YL：Young Investigator Research Lecture

YL-1 THE ROLE OF PGE2 METABOLISM IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE

CHIH-HUNG LIN

Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

Diabetic kidney disease (DKD) is one of the most common complications of diabetes. The pathogenesis is very sophisticated, involving many unique albeit inter-correlated cell types and mechanisms. Despite the efforts and recent progress in treating diabetes, deterioration of renal function is still inevitable in certain patients. Such condition emphasizes the necessity of further investigation of this disease.

Prostaglandins (PGs) play important parts in the maintenance of homoeostasis and the pathogenesis of various diseases. Many studies have proposed the roles of different PGs in the pathogenesis of DKD. As the major renal metabolite, PGE2 seems to have both protective and hazardous effects on the kidney via different EP receptors. On the contrary, knowledge about the effect of metabolism of PGE2 on DKD is still very limited.

PGE2 is a mediator with short half-life. It is catabolized by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) into 15-keto-PGE2, followed by prostaglandin reductase 2 (PTGR2), which further catalyzes 15-keto-PGE2 into 13,14-dihydro-15-keto-PGE2. Little is known about the pathophysiological functions of these PGE2-catabolizing enzymes. One intriguing fact is that the metabolites of PG might have reno-protective potential. Thus, the aim of the present study is to elucidate the role of PGE2 metabolism in the pathogenesis of DKD. By manipulating the expression of PTGR2, its effects on various phenotypes of DKD are examined.

YL-2 MOLECULAR MECHANISM BY WHICH MATERNALLY INHERITED MITOCHONDRIAL DYSFUNCTION CAUSES INSULIN RESISTANCE

YI-CHENG CHANG

Department of Internal Medicine, National Taiwan University Hospital

Type 2 diabetes is a major threat to global health. The main pathophysiological feature of type 2 diabetes is insulin resistance. However, the underlying cause by which insulin resistance develops is still not fully elucidated. In past human studies, a strong correlation between mitochondrial dysfunction and insulin resistance has been observed. Nevertheless, the casual relationship and the molecular mechanism remained to be explored.

SUV3 is a conserved nuclear-encoded mitochondrial RNA helicase, a component of mitochondrial RNA degradesome. SUV3 is essential for mitochondrial RNA homeostasis. In mammalian cells, deficiency of SUV3 causes mitochondrial RNA accumulation, DNA instability, reduction of mitochondrial copy number, and lower respiration. Deficiency of SUV3 in mice cause accelerated mitochondrial DNA mutation, reduced mitochondrial DNA copy numbers, and mitochondrial dysfunction. These phenotypes could be maternally inherited.

We found that mice carrying defective mitochondrial through maternal inheritance developed glucose intolerance and insulin resistance, accompanied with elevated free fatty acid and exercise intolerance. Indirect calorimetry indicated lower fatty acid oxidation rate of these mice. Transcriptome analysis showed that pathways involved in DNA repair and insulin signaling is significantly reduced in skeletal muscle of these mice. These data strongly indicate that maternally inherited mitochondrial function reduces insulin signaling in skeletal muscle. Preliminary analysis of mitochondrial genome using next-generation sequencing showed a trend of increased mutation load as compared to controls.

YL-3 THE RELATIONSHIP OF AMYLIN AND NEW-ONET DIABETES MELLITUS AND OBESITY

KANG-CHIH FAN

Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan Unuversity Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan, ROC

Type 2 diabetes mellitus is one of the most common diseases in the world and could lead to multiple complications to the patients such as cardiovascular disease, neuropathy, nephropathy and retinopathy. As we know,insulin resistance is one of the major pathogenesis in type 2 diabetes mellitus. In addition to insulin, multiple hormones participate in glucose regulation and homeostasis including amylin. Amylin (IAPP, islet amyloid polypeptide) is a 37-amino acid peptide that is stored in pancreatic β-cells and is co-secreted with insulin. Amylin affects glucose control through several mechanisms, including slowed gastric emptying, regulation of postprandial glucagon, and reduction of food intake. Decreased amylin level in blood was observed in patients with type 2 diabetes and type 1 diabetes according to previously clinical study. However, islet amyloid poypeptide aggregates to form islet amyloid in type 2 diabetes. Islet amyloid formation contributes to β-cells dysfunction and death. Studies in rat model transgenic for human-islet amyloid polypeptide revealed toxic effect onβ-cells apoptosis and insulin resistance. As a result, the role of amylin in the pathogenesis of diabetes is worth of studying based on our cohort study database.

Overweight is one of the common risk factors amoung patients of type 2 diabetes. The Adipose tissue in obesity patients would promote inflammatory mediators production including monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-a and interleukin-6. These inflammatory response may contribute to the increased risk for type 2 diabetes and affect the expression of adipocytokines. As a result, the relationships between amylin and obesity is one of the important issues in the field of diabetes and obesity.

Therefore, in the present study, we will use a longitudinal cohort study to analyze the relationship between plasma amylin level and new-onset diabetes mellitus and obesity. Our cohort, named Taiwan Lifestyle Study, is a community-based study, which enrolled residents from the Yunlin County, Taiwan,aged over 18 years old, who did not report the presence of diabetesduring an interview, were invited to join this prospective study from 2006 to 2012. There were 3 visits forthis prospective study, separated by 1 to 3 years.Individuals receivedquestionnaire, physical examination including blood pressure, body weight, height, waist circumference, hip circumference by trained nurses. We also conducted blood examination for estimation of biochemical, metabolic and oral glucose tolerance test, TG, high and low density cholesterol, adiponectin, leptinand insulin resistance. Abdominal computed tomography exam was also performed during follow up visit to quantify the abdominal fat tissue.

After follow up, about 60 people developed new-onset diabetes mellitus amoung 432 individuals. Diagnosis of diabetes mellitus is according to the definition of American Diabetes Association (ADA), determined by using the history of medications and the result of oral glucose tolerance test. We will measure fasting and postprandial (2 hrs) plasma amylin concentration to clarity its relationship with new-onset diabetes mellitus. Pearson’s correlation coefficient will be applied to elucidate the relationship between plasma amylin concentration and clinical characteristics such as abdominal fat by computed tomography, plasma adiponectin and leptin level. The Cox proportional hazard model will be applied to analyze whether low plasma amylin concentration is one of the risk factors for new-onset diabetes mellitus by adjusting confounders, including age, sex, BMI, family history, fasting glucose, fasting insulin and insulin sensitivity.

YL-4 THE LINKAGE BETWEEN FNDC5/IRISIN, INSULIN SECRETION AND BETA CELLS PROLIFERATION ON ISLET IN OBESITY AND HYPERGLYCEMIA

CHUNG-ZE WU

Division of Endocrinology and Metabolism, Department of Internal Medicine, Shuang Ho Hospital, Taipei, Medical University, Taipei, Taiwan, R.O.C

Irisin was recently identified as muscle-derived factor that release from muscle immediately after exercise. It is secreted from fibrinectin type III domain containing 5 (FNDC5) after the cleavage if its extracellular portion. A large bundle of studies showed irisin is associated with regulation of glucose homeostasis. In addition, irisin expression in islet was noted. However, there is few study explored the role of irisin on insulin secretion and development diabetes mellitus. In cell model, murine β cells, NIT-1 cells, were treated with normal glucose (7mM) or high glucose (25mM) for 24 or 48 hours. Culture medium were collected and irisin levels were measured by irisin ELISA. Western blot was performed for assessing intracellular FNDC5 expression in β cells. Moreover, insulin secretion rate of NIT-1 cells in normal or high glucose stimulation were assessed with after silencing FNDC5 by siRNA. In mouse model, C57B6/J and BALB/c mice were fed with chow diet and high fat diet (40%) respectively. Immunohistochemical (IHC) stains of FNDC5 on islet in each group were assessed. Irisin secretion of NIT-1 cells declined after treating with high glucose compared with normal glucose after adjust cellular proliferation. At the same time, FNDC5 intracellular expression also declined after treating with high glucose. After silencing FNDC5 by siRNA, insulin secretion rate of NIT-1 cells showed significant decelerated after treating with high glucose, but no significant difference in normal glucose. High glucose inhibits irisin excretion and FNDC5 intracellular expression on β cells. Deficiency of FNDC5 impairs insulin secretion of β cells in high glucose challenge. In high fat diet mouse, expression of FNDC5 showed no significant difference from control mouse. However, FNDC5 expression on islet showed declination in diabetic mouse model. Accordingly, FNDC5 and irisin may play an important role on insulin secretion.