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• W2057152032 abstract "The factors that regulate pancreatic beta cell proliferation are not well defined. In order to explore the role of murine placental lactogen (PL)-I (mPL-I) in islet mass regulationin vivo, we developed transgenic mice in which mPL-I is targeted to the beta cell using the rat insulin II promoter. Rat insulin II-mPL-I mice displayed both fasting and postprandial hypoglycemia (71 and 105 mg/dl, respectively) as compared with normal mice (92 and 129 mg/dl; p < 0.00005 for both). Plasma insulin concentrations were inappropriately elevated, and insulin content in the pancreas was increased 2-fold. Glucose-stimulated insulin secretion by perifused islets was indistinguishable from controls at 7.5, 15, and 20 mm glucose. Beta cell proliferation rates were twice normal (p = 0.0005). This hyperplasia, together with a 20% increase in beta cell size, resulted in a 2-fold increase in islet mass (p = 0.0005) and a 1.45-fold increase in islet number (p = 0.0012). In mice, murine PL-I is a potent islet mitogen, is capable of increasing islet mass, and is associated with hypoglycemia over the long term. It can be targeted to the beta cell using standard gene targeting techniques. Potential exists for beta cell engineering using this strategy. The factors that regulate pancreatic beta cell proliferation are not well defined. In order to explore the role of murine placental lactogen (PL)-I (mPL-I) in islet mass regulationin vivo, we developed transgenic mice in which mPL-I is targeted to the beta cell using the rat insulin II promoter. Rat insulin II-mPL-I mice displayed both fasting and postprandial hypoglycemia (71 and 105 mg/dl, respectively) as compared with normal mice (92 and 129 mg/dl; p < 0.00005 for both). Plasma insulin concentrations were inappropriately elevated, and insulin content in the pancreas was increased 2-fold. Glucose-stimulated insulin secretion by perifused islets was indistinguishable from controls at 7.5, 15, and 20 mm glucose. Beta cell proliferation rates were twice normal (p = 0.0005). This hyperplasia, together with a 20% increase in beta cell size, resulted in a 2-fold increase in islet mass (p = 0.0005) and a 1.45-fold increase in islet number (p = 0.0012). In mice, murine PL-I is a potent islet mitogen, is capable of increasing islet mass, and is associated with hypoglycemia over the long term. It can be targeted to the beta cell using standard gene targeting techniques. Potential exists for beta cell engineering using this strategy. parathyroid hormone-related protein placental lactogen murine placental lactogen base pair(s) rat insulin-II promoter radioimmunoassay It is well documented that pancreatic islet mass does not remain constant during life, but adapts to changing physiologic conditions. For example, there is a marked increase in islet proliferation during pregnancy, glucose infusion, or recovery from pancreatic resection (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar). Conversely, a reduction in islet proliferation and mass is observed in the post-partum or fasting state (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar). Islet mass may change either as a result of proliferation, hypertrophy or apoptosis of existing islet cells, or through islet neogenesis from ductal cells (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar). Understanding the mechanisms underlying islet growth and differentiation is essential not only from a physiologic and developmental standpoint, but is also likely to be important for the development of new treatment approaches to diabetes.A number of factors have been implicated in the regulation of islet mass. These include glucose itself, gastrin, transforming growth factor-α, insulin-like growth factor-1, pancreatic stone peptide and the reg family of gene products, glucagon-like peptide, islet neogenesis-associated protein, parathyroid hormone-related protein (PTHrP),1 hepatocyte growth factor, growth hormone, prolactin, and the placental lactogens (PL) (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar, 8.Swenne I. Diabetes. 1985; 34: 803-807Crossref PubMed Google Scholar, 9.Wang T.C. Bonner-Weir S. Oates P.S. Chulak M.B. Simon B. Merlino G.T. Schmidt E.V. Brand S.J. J. Clin. Invest. 1993; 92: 1349-1356Crossref PubMed Scopus (244) Google Scholar, 10.Rafaeloff R. Pittenger G.L. Barlow S.W. Qin X.F. Yan B. Rosenberg L. Duguid W.P. Vinik A.I. J. Clin. Invest. 1997; 99: 2100-2109Crossref PubMed Scopus (196) Google Scholar, 11.Vasavada R. Cavaliere C. D'Ercole A.J. Dann P. Burtis W.J. Madlener A.L. Zawalich K. Zawalich W. Philbrick W.M. Stewart A.F. J. Biol. Chem. 1996; 271: 1200-1208Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 12.Porter S.E. Sorenson R.L. Dann P. Garcia-Ocaña A. Stewart A.F. Vasavada R.C. Endocrinology. 1998; 139: 3743-3751Crossref PubMed Scopus (50) Google Scholar, 13.Otonkoski T. Cirulli V. Beattie G.M. Mally M.I. Soto G. Rubin J.S. Hayek A. Endocrinology. 1996; 137: 3131-3139Crossref PubMed Google Scholar, 14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar). Of the several factors known to affect islet growth and function in vitro, PL is one of the most potent in increasing beta cell proliferation, insulin content, and insulin secretion from islets in vitro (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar). The placental lactogens are members of the growth hormone/prolactin family (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar). In rodents, there are at least two PLs, PL-I and PL-II. PL-I is normally made in the trophoblast giant cells of the placenta, with circulating PL-I reaching peak levels during mid-gestation (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 16.Ogren L. Southard J.N. Colosi P. Linzer D.I.H. Talamantes F. Endocrinology. 1989; 125: 2253-2257Crossref PubMed Scopus (55) Google Scholar). Indirect evidence in vivo and in vitro has implicated PL as the primary factor responsible for the increase in islet mass and enhanced insulin secretion observed during pregnancy in rodents and presumably humans as well (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 16.Ogren L. Southard J.N. Colosi P. Linzer D.I.H. Talamantes F. Endocrinology. 1989; 125: 2253-2257Crossref PubMed Scopus (55) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar). To date, unique receptors for PL have not been identified. Instead, in rodents, PL interacts on islet cells with the prolactin receptor, a member of the cytokine family of receptors, which signals through the Janus kinase pathway (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 18.Bole-Feysot C. Goffin V. Edery M. Binart N. Kelley P.A. Endocr. Rev. 1998; 19: 225-268Crossref PubMed Scopus (1558) Google Scholar, 19.Stout L.E. Svensson A.M. Sorenson R.L. Endocrinology. 1997; 138: 1592-1603Crossref PubMed Scopus (50) Google Scholar).Whereas the in vitro effects of PL-I on the pancreatic islet are well documented, no long term in vivo studies exploring the role of PL in islet mass regulation have been described. To directly examine the role of PL-I on islets in vivo, a transgenic mouse model was created in which the murine placental lactogen-I (mPL-I) cDNA was targeted to and expressed in beta cells under the control of the rat insulin-II promoter (RIP). These RIP-mPL-I transgenic mice were characterized for the expression of the transgene, and the long term effect of mPL-I on islet cell physiology, beta cell proliferation, and islet mass in vivo. RIP-mPL-I mice display a marked increase in islet mass, which results from both islet hyperplasia as well as hypertrophy. These changes are associated with hypoglycemia. These findings may have relevance to strategies aimed at enhancing islet mass and function in diabetes.DISCUSSIONThese studies demonstrate that the long term in vivoexpression of mPL-I in the islets of RIP-mPL-I transgenic mice directly results in accelerated beta cell proliferation, islet hyperplasia and hypertrophy, an increase in islet mass, inappropriate hyperinsulinemia with resultant hypoglycemia, and resistance to the diabetogenic effects of streptozotocin. These in vivoresults support the findings of previous in vitro studies in which mPL-I was found to increase beta cell proliferation, insulin content, and insulin secretion (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar). In addition, these findings complement in vivo studies documenting an increase in beta cell proliferation and in islet mass in pregnancy (15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar). Finally, these studies corroborate reports demonstrating that the mid-gestational rise in islet proliferation correlates temporally with the transient mid-gestational appearance of mPL-I (15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 16.Ogren L. Southard J.N. Colosi P. Linzer D.I.H. Talamantes F. Endocrinology. 1989; 125: 2253-2257Crossref PubMed Scopus (55) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar). Taken together, these studies strongly suggest that PL is responsible for the second trimester increase in beta cell mass and function that occurs in pregnancy (15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar).The phenotype of the RIP-mPL-I mouse appears to be a direct consequence of mPL-I expression in the pancreatic islet, rather than an effect of a random integration event of the transgene, since three independent transgenic lines exhibited the same phenotype. That all three lines of transgenic mice expressed the transgene in their islets was documented using pancreatic mRNA analysis, immunohistochemistry, and immunoassay of extracts of isolated islets. One of the three lines, line 60, expressed the transgene at approximately 10-fold higher levels than the other two transgenic lines, but it is important that all three lines were demonstrated to express both the protein and the mRNA, and that the phenotype, including relative hypoglycemia, an increase in islet mass, and accelerated beta cell proliferation, was observed in each of the three lines.A tissue survey demonstrated that the RIP-II promoter used herein led to low but detectable expression of the transgene in sites other than the pancreatic beta cell. These included the liver, kidney, heart, and intestine in line 60, the brain in line 64, and no other site in line 48. These findings are typical of findings reported by others (29.Lo D. Burkly L.C. Widera G. Cowing C. Flavell R.A. Palmiter R.D. Brinster R.L. Cell. 1988; 53: 159-168Abstract Full Text PDF PubMed Scopus (286) Google Scholar, 30.Picarella D.E. Kratz A. Li C.-B. Ruddle N.H. Flavell R.A. Proc. Nat. Acad. Sci. U. S. A. 1992; 89: 10036-10040Crossref PubMed Scopus (123) Google Scholar), using less sensitive techniques such as Northern blotting and immunohistochemistry, as well as RNase protection analysis as used herein. From a pathophysiologic standpoint, four important points should be made here. First, line 48 expressed the transgene only in the beta cell and yet displayed the full spectrum of the phenotype, so it is reasonable to conclude that the phenotype is a direct result of mPL-1 expression in the islet, and not of “leaky” expression in other organs. Second, in line 64, leaky expression was observed only in the brain, supporting the conclusions described in the preceding sentence. Third, it is difficult to construct a pathophysiologic scenario for line 60 in which expression of the transgene, not in the islet but in the liver, kidney, intestine, and heart could produce hypoglycemia, an increase in islet mass and proliferation, and in pancreatic insulin content. Fourth, it is important to note that in the organs and transgenic lines in which leaky expression was observed, the levels of expression in sites outside the pancreas were dramatically lower than in the pancreas. As islets comprise only 2–3% of pancreatic mass, the level of expression of mPL-1 mRNA in the pancreatic islet of lines 60 and 64 is likely to be some 50–100 times higher than in the other tissues. These findings collectively make the critical point that mPL-1 expression in the islet, and not in other tissues, is responsible for the phenotype.Systemic mPL-I was not detected in the circulation of the RIP-mPL-I mice. This suggests that the islet phenotype was the result of local mPL-I actions within the islet. Moreover, it suggests that systemic consequences of mPL-1, such as insulin resistance, should not occur in the RIP-mPL-I mouse. The reason for the lack of measurable systemic mPL-I is not clear, but most likely reflects secretion at low levels, and/or effective clearance from the portal circulation by the liver.Histomorphometric analysis of islet mass and number in the RIP-mPL-I mouse lines demonstrated a 2-fold increase in total islet mass, with a lesser (1.45-fold) but significant increase in islet number. Importantly, the increase in islet mass and number was observed in each of the three transgenic lines. Whether the increase in islet number is real or is a histomorphometric reflection of an increase in islet size remains to be determined. The increase in islet mass was anticipated from the experience with mPL-1 in vitro and from events occurring in pregnancy as discussed above, as well as from the increased beta cell proliferation and islet cell hypertrophy observed in the RIP-mPL-I mouse.Less clear is the mechanism responsible for the inappropriate hyperinsulinemia and hypoglycemia in the RIP-mPL-I mouse. The inappropriate hyperinsulinemia in the RIP-mPL-I mouse is presumably in part a result of the islet hyperplasia, hypertrophy, and overall increase in islet mass observed. Whether a 2-fold increase in islet mass should lead on its own to increased insulin secretion and hypoglycemia is unsettled. The closest examples of this phenotype of which we are aware are the RIP-PTHrP and RIP-HGF transgenic mouse models (11.Vasavada R. Cavaliere C. D'Ercole A.J. Dann P. Burtis W.J. Madlener A.L. Zawalich K. Zawalich W. Philbrick W.M. Stewart A.F. J. Biol. Chem. 1996; 271: 1200-1208Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 12.Porter S.E. Sorenson R.L. Dann P. Garcia-Ocaña A. Stewart A.F. Vasavada R.C. Endocrinology. 1998; 139: 3743-3751Crossref PubMed Scopus (50) Google Scholar, 31.Garcia-Ocaña A. Takane K. Syed M.A. Philbrick W.M. Vasavada R.C. Stewart A.F. J. Biol. Chem. 2000; 275: 1226-1232Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar), where a similar increase in islet mass was also accompanied by inappropriately normal insulin concentrations in plasma. Thus, it may be possible that a minor increase in islet mass could, independent of individual beta cell function, lead to hyperinsulinemia. Alternatively, or in addition, hyperinsulinemia could reflect the abnormal functioning of individual islet cells, resulting in increased insulin synthesis, and/or a lowered glucose-stimulated insulin secretion threshold with resultant increases in insulin secretion. Placental lactogen has been shown to have all of the above effects on islets or on the isolated perfused pancreas in vitro (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar,15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar). We presume that the inappropriate hyperinsulinemia in the RIP-mPL-I mouse is attributable to a combination of the above factors. Finally, it is formally possible that placental lactogen secreted into the portal circulation may contribute to the hypoglycemia observed, perhaps by altering hepatic glucose uptake or glucose production. This cannot be the primary pathophysiologic feature of the phenotype, as it would not explain the increase in insulin production and the increase in islet mass and proliferation. These considerations support the concept that the primary action of placental lactogen is a direct effect on the beta cell to increase its mass and function.One might postulate that the hypoglycemia in the RIP-mPL-1 mouse could be due to increased periperal insulin sensitivity, since hypoglycemia is present in the presence of normal insulin concentrations. At least two considerations make this hypothesis unlikely. First, there is no plausible reason for there to be increased insulin sensitivity. If anything, placental lactogen is believed to be associated with peripheral insulin resistance. Second, if this mechanism were operative, one would still expect a reduction in circulating insulin concentrations and in islet mass and pancreatic insulin content, as occurs, for example in the non-involved islets in patients and rats with insulinomas, or as occurs during prolonged fasting. These are not a feature of the RIP-mPL-1 mouse.Previous reports describe a leftward shift in the insulin secretory response curve in the pregnant pancreas (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar, 17.Parsons J.A. Brelje T.C. Sorenson R.L. Endocrinology. 1992; 130: 1459-1466Crossref PubMed Scopus (187) Google Scholar). One might therefore have predicted that glucose-stimulated insulin secretion might be enhanced in isolated perfused RIP-mPL-I islets. On the other hand, one might have imagined that proliferation induced by mPL-I would be accompanied by de-differentiation of beta cells and an associated decline in insulin secretory responses to glucose. In fact, when the insulin secretory response of isolated RIP-mPL-I islets was examinedin vitro, there was no obvious difference between the insulin secretion profile of islets from transgenic mice compared with their normal littermates at the three glucose concentrations tested. Whether glucose-stimulated insulin secretion in vitroreflects the functioning of mPL-I islets in vivo is uncertain. Most previous studies examining the influence of PL or PRL on insulin secretion in vitro have employed the perfused rat pancreas (15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar). The few studies performed on isolated islets indicate that a minimum concentration of mPL-I of 50–60 ng/ml is required, over a period of 4 days, to observe any effects of mPL-I on glucose-stimulated insulin secretion in vitro (14.Brelje T.C. Scharp D.W. Lacy P.E. Ogren L. Talamantes F. Robertson M. Friesen H.G. Sorenson R.L. Endocrinology. 1993; 132: 879-887Crossref PubMed Scopus (193) Google Scholar, 15.Brelje T.C. Sorenson R.L. Horm. Metab. Res. 1997; 29: 301-307Crossref PubMed Scopus (419) Google Scholar). It seems possible, therefore, that the mPL-I concentration in the RIP-mPL-I islets is too low to cause a change in their insulin secretion profile in vitro. It is also possible that the lack of change in glucose-stimulated insulin secretion reflects a balance of two opposing effects: de-differentiation induced by mPL-I on the one hand, neutralized or balanced by a leftward shift in the insulin response to glucose on the other hand. Additionally, it is possible that the islet isolation process injures or alters the insulin secretory response to glucose. Based on what is known to occur in pregnancy and in vitro with mPL-1, we would anticipate that more extensive studies using larger numbers of islets, a broader range of glucose concentrations, a different array of insulin secretagogues, and/or in vivo studies with the perfused mouse pancreas orin vivo glucose clamp studies in the RIP-mPL-I mouse may very well demonstrate differences in the dynamics of glucose-stimulated insulin secretion by RIP-mPL-I mouse islets as compared with normal islets.The primary rationale for preparing the RIP-mPL-I mouse was to explore the potential therapeutic role for PL in enhancing islet mass and/or function in diabetes. With this idea in mind, streptozotocin was employed to induce diabetes. The RIP-mPL-I mouse was found to be streptozotocin-resistant, whereas their normal littermates exposed to the same dose of streptozotocin developed frank diabetes. The underlying physiology resulting in the maintenance of euglycemia remains to be defined. It may simply reflect the increase in islet mass in the RIP-mPL-I mouse, or may reflect proliferative or other functional changes in the RIP-mPL-I islets. Further studies will be required to define the physiology underlying this phenomenon.The RIP-mPL-I mouse, the RIP-HGF mouse, and the RIP-PTHrP mouse represent three in vivo transgenic mouse models of increased islet mass leading to inappropriate hyperinsulinemia and hypoglycemia. The three islet-targeted proteins, mPL-I, HGF, and PTHrP, act via different receptors coupled to different intracellular signaling pathways (protein kinases A and C in the case of PTHrP (32.Vasavada R.C. Garcia-Ocaña A. Massfelder T. Dann P. Stewart A.F. Rec. Prog. Hormone Res. 1998; 53: 305-340PubMed Google Scholar), MAP kinase in the case of HGF (31.Garcia-Ocaña A. Takane K. Syed M.A. Philbrick W.M. Vasavada R.C. Stewart A.F. J. Biol. Chem. 2000; 275: 1226-1232Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar), and Janus kinase in the case of mPL-I (18.Bole-Feysot C. Goffin V. Edery M. Binart N. Kelley P.A. Endocr. Rev. 1998; 19: 225-268Crossref PubMed Scopus (1558) Google Scholar,19.Stout L.E. Svensson A.M. Sorenson R.L. Endocrinology. 1997; 138: 1592-1603Crossref PubMed Scopus (50) Google Scholar)). Whereas they result in what appear to be superficially similar phenotypes, the mechanisms by which PTHrP, HGF and mPL-I increase islet mass in their respective transgenic mouse models are quite different; mPL-I and HGF cause accelerated beta cell proliferation (with a component of islet cell hypertrophy as well in the case of mPL-I), whereas PTHrP seems to affect neither, and instead likely acts by slowing the normal rate of beta cell turnover (11.Vasavada R. Cavaliere C. D'Ercole A.J. Dann P. Burtis W.J. Madlener A.L. Zawalich K. Zawalich W. Philbrick W.M. Stewart A.F. J. Biol. Chem. 1996; 271: 1200-1208Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 12.Porter S.E. Sorenson R.L. Dann P. Garcia-Ocaña A. Stewart A.F. Vasavada R.C. Endocrinology. 1998; 139: 3743-3751Crossref PubMed Scopus (50) Google Scholar). These differences in signaling pathways and phenotypes may suggest that delivery of two or more of these proteins simultaneously to the beta cell might have synergistic effects. Such studies are under way.Finally, at one level, the targeted delivery of mPL-I to the beta cell may seem pedestrian in the sense that the phenotype was largely predictable from prior in vitro studies. On the other hand, the finding that tissue-specific delivery to the beta cell of factors such as PTHrP, HGF, and mPL-I, which enhance islet mass and function, has clear implications for strategies aimed at enhancing islet mass and function in patients with diabetes. It is well documented that pancreatic islet mass does not remain constant during life, but adapts to changing physiologic conditions. For example, there is a marked increase in islet proliferation during pregnancy, glucose infusion, or recovery from pancreatic resection (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar). Conversely, a reduction in islet proliferation and mass is observed in the post-partum or fasting state (1.Finegood D.T. Scaglia L. Bonner-Weir S. Diabetes. 1995; 44: 249-256Crossref PubMed Scopus (540) Google Scholar, 2.Swenne I. Diabetologia. 1992; 35: 193-201Crossref PubMed Scopus (186) Google Scholar, 3.Korc M. J. Clin. Invest. 1993; 92: 1113-1114Crossref PubMed Scopus (22) Google Scholar, 4.Efrat S. Diabetes Rev. 1996; 4: 224-234Google Scholar, 5.Bonner-Weir S. Deery D. Leahy J.L. Weir G.C. Diabetes. 1989; 38: 49-53Crossref PubMed Google Scholar, 6.Miyaura C. Chen L. Appel M. Alam T. Inman L. Hughes S.D. Milburn J.L. Unger R.H. Newgard C.B. Mol. Endocrinol. 1991; 5: 226-234Crossref PubMed Scopus (77) Google Scholar, 7.Scaglia L. Smith F.E. Bonner-Weir S. Endocrinology. 1995; 136: 5461-5468Crossref PubMed Scopus (191) Google Scholar). Isl" @default.
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