Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

However, early GWAS of many complex diseases, including

T2DM and obesity, interrogated mainly the common variants

which tend to exhibit modest effect sizes. Furthermore, these

common variants mostly located at intergenic or intronic

region, where it is difficult to provide a clear explanation for

their functional consequences. In recent years, the advance-

ment in exome array genotyping and next-generation sequen-

cing technologies has opened up a novel means for the

discovery of low-frequency or rare variants that are enriched

in the coding regions. These new approaches have facilitated

the identification of variants that aremore likely to have strong

effects and even the population-specific variants. Ongoing

large-scale genotyping and sequencing studies will continue

to discover the low-frequency/rare and functional variants for

T2DM and obesity. In this talk, a summary of our work on

the genetics of T2DM and obesity; and the recent progress in

the genetic studies of these diseases among other East Asian

populations will be discussed.

Mitochondria in Diabetes

S07-1

ERK-c-Myc pathway as a novel pathway linking mitochondrial

dysfunction and skeletal muscle insulin resistance

Kyong Soo PARK

Department of Internal Medicine, College of

Medicine; Department of Molecular Medicine and Biopharmaceutical

Sciences; Graduate School of Convergence Science and Technology,

Seoul National University, Seoul, Korea

Mitochondrial dysfunction plays an important role in patho-

genesis of diabetes mellitus. It can affect both insulin resis-

tance and impaired insulin secretion. There are various

genetic and environmental factors contributing to mitochon-

drial dysfunction. We previously showed that mitochondrial

dysfunction is related to reduced retinoid X receptor

(RXR

)

levels which played an important role in transcriptional regu-

lation of oxidative phosphorylation(OXPHOS) genes in cybrid

cells carrying mitochondrial DNA 3243 A>G mutation.

In order to identify a novel pathway linking mitochondrial

function and insulin resistance in common form of type 2

diabetes, we performed transcriptional profiling of skeletal

muscles fromsubjectswithor without type 2 diabetesmellitus.

Through an integrative analysis of our dataset with four

previous datasets, we identified 46 core gene sets associated

with insulin resistance and focused on c-Myc with the highest

regulatory power in the network of the core gene sets. c-Myc

expression decreased in skeletal muscle from obese rodent

model. In C2C12 myotubes, c-Myc transcriptional activity

was decreased by palmitate or TNF

treatment inducing

insulin resistance. Knockdown of c-Myc decreased expression

of OXPHOS genes and PGC-1-related coactivator with no

change in PGC1

. ERK regulated c-Myc induction by insulin,

and palmitate abrogated insulin-induced c-Myc expression by

modulating ERK activation. The unbiased integrative approach

of transcriptional profiles revealed ERK-c-Myc pathway as

a novel pathway for linking mitochondrial function and

skeletal muscle insulin resistance, independent of PGC1

S07-2

Mitochondrial dysfunction and dysregulation of Ca

homeostasis in insulin insensitivity and diabetes

Chih-HaoWANG

Institute of Biochemistry and Molecular Biology,

School of Life Science, National Yang-Ming University, Taipei, Taiwan

Type 2 diabetes (T2D) and insulin resistance have attracted

great attention of biomedical researchers because of astonish-

ing increase in its prevalence. Decreased capacity of oxidative

metabolism and mitochondrial dysfunction caused by aging,

gene mutation or gene knockout are a major contributor to the

development of T2D. Recent studies indicate that alteration

of Ca

level and downstream Ca

-dependent signaling path-

ways appear to modulate the insulin signaling cascade,

resulting in insulin resistance of adipocytes. Mitochondria

and ER play an important role in the maintenance of

intracellular Ca

homeostasis and their defects may be an

etiology factor of insulin resistance and T2D. We demonstrated

that mitochondria-associated ER membranes (MAMs) are

essential for efficient communication between the ER

and mitochondria. The abnormalities in the structure and

function of MAMs in affected tissue cells in T2D and

other metabolic disorders have been an important subject

of study. Moreover, we demonstrated that dysregulation of

intracellular Ca

homeostasis resulted from mitochondrial

dysfunction or defects in the function of MAMs are involved in

the impairment of adipocyte differentiation, leading to glucose

intolerance and insulin insensitivity of mice. Based on these

observations we suggest that the role of mitochondrial dys-

function and disturbance in Ca

homeostasis warrant further

study in the development of effective therapeutics in the

prevention and medication of insulin resistance and T2D.

S07-3

Study of insulin resistance and chronic inflammation in cybrid

cells harboring diabetes-susceptible mitochondrial

haplogroups

Pei-Wen WANG

Department of Internal Medicine and Nuclear

Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang

Gung University College of Medicine, Kaohsiung, Taiwan

There is evidence that mitochondria are involved in the

development of diabetes. Quite a number of case studies such

as MIDD (maternally inherited diabetes and deafness) and

MELAS (mitochondrial encephalopathy, lactic acidosis and

stroke-like episodes) have confirmed the link between mito-

chondrial genetic variations with diabetes. However, the role

of mitochondria in the common type 2 diabetes, which has

becoming a world-wide disease, deserves more investigation.

The advantage of using a cytoplasmic hybrid (cybrid) model

to study the genetic effects of mitochondria is that the cells

have the same nuclear genomic background. Cybrids derived

from 143B osteosarcoma cell line and different mitochon-

drial haplogroups, including B4 (the major diabetes-suscep-

tible haplogroup in Chinese population), D4 (the major

diabetes-resistant haplogroup in Chinese population) and N9

(the diabetes-resistant haplogroup in Japanese population)

were developed in vitro. Cybrid cells were cultured in a

medium containing 25 mM glucose and stimulated with 0,

0.1, and 1.0 M insulin to elucidate the role of mitochondria in

the pathogenesis of insulin resistance (IR).

Upon insulin treatment, the translocation of cytoplasmic

GLUT1/GLUT4 to the cell membrane in cybrid D4 and N9 cells

increased significantly, whereas the changes in B4 cells were

not or less significant. On the contrary, the ratio of insulin-

induced JNK and P38 to Akt phosphorylation was significantly

greater in cybrid B4 cells than in cybrid D4 and N9 cells.

The levels of DCF and MitoSOX Red, which are indicative of

the oxidative stress, were significantly higher in the B4 cells

in basal conditions and after insulin treatment. Following

treatment with the antioxidant NAC, cybrid B4 cells showed

significantly reduced insulin-induced phosphorylation of P38

and increased GLUT1/GLUT4 translocation to the cell mem-

brane, suggesting NAC may divert insulin signaling from pro-

inflammation to glucose uptake.

Comparison of mitochondrial dynamics, biogenesis, bio-

energetics, autophagy and apoptosis revealed significant

difference between cybrid B4 and D4, before and after

insulin stimulation. Cybrid B4 showed a more fragmented

mitochondrial network, impaired mitochondrial biogenesis

and bioenergetics, increased apoptosis and ineffective

autophagy and a low expression of fusion-related molecules.

Upon insulin stimulation, increases in network formation,

Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1

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