PL：Plenary Lecture (1-4

PL-1 STEROID FUNCTION AND REGULATION: MOLECULAR, CELL, AND ANIMAL STUDIES

BON-CHU CHUNG

Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

Steroids are widely used in medicine and are notorious for their side effects. We aim to study novel functions of steroids in the body and their regulation, with an emphasis of steroid biosynthesis. Three different aspects of steroid functions have been the focus of our investigation.

I. Actions of neurosteroid pregnenolone

We would like to examine the action of neurosteroids in the brain in order to find a better neurosteroid for the treatment of brain diseases. We previously showed that neurosteroid pregnenolone promotes cell migration by binding to and activating microtubule-binding protein CLIP-170 to stabilize microtubules. Current research focuses on the mechanism of dynamic neurosteroid actions.

II. Regulation and functions of steroidogenic genes

The first two steps of steroid synthesis are catalyzed by enzymes encoded by CYP11A and HSD3B. In addition to influencing reproduction and endocrine metabolism, we showed that zebrafish cyp11a1 and hsd3b2 controls embryo morphogenesis. Their action mechanism during morphogenesis will bring novel insight about steroid actions.

III. Regulation of zebrafish gonad development

Zebrafish has been a popular model organism for genetic analysis, but the control of its gonad development is unclear. We would like to understand the factors that control gonad differentiation and sex determination. Both methods of candidate gene approach and transcriptome analysis will be used to understand the mode of germ cell differentiation.

PL-2 DIABETIC COMPLICATIONS: THE DISCOVERIES OF PROTECTIVE FACTORS

GEORGE KING

Harvard Medical School, Boston, MA

Diabetic complications are the leading cause of morbidity and mortality in people with diabetes. In spite of the great strides that have been made in the medical care of people with diabetes, diabetic complications are still the leading causes of kidney failure, loss of vision, limb amputation, cardiovascular disease, and now a major contributor to the development of cognitive decline and certain forms of cancers. The major known risk factors are hyperglycemia, insulin resistance, dyslipidemia, and hypertension. However, recently it is also clear that the presence and severity of the complications of diabetes are counter-balanced by endogenous protective factors which have begun to be identified. Clinical longitudinal studies have shown that a majority of people with diabetes with microalbuminuria will not progress to chronic end stage renal disease. The Joslin Medalist Study which has followed a cohort of over a thousand subjects (N = 1023) with duration of insulindependent diabetes > 50 years (mean duration = 67 years) has clearly demonstrated that over 35% of the Medalists do not have significant retinopathy, nephropathy, and neuropathy, even in the presence of hyperglycemia. Studies including the clinical characteristics, biochemical genetic and “omic” analysis of the Medalists’ blood and specific tissues such as retina or the kidney have identified protective profiles that are associated with lack of significant abnormalities in the retina and kidney, even with hyperglycemia of long duration. Analysis of the glomeruli from protected and non-protected Medalists and people with type 1 and 2 diabetes, has identified that the preservation of enzymes of glycolysis and mitochondria has the ability to preserve glomerular cells from early death and loss of function. Further, the activation of glycolytic enzyme pyruvate kinase M2 can reverse metabolic memory in animal models of diabetic nephropathy.

Similarly, the elevations of a unique retinal photoreceptor protein (RBP-3) were associated with prevention of retinopathy in the Medalists, and its overexpression prevented and stopped the progression of diabetic retinal pathology in rodent models of diabetic retinopathy. These studies of the Joslin Medalist Study have identified novel protective factors for diabetes retinopathy and nephropathy which can be used as new therapeutic agents for diabetes complications.

PL-3

台灣骨鬆及骨折防治之回顧與展望

蔡克嵩

臺大醫院 檢驗醫學科及內科

骨鬆症因盛行率高，病人數超過糖尿病，WHO 已將之定義為第二重大的流行病。骨鬆症又 以婦女停經後發生者為最大宗。 其致病的最重大因素是老化與缺乏雌激素。老化所造成之生理現 象是破骨作用增加而造骨作用減少。 依此現象看，骨鬆症實是骨代謝問題造成，屬代謝內分泌疾 病。但在台灣，骨鬆症的預防及治療，比起糖尿病及其他內分泌代謝疾病，較晚被歸類於代謝內 分泌科醫師的範圍。 測量骨量的雙光子核醫骨密儀在 1984 年左右開始引進國內。其後抑鈣素、雙磷酸類藥物、 SERM 類及 1-34 副甲胜肽、 RANKL 單株抗體等藥物陸續為台灣健保採納。 骨密儀在 1990 年後 大都改用 X 光雙能量方式，速度大增，費用也大減。 但因濫用嚴重，遭健保設限，只能給付於 已有骨鬆骨折及其他少數病人。 給付用藥則限於已有較低之骨密度，且已有脊椎或髖部骨折之病 人。 這就有如已發生中風之病患才給付高血壓藥物一樣。 另一方面，台灣的病人在使用中長期 之抗破骨細胞藥物後，發生顎骨壞死的機會遠較歐美所報告的機率高，一般民眾也較不願意接受 雙磷酸鹽甚至抗 RANKL 單株抗體之藥物治療，從而造成治療上的困擾。 此外，相對於糖尿病藥 物近十五年之快速發展而各類藥物不斷推陳出新，骨鬆新藥的發展則因種種因素而失敗，這十年 來均沒有新藥上市，殊為可惜。 對於藥物治療對象之決定，全球均漸以未來骨折風險之高低來決定，台灣也有專用之評估工 具可用。由於骨鬆骨折之原因還包括肌肉及關節問題所導致之傷害，近年來全球骨鬆骨折之防治 已將肌少症及關節疾病之防治包含在內。 由於骨鬆症的病人需要長期治療、定期檢查、衛教及追 蹤，所以我們也比照糖尿病管理，建立個案管理制度。台灣在骨鬆骨折個案管理之推動，享譽全 球。骨鬆症的治療經過四十年的發展，已建立了完整的診斷方法。骨折風險評估系統及既有的藥 物，加上神經、肌肉及關節之保健和通行的個案管理制度，可以大幅減少骨折風險。不過台灣目 前仍是全亞洲骨折最盛行的地區，值得我們醫界同仁繼續努力，一起加強防治工作。

PL-4 PRECISION MEDICINE IN DIABETES

WAYNE HUEY-HERNG SHEU

Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

Although the main feature of type 2 diabetes is chronically hyperglycemia, its etiology and pathophysiology vary greatly. With the help of advanced technology and biology, we had better understanding of diabetes and its complex traits. Globally, several precision medicine initiatives plus consortia that generate huge genotypes data while enriched phenotype data from electronic medical records or insurance data drive precision medicine to further step. The practice of precision diabetes medicine is currently confined to rare monogenic forms of the disease. However, because characterizing variation in a patient’s nuclear genome is inexpensive and easily achieved and DNA variation remains constant across the life course, it is likely that genetic sequences will feature in most patients’ clinical records. As genetic databases grow, genotypes will be increasingly used to discover new drug targets. In addition, the roles other‘omics technologies, digital imaging devices, and wearable devices will play in precision diabetes medicine. Finally, many precision medicine initiatives focus predominantly on pharmacotherapy, optimizing lifestyle (and possibly surgical) interventions using biotechnologies also has great potential for improving type 2 diabetes prevention and treatment.