My career goal is to conduct medical research and teaching in Canada. This has been set before I graduated from McGill University. During my PhD studies, I have learnt basic molecular and biochemical techniques and studied regulation of a hormone (somatostatin) gene expression. The late Dr. Yogesh C. Patel introduced me into molecular endocrinology. I took a challenge with Dr. Derek LeRoith in order to further my training at the National Institutes of Health (NIH, Bethesda, MD), by performing Cre/loxP-induced conditional gene targeting on IGF-I. We were highly successful in clarifying the role of liver-derived IGF-I in growth and metabolism. Several years ago when I designed my independent research projects I decided to march towards diabetes research, based on the facts that GH/IGF system is highly relevant to insulin production and action, my transgenic mice are very unique tools to solve the questions, and that diabetes incidence is increasing rapidly in recent years due to obesity and lack of physical activities.

MOST SIGNIFICANT CONTRIBUTIONS:

2005 The essential role of growth hormone signaling in maintaining normal pancreatic islet size, insulin production, insulin sensitivity and glucose homeostasis. Decades of research on human, rodents and in cell cultures support a key role of growth hormone signals in pancreatic islet cell growth and regulating insulin responsiveness. Using the growth hormone receptor gene deficient (GHR-/-) mice, I demonstrate that lack of growth hormone signals caused decreased islet β-cell mass and insulin production. At the same time, these mice are hyper sensitive to insulin and exhibit hypoglycemia. At least part of these effects is independent of the general growth retardation, due to their early onset and the extent of islet cell mass reduction. Interestingly, GHR-/- mice exhibit lower serum insulin level, elevated insulin sensitivity, and a lean phenotype, in contrast to human Laron syndrome. Very recently, pancreatic islet-specific expression of an IGF-I transgene compensates islet cell growth in GHR-/- mice.

2004 Tissue-specific effects of IGF-I on pancreatic islet growth and insulin production. Using Cre/loxP-mediated conditional gene targeting, I have studied the effects of IGF-I deficiency in the liver (LID) and pancreas (PID) on pancreatic islet growth and insulin production. (1) LID mice exhibit insulin resistance that results in islet cell hyperplasia and hyperinsulinemia. Insulin resistance occurs mostly in skeletal muscles and can be relieved by inhibiting growth hormone secretion. Islet hyperplasia is a secondary response thus provides no protection against streptozotocin-induced islet cell damage and diabetes. Therefore, liver-produced IGF-I enhances insulin sensitivity at least in part by inhibiting growth hormone release. (2) PID mice exhibit islet enlargement and hypoglycemia; are significantly resistant to streptozotocin-induced type 1 diabetes by preventing islet ?-cell apoptosis; and are resistant to high-fat-diet-induced type 2 diabetes by stimulating islet cell growth. Our results suggest that locally produced IGF-I within the pancreas inhibits islet cell growth, its deficiency provides a protective environment to the β-cells and a potential in combating diabetes.

2002 I have organized a virtual conference “Conditional gene targeting in mice”, invited by the journal Endocrine. Six groups of experts from the US, Sweden and Switzerland summarized achievement in 7 years using the Cre/loxP-mediated conditional gene targeting.

1999 Revised the Somatomedin Hypothesis. Using the Cre/loxP-induced conditional gene targeting, we demonstrated that lack of IGF-I production from the liver, which accounts for 75% of the circulating level, has no effect on normal growth and development. Therefore, we proposed that growth hormone acts directly on target tissues (rather than through liver IGF-I, as previously proposed) and promotes local (paracrine) production of IGF-I, thereby promoting tissue growth. It represents a breakthrough in 40 years of somatomedin research. The concept is revolutionary and has been frequently cited in over 250 articles in only 5 years.

1997 Creation of mice with loxP-tagged IGF-I gene via homologous recombination (IGF-I/loxP mice). Exon 4 of the IGF-I gene was tagged by two loxP repeats that serve as recognition sites for Cre recombinase. This is the first peptide hormone gene to be tagged, and it enables Cre-mediated conditional knockout of the IGF-I gene. As IGF-I is expressed extensively in various tissues and throughout development, international collaborations have been established to specifically knock out IGF-I in the following targets: bone, mammary gland, ovary, prostate gland, heart, brain, and pancreatic islets. We have achieved liver- and pancreatic specific and interferon-inducible IGF-I knockouts (LID & PID). More recent successes include in colon cancer (Can Res 2002; 62: 1030-1035) and the spleen (GH IGF Res 2003; 13: 254-263).