FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3208068721> ?p ?o ?g. }

• W3208068721 endingPage "100132" @default.
• W3208068721 startingPage "100132" @default.
• W3208068721 abstract "A hundred years ago, Frederick Banting and Charles Best, in the laboratory of John MacLeod at the University of Toronto, performed a historic experiment demonstrating that an extract from pancreata in which the pancreatic ducts had been ligated to allow isolation of the “internal secretion” lowered blood glucose in dogs. This experiment broke ground for a fertile field that now extends into essentially all branches of physiology, endocrinology, biochemistry, cell biology, genetics, and molecular biology. This centennial is being celebrated by the retelling of this extraordinary story and the research triumphs that mark the trajectory to the present. Several journals have already paid tribute to these events (1Sims E.K. Carr A.L.J. Oram R.A. DiMeglio L.A. Evans-Molina C. 100 years of insulin: Celebrating the past, present and future of diabetes therapy.Nat. Med. 2021; 27: 1154-1164Crossref PubMed Scopus (4) Google Scholar, 2Fralick M. Zinman B. The discovery of insulin in Toronto: Beginning a 100 year journey of research and clinical achievement.Diabetologia. 2021; 64: 947-953Crossref PubMed Scopus (8) Google Scholar, 3Lewis G.F. Brubaker P.L. The discovery of insulin revisited: Lessons for the modern era.J. Clin. Invest. 2021; 131e142239Crossref PubMed Scopus (5) Google Scholar, 4White M.F. Kahn C.R. Insulin action at a molecular level - 100 years of progress.Mol. Metab. 2021; 52: 101304Crossref PubMed Scopus (1) Google Scholar, 5Kahn C.R. 100 Years of progress in understanding insulin, its mechanism of action, and its roles in disease and diabetes therapy.Mol. Metab. 2021; 52: 101318Crossref PubMed Scopus (0) Google Scholar). We wish to highlight the role of our two ASBMB journals, The Journal of Biological Chemistry and The Journal of Lipid Research in publishing impactful biochemical studies in this field. We have selected 27 articles for republication. The choice of so few articles from a vast literature was very difficult and somewhat arbitrary, but it allows us to highlight a subset of the many great discoveries that advanced our understanding of insulin and to recognize the remarkable insights of early pioneers of this field. Many of the most important articles in the field were published in other journals and are therefore not included in this series. What comes across in reading the earlier publications in this field is how prescient were the insights and speculations of the brilliant scientists who launched and advanced this field. In threading together these stories, we have gained a new appreciation of the hard work, zealous dedication, and brilliant insights of the scientists involved in this quest. Although diabetes is principally defined by hyperglycemia, the role of lipids in diabetes has been a dominant theme in this field and we point to several highlights in this story. With the realization that a substance produced in the pancreas is capable of lowering blood glucose and is likely missing in people with diabetes, it became critical to purify and identify this substance. The first purification of insulin, from the cow pancreas, was performed by the Canadian biochemist James Collip and was used to treat the first human patient with diabetes, Leonard Thompson, in 1922. American scientists were also working on purifying insulin. The first article on insulin that was published in the JBC is a study of precipitation methods by Kimball and Murlin in 1923 (6Kimball C.P. Murlin J.R. Aqueous extracts of pancreas. 3. Some precipitation reactions of insulin.J. Biol. Chem. 1923; 58: 337-348Abstract Full Text PDF Google Scholar). They tested a series of alcohols, acetone, ether, toluene, xylene, trichloroacetic acid, and several salts. The method was to centrifuge the precipitate, resuspend in water, and immediately inject into rabbits. What is most remarkable about the article is how inconclusive it was regarding insulin’s properties. It did not promote any one precipitation method and ended by saying, “With regard to the properties of insulin as it has been observed in this laboratory, not much can be said. It is a white, amorphous powder probably insoluble in neutral water when pure. It gives no protein reactions of any kind, and the most potent that have been analyzed have had a low nitrogen content, 4 to 6% dry weight.” The real significance of that article (6Kimball C.P. Murlin J.R. Aqueous extracts of pancreas. 3. Some precipitation reactions of insulin.J. Biol. Chem. 1923; 58: 337-348Abstract Full Text PDF Google Scholar) by Kimball and Murlin, however, was the discovery of glucagon, which they described as a “hyperglycemic substance” in the pancreatic extracts used to purify insulin. Patients with diabetes went on to be treated with insulin purified from cattle or pigs. However, with the development of a radioimmunoassay by Rosalyn Yalow and Solomon Berson (7Yalow R.S. Berson S.A. Reaction of fish insulins with human insulin antiserums. Potential value in the treatment of insulin resistance.N. Engl. J. Med. 1964; 270: 1171-1178Crossref PubMed Google Scholar), it became clear that many patients developed antibodies against bovine and porcine insulin, making it less effective with time. Human insulin was not to become available until late in the 1970s, when the first genetically engineered insulin was produced in Escherichia coli by scientists at Genentech (8Goeddel D.V. Kleid D.G. Bolivar F. Heyneker H.L. Yansura D.G. Crea R. Hirose T. Kraszewski A. Itakura K. Riggs A.D. Expression in Escherichia coli of chemically synthesized genes for human insulin.Proc. Natl. Acad. Sci. U. S. A. 1979; 76: 106-110Crossref PubMed Scopus (532) Google Scholar). Rosalyn Yalow became the second woman to receive the Nobel Prize in Physiology or Medicine for her work. The first was Gerty Cori (see below). Berson and Yalow quickly realized that patients with type 2 diabetes were most often not insulin-deficient and in fact many had hyperinsulinemia. They anticipated the intense focus on insulin resistance in this field with this comment in their famous publication describing the insulin radioimmunoassay (9Yalow R.S. Berson S.A. Immunoassay of endogenous plasma insulin in man.J. Clin. Invest. 1960; 39: 1157-1175Crossref PubMed Google Scholar): “appreciation of the lack of responsiveness of blood sugar, in the face of apparently adequate amounts of insulin secreted by early maturity-onset diabetic subjects, is obviously of importance in the interpretation of the pathogenesis of this type of diabetes. However, the data at hand can only indicate that absolute insulin deficiency per se is not the cause of the hyperglycemia and suggest other possibilities that merit investigation, namely (1) abnormal tissues with a high threshold for the action of insulin; (2) an abnormal insulin that acts poorly with respect to hormonal activity in vivo but reacts well immunologically in vitro; (3) an abnormally rapid inactivation of hormonally active sites … but not of immunologically active sites on the insulin molecules; and (4) the presence of insulin antagonists. The last suggestion has been made many times by previous workers. A joint attack on the problem, utilizing both the specific immunoassay for plasma insulin and an assay method that measures the net biological effect of insulin and its inhibitors would seem to be indicated.” A pioneer in the study of post-translational processing of insulin was Don Steiner. He narrates this story in a lovingly written JBC article, published in 2011 (10Steiner D.F. Adventures with insulin in the islets of Langerhans.J. Biol. Chem. 2011; 286: 17399-17421Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). The determination of the sequence and structure of insulin by Fred Sanger in 1955 (11Ryle A.P. Sanger F. Smith L.F. Kitai R. The disulphide bonds of insulin.Biochem. J. 1955; 60: 541-556Crossref PubMed Google Scholar) (who received two Nobel Prizes for his work on protein and DNA sequencing) begged the question, are the two chains of the insulin molecule derived from a common precursor? In 1967, Don Steiner published his seminal discovery, through protein purification and pulse-chase experiments in isolated islets, of a precursor to insulin, proinsulin (12Steiner D.F. Cunningham D. Spigelman L. Aten B. Insulin biosynthesis: Evidence for a precursor.Science. 1967; 157: 697-700Crossref PubMed Google Scholar). Proinsulin consists of the insulin A and B chains connected by a peptide (C-peptide), which is cleaved off in the secretory granules before secretion of mature insulin. Steiner also recognized the utility of the C-peptide as a quantifiable marker of insulin production and β-cell function, and developed its assay in 1970 (13Melani F. Rubenstein A.H. Oyer P.E. Steiner D.F. Identification of proinsulin and C-peptide in human serum by a specific immunoassay.Proc. Natl. Acad. Sci. U. S. A. 1970; 67: 148-155Crossref PubMed Google Scholar). Steiner went on to discover several of the enzymes that process proinsulin to mature insulin. This work has had a profound impact on cell biology and endocrinology because many protein hormones, clotting factors, growth factors, receptors, and even serum albumin are synthesized as a precursor with a propeptide that is removed during its transport through the secretory pathway. The 3D structure of mature porcine insulin was solved by Dorothy Hodgkin (14Blundell T.L. Cutfield J.F. Cutfield S.M. Dodson E.J. Dodson G.G. Hodgkin D.C. Mercola D.A. Vijayan M. Atomic positions in rhombohedral 2-zinc insulin crystals.Nature. 1971; 231: 506-511Crossref PubMed Scopus (263) Google Scholar), who had applied X-ray crystallography to reveal 3D structures of several other molecules before that. She was awarded the Nobel Prize in Chemistry in 1964 for her discoveries. Not surprisingly, the 3D structure of insulin is critical for its biological activities. Graeme Bell reported in 2007 that mutations in the insulin gene that cause abnormalities in insulin maturation and folding cause diabetes (15Stoy J. Edghill E.L. Flanagan S.E. Ye H. Paz V.P. Pluzhnikov A. Below J.E. Hayes M.G. Cox N.J. Lipkind G.M. Lipton R.B. Greeley S.A. Patch A.M. Ellard S. Steiner D.F. et al.Insulin gene mutations as a cause of permanent neonatal diabetes.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 15040-15044Crossref PubMed Scopus (403) Google Scholar). Protein misfolding activates a transcriptional program, the unfolded protein response, which can ultimately lead to cell death and is now recognized as a major cause of diseases caused by missense mutations in proteins, ranging from neurological diseases to metabolic diseases. Jeremy Thorner’s discovery of the yeast protease that processes the yeast mating factor, Kex2p, led to the discovery of the convertases that process proinsulin and proglucagon (16Smeekens S.P. Avruch A.S. LaMendola J. Chan S.J. Steiner D.F. Identification of a cDNA encoding a second putative prohormone convertase related to PC2 in AtT20 cells and islets of Langerhans.Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 340-344Crossref PubMed Scopus (388) Google Scholar) and then to an entire family of proprotein convertases (17Julius D. Brake A. Blair L. Kunisawa R. Thorner J. Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor.Cell. 1984; 37: 1075-1089Abstract Full Text PDF PubMed Scopus (480) Google Scholar). Many endocrine disorders and some obesity syndromes are caused by mutations in these enzymes. Thus, the discovery of processing of proinsulin to insulin spurred a number of seminal subsequent discoveries. The pathways that link glucose sensing with insulin secretion have been at the heart of islet biology for decades. A milestone in the field was the 1984 discovery by Frances and Stephen Ashcroft at the University of Oxford that ATP-sensitive potassium (KATP) channels link ATP generation to insulin secretion (18Ashcroft F.M. Harrison D.E. Ashcroft S.J. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells.Nature. 1984; 312: 446-448Crossref PubMed Google Scholar). Metabolism of glucose in the β-cell leads to a rise in ATP, the closure of the KATP channel, and the activation of voltage-gated Ca2+ channels, leading to Ca2+ influx and insulin secretion. The KATP channel is an octamer consisting of two proteins, Kir6.1 (KCNJ11) or Kir6.2 and the sulfonylurea receptor, SUR1 (ABCC8) or SUR2. Loss-of-function mutations in SUR1 or less commonly, KCNJ11, lead to hyperinsulinism (19Huopio H. Reimann F. Ashfield R. Komulainen J. Lenko H.L. Rahier J. Vauhkonen I. Kere J. Laakso M. Ashcroft F. Otonkoski T. Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.J. Clin. Invest. 2000; 106: 897-906Crossref PubMed Google Scholar), whereas mutations in KCNJ11 that decrease ATP inhibition of KATP cause neonatal permanent neonatal diabetes (20Gloyn A.L. Pearson E.R. Antcliff J.F. Proks P. Bruining G.J. Slingerland A.S. Howard N. Srinivasan S. Silva J.M. Molnes J. Edghill E.L. Frayling T.M. Temple I.K. Mackay D. Shield J.P. et al.Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.N. Engl. J. Med. 2004; 350: 1838-1849Crossref PubMed Scopus (932) Google Scholar). Glucokinase plays a role in glucose sensing in the liver and β-cells. In the liver, glucokinase expression is regulated by insulin, and its abundance determines the capacity of the liver to metabolize glucose, which, unlike the muscle and adipose tissue, is rate-limiting for its uptake. Matschinsky and Ellerman discovered in 1968 that glucokinase is present in β-cells (21Matschinsky F.M. Ellerman J.E. Metabolism of glucose in the islets of Langerhans.J. Biol. Chem. 1968; 243: 2730-2736Abstract Full Text PDF PubMed Google Scholar). The discovery of genes causing monogenic dominantly inherited diabetes syndromes, termed maturity-onset diabetes of the young, provided valuable mechanistic information about β-cell biology (22Fajans S.S. Bell G.I. MODY: History, genetics, pathophysiology, and clinical decision making.Diabetes Care. 2011; 34: 1878-1884Crossref PubMed Scopus (185) Google Scholar). Specifically, loss-of-function mutations in glucokinase lead to diabetes (23Gloyn A.L. Odili S. Zelent D. Buettger C. Castleden H.A. Steele A.M. Stride A. Shiota C. Magnuson M.A. Lorini R. d'Annunzio G. Stanley C.A. Kwagh J. van Schaftingen E. Veiga-da-Cunha M. et al.Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.J. Biol. Chem. 2005; 280: 14105-14113Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar), whereas the rarer gain-of-function mutants cause hyperinsulinism (24Beer N.L. van de Bunt M. Colclough K. Lukacs C. Arundel P. Chik C.L. Grimsby J. Ellard S. Gloyn A.L. Discovery of a novel site regulating glucokinase activity following characterization of a new mutation causing hyperinsulinemic hypoglycemia in humans.J. Biol. Chem. 2011; 286: 19118-19126Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). This supports the role of glucokinase as a β-cell glucose sensor that determines the capacity of the β-cell to take up glucose and oxidize it in the glycolytic pathway and led to the development of glucokinase activators as a potential treatment for diabetes (25Matschinsky F.M. GKAs for diabetes therapy: Why no clinically useful drug after two decades of trying?.Trends Pharmacol. Sci. 2013; 34: 90-99Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Other maturity-onset diabetes of the young genes include transcription factors that play roles in β-cell development and in the function of the adult β-cell. Although glucose is the best-studied insulin secretagogue, amino acids can also stimulate insulin secretion. Gain-of-function mutations in glutamate dehydrogenase cause excessive amino acid–induced insulin secretion (26Li C. Najafi H. Daikhin Y. Nissim I.B. Collins H.W. Yudkoff M. Matschinsky F.M. Stanley C.A. Regulation of leucine-stimulated insulin secretion and glutamine metabolism in isolated rat islets.J. Biol. Chem. 2003; 278: 2853-2858Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). The product of glutamate dehydrogenase is mitochondrial α-ketoglutarate, raising the question how this metabolite could signal insulin secretion. An important clue came from the discovery that β-cells have an abundance of mitochondrial phosphoenolpyruvate carboxykinase, encoded by the PCK2 gene. Deletion of the gene in mice leads to a severe defect in insulin secretion (27Stark R. Pasquel F. Turcu A. Pongratz R.L. Roden M. Cline G.W. Shulman G.I. Kibbey R.G. Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion.J. Biol. Chem. 2009; 284: 26578-26590Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar) as shown by Richard Kibbey’s laboratory at Yale University. Subsequent studies have proposed that formation of phosphoenolpyruvate promotes cycling through the pyruvate kinase reaction and this is intimately connected with the closure of the ATP channel (28Abulizi A. Cardone R.L. Stark R. Lewandowski S.L. Zhao X. Hillion J. Ma L. Sehgal R. Alves T.C. Thomas C. Kung C. Wang B. Siebel S. Andrews Z.B. Mason G.F. et al.Multi-tissue acceleration of the mitochondrial phosphoenolpyruvate cycle improves whole-body metabolic health.Cell Metab. 2020; 32: 751-766.e11Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 29Lewandowski S.L. Cardone R.L. Foster H.R. Ho T. Potapenko E. Poudel C. VanDeusen H.R. Sdao S.M. Alves T.C. Zhao X. Capozzi M.E. de Souza A.H. Jahan I. Thomas C.J. Nunemaker C.S. et al.Pyruvate kinase controls signal strength in the insulin secretory pathway.Cell Metab. 2020; 32: 736-750.e5Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Unlike most other cell types, pyruvate metabolism in β-cell mitochondria partitions fairly equally between the anaplerotic route (pyruvate carboxylase) and the oxidative route (pyruvate dehydrogenase), as demonstrated by Schuit and colleagues (30Schuit F. De Vos A. Farfari S. Moens K. Pipeleers D. Brun T. Prentki M. Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in beta cells.J. Biol. Chem. 1997; 272: 18572-18579Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar). Much of the product, citrate and/or isocitrate, exit the mitochondria. As in other cell types, malonyl-CoA gates fatty acid entry into the mitochondria and subsequent β-oxidation by inhibiting carnitine palmitoyl transferase-1. Cytosolic citrate gives rise to acetyl-CoA and then malonyl-CoA. Cytosolic isocitrate can be oxidized to α-ketoglutarate, giving rise to reducing equivalents in the form of NADPH. NADPH has been suggested to play a role in amplifying insulin secretion. One pathway, proposed by Newgard and MacDonald, suggests that isocitrate dehydrogenase-2 in the cytosol produces NADPH, which reduces glutathione, and this activates the de-SUMOylating enzyme sentrin/SUMO-specific protease-1, which has as its substrate tomosyn-1, which regulates syntaxin 1A during insulin exocytosis (31Ferdaoussi M. Dai X. Jensen M.V. Wang R. Peterson B.S. Huang C. Ilkayeva O. Smith N. Miller N. Hajmrle C. Spigelman A.F. Wright R.C. Plummer G. Suzuki K. Mackay J.P. et al.Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells.J. Clin. Invest. 2015; 125: 3847-3860Crossref PubMed Scopus (96) Google Scholar, 32Ferdaoussi M. Fu J. Dai X. Manning Fox J.E. Suzuki K. Smith N. Plummer G. MacDonald P.E. SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells.Sci. Rep. 2017; 7: 248Crossref PubMed Scopus (0) Google Scholar). Fatty acids amplify insulin secretion. Blocking fatty acid oxidation enhances insulin secretion. Prentki has proposed a model whereby monoglycerides, primarily derived from hydrolysis of triglycerides, bind to Muc18 and stimulate insulin exocytosis (33Zhao S. Mugabo Y. Iglesias J. Xie L. Delghingaro-Augusto V. Lussier R. Peyot M.L. Joly E. Taïb B. Davis M.A. Brown J.M. Abousalham A. Gaisano H. Madiraju S.R. Prentki M. α/β-Hydrolase domain-6-accessible monoacylglycerol controls glucose-stimulated insulin secretion.Cell Metab. 2014; 19: 993-1007Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Fatty acids also bind to a G-protein–coupled receptor, FFA1/Gpr40, which may amplify insulin secretion through an independent route (34Briscoe C.P. Tadayyon M. Andrews J.L. Benson W.G. Chambers J.K. Eilert M.M. Ellis C. Elshourbagy N.A. Goetz A.S. Minnick D.T. Murdock P.R. Sauls Jr., H.R. Shabon U. Spinage L.D. Strum J.C. et al.The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids.J. Biol. Chem. 2003; 278: 11303-11311Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar). Beginning as early as 1902, it was postulated that the intestine produces factors that lower blood glucose. This was refined into the term “incretin” by La Barre in 1932 and was followed by numerous studies with intestinal extracts, which supported and then failed to support the role of an intestinal extract in glucose regulation (reviewed in (35Creutzfeldt W. The [pre-] history of the incretin concept.Regul. Pept. 2005; 128: 87-91Crossref PubMed Scopus (78) Google Scholar)). The development of the insulin radioimmunoassay by Yalow and Berson facilitated the search for incretins by directly measuring insulin secretion. The incretin concept was proposed in 1964 based on the observation of a much greater insulin response to an oral glucose than an intravenous glucose challenge (36Elrick H. Stimmler L. Hlad Jr., C.J. Arai Y. Plasma insulin response to oral and intravenous glucose administration.J. Clin. Endocrinol. Metab. 1964; 24: 1076-1082Crossref PubMed Google Scholar, 37McIntyre N. Holdsworth C.D. Turner D.S. New interpretation of oral glucose tolerance.Lancet. 1964; 2: 20-21Abstract PubMed Google Scholar). The first incretin hormone to be purified was glucose-dependent insulinotropic polypeptide, and its action in humans was first demonstrated in 1973 (38Dupre J. Ross S.A. Watson D. Brown J.C. Stimulation of insulin secretion by gastric inhibitory polypeptide in man.J. Clin. Endocrinol. Metab. 1973; 37: 826-828Crossref PubMed Google Scholar). The mammalian preproglucagon cDNA was cloned in 1983 by Graeme Bell. He showed that the gene encoded glucagon, the incretin glucagon-like peptide-1 (GLP1) and glucagon-like peptide-2 (39Bell G.I. Santerre R.F. Mullenbach G.T. Hamster preproglucagon contains the sequence of glucagon and two related peptides.Nature. 1983; 302: 716-718Crossref PubMed Google Scholar). The GLP1 receptor was cloned in 1992 by Bernard Thorens (40Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1.Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8641-8645Crossref PubMed Scopus (803) Google Scholar). The ground-breaking work of Habener, Holst, Drucker, and many others laid the foundation for GLP1 agonists as antidiabetic drugs. The discovery of exendin-4, isolated from Heloderma suspectum venom, provided a highly effective stable GLP1 agonist (41Goke R. Fehmann H.C. Linn T. Schmidt H. Krause M. Eng J. Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.J. Biol. Chem. 1993; 268: 19650-19655Abstract Full Text PDF PubMed Google Scholar). The development of inhibitors of a circulating protease that degrades GLP1, dipeptidyl peptidase-4 by Nancy Thornberry and Ann Weber, delivered an orally available alternative to injected GLP1 agonists (42Thornberry N.A. Weber A.E. Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.Curr. Top. Med. Chem. 2007; 7: 557-568Crossref PubMed Scopus (173) Google Scholar). Recent work has also shown that glucagon can function in a paracrine fashion to stimulate insulin secretion through the GLP1 receptor (43Capozzi M.E. Wait J.B. Koech J. Gordon A.N. Coch R.W. Svendsen B. Finan B. D’Alessio D.A. Campbell J.E. Glucagon lowers glycemia when β cells are active.JCI Insight. 2019; 5e129954Crossref PubMed Scopus (37) Google Scholar). GLP1 has numerous actions unrelated to glycemic control, including effects on the heart rate, inflammation, blood pressure, hepatic steatosis, and food intake. In addition to its production by intestinal L-cells and pancreatic α-cells, GLP1 is synthesized in the central nervous system where it regulates food intake (reviewed in (44McLean B.A. Wong C.K. Campbell J.E. Hodson D.J. Trapp S. Drucker D.J. Revisiting the complexity of GLP-1 action from sites of synthesis to receptor activation.Endocr. Rev. 2021; 42: 101-132Crossref PubMed Scopus (12) Google Scholar)). Levine and Goldstein published a landmark article in the JBC in 1949 (45Levine R. Goldstein M. Klein S. Huddlestun B. The action of insulin on the distribution of galactose in eviscerated nephrectomized dogs.J. Biol. Chem. 1949; 179: 985Abstract Full Text PDF PubMed Google Scholar), with just one page of text and one figure [see Fig. 1 in (45Levine R. Goldstein M. Klein S. Huddlestun B. The action of insulin on the distribution of galactose in eviscerated nephrectomized dogs.J. Biol. Chem. 1949; 179: 985Abstract Full Text PDF PubMed Google Scholar)]. This report is generally regarded as the first evidence that insulin stimulates hexose uptake into cells. Before 1949, many scientists believed that insulin acted by entering cells and interacting with cellular enzymes to change their activity and downstream glucose metabolism. Levine and Goldstein used galactose as a nonmetabolized sugar to follow its fate 30 min after injection of insulin into a dog. After observing an increase in the disappearance of galactose from the circulation, they presciently concluded, “The working hypothesis prompted by these data can be stated as follows: Insulin acts upon the cell membranes of certain tissues (skeletal muscle, etc.) in such a manner that the transfer of hexoses (and perhaps therapeutic substances) from the extracellular fluid into the cell is facilitated. The intracellular fate of the hexoses depends upon the availability of metabolic systems for their transformation. In the case of galactose, no further changes occur. In the case of glucose, dissimilation, glycogen storage, and transformation to fat are secondarily stimulated by the rapidity of its entry into the cell.” In 1961, Charles “Rollo” Park reported in the JBC that the rate-limiting step in the stimulation by insulin of glucose utilization by the perfused heart is transport across the plasma membrane (46Morgan H.E. Cadenas E. Regen D.M. Park C.R. Regulation of glucose uptake in muscle. II. Rate-limiting steps and effects of insulin and anoxia in heart muscle from diabetic rats.J. Biol. Chem. 1961; 236: 262-268Abstract Full Text PDF PubMed Google Scholar). Remarkably, he also discovered that anoxia stimulated glucose transport, anticipating the later work on exercise and AMPK-stimulated glucose uptake into muscle. The mechanism by which insulin stimulates glucose uptake into cells was revealed in the late 1980’s when the main insulin-sensitive glucose transporter, GLUT4 (gene name SLC2A4), was cloned by a group led by Graeme Bell and Susumu Seino at the University of Chicago (47Fukumoto H. Kayano T. Buse J.B. Edwards Y. Pilch P.F. Bell G.I. Seino S. Cloning and characterization of the major insulin-responsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues.J. Biol. Chem. 1989; 264: 7776-7779Abstract Full Text PDF PubMed Google Scholar) and by David James and Mike Mueckler (48James D.E. Strube M. Mueckler M. Molecular cloning and characterization of an insulin-regulatable glucose transporter.Nature. 1989; 338: 83-87Crossref PubMed Google Scholar). It was later shown by Sam Cushman and Tetsuro Kono that insulin promotes the translocation of GLUT4 to the plasma membrane (49Cushman S.W. Wardzala L.J. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane.J. Biol. Chem. 1980; 255: 4758-4762Abstract Full Text PDF PubMed Google Scholar, 50Goto Y. Sumida Y. Flanagan J.E. Robinson F.W. Simpson I.A. Cushman S.W. Kono T. Effects of fluorescein isothiocyanate on insulin actions in rat adipocytes.Arch. Biochem. Biophys. 1992; 293: 224-230Crossref PubMed Google Scholar). Subsequent work of Jeffrey Pessin’s group (51Thurmond D.C. Ceresa B.P. Okada S. Elmendorf J.S. Coker K. Pessin J.E. Regulation of insulin-stimulated GLUT4 translocation by Munc18c in 3T3L1 adipocytes.J. Biol. Chem. 1998; 273: 33876-33883Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar) and others (52Brewer P.D. Habtemichael E.N. Romenskaia I. Mastick C.C. Coster A.C. Insulin-regulated Glut4 translocation: Membrane protein trafficking with six distinctive steps.J. Biol. Chem. 2014; 289: 17280-17298Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar) showed that insulin-stimulated translocation of GLUT4 vesicles from intracellular stores to the plasma membrane engages the exocytotic machinery of the cell, that is, some of the same cellular machinery required for insulin exocytosis in the β-cell. The translocation of GLUT4 to the plasma membrane is not exclusively stimulated by insulin, however. In a highly impactful study, Amira Klip reported in 1990 in the JBC that exercise can also induce GLUT4 transloc" @default.
• W3208068721 created "2021-11-08" @default.
• W3208068721 creator A5011658040 @default.
• W3208068721 creator A5062442674 @default.
• W3208068721 creator A5066344931 @default.
• W3208068721 date "2021-01-01" @default.
• W3208068721 modified "2023-10-16" @default.
• W3208068721 title "The insulin centennial—100 years of milestones in biochemistry" @default.
• W3208068721 cites W10647373 @default.
• W3208068721 cites W12770584 @default.
• W3208068721 cites W141193853 @default.
• W3208068721 cites W1480001548 @default.
• W3208068721 cites W1481070153 @default.
• W3208068721 cites W1483819615 @default.
• W3208068721 cites W1495212988 @default.
• W3208068721 cites W1502613766 @default.
• W3208068721 cites W1506981847 @default.
• W3208068721 cites W1509026832 @default.
• W3208068721 cites W1516572497 @default.
• W3208068721 cites W1524030768 @default.
• W3208068721 cites W1533778697 @default.
• W3208068721 cites W1534556626 @default.
• W3208068721 cites W1537820722 @default.
• W3208068721 cites W1553733060 @default.
• W3208068721 cites W1560338125 @default.
• W3208068721 cites W1569090915 @default.
• W3208068721 cites W1573318520 @default.
• W3208068721 cites W1577657954 @default.
• W3208068721 cites W1589619983 @default.
• W3208068721 cites W1593931056 @default.
• W3208068721 cites W1594959845 @default.
• W3208068721 cites W1601102460 @default.
• W3208068721 cites W1624505911 @default.
• W3208068721 cites W1650544568 @default.
• W3208068721 cites W1909310469 @default.
• W3208068721 cites W195721858 @default.
• W3208068721 cites W1967821760 @default.
• W3208068721 cites W1970317211 @default.
• W3208068721 cites W1972590376 @default.
• W3208068721 cites W1973041446 @default.
• W3208068721 cites W1974328237 @default.
• W3208068721 cites W1975236443 @default.
• W3208068721 cites W1977128714 @default.
• W3208068721 cites W1977796924 @default.
• W3208068721 cites W1979059085 @default.
• W3208068721 cites W1983690766 @default.
• W3208068721 cites W1984413737 @default.
• W3208068721 cites W1985815865 @default.
• W3208068721 cites W1987210971 @default.
• W3208068721 cites W1987417071 @default.
• W3208068721 cites W1987802058 @default.
• W3208068721 cites W1989294105 @default.
• W3208068721 cites W1991635121 @default.
• W3208068721 cites W1993667769 @default.
• W3208068721 cites W1993836723 @default.
• W3208068721 cites W1993963200 @default.
• W3208068721 cites W1994173047 @default.
• W3208068721 cites W1994924615 @default.
• W3208068721 cites W1994989824 @default.
• W3208068721 cites W1999447199 @default.
• W3208068721 cites W2000184187 @default.
• W3208068721 cites W2000759609 @default.
• W3208068721 cites W2001827575 @default.
• W3208068721 cites W2009269237 @default.
• W3208068721 cites W2011001359 @default.
• W3208068721 cites W2012515461 @default.
• W3208068721 cites W2014154105 @default.
• W3208068721 cites W2015139192 @default.
• W3208068721 cites W2017499074 @default.
• W3208068721 cites W2026241394 @default.
• W3208068721 cites W2029911977 @default.
• W3208068721 cites W2030170677 @default.
• W3208068721 cites W2030610610 @default.
• W3208068721 cites W2038594687 @default.
• W3208068721 cites W2038741829 @default.
• W3208068721 cites W2038924426 @default.
• W3208068721 cites W2040692229 @default.
• W3208068721 cites W2045382437 @default.
• W3208068721 cites W2047037226 @default.
• W3208068721 cites W2051743127 @default.
• W3208068721 cites W2052715791 @default.
• W3208068721 cites W2053127486 @default.
• W3208068721 cites W2058668243 @default.
• W3208068721 cites W2061274996 @default.
• W3208068721 cites W2069599670 @default.
• W3208068721 cites W2069988949 @default.
• W3208068721 cites W2070892520 @default.
• W3208068721 cites W2074092708 @default.
• W3208068721 cites W2074501705 @default.
• W3208068721 cites W2080863734 @default.
• W3208068721 cites W2092045274 @default.
• W3208068721 cites W2092777252 @default.
• W3208068721 cites W2095449282 @default.
• W3208068721 cites W2102683312 @default.
• W3208068721 cites W2102964449 @default.
• W3208068721 cites W2104389135 @default.
• W3208068721 cites W2110079579 @default.
• W3208068721 cites W2111295274 @default.

• next