WS Working Group Symposium (1-2

WS1-1

ISLET BIOLOGY AND TRANSPLANTATION

J-H JUANG

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, Taiwan

The pancreatic islets of Langerhans have been intensively investigated, largely because of their central role in the pathogenesis of type 1 and type 2 diabetes mellitus. Research studies centered on the development of different forms of diabetes and provide further impetus for the quest to find a “cure.” Restoring -cell mass and reversing diabetes can be accomplished by two approaches: either by endogenous regeneration of cells or transplantation of cells from exogenous sources; recent advancements in science and technology have facilitated progress in both. The following are examples

It has been shown all-trans retinoid acid (ATRA) hinders the development of autoimmune diabetes by inducing immune tolerance status. Meanwhile, exendin-4 stimulates growth and differentiation of cells as well as exerts antiapoptotic effect on cells. Thus, we tested if the combination therapy with ATRA and exendin-4 could prevent and rescue diabetes in NOD mice with and without islet transplantation. We found ATRA and ATRA plus exendin-4 treatment delayed the onset of diabetes. However, after the onset of autoimmune diabetes, ATRA and/or exendin-4 treatment is unable to reverse hyperglycemia or improve survival in NOD mice with and without islet transplantation.

To better understand the fate of islet isografts and allografts, we utilized a magnetic resonance (MR) imaging technique to monitor mouse islets labeled with a novel MR contrast agent, chitosancoated superparamagnetic iron oxide (CSPIO) nanoparticles. After incubation of mouse islets with CSPIO, TEM showed CSPIO in endocytotic vesicles of and cells at 8 h. Incubation with CSPIO did not affect insulin secretion and death rates of islets. After syngeneic and allogeneic transplantation, grafts of CSPIO-labeled islets were visualized on MR scans as persistent hypointense areas. At 8 weeks after syngeneic transplantation and 31 days after allogeneic transplantation, histology of CSPIO-labeled islet grafts showed colocalized insulin and iron staining in the same areas but the size of allografts decreased with time. TEM with elementary iron mapping demonstrated CSPIO distributed in the cytoplasm of islet cells, which maintained intact ultrastructure.

WS1-2

THROID CANCER CELL BIOLOGY

S-T CHEN

Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taiwan, R.O.C.

The normal thyrocytes are highly differentiated TSH-dependent iodine concentrating hormone secreting cells. Cancers develop in thyroid because of intrinsic and/or extrinsic factors that lead to genetic mutations, DNA methylations, aberrant RNA/protein and miRNA expression. The frequently found molecular markers such as RAS, BRAF, RET/PTC and PTEN mutations lead to oncogenic activation and/or suppressor gene inactivation through integrating PI3K and MPAK pathways and eventually ensure tumorigenesis. Cancer cells gain eternity and metastasis abilities in expense of losing differentiation, that is, the ability to produce thyroglobulin and concentrate iodine. Although the mechanism of dedifferentiation is not fully understood, certain histone deacetylase inhibitors do restore the expression of NIS gene in vitro as well as in vivo. and enhancing aerobic glycolysis through the activation of transcription factors and coactivators such as HIF1a and PGC1a under AMPK regulation. In correspondence, treatment with metformin, an AMPK activator, was found to associate with decreased thyroid cancer risk and improved patient survival.

Cancer metastases involves complex local as well as systemic factors, which include the ability of cancer cells to invade the surrounding normal host tissues including small lymphatic or vascular channels, survival from the host immune surveillance, and finally, colonization and growth of the disseminated tumor cells. The preference of hematogenous and lymphatic spread of follicular and treatment.

WS1-3

GENETIC STUDIES IN OBESITY AND DIABETES

Recent progress in genetic studies, especially with the advent of genomewide association studies (GWAS) and next-generation sequencing greatly forward our understanding towards these two complex human traits.

For obesity, currently ~97 common variants are associated with BMI variations, which account > 20% of BMI variation. Pathway analysis provides strong support for the genes involved in central nervous system process, insulin secretion and action, energy metabolism, lipid biology/adipogenesis, RNA binding protein, MAP kinase singling, and cell proliferation/survival. The FTO gene is now believed to harbor an enhancer of a downstream gene involved in browning of fat cells.

For, type 2 diabetes mellitus and related glycemic traits, including fasting glucose and insulin resistance index identified ~ 100 common variants association with glycemic traits. Most genes are involved in insulin secretion and beta cell survival/proliferation. Other genes included nocturnal rhythm, adrenergic signaling, and lipid synthesis.

Although traits identified form large-scale genome-wide association study only can explained < 20 % of heritability of BMI or type 2 diabetes. Recent whole-genome sequencing did not identify rare variants associated with obesity and diabetes that can explain the “missing heritability”. In addition, most of GWAS or monogenic diabetes/obesity.

WS2-1

DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS: AN UPDATE

Gestational diabetes mellitus (GDM) is defined when diabetes is diagnosed during pregnancy for the first time. Women with GDM have increased risk for adverse perinatal outcomes, including macrosomia, birth trauma, jaundice, respiratory distress syndrome, primary cesarean section, and maternal hypertensive disorders. After delivery, 15-50% of women with GDM develop type 2 diabetes later in life. Besides, children and adolescents with higher birth weight are associated increased risk of obesity and diabetes as well.

The diagnosis of GDM is firstly proposed by O’Sullivan, using 100g, 3-hour oral glucose tolerance tests (OGTT) to predict maternal diabetes after delivery. In 1982, Carpenter and Coustan (C&C) revised the cutoffs again, since the risk of adverse fetal outcomes increases above these cutoffs. In clinical practice, the 100g OGTT is usually preceded by a 50g glucose challenge test (GCT) as a screening test. In 2008, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study used 75g, 2-hour OGTT to define cutoffs which predict adverse fetal and maternal outcomes. Based on the findings, the International Association of the Diabetes and Pregnancy Study Group (IADPSG) proposed a new diagnostic strategy using 75g OGTT, which was adopted by the ADA in 2011. In our hospital, we adopted the IADPSG criteria since 2011 until now. Our college compares the perinatal outcome between two groups using the C&C criteria and the IADPSG criteria. The result show that adopting the IADPSG criteria improves perinatal outcomes and is cost-efficient, at the expense of increased prevalence of GDM.

WS2-2

SCREENING OF GESTATIONAL DIABETES MELLITUS: EXPERIENCE IN TAIWAN

Pregnant women with gestational diabetes mellitus (GDM) have higher risk for adverse perinatal outcomes, including macrosomia, birth trauma, neonatal jaundice, infant respiratory distress syndrome, hypertensive disorders of pregnancy, and the need for primary cesarean section. In addition, 15-50% of these GDM women develop type 2 diabetes later in life. Furthermore, based on reports from our group and others, children and adolescents with higher birth weight are associated with increased risk of obesity and diabetes. Therefore, we sometimes call GDM “a disease across two generations”.

It is thus imperative to screen and diagnose GDM since timely intervention can alter the development of short and long-term complications in both the mother and child. However, it is currently lack of consensus on a method for screening given the uncertainty of which subjects can truly methods, one is selective and the other is universal. The selective screening is risk-based, using traditional risk factors (e.g., previous history of GDM, a family history of diabetes) to select women at risk, who will proceed with biochemical screening. However, one-third to near half of women with GDM by this method would be missed. In this way, most guidelines prior to 1995 recommended universal biochemical screening.

The most adopted biochemical exam is an oral glucose tolerance test (OGTT), including two-step approach with a glucose tolerance test plus a 3-hour OGTT and one-step 2-hour OGTT. This is actually time-consuming for mothers and labor-intensive for the laboratory. Some women may feel nauseated, sweaty, or lightheaded after drinking the glucose solution, which results in moderately high “no-show” rate in the two-step screening. Several alternative screening methods have been advocated to decrease the need of OGTT, i.e., methods that combine risk factors, glucose challenge tests, fasting glucose levels or risk prediction algorithms. In this presentation, I will introduce one of alternative screening

WS2-3

TREATMENT OF GESTATIONAL DIABETES MELLITUS

H-Y LI

National Taiwan University Hospital, Taipei, Taiwan

Gestational diabetes mellitus (GDM) results in increased risk of various pregnancy complications, for GDM in Taiwan follows the recommendation from the 5th International Workshop-conference on GDM, including fasting plasma glucose 95 mg/dl, 1-hour postmeal plasma glucose 140 mg/dl, and 2-hour postmeal plasma glucose 120 mg/dl. If glycemic control fails to achieve these goals by including regular insulin, NPH, insulin aspart, insulin lispro and insulin detemir, can be used to control GDM. The initial dose and titration methods will be discussed in the talk. Metformin and glyburide can be considered to treat GDM. Metformin has been shown to have better glycemic and weight control than insulin, and it may be a better choice than glyburide. Glyburide has been shown to be able to achieve similar glycemic control, compared with insulin. However, glyburide is associated with an increased birth weight and a higher risk of neonatal hypoglycemia. The long-term effect for the use of glyburide and metformin remains unknown. Six to twelve weeks after delivery, an oral glucose tolerance test should be arranged to diagnose if the woman has diabetes or not.