mol. Sci. 2021, 22, 1030. https://doi.org/10.3390/ijms22031030 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 12 Int. J. Mol. Sci. 2021, 22, 1030 2 of 12 is due to genetics [11,12], with an association between parental history deriving from in- heritedfrom inherited traits but traits also butenvironmental also environmental factors [13] factors. The [ 13genetic]. The analysis genetic analysisof large cohorts, of large mainlycohorts, originating mainly originating from genome from wide genome association wide association (GWAS) (GWAS)data, complemented data, complemented by anal- ysesby analyses of exome of- and exome- genome and genomesequence sequence data, has data, raised has questions raised questions concerning concerning the “missing the “missingheritability” heritability” and the biological and the biological space occupied space occupied by numerous by numerous common common variants, variants, with a smallwith acausality small causality dispersed dispersed throughout throughout the human the human genome genome and andmany many of them of them located located in regulatoryin regulatory intronic intronic areas areas [14 [–1417]–17. ]. Figure 1. The Nobel Prize certificate to Banting and Macleod signed by the 21 members of the Nobel Prize committee. Figure 1. The Nobel Prize certificate to Banting and Macleod signed by the 21 members of the Nobel Prize committee. From From the Nobel Foundation. In his 1925 Nobel Lecture, Macleod closed by raising the question—what is the mechanism the Nobel Foundation. In his 1925 Nobel Lecture, Macleod closed by raising the question—what is the mechanism of insulin of insulin action in the body? action in the body? Because all cellular processes involve scale-free networks, their study at a network Because all cellular processes involve scale-free networks, their study at a network level has been an important recent focus in cell biology and medicine and can be used to level has been an important recent focus in cell biology and medicine and can be used understandto understand the thegenotype/phenotype genotype/phenotype relationship relationship [18– [2018]–. In20 ].2007, In 2007, the first the diseasome first diseasome con- structedconstructed by the by themathematician mathematician Albert Albert Barabasi Barabasi from from the theOnline Online Mendelian Mendelian Inheritance Inheritance in Manin Man database database (OMIM) (OMIM) showed showed that that T2D T2D occupies occupies a central a central hub hub[21]. [In21 ].2018, In 2018, the first the T2D first Int. J. Mol. Sci. 2021, 22, 1030 3 of 12 T2D physical protein–protein interactions network (PPIN), constructed from validated variants, termed diabetes protomodule, displayed the proteins’ hepatic nuclear factors HNF4A and HNF1A as central nodes [22] (Figure2). The HNF1A variant identified by whole-exome sequencing in a homogeneous Latino cohort is an example of a rare variant with a high causality at a population level [23]. SLC2A2 INSR E2F3 ESR1 GRB14 BCL2 ATIC CDK2 FUBP1 Type 2 diabetes Type 1 diabetes HMGA1 BMI/Lipids/Obesity HNF4A INSR Candidates DDX39B Multiple diabetes factors ATIC CDK2 ADIPOQ TNXB PEAK1 ZNRD1 TAF11 DMXL2 PRKD2 NELFE PTPRD VPS33B CDH13 SPOCK1 E2F3 GTF2H4 TYK2 MTNR1B AP1S1 CD74 ITPR3 AP1G1 KLF11 ATP2A1 FOXA2 RARB PCSK9 LTA TCF7L2 HLA-DMA TNF MTCH2 HLA-DQA2 HIST1H2BF CAPN10 BDNF SLC2A2 HLA-DQA1 KIAA1671 AVP AVPR2 DDX39B SEC24A HLA-DQB2 HNF1B KNG1 RPTOR HLA-DRA FUBP1 PTPN1 ATIC PPARGC1B HLA-DPB1 GPANK1 PROX1 ANK1 ITPR1 NISCH CAPZB FLOT1 FLOT1 PTPLAD1 AP1B1 SLC2A2 HLA-F MADD CLTC LDLR DNAJC6 BTN2A1 AKR1C2 NCAM2 TCF19 POU5F1 NUDT3 SEC31A NTRK2 SHP1 HIP1 HLA-C FAM13A EHMT2 FAF1 FHIT BCL2 IRS2 DDR1 ATP2A2 AP2M1 IRS2 SEC24C C2 IGF1R SEC61A1 HLA-DMA APOM GRB14 SEC23A AP4B1 HNF1A GRB14 B2M AP1M1 APOA4 HLA-DOB MRPL33 ITIH4 TP53BP2 INSR KRT6A HLA-DQA1 PTPRO FOXO3 FOXO3 SCARB1 APOB IRS1 PTPN1 ADCY3 AGPAT1 CEACAM1 GNB4 E2F3 ESR1 IGF1R SLC25A5 ALB GPANK1 IGF1 MACROD1 PTPRF CAV1 PHB2 APOC2 IRS1 ALDH2 BCL3 KCNMA1 HLA-DRA HLA-DQA2 HNF1B PDIA3 ESR1 APOC1 CTNNB1 ADRB2 HLA-DQB2 TBL2 LEPR SH2B1 HNF4A MAP2K5 ENPP1 SDC1 DDX39B NR0B2 INSR BLK VPS45 MTNR1B MAEA DDR1 MAP2K5 BAG6 NSF APOE KANK1 AHSG GABBR1 CFB FUBP1 INS HNF1A HLA-DOA CCNE1 CREBBP RAP1A SDC3 HLA-DPB1 ABCF1 IGF2 BCL2 HPX TF FHIT CDKAL1 GNAT2 GRK5 GBE1 NCK2 TCF4 CDK2 APOA1 GCKR HMGA2 GAPDH FGA HIST1H3B BAG6 GDF5 SND1 MTHFD1 ADCY3 LEP HNF4A BCL3 HLA-B KRT16 LRIG1 ABCG8 KLF11 RBMS1 GNAI2 OAS1 HMGA1 NEUROD1 ACTB FLNA TTN AKT2 PROX1 EP300 GNAI3 HMGA1 AKT2 PLTP SH2B3 CFB QPCTL ERBB3 NCL ITGA4 KCNMA1 ERBB3 TOMM40 GTPBP4 PPARG LRIG1 ERBB4 VTN IDE KNG1 GCK CLIP1 FAF1 JAZF1 POMC RAC1 C3 PARK2 RAB7A STAT1 GOLGA2 COPB1 POU5F1 GPD2 SNX3 APOC1 PEPD TMED10 LYRM4 RHOA TMED2 IGF1 GABBR1 HLA-B KIF11 PA2G4 ADRB2 COPZ1 NR0B2 AVPR2 ACSL1 APOB COPA TCF19 DAB1 SEC22B RAB1B HLA-F TUBB SPTAN1 GHRL HMGA2 ARCN1 POLR2A APOE IFIH1 KIF5A INS APOA5 GOSR1 C2 COPE OAS1 ANK1 PLTP TCF4 GTF2H4 GBF1 SDC3 AVP MAGI3 HLA-C NECTIN2 PPP1R18 KIF11 HIP1 HSD17B12 CCDC93 MRAP2 CD226 COPG1 SCARB1 TAP2 ADRB3 SURF4 LDLR BCL2L15 NELFE GOSR2 TMED9 FTO VARS MC3R KDELR1 TMED7 RAB5B TAP1 RNF5 LPL NEUROD1 RABEP1 LIPC GNAT2 AGRP TAL1 SGF29 TRIM26 PCSK9 SCARB2 POMC RABEP2 PSMB8 MC4R ZZZ3 CETP ABHD16A Hybrid module Diabetes protomodule Figure 2. Diabetes-associated genes form a protomodule. 184 genes at risk of T2D are here validated in a single component proteins–proteins interaction network of 309 iterations called protomodule. The general topology of the protomodule is characteristic of a disease network with the presence of few central hubs of a large size, surrounded by numerous peripheral hubs of a smaller size.