{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:07:52Z","timestamp":1791205672133,"version":"4.1.0"},"reference-count":70,"publisher":"American Diabetes Association","issue":"7","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,7,1]]},"abstract":"<jats:p>Type 2 diabetes is characterized by defects in insulin secretion and action and is preceded by impaired fasting glucose (IFG). The islet anatomy in IFG and type 2 diabetes reveals an \u223c50 and 65% deficit in \u03b2-cell mass, with increased \u03b2-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Defects in insulin action include both hepatic and extrahepatic insulin resistance. The relationship between changes in \u03b2-cell mass, \u03b2-cell function, and insulin action leading to type 2 diabetes are unresolved, in part because it is not possible to measure \u03b2-cell mass in vivo, and most available animal models do not recapitulate the islet pathology in type 2 diabetes. We evaluated the HIP rat, a human IAPP transgenic rat model that develops islet pathology comparable to humans with type 2 diabetes, at age 2 months (nondiabetic), 5 months (with IFG), and 10 months (with diabetes) to prospectively examine the relationship between changes in islet morphology versus insulin secretion and action. We report that increased \u03b2-cell apoptosis and impaired first-phase insulin secretion precede the development of IFG, which coincides with an \u223c50% defect in \u03b2-cell mass and onset of hepatic insulin resistance. Diabetes was characterized by \u223c70% deficit in \u03b2-cell mass, progressive hepatic and extrahepatic insulin resistance, and hyperglucagonemia. We conclude that IAPP-induced \u03b2-cell apoptosis causes defects in insulin secretion and \u03b2-cell mass that lead first to hepatic insulin resistance and IFG and then to extrahepatic insulin resistance, hyperglucagonemia, and diabetes. We conclude that a specific \u03b2-cell defect can recapitulate the metabolic phenotype of type 2 diabetes and note that insulin resistance in type 2 diabetes may at least in part be secondary to \u03b2-cell failure.<\/jats:p>","DOI":"10.2337\/db05-1672","type":"journal-article","created":{"date-parts":[[2006,6,27]],"date-time":"2006-06-27T18:39:44Z","timestamp":1151433584000},"page":"2106-2114","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":126,"title":["\u03b2-Cell Deficit Due to Increased Apoptosis in the Human Islet Amyloid Polypeptide Transgenic (HIP) Rat Recapitulates the Metabolic Defects Present in Type 2 Diabetes"],"prefix":"10.2337","volume":"55","author":[{"given":"Aleksey V.","family":"Matveyenko","sequence":"first","affiliation":[{"name":"From the Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Butler","sequence":"additional","affiliation":[{"name":"From the Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031209350735200_R1","doi-asserted-by":"crossref","unstructured":"Bjorntorp P: Abdominal obesity and the development of noninsulin-dependent diabetes mellitus. Diabetes Metab Rev\u20084:615\u2013622,1988","DOI":"10.1002\/dmr.5610040607"},{"key":"2022031209350735200_R2","doi-asserted-by":"crossref","unstructured":"Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ: Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes\u200845:633\u2013638,1996","DOI":"10.2337\/diab.45.5.633"},{"key":"2022031209350735200_R3","doi-asserted-by":"crossref","unstructured":"Yki-Jarvinen H: Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia\u200838:1378\u20131388,1995","DOI":"10.1007\/BF00400597"},{"key":"2022031209350735200_R4","doi-asserted-by":"crossref","unstructured":"DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: a balanced overview. Diabetes Care\u200815:318\u2013368,1992","DOI":"10.2337\/diacare.15.3.318"},{"key":"2022031209350735200_R5","doi-asserted-by":"crossref","unstructured":"Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC: Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care\u200817:961\u2013969,1994","DOI":"10.2337\/diacare.17.9.961"},{"key":"2022031209350735200_R6","doi-asserted-by":"crossref","unstructured":"Polonsky KS, Given BD, Van Cauter E: Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest\u200881:442\u2013448,1988","DOI":"10.1172\/JCI113339"},{"key":"2022031209350735200_R7","doi-asserted-by":"crossref","unstructured":"Perley MJ, Kipnis DM: Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J Clin Invest\u200846:1954\u20131962,1967","DOI":"10.1172\/JCI105685"},{"key":"2022031209350735200_R8","doi-asserted-by":"crossref","unstructured":"Boden G, Soeldner JS, Gleason RE, Marble A: Elevated serum human growth hormone and decreased serum insulin in prediabetic males after intravenous tolbutamide and glucose. J Clin Invest\u200847:729\u2013739,1968","DOI":"10.1172\/JCI105768"},{"key":"2022031209350735200_R9","doi-asserted-by":"crossref","unstructured":"van Haeften TW, Dubbeldam S, Zonderland ML, Erkelens DW: Insulin secretion in normal glucose-tolerant relatives of type 2 diabetic subjects: assessments using hyperglycemic glucose clamps and oral glucose tolerance tests. Diabetes Care\u200821:278\u2013282,1998","DOI":"10.2337\/diacare.21.2.278"},{"key":"2022031209350735200_R10","doi-asserted-by":"crossref","unstructured":"Seltzer HS, Allen EW, Herron AL Jr, Brennan MT: Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest\u200846:323\u2013335,1967","DOI":"10.1172\/JCI105534"},{"key":"2022031209350735200_R11","doi-asserted-by":"crossref","unstructured":"Temple RC, Carrington CA, Luzio SD, Owens DR, Schneider AE, Sobey WJ, Hales CN: Insulin deficiency in non-insulin-dependent diabetes. Lancet\u20081:293\u2013295,1989","DOI":"10.1016\/S0140-6736(89)91306-8"},{"key":"2022031209350735200_R12","doi-asserted-by":"crossref","unstructured":"Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC: \u03b2-Cell deficit and increased \u03b2-cell apoptosis in humans with type 2 diabetes. Diabetes\u200852:102\u2013110,2003","DOI":"10.2337\/diabetes.52.1.102"},{"key":"2022031209350735200_R13","doi-asserted-by":"crossref","unstructured":"Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH: Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci U S A\u200891:10878\u201310882,1994","DOI":"10.1073\/pnas.91.23.10878"},{"key":"2022031209350735200_R14","doi-asserted-by":"crossref","unstructured":"Tomita T, Doull V, Pollock HG, Krizsan D: Pancreatic islets of obese hyperglycemic mice (ob\/ob). Pancreas\u20087:367\u2013375,1992","DOI":"10.1097\/00006676-199205000-00015"},{"key":"2022031209350735200_R15","doi-asserted-by":"crossref","unstructured":"Donath MY, Gross DJ, Cerasi E, Kaiser N: Hyperglycemia-induced \u03b2-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes\u200848:738\u2013744,1999","DOI":"10.2337\/diabetes.48.4.738"},{"key":"2022031209350735200_R16","doi-asserted-by":"crossref","unstructured":"Portha B, Giroix MH, Serradas P, Gangnerau MN, Movassat J, Rajas F, Bailbe D, Plachot C, Mithieux G, Marie JC: \u03b2-Cell function and viability in the spontaneously diabetic GK rat: information from the GK\/Par colony. Diabetes\u200850 (Suppl. 1):S89\u2013S93,2001","DOI":"10.2337\/diabetes.50.2007.S89"},{"key":"2022031209350735200_R17","doi-asserted-by":"crossref","unstructured":"Butler PC, Chou J, Carter WB, Wang YN, Bu BH, Chang D, Chang JK, Rizza RA: Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes\u200839:752\u2013756,1990","DOI":"10.2337\/diabetes.39.6.752"},{"key":"2022031209350735200_R18","doi-asserted-by":"crossref","unstructured":"Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science\u2008300:486\u2013489,2003","DOI":"10.1126\/science.1079469"},{"key":"2022031209350735200_R19","doi-asserted-by":"crossref","unstructured":"Westermark P, Engstrom U, Johnson KH, Westermark GT, Betsholtz C: Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A\u200887:5036\u20135040,1990","DOI":"10.1073\/pnas.87.13.5036"},{"key":"2022031209350735200_R20","doi-asserted-by":"crossref","unstructured":"Betsholtz C, Svensson V, Rorsman F, Engstrom U, Westermark GT, Wilander E, Johnson K, Westermark P: Islet amyloid polypeptide (IAPP): cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus. Exp Cell Res\u2008183:484\u2013493,1989","DOI":"10.1016\/0014-4827(89)90407-2"},{"key":"2022031209350735200_R21","doi-asserted-by":"crossref","unstructured":"Howard CF Jr: Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia\u200829:301\u2013306,1986","DOI":"10.1007\/BF00452067"},{"key":"2022031209350735200_R22","doi-asserted-by":"crossref","unstructured":"O\u2019Brien TD: Pathogenesis of feline diabetes mellitus. Mol Cell Endocrinol\u2008197:213\u2013219,2002","DOI":"10.1016\/S0303-7207(02)00265-4"},{"key":"2022031209350735200_R23","doi-asserted-by":"crossref","unstructured":"King H, Aubert RE, Herman WH: Global burden of diabetes,1995\u20132025: prevalence, numerical estimates, and projections. Diabetes Care\u200821:1414\u20131431, 1998","DOI":"10.2337\/diacare.21.9.1414"},{"key":"2022031209350735200_R24","doi-asserted-by":"crossref","unstructured":"Hoppener JW, Oosterwijk C, Nieuwenhuis MG, Posthuma G, Thijssen JH, Vroom TM, Ahren B, Lips CJ: Extensive islet amyloid formation is induced by development of type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model. Diabetologia\u200842:427\u2013434,1999","DOI":"10.1007\/s001250051175"},{"key":"2022031209350735200_R25","doi-asserted-by":"crossref","unstructured":"Butler AE, Janson J, Soeller WC, Butler PC: Increased \u03b2-cell apoptosis prevents adaptive increase in \u03b2-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes\u200852:2304\u20132314,2003","DOI":"10.2337\/diabetes.52.9.2304"},{"key":"2022031209350735200_R26","doi-asserted-by":"crossref","unstructured":"Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC: Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A\u200893:7283\u20137288,1996","DOI":"10.1073\/pnas.93.14.7283"},{"key":"2022031209350735200_R27","doi-asserted-by":"crossref","unstructured":"Couce M, Kane LA, O\u2019Brien TD, Charlesworth J, Soeller W, McNeish J, Kreutter D, Roche P, Butler PC: Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and \u03b2-cell dysfunction. Diabetes\u200845:1094\u20131101,1996","DOI":"10.2337\/diab.45.8.1094"},{"key":"2022031209350735200_R28","doi-asserted-by":"crossref","unstructured":"Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC: Diabetes due to a progressive defect in \u03b2-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. Diabetes\u200853:1509\u20131516,2004","DOI":"10.2337\/diabetes.53.6.1509"},{"key":"2022031209350735200_R29","doi-asserted-by":"crossref","unstructured":"Butler PC, Rizza RA: Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or NIDDM patients. Diabetes\u200840:73\u201381,1991","DOI":"10.2337\/diabetes.40.1.73"},{"key":"2022031209350735200_R30","doi-asserted-by":"crossref","unstructured":"Butler PC, Kryshak EJ, Schwenk WF, Haymond MW, Rizza RA: Hepatic and extrahepatic responses to insulin in NIDDM and nondiabetic humans: assessment in absence of artifact introduced by tritiated nonglucose contaminants. Diabetes\u200839:217\u2013225,1990","DOI":"10.2337\/diab.39.2.217"},{"key":"2022031209350735200_R31","unstructured":"Meier JJ, Butler PC: Insulin secretion. In Endocrinology. 5th ed. DeGroot LJ, Jameson JL, Eds. Philadelphia, Elsevier Saunders,2005, p.961\u2013973"},{"key":"2022031209350735200_R32","doi-asserted-by":"crossref","unstructured":"Robertson RP, Zhang HJ, Pyzdrowski KL, Walseth TF: Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. J Clin Invest\u200890:320\u2013325,1992","DOI":"10.1172\/JCI115865"},{"key":"2022031209350735200_R33","doi-asserted-by":"crossref","unstructured":"Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP: Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci U S A\u200896:10857\u201310862,1999","DOI":"10.1073\/pnas.96.19.10857"},{"key":"2022031209350735200_R34","doi-asserted-by":"crossref","unstructured":"Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY: Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest\u2008110:851\u2013860,2002","DOI":"10.1172\/JCI200215318"},{"key":"2022031209350735200_R35","doi-asserted-by":"crossref","unstructured":"Matschinsky F, Liang Y, Kesavan P, Wang L, Froguel P, Velho G, Cohen D, Permutt MA, Tanizawa Y, Jetton TL, et al.: Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest\u200892:2092\u20132098,1993","DOI":"10.1172\/JCI116809"},{"key":"2022031209350735200_R36","doi-asserted-by":"crossref","unstructured":"Maechler P, Wollheim CB: Mitochondrial function in normal and diabetic beta-cells. Nature\u2008414:807\u2013812,2001","DOI":"10.1038\/414807a"},{"key":"2022031209350735200_R37","doi-asserted-by":"crossref","unstructured":"Kawasaki F, Matsuda M, Kanda Y, Inoue H, Kaku K: Structural and functional analysis of pancreatic islets preserved by pioglitazone in db\/db mice. Am J Physiol Endocrinol Metab\u2008288:E510\u2013E518,2005","DOI":"10.1152\/ajpendo.00128.2004"},{"key":"2022031209350735200_R38","doi-asserted-by":"crossref","unstructured":"Harding HP, Ron D: Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes\u200851 (Suppl. 3):S455\u2013S461,2002","DOI":"10.2337\/diabetes.51.2007.S455"},{"key":"2022031209350735200_R39","doi-asserted-by":"crossref","unstructured":"Kaufman RJ: Orchestrating the unfolded protein response in health and disease. J Clin Invest\u2008110:1389\u20131398,2002","DOI":"10.1172\/JCI0216886"},{"key":"2022031209350735200_R40","doi-asserted-by":"crossref","unstructured":"Ohsawa H, Kanatsuka A, Yamaguchi T, Makino H, Yoshida S: Islet amyloid polypeptide inhibits glucose-stimulated insulin secretion from isolated rat pancreatic islets. Biochem Biophys Res Commun\u2008160:961\u2013967,1989","DOI":"10.1016\/0006-291X(89)92529-1"},{"key":"2022031209350735200_R41","doi-asserted-by":"crossref","unstructured":"Tedstone AE, Nezzer T, Hughes SJ, Clark A, Matthews DR: The effect of islet amyloid polypeptide (amylin) and calcitonin gene-related peptide on glucose removal in the anaesthetized rat and on insulin secretion from rat pancreatic islets in vitro. Biosci Rep\u200810:339\u2013345,1990","DOI":"10.1007\/BF01117233"},{"key":"2022031209350735200_R42","doi-asserted-by":"crossref","unstructured":"Larsen MO, Rolin B, Wilken M, Carr RD, Gotfredsen CF: Measurements of insulin secretory capacity and glucose tolerance to predict pancreatic \u03b2-cell mass in vivo in the nicotinamide\/streptozotocin Go\u0308ttingen minipig, a model of moderate insulin deficiency and diabetes. Diabetes\u200852:118\u2013123,2003","DOI":"10.2337\/diabetes.52.1.118"},{"key":"2022031209350735200_R43","doi-asserted-by":"crossref","unstructured":"Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med\u2008344:1343\u20131350,2001","DOI":"10.1056\/NEJM200105033441801"},{"key":"2022031209350735200_R44","doi-asserted-by":"crossref","unstructured":"Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med\u2008346:393\u2013403,2002","DOI":"10.1056\/NEJMoa012512"},{"key":"2022031209350735200_R45","doi-asserted-by":"crossref","unstructured":"Kahn CR: Banting Lecture: Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes\u200843:1066\u20131084,1994","DOI":"10.2337\/diab.43.8.1066"},{"key":"2022031209350735200_R46","doi-asserted-by":"crossref","unstructured":"Mulder H, Ahren B, Sundler F: Islet amyloid polypeptide and insulin gene expression are regulated in parallel by glucose in vivo in rats. Am J Physiol\u2008271:E1008\u2013E1014,1996","DOI":"10.1152\/ajpendo.1996.271.6.E1008"},{"key":"2022031209350735200_R47","doi-asserted-by":"crossref","unstructured":"Katayama T, Imaizumi K, Honda A, Yoneda T, Kudo T, Takeda M, Mori K, Rozmahel R, Fraser P, George-Hyslop PS, Tohyama M: Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer\u2019s disease-linked presenilin-1 mutations. J Biol Chem\u2008276:43446\u201343454,2001","DOI":"10.1074\/jbc.M104096200"},{"key":"2022031209350735200_R48","doi-asserted-by":"crossref","unstructured":"Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M: Induction of neuronal death by ER stress in Alzheimer\u2019s disease. J Chem Neuroanat\u200828:67\u201378,2004","DOI":"10.1016\/j.jchemneu.2003.12.004"},{"key":"2022031209350735200_R49","doi-asserted-by":"crossref","unstructured":"Song SH, McIntyre SS, Shah H, Veldhuis JD, Hayes PC, Butler PC: Direct measurement of pulsatile insulin secretion from the portal vein in human subjects. J Clin Endocrinol Metab\u200885:4491\u20134499,2000","DOI":"10.1210\/jc.85.12.4491"},{"key":"2022031209350735200_R50","doi-asserted-by":"crossref","unstructured":"Porksen N, Munn S, Steers J, Vore S, Veldhuis J, Butler P: Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am J Physiol\u2008269:E478\u2013E488,1995","DOI":"10.1152\/ajpendo.1995.269.3.E478"},{"key":"2022031209350735200_R51","doi-asserted-by":"crossref","unstructured":"Porksen N, Munn S, Steers J, Veldhuis JD, Butler PC: Effects of glucose ingestion versus infusion on pulsatile insulin secretion: the incretin effect is achieved by amplification of insulin secretory burst mass. Diabetes\u200845:1317\u20131323,1996","DOI":"10.2337\/diabetes.45.10.1317"},{"key":"2022031209350735200_R52","doi-asserted-by":"crossref","unstructured":"Larsen MO, Gotfredsen CF, Wilken M, Carr RD, Porksen N, Rolin B: Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity, regularity and entrainment of pulsatile insulin secretion in Gottingen minipigs. Diabetologia\u200846:195\u2013202,2003","DOI":"10.1007\/s00125-002-1011-6"},{"key":"2022031209350735200_R53","doi-asserted-by":"crossref","unstructured":"Kjems LL, Kirby BM, Welsh EM, Veldhuis JD, Straume M, McIntyre SS, Yang D, Lefebvre P, Butler PC: Decrease in \u03b2-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig. Diabetes\u200850:2001\u20132012,2001","DOI":"10.2337\/diabetes.50.9.2001"},{"key":"2022031209350735200_R54","doi-asserted-by":"crossref","unstructured":"Laedtke T, Kjems L, Porksen N, Schmitz O, Veldhuis J, Kao PC, Butler PC: Overnight inhibition of insulin secretion restores pulsatility and proinsulin\/insulin ratio in type 2 diabetes. Am J Physiol Endocrinol Metab\u2008279:E520\u2013E528,2000","DOI":"10.1152\/ajpendo.2000.279.3.E520"},{"key":"2022031209350735200_R55","doi-asserted-by":"crossref","unstructured":"Komjati M, Bratusch-Marrain P, Waldhausl W: Superior efficacy of pulsatile versus continuous hormone exposure on hepatic glucose production in vitro. Endocrinology\u2008118:312\u2013319,1986","DOI":"10.1210\/endo-118-1-312"},{"key":"2022031209350735200_R56","doi-asserted-by":"crossref","unstructured":"Bratusch-Marrain PR, Komjati M, Waldhausl WK: Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type I diabetic humans. Diabetes\u200835:922\u2013926,1986","DOI":"10.2337\/diabetes.35.8.922"},{"key":"2022031209350735200_R57","doi-asserted-by":"crossref","unstructured":"Goodner CJ, Sweet IR, Harrison HC Jr: Rapid reduction and return of surface insulin receptors after exposure to brief pulses of insulin in perifused rat hepatocytes. Diabetes\u200837:1316\u20131323,1988","DOI":"10.2337\/diabetes.37.10.1316"},{"key":"2022031209350735200_R58","doi-asserted-by":"crossref","unstructured":"Hirashima Y, Tsuruzoe K, Kodama S, Igata M, Toyonaga T, Ueki K, Kahn CR, Araki E: Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase\/Akt pathway. J Endocrinol\u2008179:253\u2013266,2003","DOI":"10.1677\/joe.0.1790253"},{"key":"2022031209350735200_R59","doi-asserted-by":"crossref","unstructured":"Meier JJ, Veldhuis JD, Butler PC: Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes\u200854:1649\u20131656,2005","DOI":"10.2337\/diabetes.54.6.1649"},{"key":"2022031209350735200_R60","doi-asserted-by":"crossref","unstructured":"Johnson KH, O\u2019Brien TD, Betsholtz C, Westermark P: Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med\u2008321:513\u2013518,1989","DOI":"10.1056\/NEJM198908243210806"},{"key":"2022031209350735200_R61","doi-asserted-by":"crossref","unstructured":"Tabata H, Hirayama J, Sowa R, Furuta H, Negoro T, Sanke T, Nanjo K: Islet amyloid polypeptide (IAPP\/amylin) causes insulin resistance in perfused rat hindlimb muscle. Diabetes Res Clin Pract\u200815:57\u201361,1992","DOI":"10.1016\/0168-8227(92)90068-3"},{"key":"2022031209350735200_R62","doi-asserted-by":"crossref","unstructured":"DeFronzo RA, Simonson D, Ferrannini E: Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia\u200823:313\u2013319,1982","DOI":"10.1007\/BF00253736"},{"key":"2022031209350735200_R63","doi-asserted-by":"crossref","unstructured":"Yki-Jarvinen H: Glucose toxicity. Endocr Rev\u200813:415\u2013431,1992","DOI":"10.1210\/er.13.3.415"},{"key":"2022031209350735200_R64","doi-asserted-by":"crossref","unstructured":"Ritzel R, Butler AE, Rizza RA, Veldhuis JD, Butler PC: Relationship between \u03b2-cell mass and fasting blood glucose concentration in humans. Diabetes Care\u200829:717\u2013718,2006","DOI":"10.2337\/diacare.29.03.06.dc05-1538"},{"key":"2022031209350735200_R65","doi-asserted-by":"crossref","unstructured":"Gotoh M, Monden M, Okamura J, Mori T, Shima K: Insulin and glucagon secretion after pancreatectomies: correlation of secretion and hormonal contents of remaining pancreas. Diabetes\u200838:861\u2013867,1989","DOI":"10.2337\/diab.38.7.861"},{"key":"2022031209350735200_R66","doi-asserted-by":"crossref","unstructured":"Goodner CJ, Koerker DJ, Weigle DS, McCulloch DK: Decreased insulin- and glucagon-pulse amplitude accompanying \u03b2-cell deficiency induced by streptozocin in baboons. Diabetes\u200838:925\u2013931,1989","DOI":"10.2337\/diabetes.38.7.925"},{"key":"2022031209350735200_R67","doi-asserted-by":"crossref","unstructured":"Kendall DM, Sutherland DE, Najarian JS, Goetz FC, Robertson RP: Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med\u2008322:898\u2013903,1990","DOI":"10.1056\/NEJM199003293221305"},{"key":"2022031209350735200_R68","doi-asserted-by":"crossref","unstructured":"Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW: Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci U S A\u200890:7951\u20137955,1993","DOI":"10.1073\/pnas.90.17.7951"},{"key":"2022031209350735200_R69","doi-asserted-by":"crossref","unstructured":"Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW: Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci\u200813:1676\u20131687,1993","DOI":"10.1523\/JNEUROSCI.13-04-01676.1993"},{"key":"2022031209350735200_R70","doi-asserted-by":"crossref","unstructured":"Ritzel RA, Butler PC: Replication increases \u03b2-cell vulnerability to human islet amyloid polypeptide-induced apoptosis. Diabetes\u200852:1701\u20131708,2003","DOI":"10.2337\/diabetes.52.7.1701"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/55\/7\/2106\/384991\/zdb00706002106.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/55\/7\/2106\/384991\/zdb00706002106.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:06:33Z","timestamp":1667405193000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/55\/7\/2106\/14172\/Cell-Deficit-Due-to-Increased-Apoptosis-in-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,7,1]]},"references-count":70,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2006,7,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db05-1672","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,7,1]]}}}