Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis

Eisenbarth, 1986, Type I diabetes mellitus. A chronic autoimmune disease, The New England Journal of Medicine, 314, 1360, 10.1056/NEJM198605223142106 Chatenoud, 2007, CD3-specific antibodies: a portal to the treatment of autoimmunity, Nature Reviews Immunology, 7, 622, 10.1038/nri2134 von Herrath, 2007, Type 1 diabetes as a relapsing-remitting disease?, Nature Reviews Immunology, 7, 988, 10.1038/nri2192 van Belle, 2011, Type 1 diabetes: etiology, immunology, and therapeutic strategies, Physiological Reviews, 91, 79, 10.1152/physrev.00003.2010 Ziegler, 2013, Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children, JAMA, 309, 2473, 10.1001/jama.2013.6285 Pugliese, 2016, Insulitis in the pathogenesis of type 1 diabetes, Pediatric Diabetes, 17, 31, 10.1111/pedi.12388 Skowera, 2008, CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope, The Journal of Clinical Investigation, 118, 3390 Brozzi, 2015, Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms, Diabetologia, 58, 2307, 10.1007/s00125-015-3669-6 Herold, 2015, Beta cell death and dysfunction during type 1 diabetes development in at-risk individuals, The Journal of Clinical Investigation, 125, 1163, 10.1172/JCI78142 Gianani, 2006, Initial results of screening of nondiabetic organ donors for expression of islet autoantibodies, Journal of Clinical Endocrinology & Metabolism, 91, 1855, 10.1210/jc.2005-1171 In't Veld, 2007, Screening for insulitis in adult autoantibody-positive organ donors, Diabetes, 56, 2400, 10.2337/db07-0416 Rodriguez-Calvo, 2017, Increase in pancreatic proinsulin and preservation of beta cell mass in autoantibody positive donors prior to type 1 diabetes onset, Diabetes, 10.2337/db16-1343 Diedisheim, 2016, Beta-cell mass in nondiabetic autoantibody-positive subjects: an analysis based on the network for pancreatic organ donors database, Journal of Clinical Endocrinology & Metabolism, 101, 1390, 10.1210/jc.2015-3756 Sherry, 2006, Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes, Diabetes, 55, 3238, 10.2337/db05-1034 Sreenan, 1999, Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse, Diabetes, 48, 989, 10.2337/diabetes.48.5.989 Campbell-Thompson, 2016, Insulitis and beta-cell mass in the natural history of type 1 diabetes, Diabetes, 65, 719, 10.2337/db15-0779 Srikanta, 1984, Pre-type I diabetes. Linear loss of beta cell response to intravenous glucose, Diabetes, 33, 717, 10.2337/diab.33.8.717 Chase, 2001, First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes, The Journal of Pediatrics, 138, 244, 10.1067/mpd.2001.111274 Keskinen, 2002, First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes, Diabetologia, 45, 1639, 10.1007/s00125-002-0981-8 Koskinen, 2016, Reduced beta-cell function in early preclinical type 1 diabetes, European Journal of Endocrinology, 174, 251, 10.1530/EJE-15-0674 Sosenko, 2006, Patterns of metabolic progression to type 1 diabetes in the diabetes prevention trial-type 1, Diabetes Care, 29, 643, 10.2337/diacare.29.03.06.dc05-1006 Andersson, 2013, Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study, Pediatric Diabetes, 14, 341, 10.1111/pedi.12023 Sosenko, 2013, Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants, Diabetes, 62, 4179, 10.2337/db13-0656 Gepts, 1965, Pathologic anatomy of the pancreas in juvenile diabetes mellitus, Diabetes, 14, 619, 10.2337/diab.14.10.619 Gepts, 1978, Islet cell survival determined by morphology. An immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus, Diabetes, 27, 251, 10.2337/diab.27.1.S251 Junker, 1977, An autopsy study of the islets of Langerhans in acute-onset juvenile diabetes mellitus, Acta Pathologica et Microbiologica Scandinavica. Section A, Pathology, 85, 699, 10.1111/j.1699-0463.1977.tb00461.x Kloppel, 1984, Morphometric evidence for a striking B-cell reduction at the clinical onset of type 1 diabetes, Virchows Archiv A Pathological Anatomy and Histopathology, 403, 441, 10.1007/BF00737292 Butler, 2007, Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis, Diabetologia, 50, 2323, 10.1007/s00125-007-0794-x Leete, 2016, Differential insulitic profiles determine the extent of beta-cell destruction and the age at onset of type 1 diabetes, Diabetes, 65, 1362, 10.2337/db15-1615 Sherry, 2005, Natural history of beta-cell function in type 1 diabetes, Diabetes, 54, S32, 10.2337/diabetes.54.suppl_2.S32 Steele, 2004, Insulin secretion in type 1 diabetes, Diabetes, 53, 426, 10.2337/diabetes.53.2.426 Klinke, 2011, Age-corrected beta cell mass following onset of type 1 diabetes mellitus correlates with plasma C-peptide in humans, PLoS One, 6, e26873, 10.1371/journal.pone.0026873 Barker, 2014, Age-dependent decline of beta-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study, Diabetes, Obesity & Metabolism, 16, 262, 10.1111/dom.12216 Dost, 2007, Shorter remission period in young versus older children with diabetes mellitus type 1, Experimental and Clinical Endocrinology & Diabetes, 115, 33, 10.1055/s-2007-948214 Akirav, 2008, Beta-cell mass and type 1 diabetes: going, going, gone?, Diabetes, 57, 2883, 10.2337/db07-1817 Chmelova, 2015, Distinct roles of beta-cell mass and function during type 1 diabetes onset and remission, Diabetes, 64, 2148, 10.2337/db14-1055 Tersey, 2012, Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model, Diabetes, 61, 818, 10.2337/db11-1293 Meier, 2006, Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes, Diabetologia, 49, 1838, 10.1007/s00125-006-0308-2 Willcox, 2010, Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes, Diabetologia, 53, 2020, 10.1007/s00125-010-1817-6 Levitt, 2011, Glucose stimulates human beta cell replication in vivo in islets transplanted into NOD-severe combined immunodeficiency (SCID) mice, Diabetologia, 54, 572, 10.1007/s00125-010-1919-1 Meier, 2005, Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?, Diabetologia, 48, 2221, 10.1007/s00125-005-1949-2 Poudel, 2015, Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes, Endocrine, 49, 693, 10.1007/s12020-015-0534-9 Keenan, 2010, Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study, Diabetes, 59, 2846, 10.2337/db10-0676 Coppieters, 2011, Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals, Diabetes/Metabolism Research and Reviews, 27, 746, 10.1002/dmrr.1246 O'Meara, 1995, Alterations in the patterns of insulin secretion before and after diagnosis of IDDM, Diabetes Care, 18, 568, 10.2337/diacare.18.4.568 Tsai, 2006, The rise and fall of insulin secretion in type 1 diabetes mellitus, Diabetologia, 49, 261, 10.1007/s00125-005-0100-8 Greenbaum, 2009, Preservation of beta-cell function in autoantibody-positive youth with diabetes, Diabetes Care, 32, 1839, 10.2337/dc08-2326 Sherr, 2014, Characterization of residual beta cell function in long-standing type 1 diabetes, Diabetes/Metabolism Research and Reviews, 30, 154, 10.1002/dmrr.2478 Wang, 2012, Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay, Diabetes Care, 35, 465, 10.2337/dc11-1236 Oram, 2014, The majority of patients with long-duration type 1 diabetes are insulin microsecretors and have functioning beta cells, Diabetologia, 57, 187, 10.1007/s00125-013-3067-x Oram, 2015, Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors, Diabetes Care, 38, 323, 10.2337/dc14-0871 Brush, 1944, Initial stabilization of the diabetic child, American Journal of Diseases of Children, 67, 429 Jackson, 1940, Stabilization of the diabetic child, American Journal of Diseases of Children, 59, 332 Block, 1973, Sequential changes in beta-cell function in insulin-treated diabetic patients assessed by C-peptide immunoreactivity, The New England Journal of Medicine, 288, 1144, 10.1056/NEJM197305312882202 Kaas, 2012, Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes, Pediatric Diabetes, 13, 51, 10.1111/j.1399-5448.2011.00812.x Scholin, 2011, Proinsulin/C-peptide ratio, glucagon and remission in new-onset Type 1 diabetes mellitus in young adults, Diabetic Medicine, 28, 156, 10.1111/j.1464-5491.2010.03191.x Abdul-Rasoul, 2006, 'The honeymoon phase' in children with type 1 diabetes mellitus: frequency, duration, and influential factors, Pediatric Diabetes, 7, 101, 10.1111/j.1399-543X.2006.00155.x Chase, 2004, Redefining the clinical remission period in children with type 1 diabetes, Pediatric Diabetes, 5, 16, 10.1111/j.1399-543X.2004.00034.x Muhammad, 1999, Partial remission phase of diabetes in children younger than age 10 years, Archives of Disease in Childhood, 80, 367, 10.1136/adc.80.4.367 Scholin, 1999, Factors predicting clinical remission in adult patients with type 1 diabetes, Journal of Internal Medicine, 245, 155, 10.1046/j.1365-2796.1999.00426.x Scholin, 2004, Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in Type 1 diabetes, Diabetic Medicine, 21, 447, 10.1111/j.1464-5491.2004.01175.x Karges, 2004, Complete long-term recovery of beta-cell function in autoimmune type 1 diabetes after insulin treatment, Diabetes Care, 27, 1207, 10.2337/diacare.27.5.1207 Kahn, 2006, Mechanisms linking obesity to insulin resistance and type 2 diabetes, Nature, 444, 840, 10.1038/nature05482 Meigs, 2006, Body mass index, metabolic syndrome, and risk of type 2 diabetes or cardiovascular disease, Journal of Clinical Endocrinology & Metabolism, 91, 2906, 10.1210/jc.2006-0594 Kahn, 1993, Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function, Diabetes, 42, 1663, 10.2337/diab.42.11.1663 Ogilvie, 1933, The islands of langerhans in 19 cases of obesity, Journal of Pathology and Bacteriology, 37, 473, 10.1002/path.1700370314 Yoon, 2003, Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea, Journal of Clinical Endocrinology & Metabolism, 88, 2300, 10.1210/jc.2002-020735 Hanley, 2010, {beta}-Cell mass dynamics and islet cell plasticity in human type 2 diabetes, Endocrinology, 151, 1462, 10.1210/en.2009-1277 Matsumoto, 2004, Improvement in islet yield from obese donors for human islet transplants, Transplantation, 78, 880, 10.1097/01.TP.0000134396.03440.1E Brandhorst, 1995, Body mass index of pancreatic donors: a decisive factor for human islet isolation, Experimental and Clinical Endocrinology & Diabetes, 103, 23 Butler, 2003, Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes, Diabetes, 52, 102, 10.2337/diabetes.52.1.102 Rahier, 2008, Pancreatic beta-cell mass in European subjects with type 2 diabetes, Diabetes, Obesity & Metabolism, 10, 32, 10.1111/j.1463-1326.2008.00969.x Saisho, 2013, Beta-cell mass and turnover in humans: effects of obesity and aging, Diabetes Care, 36, 111, 10.2337/dc12-0421 Mezza, 2014, Insulin resistance alters islet morphology in nondiabetic humans, Diabetes, 63, 994, 10.2337/db13-1013 Yoneda, 2013, Predominance of beta-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes, Journal of Clinical Endocrinology & Metabolism, 98, 2053, 10.1210/jc.2012-3832 Ferrannini, 1997, Insulin resistance and hypersecretion in obesity. European group for the Study of Insulin Resistance (EGIR), The Journal of Clinical Investigation, 100, 1166, 10.1172/JCI119628 Seltzer, 1967, Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus, The Journal of Clinical Investigation, 46, 323, 10.1172/JCI105534 Lillioja, 1993, Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians, The New England Journal of Medicine, 329, 1988, 10.1056/NEJM199312303292703 Camastra, 2005, beta-cell function in morbidly obese subjects during free living: long-term effects of weight loss, Diabetes, 54, 2382, 10.2337/diabetes.54.8.2382 Polonsky, 1988, Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects, The Journal of Clinical Investigation, 81, 442, 10.1172/JCI113339 Perley, 1966, Plasma insulin responses to glucose and tolbutamide of normal weight and obese diabetic and nondiabetic subjects, Diabetes, 15, 867, 10.2337/diab.15.12.867 Mezghenna, 2011, Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity, Diabetologia, 54, 2856, 10.1007/s00125-011-2264-8 Rahier, 1983, Cellular composition of the human diabetic pancreas, Diabetologia, 24, 366, 10.1007/BF00251826 Guiot, 2001, No decrease of the beta-cell mass in type 2 diabetic patients, Diabetes, 50, S188, 10.2337/diabetes.50.2007.S188 Sakuraba, 2002, Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients, Diabetologia, 45, 85, 10.1007/s125-002-8248-z Inaishi, 2016, Effects of Obesity and diabetes on alpha- and beta-cell mass in surgically resected human pancreas, Journal of Clinical Endocrinology & Metabolism, 101, 2874, 10.1210/jc.2016-1374 Kloppel, 1985, Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited, Survey and Synthesis of Pathology Research, 4, 110 Clark, 1988, Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes, Diabetes Research, 9, 151 Deng, 2004, Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects, Diabetes, 53, 624, 10.2337/diabetes.53.3.624 Marchetti, 2007, The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients, Diabetologia, 50, 2486, 10.1007/s00125-007-0816-8 Marchetti, 2004, Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin, Journal of Clinical Endocrinology & Metabolism, 89, 5535, 10.1210/jc.2004-0150 Gastaldelli, 2004, Beta-cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study, Diabetologia, 47, 31, 10.1007/s00125-003-1263-9 Holman, 1998, Assessing the potential for alpha-glucosidase inhibitors in prediabetic states, Diabetes Research and Clinical Practice, 40, S21, 10.1016/S0168-8227(98)00038-2 Jensen, 2002, Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S., Diabetes, 51, 2170, 10.2337/diabetes.51.7.2170 Ward, 1984, Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus, The Journal of Clinical Investigation, 74, 1318, 10.1172/JCI111542 Ferrannini, 2005, Beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis, Journal of Clinical Endocrinology & Metabolism, 90, 493, 10.1210/jc.2004-1133 Osei, 1997, Pathogenetic mechanisms of impaired glucose tolerance and type II diabetes in African-Americans. The significance of insulin secretion, insulin sensitivity, and glucose effectiveness, Diabetes Care, 20, 396, 10.2337/diacare.20.3.396 Kendall, 1990, Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans, The New England Journal of Medicine, 322, 898, 10.1056/NEJM199003293221305 Robertson, 2002, Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients, Transplantation, 73, 736, 10.1097/00007890-200203150-00013 Brunzell, 1976, Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests, Journal of Clinical Endocrinology & Metabolism, 42, 222, 10.1210/jcem-42-2-222 Lang, 1981, Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man, Diabetes, 30, 435, 10.2337/diab.30.5.435 Polonsky, 1988, Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus, The New England Journal of Medicine, 318, 1231, 10.1056/NEJM198805123181903 Schauer, 2016, Clinical Outcomes of metabolic surgery: efficacy of glycemic control, weight loss, and remission of diabetes, Diabetes Care, 39, 902, 10.2337/dc16-0382 Jorgensen, 2012, Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance, American Journal of Physiology. Endocrinology and Metabolism, 303, E122, 10.1152/ajpendo.00073.2012 Guidone, 2006, Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery, Diabetes, 55, 2025, 10.2337/db06-0068 Polyzogopoulou, 2003, Restoration of euglycemia and normal acute insulin response to glucose in obese subjects with type 2 diabetes following bariatric surgery, Diabetes, 52, 1098, 10.2337/diabetes.52.5.1098 Malandrucco, 2012, Very-low-calorie diet: a quick therapeutic tool to improve beta cell function in morbidly obese patients with type 2 diabetes, American Journal of Clinical Nutrition, 95, 609, 10.3945/ajcn.111.023697 Lim, 2011, Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol, Diabetologia, 54, 2506, 10.1007/s00125-011-2204-7 Accili, 2016, When beta-cells fail: lessons from dedifferentiation, Diabetes, Obesity & Metabolism, 18, 117, 10.1111/dom.12723 Talchai, 2012, Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure, Cell, 150, 1223, 10.1016/j.cell.2012.07.029 Wang, 2014, Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy, Cell Metabolism, 19, 872, 10.1016/j.cmet.2014.03.010 Butler, 2016, Beta-cell deficit in obese type 2 diabetes, a minor role of beta-cell dedifferentiation and degranulation, Journal of Clinical Endocrinology & Metabolism, 101, 523, 10.1210/jc.2015-3566 Cinti, 2016, Evidence of beta-cell dedifferentiation in human type 2 diabetes, Journal of Clinical Endocrinology & Metabolism, 101, 1044, 10.1210/jc.2015-2860 Md Moin, 2016, Increased frequency of hormone negative and polyhormonal endocrine cells in lean individuals with type 2 diabetes, Journal of Clinical Endocrinology & Metabolism, 101, 3628, 10.1210/jc.2016-2496 Guo, 2013, Inactivation of specific beta cell transcription factors in type 2 diabetes, The Journal of Clinical Investigation, 123, 3305, 10.1172/JCI65390 Meier, 2009, Functional assessment of pancreatic beta-cell area in humans, Diabetes, 58, 1595, 10.2337/db08-1611 Weyer, 1999, The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus, The Journal of Clinical Investigation, 104, 787, 10.1172/JCI7231 Porksen, 2002, The in vivo regulation of pulsatile insulin secretion, Diabetologia, 45, 3, 10.1007/s125-002-8240-x Porksen, 2002, Pulsatile insulin secretion: detection, regulation, and role in diabetes, Diabetes, 51, S245, 10.2337/diabetes.51.2007.S245 Matveyenko, 2012, Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling, Diabetes, 61, 2269, 10.2337/db11-1462 Leahy, 1992, Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion, Diabetes Care, 15, 442, 10.2337/diacare.15.3.442 Leahy, 2010, Targeting beta-cell function early in the course of therapy for type 2 diabetes mellitus, Journal of Clinical Endocrinology & Metabolism, 95, 4206, 10.1210/jc.2010-0668 Meier, 2013, Role of reduced β-cell mass versus impaired β-cell function in the pathogenesis of type 2 diabetes, Diabetes Care, 36, S113, 10.2337/dcS13-2008 Kahn, 2009, The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality, Diabetologia, 52, 1003, 10.1007/s00125-009-1321-z Pancreatic beta-cell mass or beta-cell function? That is the question!, (2008). Matveyenko, 2008, Relationship between beta-cell mass and diabetes onset, Diabetes, Obesity & Metabolism, 10, 23, 10.1111/j.1463-1326.2008.00939.x Defronzo, 2009, Banting lecture. from the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus, Diabetes, 58, 773, 10.2337/db09-9028 Saxena, 2007, Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels, Science, 316, 1331, 10.1126/science.1142358 Scott, 2007, A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants, Science, 316, 1341, 10.1126/science.1142382 Zeggini, 2007, Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes, Science, 316, 1336, 10.1126/science.1142364 Krogvold, 2015, Function of isolated pancreatic islets from patients at onset of type 1 diabetes: insulin secretion can be restored after some days in a nondiabetogenic environment in vitro: results from the DiViD Study, Diabetes, 64, 2506, 10.2337/db14-1911 Lupi, 2004, Improved insulin secretory function and reduced chemotactic properties after tissue culture of islets from type 1 diabetic patients, Diabetes/Metabolism Research and Reviews, 20, 246, 10.1002/dmrr.460 Conget, 1993, Human pancreatic islet function at the onset of type 1 (insulin-dependent) diabetes mellitus, Diabetologia, 36, 358, 10.1007/BF00400241 Johnson, 2002, Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells, Proceedings of the National Academy of Sciences of the United States of America, 99, 14566, 10.1073/pnas.222099799 De Marchi, 2014, Calcium co-regulates oxidative metabolism and ATP synthase-dependent respiration in pancreatic beta cells, The Journal of Biological Chemistry, 289, 9182, 10.1074/jbc.M113.513184 Dolai, 2016, Synaptotagmin-7 functions to replenish insulin granules for exocytosis in human islet beta-cells, Diabetes, 65, 1962, 10.2337/db15-1436 Braun, 2008, Voltage-gated ion channels in human pancreatic beta-cells: electrophysiological characterization and role in insulin secretion, Diabetes, 57, 1618, 10.2337/db07-0991 Brissova, 2005, Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy, The Journal of Histochemistry and Cytochemistry, 53, 1087, 10.1369/jhc.5C6684.2005 Arnush, 1998, IL-1 produced and released endogenously within human islets inhibits beta cell function, The Journal of Clinical Investigation, 102, 516, 10.1172/JCI844 Dorrell, 2011, Transcriptomes of the major human pancreatic cell types, Diabetologia, 54, 2832, 10.1007/s00125-011-2283-5 Cnop, 2014, RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate, Diabetes, 63, 1978, 10.2337/db13-1383 Fadista, 2014, Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism, Proceedings of the National Academy of Sciences of the United States of America, 111, 13924, 10.1073/pnas.1402665111 Bugliani, 2013, Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction, Molecular and Cellular Endocrinology, 367, 1, 10.1016/j.mce.2012.12.001 Wang, 2016, Single-cell transcriptomics of the human endocrine pancreas, Diabetes, 65, 3028, 10.2337/db16-0405 Li, 2016, Single-cell transcriptomes reveal characteristic features of human pancreatic islet cell types, EMBO Reports, 17, 178, 10.15252/embr.201540946 Muraro, 2016, A single-cell transcriptome atlas of the human pancreas, Cell Systems, 3, 10.1016/j.cels.2016.09.002 Segerstolpe, 2016, Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes, Cell Metabolism, 24, 593, 10.1016/j.cmet.2016.08.020 Lawlor, 2016, Single cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes, Genome Research Xin, 2016, RNA sequencing of single human islet cells reveals type 2 diabetes genes, Cell Metabolism, 24, 608, 10.1016/j.cmet.2016.08.018 Arystarkhova, 2013, Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase, The Journal of Biological Chemistry, 288, 7077, 10.1074/jbc.M112.401190 Nyblom, 2009, Apoptotic, regenerative, and immune-related signaling in human islets from type 2 diabetes individuals, Journal of Proteome Research, 8, 5650, 10.1021/pr9006816 Wang, 2016, Single-cell mass cytometry analysis of the human endocrine pancreas, Cell Metabolism, 24, 616, 10.1016/j.cmet.2016.09.007 Benthuysen, 2016, Advances in beta cell replacement and regeneration strategies for treating diabetes, The Journal of Clinical Investigation, 126, 3651, 10.1172/JCI87439 Pagliuca, 2014, Generation of functional human pancreatic beta cells in vitro, Cell, 159, 428, 10.1016/j.cell.2014.09.040 Rezania, 2014, Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells, Nature Biotechnology, 32, 1121, 10.1038/nbt.3033 Russ, 2015, Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro, The EMBO Journal, 34, 1759, 10.15252/embj.201591058 Vegas, 2016, Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice, Nature Medicine, 22, 306, 10.1038/nm.4030 Millman, 2016, Generation of stem cell-derived beta-cells from patients with type 1 diabetes, Nature Communications, 7, 11463, 10.1038/ncomms11463 Boj, 2015, Organoid models of human and mouse ductal pancreatic cancer, Cell, 160, 324, 10.1016/j.cell.2014.12.021 Huang, 2015, Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids, Nature Medicine, 21, 1364, 10.1038/nm.3973 Hohwieler, 2017, Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling, Gut, 66, 473, 10.1136/gutjnl-2016-312423 Grapin-Botton, 2016, Three-dimensional pancreas organogenesis models, Diabetes, Obesity & Metabolism, 18, 33, 10.1111/dom.12720 Dorrell, 2016, Human islets contain four distinct subtypes of beta cells, Nature Communications, 7, 11756, 10.1038/ncomms11756 Arda, 2016, Age-dependent pancreatic gene regulation reveals mechanisms governing human beta cell function, Cell Metabolism, 23, 909, 10.1016/j.cmet.2016.04.002 Marselli, 2014, Are we overestimating the loss of beta cells in type 2 diabetes?, Diabetologia, 57, 362, 10.1007/s00125-013-3098-3 Speier, 2003, A novel approach to in situ characterization of pancreatic beta-cells, Pflugers Archiv, 446, 553, 10.1007/s00424-003-1097-9 Poosti, 2015, Precision-cut kidney slices (PCKS) to study development of renal fibrosis and efficacy of drug targeting ex vivo, Disease Models & Mechanisms, 8, 1227 de Graaf, 2010, Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies, Nature Protocols, 5, 1540, 10.1038/nprot.2010.111 Wang, 2015, Cardiac tissue slices: preparation, handling, and successful optical mapping, American Journal of Physiology. Heart and Circulatory Physiology, 308, H1112, 10.1152/ajpheart.00556.2014 Rodriguez-Diaz, 2012, Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function, Proceedings of the National Academy of Sciences of the United States of America, 109, 21456, 10.1073/pnas.1211659110 Meneghel-Rozzo, 2004, In vivo and in vitro development of mouse pancreatic beta-cells in organotypic slices, Cell & Tissue Research, 316, 295, 10.1007/s00441-004-0886-6 Rose, 2007, Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats, The Journal of General Physiology, 129, 493, 10.1085/jgp.200609604 Speier, 2007, Cx36-mediated coupling reduces beta-cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics, Diabetes, 56, 1078, 10.2337/db06-0232 Speier, 2005, KATP-channels in beta-cells in tissue slices are directly modulated by millimolar ATP, Molecular and Cellular Endocrinology, 230, 51, 10.1016/j.mce.2004.11.002 Huang, 2011, Unperturbed islet alpha-cell function examined in mouse pancreas tissue slices, Journal of Physiology, 589, 395, 10.1113/jphysiol.2010.200345 Huang, 2013, In situ electrophysiological examination of pancreatic alpha cells in the streptozotocin-induced diabetes model, revealing the cellular basis of glucagon hypersecretion, Diabetes, 62, 519, 10.2337/db11-0786 Dolensek, 2013, The relationship between membrane potential and calcium dynamics in glucose-stimulated beta cell syncytium in acute mouse pancreas tissue slices, PLoS One, 8, e82374, 10.1371/journal.pone.0082374 Marciniak, 2013, Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ, PLoS One, 8, e78706, 10.1371/journal.pone.0078706 Stozer, 2013, Glucose-stimulated calcium dynamics in islets of Langerhans in acute mouse pancreas tissue slices, PLoS One, 8, e54638, 10.1371/journal.pone.0054638 Stozer, 2013, Functional connectivity in islets of Langerhans from mouse pancreas tissue slices, PLoS Computational Biology, 9, e1002923, 10.1371/journal.pcbi.1002923 Marciniak, 2014, Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology, Nature Protocols, 9, 2809, 10.1038/nprot.2014.195 Cohrs, 2017, Vessel network architecture of adult human islets promotes distinct cell-cell interactions in situ and is altered after transplantation, Endocrinology, 10.1210/en.2016-1184 Karimian, 2013, Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats, Diabetes, 62, 2968, 10.2337/db13-0164 Ehehalt, 2015, Blood glucose homeostasis in the course of partial pancreatectomy–evidence for surgically reversible diabetes induced by cholestasis, PLoS One, 10, e0134140, 10.1371/journal.pone.0134140 Kilimnik, 2012, Quantification of islet size and architecture, Islets, 4, 167, 10.4161/isl.19256 Levy, 1998, Correct homeostasis model assessment (HOMA) evaluation uses the computer program, Diabetes Care, 21, 2191, 10.2337/diacare.21.12.2191 Matthews, 1985, Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, Diabetologia, 28, 412, 10.1007/BF00280883 Osundiji, 2012, Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion, Diabetes, 61, 321, 10.2337/db11-1050 Nano, 2016, Islet volume and indexes of beta-cell function in humans, Cell Transplantation, 25, 491, 10.3727/096368915X688498 Robertson, 2015, Assessment of beta-cell mass and alpha- and beta-cell survival and function by arginine stimulation in human autologous islet recipients, Diabetes, 64, 565, 10.2337/db14-0690 Ryan, 2002, Successful islet transplantation: continued insulin reserve provides long-term glycemic control, Diabetes, 51, 2148, 10.2337/diabetes.51.7.2148 Teuscher, 1998, Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass, Diabetes, 47, 324, 10.2337/diabetes.47.3.324 Meier, 2012, Pancreatic diabetes manifests when beta cell area declines by approximately 65% in humans, Diabetologia, 55, 1346, 10.1007/s00125-012-2466-8 Brelje, 1993, Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy, Endocrinology, 132, 879, 10.1210/endo.132.2.8425500 Gravena, 2002, Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans, Journal of Endocrinology, 173, 73, 10.1677/joe.0.1730073 Henquin, 2006, Nutrient control of insulin secretion in isolated normal human islets, Diabetes, 55, 3470, 10.2337/db06-0868 Farilla, 2003, Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets, Endocrinology, 144, 5149, 10.1210/en.2003-0323 Lupi, 1997, Effects of glibenclamide and metformin (alone or in combination) on insulin release from isolated human pancreatic islets, Acta Diabetologica, 34, 46, 10.1007/s005920050065 Butler, 2010, Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy, Diabetologia, 53, 2167, 10.1007/s00125-010-1809-6 Sweet, 2004, Non-invasive imaging of beta cell mass: a quantitative analysis, Diabetes Technology & Therapeutics, 6, 652, 10.1089/dia.2004.6.652 Malosio, 2015, MR imaging monitoring of iron-labeled pancreatic islets in a small series of patients: islet fate in successful, unsuccessful, and autotransplantation, Cell Transplantation, 24, 2285, 10.3727/096368914X684060 Saudek, 2010, Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans, Transplantation, 90, 1602, 10.1097/TP.0b013e3181ffba5e Toso, 2008, Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling, American Journal of Transplantation, 8, 701, 10.1111/j.1600-6143.2007.02120.x Bennet, 2000, Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes, Upsala Journal of Medical Sciences, 105, 125, 10.1517/03009734000000059 Leoni, 2010, Functional MRI characterization of isolated human islet activation, NMR in Biomedicine, 23, 1158, 10.1002/nbm.1542 Botsikas, 2012, Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients, Islets, 4, 243, 10.4161/isl.20857 Eich, 2007, Visualization of early engraftment in clinical islet transplantation by positron-emission tomography, The New England Journal of Medicine, 356, 2754, 10.1056/NEJMc070201 Eriksson, 2016, Positron emission tomography to assess the outcome of intraportal islet transplantation, Diabetes, 65, 2482, 10.2337/db16-0222 Goland, 2009, 11C-dihydrotetrabenazine PET of the pancreas in subjects with long-standing type 1 diabetes and in healthy controls, Journal of Nuclear Medicine, 50, 382, 10.2967/jnumed.108.054866 Normandin, 2012, In vivo imaging of endogenous pancreatic beta-cell mass in healthy and type 1 diabetic subjects using 18F-fluoropropyl-dihydrotetrabenazine and PET, Journal of Nuclear Medicine, 53, 908, 10.2967/jnumed.111.100545 Eriksson, 2014, Positron emission tomography ligand [11C]5-hydroxy-tryptophan can be used as a surrogate marker for the human endocrine pancreas, Diabetes, 63, 3428, 10.2337/db13-1877 Brom, 2014, Non-invasive quantification of the beta cell mass by SPECT with (1)(1)(1)In-labelled exendin, Diabetologia, 57, 950, 10.1007/s00125-014-3166-3 Mandel, 1982, Organ culture of fetal mouse and fetal human pancreatic islets for allografting, Diabetes, 31, 39, 10.2337/diab.31.4.S39 Hayek, 1997, Experimental transplantation of human fetal and adult pancreatic islets, Journal of Clinical Endocrinology & Metabolism, 82, 2471 Fransson, 2015, Mesenchymal stromal cells support endothelial cell interactions in an intramuscular islet transplantation model, Regenerative Medicine Research, 3, 1, 10.1186/s40340-015-0010-9 Meier, 2014, Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow, PLoS One, 9, e91268, 10.1371/journal.pone.0091268 Zaldumbide, 2013, Genetically engineered human islets protected from CD8-mediated autoimmune destruction in vivo, Molecular Therapy, 21, 1592, 10.1038/mt.2013.105 Gargani, 2013, Adaptive changes of human islets to an obesogenic environment in the mouse, Diabetologia, 56, 350, 10.1007/s00125-012-2775-y Westermark, 1995, Rapid deposition of amyloid in human islets transplanted into nude mice, Diabetologia, 38, 543, 10.1007/BF00400722 Shiroki, 1994, Human peripheral blood lymphocyte reconstituted severe combined immunodeficient (hu-PBL-SCID) mice. A model for human islet allograft rejection, Transplantation, 57, 1555, 10.1097/00007890-199457110-00004 Wang, 2015, A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication, Nature Medicine, 21, 383, 10.1038/nm.3820 Dai, 2016, Stress-impaired transcription factor expression and insulin secretion in transplanted human islets, The Journal of Clinical Investigation, 126, 1857, 10.1172/JCI83657 Abdulreda, 2016, Liraglutide compromises pancreatic beta cell function in a humanized mouse model, Cell Metabolism, 23, 541, 10.1016/j.cmet.2016.01.009 Fowler, 2005, Assessment of pancreatic islet mass after islet transplantation using in vivo bioluminescence imaging, Transplantation, 79, 768, 10.1097/01.TP.0000152798.03204.5C Berclaz, 2016, Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging, Diabetologia, 59, 550, 10.1007/s00125-015-3819-x Chen, 2016, Alterations in beta-cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset, Diabetes, 65, 2676, 10.2337/db15-1718 Speier, 2008, Noninvasive in vivo imaging of pancreatic islet cell biology, Nature Medicine, 14, 574, 10.1038/nm1701 Speier, 2011, Experimental approaches for high-resolution in vivo imaging of islet of Langerhans biology, Current Diabetes Reports, 11, 420, 10.1007/s11892-011-0207-x