Plenary Lectures

Although the classical motor cortex (area 4 of Brodmann) plays a clinically definable lead role in the control of movement, the great majority of neocortical areas, even sensory areas like the primary visual cortex (Bromann's area 17) have large pyramidal cells in layer 5 that innervate subcortical motor centers. The anatomical basis of this apparently widespread motor function of the cerebral cortex will be explored.


Plenary Lecture 2
The Masato Kasuga Award for outstanding scientific achievement presentation and lecture N. Kubota Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo, Japan Naoto Kubota is an Associate Professor in the Department of Clinical Nutrition Therapy at the University of Tokyo where he has been a member of Department of Diabetes and Metabolic Diseases, Graduate School of Medicine since 1998. He currently serves as the Director of Department of Clinical Nutrition Therapy at the University of Tokyo Hospital.
He is a certified Physician of the Japanese Society of Internal Medicine, Bariatrician of Japan Society for the Study of Obesity, and also Specialist of the Japan Diabetes Society and Japan Society of Metabolism and Clinical Nutrition.
In 2001, Dr. Kubota's co-research with Dr. Kadowaki and other 3 members was awarded the Baelz Prize. He is also the winner of the Lilly Prize (The Japan Diabetes Society) in 2008 followed by Scientific Encouragement Award (Japan The development of type 2 diabetes involves both a reduction in insulin secretion and an increase in insulin resistance, but involvement of insulin resistance associated with lifestyle changes, in particular, is said to play a major role in the background of the explosive growth in numbers of type 2 diabetes patients in recent years. Insulin resistance is a pathological state in which insulin action is impaired due to a variety of causes, and understanding physiological insulin signaling mechanisms and elucidating their pathophysiological roles is essential to preventing the onset and progression of type 2 diabetes and its complications.
I have identified that the nuclear receptor PPARc is a thrifty gene, and a key molecule linked to obesity and insulin resistance. PPARc was later reported to be a type 2 diabetes susceptibility gene in humans. This research not only identified PPARc's new functions, but also contributed greatly to the study of type 2 diabetes susceptibility genes in humans. Moreover, a global expression analysis that used the adipose tissues of heterozygous PPARc-deficient mice revealed adiponectin expression was found to be high along with leptin, and I produced adiponectin knockout mice, whose analyses directly proved that adiponectin was an insulin-sensitizing hormone in vivo. I also clarified that a thiazolidine derivative, which is PPARc's synthetic ligand used as a diabetes treatment drug, improved insulin resistance in an adiponectin-dependent and adiponectin-independent manner. I also discovered adiponectin's new actions that until that time had been completely unknown, namely, activating AMP kinase in the hypothalamic arcuate nucleus, increasing appetite, and suppressing energy consumption.
I took note of the insulin receptor substrate (IRS) that exists underneath insulin receptors, and has proven, through analysis of systemic and organ-specific IRS-knockout mice, that IRS was the key molecule for physiological insulin actions as well as obesity-related insulin resistance. I showed that in pancreatic beta cells IRS-2 plays a crucial role in physiological insulin actions and in their compensatory proliferation in response to insulin resistance. Meanwhile, I found that, in the liver, the existence of a functional relay between IRS-1 and IRS-2 in insulin signaling during fasting and after refeeding; IRS-1 functions primarily after refeeding and I RS-2 functions mainly during fasting and immediately after the start of refeeding. Moreover, I showed that endothelial insulin signaling mediates insulin-stimulated capillary recruitment and increase of interstitial insulin concentrations and, as a consequence, facilitates glucose uptake by the skeletal muscle. Thus, treatment directed at improving insulin signaling in the endothelial cells may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance. Recently I have been investigating selective insulin resistance in the liver, hoping that it could lead to the elucidation of its molecular mechanism.
Prof. Juliana Chan is Professor of Medicine and Therapeutics, Director of the Hong Kong Institute of Diabetes and Obesity and co-director of the International Diabetes Federation Centre of Education at the Chinese University Hong Kong, Prince of Wales Hospital. She is also the Chief Executive Officer of the Asia Diabetes Foundation. She graduated from Liverpool University, United Kingdom, with accreditations in Endocrinology and Clinical Pharmacology.
In 1995, she established the Hong Kong Diabetes Registry to first report the Asian phenotypes characterized by low/normal body mass index, visceral obesity, early age of diagnosis driven by high prevalence of childhood obesity and gestational diabetes and a propensity for developing renal disease and cancer. Using cohorts, databases and biobanks, her team has contributed to the global discovery of chromosomal regions and novel genes for type 2 diabetes. In 2007, she developed the web-based Joint Asia Diabetes Evaluation (JADE) Program incorporating risk algorithms, personalized reporting, regular feedback and decision support for quality improvement and research purposes. She has supervised 50 postgraduate students and fellows, co-authored 500 peer-reviewed articles and 20 book chapters and regularly organizes postgraduate courses and international meetings to promote scientific training and professional education. She is a leading investigator in large-scale multiomic projects supported by the US National Institute of Health and Hong Kong Government in diabetes. She is a consultant to the Hong Kong Government, multinational companies, World Health Organization and International Diabetes Federation on the subject of diabetes. She has been interviewed by the Lancet on the CUHK-PWH diabetes care model, and awarded the China Women Physicians Association Intercontinental Innovation Award in Clinical Research. FROM EPIDEMIOLOGY TO PERSONALIZED MEDICINE IN DIABETES: With increasing globalization and East-West exchanges, Hong Kong witnessed an explosion of diabetes in the early 1990s with a disproportionate burden among the young and middle aged. Based on clinical observations and using large cohorts, databases and biobanks, we first reported the Asian phenotypes characterized by normal body weight with increased abdominal adiposity. The increased risk of gestational diabetes combined with exposure to poor nutrition in utero and overnutrition in later life has led to high prevalence of childhood obesity and young onset diabetes, affecting 1 in 5 adult patients. Apart from phenotypic heterogeneity, long disease duration and treatment gaps have put these young subjects at high risk of premature mortality and multiple morbidities. Genetic, environmental and psychosocial-behavioral factors interact in a complex manner to increase the risk of renal disease and cancer as leading causes of death. Using linkage analysis, genome-wide association studies and multiomic analysis, we have discovered novel loci for young onset diabetes and its complications which are implicated in developmental biology, beta cell metabolism and cell signalling pathways. By adopting the principles of clinical trials using protocols to facilitate measurements and monitoring, we further demonstrated the benefits of using task delegation, information technology, risk stratification and decision support on control of cardiometabolic risk factors, hospitalizations, morbidities and mortality. While these epidemiological discoveries are highly applicable to many populations undergoing rapid transition in developing areas, the combined use of molecular markers and care protocols provides a promising, sustainable and personalized solution for prevention and control of diabetes. The adipose tissue, previously considered as an inert energy store, is now recognized as an important endocrine organ that secretes a variety of bioactive peptides, known as adipokines or adipocytokines. Since the identification of leptin as a fat-derived hormone, an increasing number of adipokines have been identified through gene expression profiling and proteomic techniques, and shown to impact on glucose and lipid metabolism, energy homeostasis and inflammation. Dysregulated secretion of various adipokines has been demonstrated in the obese state, leading to chronic low-grade systemic inflammation and insulin resistance which, at least in part, explain why obesity is responsible for 58% of the cases of diabetes and 21% of ischemic heart disease worldwide. Of the known adipokines, adiponectin and adipocyte fatty acid binding protein (A-FABP) have the highest circulating levels in humans and are biomarkers predictive of type 2 diabetes, with increased risk being conferred by low adiponectin or high A-FABP levels. On the other hand, we have shown that, in obese individuals, the adipose tissue becomes one of the major sources of fibroblast growth factor 21 (FGF21), a hormone generally held to be a hepatokine. Beneficial metabolic effects of FGF21 have been demonstrated in animal studies and more recently, in humans, in part mediated through inducing the secretion of adiponectin. Paradoxically, high levels of FGF21 are found in obesity and type 2 diabetes, suggesting the presence of FGF21 resistance, analogous to leptin resistance in obesity. Recent studies have attributed this FGF21 resistance to adipose tissue inflammation and changes in microRNA expression, demonstrated in animal and human studies. High FGF21 levels have been found to predict the development of type 2 diabetes and diabetic nephropathy, whereas reduced FGF21 levels are found in autoimmune diabetes. The methodological difficulties that limit the clinical use of some adipokines, such as RBP-4 and angiopoietin-like-protein 4, as biomarkers in clinical diabetes and diabetic complications, will be reviewed. The relative contribution of the adipokines which have been implicated in glucose metabolism, with regard to the prediction and treatment of clinical diabetes, will be discussed.