β-Cell mass plasticity in type 2 diabetes

Diabetes, Obesity and Metabolism

Volumn 6, Issue 5, 2004, Pages 319-331

  Del Prato, S ^a   Wishner, W J ^b   Gromada, J ^c   Schluchter, Belinda J ^b  

^a UNIVERSITY OF PISA   (Italy)

^b ELI LILLY AND COMPANY   (United States)

^c Lilly Research Laboratories   (Germany)

Author keywords

Diabetes; Insulin resistance; Plasticity; Preservation; Cell mass

Indexed keywords

AMYLIN; FATTY ACID; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; INSULIN; INSULIN RECEPTOR; METFORMIN; PARATHYROID HORMONE RELATED PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PIOGLITAZONE; PLACENTA LACTOGEN; POTASSIUM CHANNEL STIMULATING AGENT; PROTEIN KINASE B; ROSIGLITAZONE; SCATTER FACTOR; SULFONYLUREA DERIVATIVE; TROGLITAZONE;

APOPTOSIS; CELL COUNT; CELL DIFFERENTIATION; CELL FUNCTION; CELL SURVIVAL; CELL VOLUME; DISEASE COURSE; DRUG MECHANISM; FATTY ACID BLOOD LEVEL; GLUCOSE HOMEOSTASIS; HEREDITY; HUMAN; INSULIN RELEASE; INSULIN SENSITIVITY; INVOLUTION; MOLECULAR MECHANICS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; OXIDATIVE STRESS; PANCREAS ISLET BETA CELL; PLASTICITY; REVIEW;

EID: 4444378429     PISSN: 14628902     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1462-8902.2004.00360.x     Document Type: Review

References (114)

1. Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 1995; 44: 1386-1391.
2. Lillioja S, Mott DM, Spraul M et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med 1993; 329: 1988-1992.
3. Lundgren H, Bengtsson C, Blohme G, Lapidus L, Waldenstrom J. Fasting serum insulin concentration and early insulin response as risk determinants for developing diabetes. Diabet Med 1990; 7: 407-413.
4. Kahn SE. Regulation of β-cell function in vivo: From health to disease. Diabetes Rev 1996; 4: 372-389.
5. Efrat S. Prospects for treatment of type 2 diabetes by expansion of the β-cell mass. Diabetes 2001; 50 (Suppl. 1): S189-S190.
6. Porte D Jr. Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications. Diabetes Metab Res Rev 2001; 17: 181-188.
7. Bernard-Kargar C, Ktorza A. Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes 2001; 50 (Suppl. 1): S30-S35.
8. Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 1997; 138: 1736-1741.
9. Bonner-Weir S. Life and death of the pancreatic β-cells. Trends Endocrinol Metab 2000; 11: 375-378.
10. Bonner-Weir S. β-cell turnover: its assessment and implications. Diabetes 2001; 50 (Suppl. 1): S20-S24.
11. Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren P-O, Orrenius S. Role of apoptosis in pancreatic β-cell death in diabetes. Diabetes 2001; 50: S44-S47.
12. Mandrup-Poulsen T. Beta-cell apoptosis: stimuli and signaling. Diabetes 2001; 50 (Suppl. 1): S58-S63.
13. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102-110.
14. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 1993; 42: 1715-1720.
15. Lipsett M, Finegood DT. β-cell neogenesis during prolonged hyperglycemia in rats. Diabetes 2002; 51: 1834-1841.
16. Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A. β-cell adaptation and decompensation during the progression of diabetes. Diabetes 2001; 50 (Suppl. 1): S154-S159.
17. Efrat S. Genetically engineered pancreatic β-cell lines for cell therapy of diabetes. Ann N Y Acad Sci 1999; 875: 286-293.
18. Vinik A, Pittenger G, Rafaeloff R, Rosenberg L, Duguid W. Determinants of pancreatic islet cell mass: a balance between neogenesis and senescence/apoptosis. Diabetes Rev 1996; 4: 235-263.
19. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003; 46: 3-19.
20. Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 1985; 4: 110-125.
21. Bonner-Weir S, Leahy JL, Weir GC. Induced rat models of noninsulin-dependent diabetes. In: Shafrir E, Renold AE eds. Frontiers in Diabetes Research: Lessons from Animals Diabetes II. London: John Libbey and Company Limited, 1988; 295-300.
22. Leahy JL, Bonner-Weir S, Weir GC. Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion after an incomplete pancreatectomy. J Clin Invest 1988; 81: 1407-1414.
23. Laybutt DR, Sharma A, Sgroi DC, Gaudet J, Bonner-Weir S, Weir GC. Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J Biol Chem 2002; 277: 10912-10921.
24. Laybutt DR, Kaneto H, Hasenkamp W et al. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia. Diabetes 2002; 51: 413-423.
25. Kahn SE. The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 4047-4058.
26. Holman RR. Assessing the potential for α-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract 1998; 40 (Suppl. 1): S21-S25.
27. Moore A, Bonner-Weir S, Weissleder R. Noninvasive in vivo measurement of β-cell mass in mouse model of diabetes. Diabetes 2001; 50: 2231-2236.
28. Larsen MO, Rolin B, Wilken M, Carr RD, Gotfredsen CF. Measurements of insulin secretory capacity and glucose tolerance to predict pancreatic β-cell mass in vivo in the nicotinamide/streptozotocin Göttingen minipig, a model of moderate insulin deficiency and diabetes. Diabetes 2003; 52: 118-123.
29. Clark A, Wells CA, Buley ID et al. Islet amyloid, increased A-cells, reduced B-cells and endocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988; 9: 151-159.
30. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia 2002; 45: 85-96.
31. Guiot Y, Sempoux C, Moulin P, Rahier J. No decrease of the β-cell mass in type 2 diabetic patients. Diabetes 2001; 50 (Suppl. 1): S188.
32. Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger RH. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 1982; 31: 694-700.
33. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia 1983; 24: 366-371.
34. Pick A, Clark J, Kubstrup C et al. Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetic fatty rat. Diabetes 1998; 47: 358-364.
35. Bonner-Weir S, Deery D, Leahy JL, Weir GC. Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion. Diabetes 1989; 38: 49-53.
36. Grill V, Björklund A. Overstimulation and β-cell function. Diabetes 2001; 50 (Suppl. 1): S122-S124.
37. Laybutt DR, Glandt M, Xu G et al. Critical reduction in β-cell mass results in two distinct outcomes over time. J Biol Chem 2003; 278: 2997-3005.
38. Pelengaris S, Khan M, Evan GI. Suppression of myc-induced apoptosis in β cells exposes multiple oncogenic properties of myc and triggers carcinogenic progression. Cell 2002; 109: 321-334.
39. Laybutt DR, Weir GC, Kaneto H et al. Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 2002; 51: 1793-1804.
40. Laybutt R, Hasenkamp W, Groff A et al. Beta-cell adaptation to hyperglycemia. Diabetes 2001; 50 (Suppl. 1): S180-S181.
41. Leibowitz G, Melloul D, Yuli M et al. Defective glucose-regulated insulin gene expression associated with PDX-1 deficiency in the Psammommys obesus model of type 2 diabetes. Diabetes 2001; 50 (Suppl. 1): S138-S139.
42. Stoffers DA, Thomas MK, Habener JF. Homeodomain protein IDX-1: a master regulator of pancreas development and insulin gene expression. Trends Endocrinol Metab 1997; 8: 145-151.
43. Finegood DT, Topp BG. β-cell deterioration - prospects for reversal or prevention. Diabetes Obes Metab 2001; 3 (Suppl. 1): S20-S27.
44. Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. β-Cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-β-cell relationships. Proc Natl Acad Sci USA 1994; 91: 10878-10882.
45. Zhou Y, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest 1994; 93: 870-876.
46. Zhou Y, Grill VE. Long-term exposure to fatty acids and ketones inhibits β-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab 1995; 80: 1584-1590.
47. Lupi R, Del Guerra S, Fierabracci V et al. Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes 2002; 51 (Suppl. 1): S134-S137.
48. Marselli L, Bambini MC, Lupi R et al. Rosiglitazone partially prevents free-fatty acid-induced cytotoxicity in human pancreatic islet cells. Diabetologia 2002; 45 (Suppl. 1): A161, 494 (abstract).
49. Lupi R, Dotta F, Marselli L et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that β-cell death is caspase mediated, partially dependent on ceramide pathway, and bcl-2 regulated. Diabetes 2002; 51: 1437-1442.
50. Sreenan S, Sturis J, Pugh W, Burant CF, Polonsky KS. Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol 1996; 271: E742-E747.
51. Unger RH, Zhou Y-T. Lipotoxicity of β-cells in obesity and in other causes of fatty acid spillover. Diabetes 2001; 50 (Suppl. 1): S118-S121.
52. Lupi R, Del Guerra S, Marselli L et al. Rosiglitazone prevents the impairment of human islet function induced by fatty-acids: evidence for a role PPARin the modulation of insulin secretion. Am J Physiol Endocrinol Metab 2004; 286: E560-567.
53. Shimabukuro M, Zhou Y-T, Lee Y, Unger RH. Troglitazone lowers islet fat and restores β cell function of Zucker diabetic fatty rats. J Biol Chem 1998; 273: 3547-3550.
54. Briaud I. Kelpe C, Johnson L, Tran P, Poitout V. Differential effects of hyperlipidemia on insulin secretion in islets of Langerhans from hyperglycemic versus normoglycemic rats. Diabetes 2002; 51: 662-668.
55. Poitout V, Robertson RP. Minireview: secondary β-cell failure in type 2 diabetes - a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002; 143: 339-342.
56. Lukinius A, Wilander E, Westermark GT, Engstrom U, Westermark P. Co-localization of islet amyloid polypeptide and insulin in the B cell secretary granules of the human pancreatic islets. Diabetologia 1989; 32: 240-244.
57. Kahn SE, Verchere CB, Andrikopoulos S et al. Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans. Diabetes 1998; 47: 640-645.
58. Enoki S, Mitsukawa T, Takemura J et al. Plasma islet amyloid polypeptide levels in obesity, impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1992; 15: 97-102.
59. Leighton B, Cooper GJ. Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 1988; 335: 632-635.
60. Silvestre RA, Peiro' E, De'Gano P, Miralles P, Marco J. Inhibitory effect of rat amylin on the insulin responses to glucose and arginine in the perfused rat pancreas. Regul Pept 1990; 31: 23-31.
61. Cooper GJ, Day AJ, Willis AC, Roberts AN, Reid KB, Leighton B. Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. Biochim Biophys Acta 1989; 1014: 247-258.
62. Sempoux C, Guiot Y, Dubois D, Moulin P, Rahier J. Human type 2 diabetes: morphological evidence for abnormal β-cell function. Diabetes 2001; 50 (Suppl. 1): S172-S177.
63. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 1999; 48: 241-253.
64. Hayden MR, Tyagi SC. Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. Pancreas 2002; 3: 86-108.
65. Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 1999; 48: 491-498.
66. Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 1994; 368: 756-760.
67. Wang F, Hull RL, Vidal J, Cnop M, Kahn SE. Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes 2001; 50: 2514-2520.
68. Kaneto H, Kajimoto Y, Miyagawa J et al. Beneficial effects of antioxidants in diabetes: possible protection of pancreatic β-cells against glucose toxicity. Diabetes 1999; 48: 2398-2406.
69. Pipeleers D, Hoorens A, Marichal-Pipeleers M, Van de Casteel M, Bouwens L, Ling Z. Role of pancreatic β-cells in the process of β-cell death. Diabetes 2001; 50 (Suppl. 1): S52-S57.
70. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 2003; 52: 1-8.
71. Saltiel AR, Kahn CR. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001; 414: 799-806.
72. Patanè G, Piro S, Rabuazzo AM, Anello M, Vigneri R, Purrello F. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic β-cells. Diabetes 2000; 49: 735-740.
73. Lupi R, Del Guerra S, Marselli L et al. PPARgamma ligand specificity in the modulation of insulin release from isolated human islets in response to fatty acid incubation. Diabetologia 2002; 45: A161, 493 (abstract).
74. Kawai T, Hirose H, Seto Y et al. Troglitazone ameliorates lipotoxicity in the β-cell line INS-1 expressing PPAR gamma. Diabetes Res Clin Pract 2002; 56: 83-92.
75. Hevener AL, Reichart D, Janez A, Olefsky J. Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male Wistar rats. Diabetes 2001; 50: 2316-2322.
76. Porter LE, Freed MI, Jones NP et al. Rosiglitazone improves β-cell function as measured by proinsulin/insulin ratio in patients with type 2 diabetes. Diabetes 2000; 49 (Suppl. 1): 495 (abstract).
77. Prigeon RL, Kahn SE, Porte D. Effect of troglitazone on b cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 1998; 83: 819-823.
78. Mei Jia D, Otsuki M. Troglitazone stimulates pancreatic growth in normal rats. Pancreas 2002; 24: 303-312.
79. Buchanan TA, Xiang AH, Peters RK et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002; 51: 2796-2803.
80. Buchanan TA, Xiang AH, Peters RK et al. Response of pancreatic β-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. Diabetes 2000; 49: 782-788.
81. Xiang A, Peters R, Kjos S et al. Continued protection from diabetes during treatment of the TRIPOD cohort with pioglitazone. Diabetes 2003; 52 (Suppl. 1): A75.
82. Jackson RL, Guthrie RA, Murthy DYN. Insulin treatment of children with late chemical diabetes. Metabolism 1973; 22: 403-411.
83. Turner RC, McCarthy ST, Holman RR, Harris E. Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J 1976; 1: 1252-1254.
84. Ilkova H, Glaser B, Tunckale A et al. Induction of long-term glycemic control in newly diagnosed patients by transient intensive insulin treatment. Diabetes Care 1997; 20: 1353-1356.
85. Withers DJ, Gutierrez JS, Towery H et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998; 391: 900-904.
86. Liu W, Chin-Chance C, Lee E-J, Lowe WL Jr. Activation of phosphatidylinositol 3-kinase contributes to insulin-like growth factor I-mediated inhibition of pancreatic β-cell death. Endocrinology 2002; 143: 3802-3812.
87. Lingohr MK, Buettner R, Rhodes CJ. Pancreatic β-cell growth and survival - a role in obesity-linked type 2 diabetes? Trends Mol Med 2002; 8: 375-384.
88. Bloomgarden ZT. Treatment issues in type 2 diabetes. Diabetes Care 2002; 25: 614-619.
89. Nielsen JH, Galsgaard ED, Moldrup A et al. Regulation of β-cell mass by hormones and growth factors. Diabetes 2001; 50 (Suppl. 1): S25-S29.
90. Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 1999; 42: 856-864.
91. Doyle ME, Egan JM. Glucagon-like peptide-1. Recent Prog Horm Res 2001; 56: 377-399.
92. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both β-cell replication and neogenesis, resulting in increased β-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270-2276.
93. Wang Y, Perfetti R, Greig NH et al. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 1997; 99: 2883-2889.
94. Zhou J, Wang X, Pineyro MA, Egan JM. Glucagon-like peptide-1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells. Diabetes 1999; 48: 2358-2366.
95. Drucker DJ. The glucagon-like peptides. Endocrinology 2001; 142: 521-527.
96. Ashcroft FM. Adenosine 5′-triphosphate-sensitive potassium channels. Annu Rev Neurosci 1988; 11: 97-118.
97. + channels in cell survival and differentiation in the endocrine pancreas. Diabetes 2001; 50 (Suppl. 1): S48-S51.
98. Bjork E, Berne C, Kampe O, Wibell L, Oskarsson P, Karlsson FA. Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes. Diabetes 1996; 45: 1427-1430.
99. Rasmussen SB, Sorensen TS, Hansen JB, Mandrup-Poulsen T, Hornum L, Markholst H. Functional rest through intensive treatment with insulin and potassium channel openers preserves residual β-cell function and mass in acutely diabetic BB rats. Horm Metab Res 2000; 32: 294-300.
100. Kullin M, Li Z, Hansenn B, Bjork E, Sandler S, Karlsson FA. K (ATP) channel openers protect rat islets against the toxic effect of streptozotocin. Diabetes 2000; 49: 1131-1136.
101. Palmer JP. β-cell rest and recovery - does it bring patients with latent autoimmune diabetes in adults to euglycemia? Ann N Y Acad Sci 2002; 958: 89-98.
102. Accili D. A kinase in the life of the β cell. J Clin Invest 2001; 108: 1575-1576.
103. Birnbaum M. Overexpression of the protein kinase Akt/PKB in the mouse beta cell (abstract). Beta Cell Biology in the 21st Century, 2001 November 26-28. Bethesda, MD: National Institute of Diabetes & Digestive & Kidney Diseases, 2001, 10.
104. Wrede CE, Dickson LM, Lingohr MK, Briaud I, Rhodes CJ. Protein kinase b/Akt prevents fatty acid-induced apoptosis in pancreatic β-cells (INS-1). J Biol Chem 2002; 277: 49676-49684.
105. García-Ocaña A, Vasavada RC, Cebrian A et al. Transgenic overexpression of hepatocyte growth factor in the β-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes 2001; 50: 2752-2762.
106. Vasavada RC, Garcia-Ocaña A, Zawalich WS et al. Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia. J Biol Chem 2000; 275: 15399-15406.
107. Cebrian A, García-Ocaña A, Takane KK, Sipula D, Stewart AF, Vasavada RC. Overexpression of parathyroid hormone-related protein inhibits pancreatic β-cell death in vivo and in vitro. Diabetes 2002; 51: 3003-3013.
108. Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 1999; 96: 329-339.
109. Leibiger IB, Leibiger B, Berggren P-O. Insulin feedback action on pancreatic β-cell function. FEBS Lett 2002; 532: 1-6.
110. Kushner JA, Jing Y, Schubert M et al. Pdxl restores β-cell function in IRS-2 knockout mice. J Clin Invest 2002; 109: 1193-1201.
111. Yoshida S, Kajimoto Y, Yasuda T et al. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Diabetes 2002; 51: 2505-2513.
112. Mayerson AB, Hundal RS, Dufour S et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797-802.
113. Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001; 414: 821-827.
114. Lingohr MK, Dickson LM, McCuaig JF, Hugl SR, Twardzik DR, Rhodes CJ. Activation of IRS-2 mediated signal transduction by IGF-1, but not TGF-α or EGF, augments pancreatic β-cell proliferation. Diabetes 2002; 51: 966-976.