Targeted Expression of Placental Lactogen in the Beta Cells of Transgenic Mice Results in Beta Cell Proliferation, Islet Mass Augmentation, and Hypoglycemia

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 regulation in 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.

Glial Cell Line-Derived Neurotrophic Factor Increases β-Cell Mass and Improves Glucose Tolerance

“…The ratio of plasma insulin to blood glucose was higher in the GDNF-tg mice compared to WT mice. This is similar to what was observed in transgenic mice that overexpress placental lactogen in β-cells that also have increased β-cell mass 20 . The capacity of GDNF to diminish chemically induced β-cell destruction was also demonstrated in vivo.…”

“…Our studies demonstrate a three-fold increase in β-cell mass in GDNF-tg mice compared to WT mice. This degree of enhancement is similar to the three-fold increase in β-cell mass observed in other growth factor overexpression studies, including PTH-RP and placental lactogen 20,21 . It is important to note that the effects of GDNF on β-cells is not a systemic effect as serum GDNF levels have been measured in GDNF-tg mice and are no different from littermate controls 10 .…”

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

“…However, exogenous addition of lactogenic peptides did not confer complete protection against GLT-mediated beta cell death. Previously, we found that lactogens can protect rodent beta cells against other cell death inducers including STZ and DEX [23][24][25][26]. Recent findings show that PRL also protects human beta cells against different cell death inducers, including cytokines, hydrogen peroxide and serum-starvation [28,29].…”

“…Mouse strains These studies used 3-6-month-old male and female RIP-mPl1 transgenic mice bred onto a CD-1 background [24,25], and 3-8-month-old male and female Bclxl lox/lox mice [30] kindly provided by L. Hennighausen (National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, USA). All studies were performed with the approval of, and in accordance with, guidelines established by the University of Pittsburgh Institutional Animal Care and Use Committee, and principles of laboratory animal care were followed.…”

“…RIP-mPl1 transgenic mice are hypoglycaemic and hyperinsulinaemic, and display beta cell hyperplasia as a result of increased beta cell proliferation. These mice are also resistant to the diabetogenic and cytotoxic effects of the beta cell toxin streptozotocin (STZ) [24][25][26]. Studies from our group and others have found that lactogens improve beta cell survival against specific cell-death inducers, including STZ, cytokines, reactive oxygen species and the glucocorticoid, dexamethasone (DEX) [24][25][26][27][28][29].…”