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Jun-Li Liu, Ph.D. Associate Professor |
Research:
- Pancreatic islet cell growth, survival and regeneration;
- Transgenic and knockout mice;
- Growth hormone and IGF-I;
- Reg family proteins
Insufficient islet β-cell mass is the root cause of autoimmunity-induced type 1 diabetes (T1DM) and a key element in type 2 diabetes (T2DM) associated with insulin resistance. In T2DM, amyloid deposits and/or hyperglycemia cause β-cell apoptosis and diminished cell mass. A normal β-cell mass is maintained by at least four independent mechanisms: mitogenic replication, cell size, neogenesis (transformed from other pancreatic cells) and apoptosis. The sum of the rates of β-cell replication, hypertrophy and neogenesis, minus the rate of apoptosis is the net rate of β-cell growth. Various growth factors have been reported to stimulate islet cell growth. In a therapeutic setting, β-cell mass can also be supplemented by islet transplantation where growth factors have been found to promote the survival and/or expansion of transplanted cells in rodents. Unfortunately very few of these factors have been proven potent and specific enough for clinical applications.
Insulin-like growth factor I (IGF-I) is a peptide hormone mainly produced from the liver. Other tissues also generate IGF-I at lower and variable levels. As its name accurately reflects, IGF-I has two major biological functions: promoting cell growth (growth factor) and regulating glucose metabolism (insulin-like). Thus, IGF-I is potentially useful to expand pancreatic islets (growth) and to complement insulin (metabolism) in both types of diabetes mellitus. Currently, we are using a robust, pancreatic islet-enriched overexpression to study the effects on pancreatic islet cell growth, cell death, glucose-stimulated insulin secretion, and hepatic glucose production.
Reg family proteins were first discovered for their role in pancreatic islet cell growth and regeneration, started from Reg1 and INGAP (Reg3d). Recently, I have found that new members of the family, especially Reg2 and Reg3b, were activated in the pancreas under two conditions; i.e. in the pancreatic IGF-I gene deficient (PID) mice where I have reported islet enlargement and protection against type 1 diabetes; and in wild-type mice after being made diabetic by streptozotocin, when undergoing islet regeneration and recovery from the damage. Under those conditions, changes in Reg1 and INGAP (the two known growth factors) were only marginal. Moreover, Reg2 has been demonstrated to be expressed predominantly in islet b-cells and to play a dual role of growth factor and b-cell autoantigene; gene knockout studies demonstrated that Reg3b is a critical growth factor for the liver regeneration. I propose that Reg2 and Reg3b promote islet cell growth and regeneration and can potentially be used to combat T1DM. Elucidation of their actions and identification of their molecular targets should provide fundamental insight into the biology of these proteins and lead to the design and development of novel strategies aimed at improving the islet function and combating the development of diabetes mellitus.
Selected Publications:
Y Lu, PL Herrera, Y Guo, D Sun, Z Tang, D LeRoith, and JL Liu. Pancreatic specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 2004; 53: 3131-3141
JL Liu, KT Coschigano, K Robertson, M Lipsett, Y Guo, JJ Kopchick, U Kumar, and YL Liu. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol 2004; 287: E405-413
Z Tang, R Yu, Y Lu, AF Parlow and JL Liu. Age-dependent onset of liver-specific IGF-I gene deficiency and its persistence in old age: implications for postnatal growth and insulin resistance in LID mice. Amer J Physiol 2005; 289: E288-295
Y Guo, Y Lu, D Houle, K Robertson, Z Tang, JJ Kopchick, YL Liu and JL Liu. Pancreatic islet-specific expression of an IGF-I transgene compensates islet cell growth in growth hormone receptor gene deficient mice. Endocrinology 2005; 146: 2602–2609
K Robertson, JJ Kopchick and JL Liu. Growth hormone receptor deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice. Amer J Physiol 2006；291: E491-498
Y Lu, A Ponton, H Okamoto, S Takasawa, PL Herrera, and JL Liu. Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas. Amer J Physiol 2006; 291: E50-8
K Robertson, Y Lu, B Li, Q Su, PK Lund and JL Liu. A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia and significant resistance to experimental diabetes. Amer J Physiol-Endo Metab 2008; 294: E928-38
K De Jesus, X Wang and JL Liu. A general IGF-I overexpression effectively rescued somatic growth and bone deficiency in mice caused by growth hormone receptor knockout. Growth Factors 2009; 27: 438-447
W Cui, K De Jesus, H Zhao, S Takasawa, B Shi, CB Srikant and JL Liu. Overexpression of Reg3α gene increased cell growth and the levels of cyclin D1 and cdk4 in insulinoma cells. Growth Factors 2009; 27(3): 195-202