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1925, 1943, 1984, 1991, 2017, 2032, 2058, 2115, 2154, 2191, 2204, 2215, 2228, 2233, 2243, 2270, 2281, 2288, 2337, 2402, 2513, 2574, 2581, 2600, 2629, 2686, 2726, 2749, 2817, 2841, 2989, 3053, 3057, 3087, 3118, 3171, 3308, 3336, 3366, 3399, 3500], 'regulation': [192, 351, 424, 458, 511, 887, 2688], 'carbohydrate': [194, 513], 'metabolism': [195, 514, 1391, 2400], '(2),': [196], 'thus': [197, 257], 'paving': [198], 'way': [200, 1098], 'what': [205, 1126, 2500], 'would': [206, 2612], 'be': [207, 1193, 2098, 2756, 2786, 2807, 2870], 'known': [209, 1129, 1681, 2387], 'as': [210, 269, 399, 431, 433, 837, 858, 860, 1131, 1182, 1184, 1246, 1319, 1628, 2195, 2365, 2367, 2390, 2425, 2452, 2454, 2505, 2593, 2696, 2768], 'insulin': [211, 250, 268, 278, 307, 553, 578, 588, 674, 722, 736, 746, 758, 788, 795, 825, 833, 853, 889, 919, 949, 962, 1006, 1018, 1033, 1048, 1059, 1088, 1106, 1117, 1144, 1173, 1178, 1203, 1216, 1240, 1296, 1314, 1343, 1359, 1418, 1429, 1448, 1467, 1500, 1528, 1562, 1577, 1596, 1610, 1637, 1684, 1732, 1750, 1888, 1987, 1999, 2019, 2029, 2041, 2046, 2055, 2089, 2114, 2149, 2152, 2167, 2170, 2177, 2189, 2234, 2285, 2306, 2373, 2409, 2438, 2598, 2620, 2664, 2684, 2713, 2730, 2736, 2745, 2783, 2800, 2819, 2850, 2888, 3086, 3134, 3169, 3199, 3249, 3273, 3335, 3358, 3403, 3439], 'Banting': [213, 336, 557, 1090, 1592, 1734, 2625, 2977], 'his': [215, 1092, 2470, 2627], 'colleagues': [216, 559, 1093, 1594, 2471, 2628], '1921': [218], 'Although': [220, 1486, 2488], 'prior': [221], 'researchers': [222, 655, 713, 780, 1599, 1909, 2287], 'had': [223, 1118, 1600, 1768], 'made': [224], 'pivotal': [225, 1425], 'contributions': [226], 'toward': [227, 1291], 'characterization': [228], 'effects': [232, 966, 1546], 'on': [233, 651, 2808], 'metabolism,': [235, 357, 2699], 'MacLeod': [243], 'almost': [244], 'immediately': [245, 572], 'demonstrated': [246, 293, 752, 782, 952, 2159], 'therapeutic': [247, 2780, 2813, 2862], 'efficacy': [248, 1171], 'treatment': [253, 330, 2596, 2991], 'mellitus,': [256, 1135, 2610], 'opening': [258], 'much-needed': [260], 'opportunity': [261], 'mass': [263], 'production': [264, 1037, 1611, 2110], 'commercialization': [266, 1878, 1996], 'life-saving': [271, 275, 1121], 'treatment.': [273], 'Indeed,': [274, 369, 590, 1181, 1947, 2578], 'advances': [276, 420, 454, 680, 938, 1897, 2336, 2347, 2580, 2816], 'therapy': [279, 308, 2622, 2801], 'are': [280, 309, 507, 824, 967, 974, 2257, 2431, 2936], 'highlighted': [281, 2679], 'Epidemiology': [285], 'Diabetes': [287, 3037, 3044, 3064, 3314], 'Interventions': [288, 3045], 'Complications': [290, 3040, 3047], 'trial': [291], 'modern': [295], 'mortality': [296], 'rates': [297, 1261], 'patients': [299, 1252, 1346, 1841, 1855, 2514, 2575, 2833], 'with': [300, 305, 546, 552, 1125, 1253, 1347, 1382, 1465, 1654, 1714, 1724, 1842, 1856, 1972, 2100, 2420, 2433, 2515, 2576, 2834, 2874, 3310], 'Type': [301, 547, 1132, 1254, 1263, 1348, 1451, 1531, 1857, 1860, 1926, 1944, 2081, 2216, 2252, 2274, 2517, 2601, 2607], '1': [302, 548, 1133, 1858, 1927, 2518, 2602, 3055, 3502], 'treated': [304, 551], 'intensive': [306, 1743, 2527], 'essentially': [310], 'indistinguishable': [311], 'those': [313, 1198, 1212], 'observed': [314], 'general': [317, 3062], 'population': [318], '(3).In': [319], 'addition': [320], 'obvious': [323, 1120], 'significance': [324], 'discovering': [326], 'implementing': [328], 'diabetes,': [332, 364, 2254], 'et': [337, 1735], 'al.': [338, 1736], 'ushered': [339, 1738], 'an': [341, 1119, 1136, 1205, 1310, 1502, 1740, 1998, 2265, 2465, 2653, 2774], 'era': [342, 1741], 'experimental': [344, 883, 1982], 'insulin’s': [347, 426, 460, 649, 1727, 2644, 2897], 'role': [348, 2269], 'essential': [353, 2692], '(e.g.,': [355, 363, 982, 1067, 1075, 1551, 1887, 1965, 2039, 2045], 'nutrient': [356], 'reproduction,': [358], 'growth,': [359], 'etc.)': [360, 989], 'pathophysiological': [362, 1249, 1522], 'obesity,': [365], 'cancer,': [366], 'neurodegeneration)': [367], 'conditions.': [368], 'majority': [371, 1807], '“early”': [373], 'this': [376, 410, 438, 992, 1299, 1490, 1761, 1948, 2093, 2492, 2582, 2591, 2648, 2705, 3466], 'area': [377, 1503, 2584, 2654], 'performed': [379, 1792], 'trained': [381], 'physiologists,': [382], 'pioneered': [383], 'leadership': [386], 'Macleod,': [389], 'Professor': [390], 'Physiology,': [392], 'enrollment': [395], 'Best': [398, 2979], 'physiology': [401, 944, 2283, 2642], 'graduate': [402], 'Toronto.': [408], 'Correspondingly,': [409], 'editorial': [411], 'discusses': [412], 'some': [413, 1771], 'key': [416, 452, 645, 959, 1248, 1848, 1883, 1895, 2033, 2368], 'discoveries': [418, 741, 871, 1432], 'related': [421, 455, 2035], 'action,': [427, 461, 1174, 1728], 'secretion,': [428, 462, 2286, 2647], 'therapeutics,': [430], 'well': [432, 2366, 2503], 'future': [434, 2776, 2798], 'implications': [435], 'arising': [436, 2560], 'trailblazing': [439], 'over': [443, 633], 'past': [445], '100': [446, 2636], 'years': [447, 2637], '(FIGURE': [448], '1).FIGURE': [449], '1.Timeline': [450], 'therapeutics.': [464], 'GLUT4,': [465], 'transporter': [467, 693], 'type': [468, 694, 896, 972, 3054, 3311], '4;': [469], 'ES,': [470], 'embryonic': [471, 2536], 'stem': [472, 477, 2566, 2852, 2875], 'cell;': [473], 'iPSC,': [474], 'induced': [475], 'pluripotent': [476, 2565], 'cell.Download': [478], 'figureDownload': [479], 'PowerPointBreakthroughs': [480], 'Physiology': [483, 1584], 'Pathophysiology': [485, 1586], 'Insulin': [487, 1588, 3116, 3163], 'ActionAs': [488], 'previously': [489, 1055, 2758], 'mentioned,': [490], 'century,': [497], 'multiple': [498, 2205], 'secretory': [502, 2056, 2090, 2094, 2226, 2307, 2439], 'products': [503, 2877], 'involved': [508], 'mainly': [515], 'through': [516, 616, 2851], 'stimulation': [518, 2407], 'disposal': [521, 586, 615], 'peripheral': [524, 2192], 'tissues': [525, 2193], 'body.': [528], 'concept': [530, 1238], 'beautifully': [532], 'illustrated': [533], 'observing': [535], 'published': [536, 1325], 'chart': [538, 564], 'data': [539], 'Leonard': [541, 562], 'Thompson,': [542], '14-yr-old': [544], 'boy': [545], 'first': [550, 1235, 1668, 1704, 2077], 'extract': [554, 579], 'prepared': [555, 2958], 'Notably,': [561, 1044], 'Thompson’s': [563], 'illustrates': [565], 'sudden': [566], 'drops': [567], 'urine': [569], 'concentrations': [571], 'following': [573, 1150], 'subcutaneous': [574], 'injections': [575], 'implicating': [580], 'acute': [582], 'mediation': [583], 'not': [591, 2258], 'long': [592], 'after': [593], 'were': [599, 714, 761, 1433, 2122], 'able': [600, 715], 'definitively': [602], 'demonstrate': [603, 2209], 'skeletal': [605, 706, 1004, 1362, 2196, 3088], 'muscle': [606, 707, 1363, 1516], 'major': [609, 1772, 1866, 2812], 'organ': [610, 898], 'responsible': [611, 1445, 2533], 'enhancement': [617], 'plasma': [619, 669, 3128, 3334], 'membrane': [620, 670, 3129], 'transport': [621], 'cellular': [623, 1941, 2403, 2558, 2693], 'storage': [624, 1041], 'glucose.': [626, 3414], 'Advances': [627], 'molecular': [629, 682, 2338], 'techniques': [632, 1339, 2142], 'course': [635], 'resulted': [640, 912, 1990], 'detailed': [642], 'elucidation': [643], 'mechanistic': [646], 'underpinnings': [647], 'underlying': [648], 'action': [650, 747, 890, 1049, 1107, 1449, 1580, 2645, 2714, 2746, 2898], 'uptake.': [653], 'First,': [654, 1775], 'identified': [656, 1236], 'putative': [658], 'insulin-responsive': [659, 691], 'transporters': [661], 'translocate': [662], 'cytosolic': [665], 'compartment': [666], 'response': [672, 2057, 2116, 2229, 2308, 3411], 'administration': [675], 'vivo': [677, 1316, 2018, 2282], '(4).': [678, 711], 'Subsequently,': [679, 779, 1333], 'cloning': [683, 2341], 'technology': [684, 907], 'identification': [688, 1615, 1875], '4': [695], 'protein,': [696], 'primary': [698, 1521], 'mediator': [699], 'insulin-stimulated': [701], 'uptake': [703, 1011, 1021, 1365, 2397], 'adipose': [709, 1016], 'tissue': [710, 1915, 3092], 'Concurrently,': [712, 1688], 'characterize': [717, 1670, 1932], 'triggering': [719], 'effect': [720, 1221], 'binding': [723, 793, 3122], 'its': [725, 3131], 'cognate': [726], 'receptor': [727, 737, 789, 803, 826, 876, 920, 1563, 3170], 'P.': [729], 'De': [730], 'Meyts)': [731], 'corresponding': [734, 813], 'downstream': [735], 'signaling': [738, 834, 854, 963, 1578, 2531, 2665, 2685, 2748, 2784], 'cascades.': [739], 'Seminal': [740], 'understanding': [744, 1292, 2353, 2912], 'early': [750, 1183, 1689, 1833, 2120, 2246, 2453, 2880], '1970s': [751], 'existence': [754, 1160, 2161], 'cell': [756, 801, 895, 971, 1083, 1673, 1721, 1885, 2567], 'surface': [757, 802], 'receptors,': [759], 'subsequently': [762], 'exhibit': [765], 'classic': [766], 'enzymatic': [767], 'tyrosine': [768, 806, 1571, 3165], 'kinase': [769], 'activity': [770, 3437], 'within': [771], 'regulatory': [772], 'α-': [773], 'catalytic': [775], 'β-receptor': [776], 'subunits': [777], '(5).': [778], 'eloquently': [781], 'functionality': [785], 'α-subunit': [798], 'leading': [804, 1568, 2441], 'autophosphorylation': [807], 'β-subunit': [810], '(6)': [811], 'phosphorylation': [814, 1559, 1572, 3166], 'endogenous': [817, 1609, 2562, 2849, 3333], 'substrate': [818, 827], 'proteins,': [819], 'most': [820, 2671, 2721], 'notable': [821], '(IRS)': [828], 'proteins.': [829], 'To': [830], 'date,': [831, 1244, 1955], 'pathway': [835, 2440, 2666], 'stands': [836, 1245, 1317, 1627], 'one': [838, 2468, 2668, 2718, 2920], 'more': [841, 1541, 1930, 2634], 'complex': [842], 'evolutionary': [844], 'conserved': [845], 'biological': [846, 2140], 'systems,': [847], 'signified': [848], 'remarkable': [850], 'homology': [851, 956], 'intermediaries': [855, 1550], 'animals': [857], 'primitive': [859], 'Caenorhabditis': [861], 'elegans': [862], 'Drosophila': [864], 'melanogaster': [865], 'mammals.The': [869], 'mechanisms': [873, 1444, 1607, 1748, 2304, 3271], 'regulating': [874, 1495, 2305], 'insulin-insulin': [875], 'interactions': [877], 'have': [878, 2200, 2350, 2824], 'spurred': [879], 'virtually': [892], 'every': [893], 'mammalian': [894], 'system.': [899, 3174], 'Congruently,': [900], 'advent': [902], 'Cre-LoxP': [904], 'gene': [905], 'deletion': [906], 'late': [910, 2604], '1990s': [911], 'development': [915, 1301, 1708, 1959, 1993, 2023, 2272, 2325, 2421], 'several': [917], 'cell-specific': [918, 998, 1045], 'knockout': [921], 'mouse': [922], 'models': [923], 'laboratory': [926], 'C.': [928, 3391], 'Ronald': [929], 'Kahn,': [930], 'strategy': [932, 2863], 'has': [934, 1217, 1288], 'profound': [937], 'study': [941, 2728], 'insulin-regulated': [943], '(7).': [945, 990], 'Cumulatively,': [946], 'studies': [947, 1691, 1871, 2237, 2278, 2551, 3365], 'receptor-deficient': [950], 'mice': [951, 3193, 3442], 'despite': [954], 'unique': [955], 'components': [960], 'cascade,': [964], 'highly': [968], 'specific': [969, 1881, 3121], 'strongly': [975], 'influenced': [976], 'organism’s': [979], 'state': [981], 'age,': [983], 'gender,': [984], 'nutritional': [985], 'state,': [986], 'sleep/wake': [987], 'cycle,': [988], 'Considering': [991], 'caveat,': [993], 'decades': [994, 996, 1436, 1827, 1829, 2412, 2525], 'upon': [995, 1828], 'established': [1001, 1416, 2241, 2416], 'muscle,': [1005, 3089], 'functions': [1007, 2694], 'promote': [1009, 1556], 'glycogen': [1013, 1040], 'synthesis.': [1014], 'In': [1015, 1030, 1298, 1411, 2379, 2704, 2732], 'tissue,': [1017], 'stimulates': [1019, 1039, 3164], 'lipogenesis,': [1023], 'while': [1024], 'promoting': [1025], 'inhibition': [1027], 'lipolysis.': [1029], 'liver,': [1032], 'inhibits': [1034], 'hepatic': [1035, 1371], 'lipogenesis.': [1043], 'analysis': [1046], 'also': [1050, 1095, 1415, 1737, 1989, 2296, 2415], 'provided': [1051, 1702, 2075], 'novel': [1052, 2788], 'information': [1053], 'regarding': [1054], 'unappreciated': [1056, 2759], 'roles': [1057], 'vascular': [1065, 1068], 'endothelium': [1066], 'hemodynamics),': [1069], 'central': [1070, 2751], 'nervous': [1071, 2752], 'system': [1072, 2753], 'behavioral': [1073], 'feeding),': [1076], 'even': [1078], 'autocrine': [1079], 'islet': [1082, 1672, 1720, 1838, 1884, 1936, 2327], 'function': [1084, 2227, 2389], '(7).The': [1085], '(1)': [1094], 'paved': [1096], 'groundbreaking': [1100, 1321, 2346], 'pathophysiology': [1104, 1294, 2053, 2250], 'disorders.': [1110], 'At': [1111], 'time,': [1113], 'benefit': [1122], 'individuals': [1124], 'now': [1128, 1130, 1679, 2349, 2385, 2502], 'autoimmune': [1137, 1919, 2516], 'disease': [1138], 'characterized': [1139, 1165, 2086], 'near-complete': [1141], 'destruction': [1142, 1924], 'producing': [1145], 'β-cells.': [1147, 2311, 2543], 'However,': [1148, 1754], 'shortly': [1149], 'started': [1156, 2623], 'postulate': [1158], 'condition': [1164, 1478], 'hyperglycemia': [1167], 'attributed': [1168], 'reduced': [1170, 1570], 'rather': [1175, 2263], 'than': [1176, 2635, 2872], 'absolute': [1177], 'deficiency': [1179, 2599], '(8).': [1180], '1936': [1185], 'Harold': [1186], 'Himsworth': [1187, 1232, 1458, 3217], '(8)': [1188, 1459], '“…diabetics': [1191], 'can': [1192], 'differentiated': [1194], 'two': [1196, 2477], 'types:': [1197], 'whom': [1200, 1214], 'injected': [1202], 'produces': [1204], 'immediate': [1206], 'suppression': [1207], 'hyperglycemia;': [1210], 'little': [1218], 'or': [1219, 1477, 1493, 2563, 2934], 'no': [1220, 1781], 'suppressing': [1223], 'hyperglycemia.”': [1225], 'By': [1226], 'all': [1227, 2548, 2691], 'accounts,': [1228], '1930s': [1234], 'resistance,': [1241], 'which,': [1242], 'defect': [1250, 2095], '2': [1255, 1264, 1349, 1452, 1532, 1861, 1945, 2082, 2217, 2253, 2275, 2608, 3312], 'mellitus.': [1257, 2520, 2994, 3222], 'Given': [1258], 'epidemic': [1260], 'throughout': [1267], 'stages': [1270, 2605], '21st': [1277], 'centuries,': [1278], 'significant': [1280, 2660], 'amount': [1281], 'resources': [1284], 'brain': [1286], 'power': [1287], 'been': [1289, 2202], 'dedicated': [1290], 'resistance.': [1297, 3252, 3274], 'regard,': [1300, 2706], 'clamp': [1305, 1338, 1378, 3243], 'technique': [1306], 'designed': [1307, 2946], 'measure': [1309, 1389], 'individual’s': [1311], 'sensitivity': [1312, 1498, 2153, 2168, 2190, 3404, 3408], 'out': [1318], 'origination': [1323], '(first': [1324], 'Journal': [1329], 'Physiology)': [1331], '(9).': [1332], 'investigators': [1334], 'world-wide': [1335], 'used': [1336], 'establish': [1341, 2144], 'resistance': [1344, 1529, 3200], 'largely': [1352, 2183], 'impaired': [1356, 1447, 2744], 'ability': [1357], 'stimulate': [1361], 'failure': [1368, 2102], 'suppress': [1370], 'production.': [1373], 'Complementing': [1374], 'this,': [1375], 'hyperglycemic': [1377], 'developed': [1380], 'along': [1381], 'use': [1384], 'tracer': [1386], 'methodology': [1387], 'liver': [1390, 1422, 1518], 'kinetics': [1394], 'last': [1398], 'postdoctoral': [1399], 'fellow': [1400], 'Mladen': [1404], 'Vranic': [1405], 'Toronto).': [1410], 'parallel,': [1412], 'it': [1413, 1536, 1755, 1790, 2496, 2738], 'clearance': [1419], 'regulator': [1426], 'circulating': [1428], 'levels.': [1430], 'These': [1431, 1824, 2119, 2198, 2521], 'collective': [1438], 'efforts': [1439, 2299, 2528], 'categorize': [1443], 'diabetes.': [1453, 1946, 2577, 2865, 3313], 'Interestingly,': [1454], '1930s,': [1457], 'astutely': [1460], 'predicated': [1461], '“the': [1463], 'efficiency': [1464], 'acts': [1468], 'body': [1471, 1481], 'governed': [1473], 'unknown': [1475], 'factor': [1476], 'renders': [1480], 'sensitive': [1482], 'insulin.”': [1485], 'search': [1488, 2614], 'elusive': [1491], '“factor”': [1492], '“condition”': [1494], 'our': [1496, 1809, 2911, 2928], 'body’s': [1497], 'remains': [1501, 2494, 2652, 2667, 2856], 'active': [1505, 2266, 2656], 'investigation,': [1506], 'suggests': [1510], 'ectopic': [1512], 'lipid': [1513, 1549, 1938], 'accumulation': [1514], 'contributor': [1523, 2760], 'induction': [1526, 2211], '(10).': [1534], 'Mechanistically,': [1535], 'appears': [1537, 2754, 2805, 2868], 'include,': [1539], 'among': [1540], 'intricate': [1542], 'mechanisms,': [1543], 'deleterious': [1545], 'intracellular': [1548], 'diacylglycerols': [1552], 'ceramides),': [1554], 'repressive': [1557], 'Ser/Thr': [1558], 'associated': [1565, 1713, 2099, 2419, 2432], 'IRS': [1566], 'proteins': [1567], 'consequent': [1574], 'repression': [1575], '(10).Breakthroughs': [1581], 'SecretionBy': [1589], 'time': [1591, 1795], 'isolated': [1595], '1921,': [1598], 'already': [1601, 2825], 'begun': [1602], 'unravel': [1604], 'secretion.': [1613, 1753], 'Langerhans': [1621, 3019], 'microscopy': [1623], '1869': [1625], 'still': [1626, 1779, 2554, 2855], 'storied': [1634], 'history': [1635], 'biology.': [1638], 'Langerhans’s': [1639], 'astute': [1640], 'observation': [1641, 2466], '“…usually': [1643], 'round': [1644, 1655], 'groups': [1645], 'cells': [1647, 1653], 'composed': [1648], 'small,': [1650], 'irregular': [1651], 'polygonal': [1652], 'nucleus….”': [1656], 'confirmed': [1658, 1832], 'expanded': [1660, 1976, 2126], 'M.': [1662], 'A.': [1663, 3081], 'Lane': [1664], 'subtypes': [1674], 'β-': [1676], 'α-cells,': [1678], 'commonly': [1680, 2386], 'secrete': [1683], 'glucagon': [1686], '(2).': [1687, 2487], 'histological': [1690], 'pancreas': [1694, 1817, 1913, 1963, 1980, 2475], 'indication': [1705], '“destructive': [1715, 1837], 'lesions”': [1716, 1839], 'confined': [1717], 'types': [1722, 1886], '(2).As': [1723], 'production,': [1751, 2374], 'important': [1757, 2740], 'note': [1759], 'line': [1762, 1949, 2313, 2649], 'research,': [1764, 2316], 'least': [1766], 'initially,': [1767], 'overcome': [1770], 'methodological': [1773], 'hurdles.': [1774], 'there': [1776], '(and': [1778, 2328], 'is)': [1780], 'realistic': [1782], 'means': [1783], 'obtain': [1785], 'human': [1786, 1815, 1912, 1962, 1979], 'samples': [1788], 'unless': [1789], 'autopsy': [1797, 1914], '(or': [1798], 'during': [1799, 2069], 'surgery).': [1801], 'Thus': [1802], 'vast': [1806], 'knowledge': [1810], 'about': [1811], 'morphology': [1813], 'endocrine': [1816], 'stems': [1818], 'uniquely': [1819], 'autopsy-derived': [1821], 'tissue.': [1823], 'limitations': [1825], 'notwithstanding,': [1826], 'morphological': [1834, 1849], 'observations': [1835, 2034, 2121, 2199, 2522], 'and,': [1845, 1929], 'importantly,': [1846], 'defined': [1847], 'abnormalities': [1850], '(11).': [1864], 'scientific': [1867, 1896, 2661, 2724], 'breakthrough': [1868, 2128], 'advancing': [1869], 'these': [1870, 2345, 2550], 'arose': [1872], 'subsequent': [1877, 1995, 2406], 'antibodies': [1880], 'glucagon),': [1890], 'opened': [1892], 'opportunities': [1893], 'immunohistochemical': [1899], 'immunofluorescent': [1901], 'techniques.': [1902, 2342], 'From': [1903, 3192], 'mid-20th': [1905], 'until': [1907], 'now,': [1908], 'successfully': [1910], 'utilized': [1911, 2137], 'define': [1917], 'nature': [1920], 'β-cell': [1923, 2225, 2383, 2443, 2572], 'recently,': [1931], 'presence': [1934], 'amyloidosis,': [1937], 'infiltration,': [1939], 'dedifferentiation': [1942], 'continuing': [1953], 'aided': [1956], 'national': [1961], 'biobanks': [1964], 'Network': [1967], 'Pancreatic': [1969, 2987, 3434], 'Organ': [1970], 'donors': [1971], 'Diabetes),': [1973], 'greatly': [1975, 2024, 2321], 'accessibility': [1977], 'research.Advances': [1983], 'methods': [1985], 'immunodetection': [1988], 'immunoassay': [2000], 'Rosalyn': [2003], 'Yalow': [2004, 3327], 'Solomon': [2006], 'Berson),': [2007], 'quickly': [2009], 'became': [2010], 'cornerstone': [2012], 'secretion': [2020, 2030, 2112, 2150, 2171, 2178, 2716, 2900, 3250], '(12).': [2021], 'accelerated': [2025], 'investigations': [2027], 'resulting': [2031, 2401], 'temporal': [2037], 'dynamics': [2038], 'pulsatile': [2040], 'secretion),': [2042], 'nutrient-responsiveness,': [2043], 'exocytosis': [2044, 2377], 'granule': [2047], 'formation': [2048], 'maturation),': [2050], 'humans.': [2059, 2155], 'Specifically,': [2060], 'Perley': [2065, 3353], 'Kipnis': [2067, 3355], '(13)': [2068], 'part': [2072], '1960s': [2074], 'concrete': [2078], 'evidence': [2079], 'defective': [2088], 'response.': [2091], 'Importantly,': [2092, 2411], 'appeared': [2096], 'β-cells': [2105, 2181, 2256, 2357, 2512], 'adaptively': [2107], 'augment': [2108], 'obesity.': [2118], 'further': [2123, 2839], 'reproduced': [2124, 2203], 'Bergman,': [2131], 'Phillips,': [2132], 'Cobelli': [2134, 3390], '(14),': [2135], 'modeling': [2141], 'mathematical': [2146], 'relationship': [2147, 2165], 'between': [2148, 2166], 'hyperbolic': [2164], 'implying': [2172], 'extent': [2175], 'degree': [2187], 'such': [2194, 2424, 2695, 2767], 'muscle.': [2197], 'since': [2201], 'epidemiological': [2206], 'cohorts': [2207], 'intolerance': [2214], 'failed': [2222], 'adaptation': [2223], 'decline': [2232], 'sensitivity.': [2235], 'clearly': [2240], 'that,': [2242], 'contrast': [2244], 'views': [2247], 'merely': [2259], '“passive': [2260], 'bystanders,”': [2261], 'but': [2262], 'play': [2264], 'diabetes.Congruent': [2276], 'exploring': [2279], 'devoted': [2297], 'considerable': [2298], 'elucidate': [2301], 'ongoing,': [2319], 'advanced': [2322], 'single': [2330], 'β-cell)': [2331], 'isolation': [2332], 'procedures': [2333], 'concurrent': [2335], 'genomics': [2339], 'Thanks': [2343], 'we': [2348], 'comprehensive': [2352], 'how': [2355], 'sense,': [2358], 'uptake,': [2359], 'metabolize': [2360], 'respond': [2362], 'signals': [2370], 'mediate': [2372], 'processing,': [2375], '(15).': [2378], 'short,': [2380], 'sensor,': [2393], 'links': [2395], 'oxidative': [2399], 'depolarization': [2404], 'exocytosis.': [2410], 'conditions': [2418, 2766], 'glucotoxicity,': [2426], 'lipotoxicity,': [2427], 'proteotoxicity,': [2428], 'inflammation': [2430], 'distinct': [2434], 'perturbations': [2435], 'dysfunction': [2444], 'common': [2445], 'pathogenesis': [2448, 2763], '(15).Finally,': [2451], '1901,': [2455], 'Eugene': [2456], 'Opie': [2457, 3006], '(a': [2458], 'pathologist': [2459], 'Johns': [2461], 'Hopkins': [2462], 'University)': [2463], 'described': [2464, 2504], '“…in': [2473], 'diabetics,': [2478], 'Sobolew': [2479], 'unable': [2481], 'discover': [2483], 'islands': [2484, 3017], 'Langerhans”': [2486], 'context': [2490, 2734], 'statement': [2493], 'debated,': [2495], 'likely': [2497], 'referred': [2498], 'near': [2507, 2843], 'complete': [2508, 2613], 'absence': [2509], 'delineate': [2530], 'pathways': [2532], 'development,': [2537], 'maturation,': [2538], 'expansion': [2540], 'overarching': [2545], 'goal': [2546], 'was,': [2552], 'remains,': [2555], 'develop': [2557], 'therapies': [2559], 'exogenous': [2564], 'sources': [2568], 'capable': [2569], 'restoring': [2571], 'numbers': [2573], 'recent': [2579, 2723], 'exciting': [2583, 2722], 'support': [2587], 'feasibility': [2589], 'approach': [2592, 2789], 'long-anticipated': [2595], 'ultimate': [2617], 'source': [2618], 'replacement': [2621, 2847], '1921.What': [2630], 'Future': [2632], 'Holds?After': [2633], 'investigation': [2658], 'investments.': [2662], 'tackled': [2672], 'puzzles': [2674], 'date.': [2676], 'recognition': [2682], 'nearly': [2690], 'proliferation,': [2697], 'apoptosis,': [2698], 'autophagy,': [2700], 'many': [2702, 3083], 'more.': [2703], 'revelation': [2708], 'circadian-mediated': [2710], 'breakthroughs': [2725], 'physiology.': [2731], 'pathophysiology,': [2737], 'highlight': [2742], 'neurodegenerative': [2765, 2794], 'Alzheimer’s': [2769], 'disease.': [2770], 'realization': [2772], 'raises': [2773], 'intriguing': [2775], 'possibility': [2777, 2867], 'modulation': [2781], 'may': [2785], 'prevent': [2791], 'and/or': [2792], 'treat': [2793], 'diseases.': [2795], 'Moreover,': [2796], 'cusp': [2810], 'breakthroughs.': [2814], 'Technological': [2815], 'automated': [2818], 'delivery': [2820], 'sensing': [2823], 'significantly': [2826], 'improved': [2827], 'quality': [2829], 'life': [2831], 'poised': [2837], 'refinements': [2840], 'future.': [2844], 'Ultimately,': [2845], 'cell-based': [2853, 2876], 'approaches': [2854], '“holy': [2858], 'grail”': [2859], 'closer': [2871], 'ever': [2873], 'currently': [2878], 'undergoing': [2879], 'phase': [2881], 'clinical': [2882], 'trials.': [2883], 'Overall,': [2884], 'ensuing': [2891], '100-year': [2892], 'odyssey': [2893], 'underscores': [2901], 'importance': [2903], 'betterment': [2909], 'diseases': [2915], 'remain': [2919], 'greatest': [2923], 'public': [2924], 'health': [2925], 'challenges': [2926], 'time.No': [2929], 'conflicts': [2930], 'interest,': [2932], 'financial': [2933], 'otherwise,': [2935], 'declared': [2937], 'authors.A.M.,': [2940], 'G.S.,': [2941, 2949, 2955, 2961, 2969], 'A.K.': [2943, 2951, 2957, 2963, 2971], 'conceived': [2944], 'research;': [2947], 'A.M.,': [2948, 2954, 2960, 2968], 'drafted': [2952], 'manuscript;': [2953, 2967], 'figures;': [2959], 'edited': [2964], 'revised': [2966], 'approved': [2972], 'final': [2973], 'version': [2974], 'manuscript.References1.': 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'117–214,': [3448], '2018.': [3449], 'doi:10.1152/physrev.00008.2017.': [3450], 'ScholarAUTHOR': [3456], 'NOTESMatveyenko.[email': [3457], 'protected]edu': [3458], 'Back': [3459], 'Top': [3461], 'Next': [3462], 'FiguresReferencesRelatedInformation': [3463], 'More': [3464], 'issue': [3467], '>': [3468], 'Volume': [3469], '36Issue': [3470], '4July': [3471], '2021Pages': [3472], '197-200': [3473], 'Crossmark': [3474], 'Copyright': [3475], '&': [3476], 'PermissionsCopyright': [3477], '©': [3478], '2021': [3479, 3489, 3493, 3498, 3504], 'Int.': [3480], 'Union': [3481], 'Physiol.': [3482, 3484], 'Sci./Am.': [3483], 'Soc.https://doi.org/10.1152/physiol.00016.2021PubMed34159804History': [3485], 'Received': [3486], '10': [3487, 3491], 'May': [3488, 3492], 'Accepted': [3490], 'Published': [3494, 3499], 'online': [3495], '23': [3496], 'June': [3497], 'print': [3501], 'July': [3503], 'Metrics': [3505], 'Downloaded': [3506], '1,264': [3507], 'times': [3508]}, 'cited_by_api_url': 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