Diabetes Research and Clinical Practice - Volume 120 - Supplement 1

mitochondrial DNA (mtDNA) content, and ATP production

were observed only in cybrid D4. In cybrid B4, the imbalance of

mitochondrial dynamics and impaired biogenesis and bio-

energetics, and increased apoptosis were significantly

improved in response to antioxidant treatment.

We concluded that the diabetes-susceptible mtDNA variants

are themselves resistant to insulin. Mitochondria play an

independent role in the pathogenesis of IR, possibly through

altered production of intracellular ROS.

S07-4

Metabolism-secretion coupling in diabetic islets

Shimpei FUJIMOTO

Department of Endocrinology, Metabolism

and Nephropathy, Kochi University, Kochi, Japan

One of the characteristics of type 2 diabetes (T2DM) is that the

insulin secretory response of

-cells is selectively impaired

to glucose. In the GK rat, a genetic model of non-obese T2DM,

glucose-induced insulinsecretion (GIIS) is selectively impaired.

The intracellular ATP elevation induced by high glucose is

impaired in GK rats as well as in patients with T2DM. The

impaired insulinotropic action of glucose in diabetic

-cells

may be attributable to deficient ATP production derived from

impaired glucose metabolism. Although there is evidence

that islets in GK rat and human T2DM are oxidatively stressed,

the association between oxidative stress and impaired intra-

cellular ATP elevation in islets is yet unclear.

We propose that endogenous generation of reactive oxygen

species (ROS) by activation of Src, a non-receptor protein-

tyrosine kinase, plays an important role in GIIS in GK islets. Src

was activated, which causes ROS production and mitochon-

drial dysfunction, in GK islets. Src inhibition decreased ROS

production and restored the impairment of GIIS and ATP

elevation in GK islets. In addition, GLP-1 signaling decreased

Src activation and ROS production, and ameliorated impaired

ATP elevation by high glucose dependently on Epac in GK

islets.

12-h suppression of ROS by exposure to tempol, a superoxide

dismutase mimic, plus ebselen, a glutathione peroxidase

mimic (TE-treatment) improved GIIS and ATP elevation in

GK islets. ATP production from mitochondrial fraction of GK

islets in the presence of pyruvate and malate was not altered

by TE-treatment. Lactate production was markedly increased

in GK islets, which can reduce supply of pyruvate to

mitochondria, together with reduced NADH-FADH2 supply

to mitochondria due to reduced glycerol phosphate shuttle

activity, leading to reduced ATP production. TE-treatment

reduced lactate production and protein expression of lactate

dehydrogenase (LDH) and hypoxia-inducible factor 1

(HIF1

)

which regulates LDH expression. These results indicate that

the Warburg-like effect, the characteristic aerobic metabo-

lism in cancer cells by which lactate is overproduced with

reduced linking tomitochondria metabolism, plays an import-

ant role in impairedmetabolism-secretion coupling in diabetic

-cells and suggest that ROS reduction can improve mito-

chondrial metabolism by suppressing lactate overproduction

through inhibition of HIF1

stabilization.

The Role of Epigenetics in Diabetes and

its Complications

S10-3

Co-localization of NFIA and PPAR

controls the brown fat gene

program

Hironori WAKI

, Yuta HIRAIKE

, Jing YU

Masahiro NAKAMURA

, Kana MIYAKE

, Gaku NAGANO

Ken SUZUKI

, Ryo NAKAKI

, Hirofumi KOBAYASHI

, Wei SUN

Tomohisa AOYAMA

, Yusuke HIROTA

, Haruya OHNO

Kenji OKI

, Masayasu YONEDA

, Shogo YAMAMOTO

Shuichi TSUTSUMI

, Hiroyuki ABURATANI

Toshimasa YAMAUCHI

, Takashi KADOWAKI

Department of

Diabetes and Metabolic Diseases, Graduate School of Medicine, The

University of Tokyo,

Genome Science Division, Research Center for

Advanced Science and Technology, The University of Tokyo, Tokyo,

Department of Molecular and Internal Medicine, Graduate School of

Biomedical and Health Sciences, Hiroshima University, Hiroshima,

Japan

Brown fat dissipates energy as heat and protects against

obesity. Here, we identified nuclear factor I-A (NFIA) as a novel

transcriptional regulator of brown fat by a genome-wide open

chromatin analysis of murine brown and white fat followed by

motif analysis of brown-fat-specific open chromatin regions.

NFIA and the adipogenic master regulator, PPAR

, co-localize

at the brown-fat-specific enhancers. Moreover, the binding

of NFIA precedes and facilitates the binding of PPAR

, leading

to increased chromatin accessibility and active transcrip-

tion. Introduction of NFIA into myoblasts results in brown

adipocyte differentiation. Conversely, the brown fat of NFIA

knockout mice displays impaired expression of the brown-fat-

specific genes and reciprocal elevation of muscle genes.

Finally, expression of NFIA and the brown-fat-specific genes

is positively correlated in human brown fat. These results

indicate that NFIA is a key transcriptional regulator of brown

fat and exerts its effects by co-localizing with PPAR

at cell-

type-specific enhancers.

Environmental Pollutants and Diabetes

S17-1

Obesity and diabetes: roles of circulating environmental

pollutants and its mitochondria inhibiting activity in

pathogenesis

Youngmi Kim PAK

, Wook Ha PARK

, Nam-Han CHO

Man Suk OH

, Hong Kyu LEE

Department of Physiology, College

of Medicine, Kyung Hee University, Seoul,

Department of

Epidemiology, College of Medicine, Ajou University, Kyung-Ki-Do,

Suwon,

Department of Statistics, Ewha Womans,

Department

of Internal Medicine, College of Medicine, Eulji-University, Seoul,

Korea

Environmental chemicals have emerged as an important

causal factor of obesity and diabetes, but their target has

not been well understood. Based on the recognized role of

abnormal mitochondrial function in diabetic pathogenesis,

environmental pollutants were suspected to disrupt mito-

chondrial activities. Previously, we showed that in a case-

control study, serum of diabetic or insulin resistant patients

contained 30

–

50% higher in levels of environmental pollutants

and 20% lower in mitochondria stimulating activities than

the normal subjects. Total serum environmental pollutant

levels were indirectly analyzed by assessing aryl hydrocarbon

receptor (AhR) ligand-dependent transcription activities

(AhRT) in sample sera. Mitochondria inhibiting activities of

the subject sera were monitored by ATP contents and reactive

oxygen species (ROS) amount in the serum-treated cells.

Prospective study confirmed that AhRTwas a strong predictive

parameter for developing diabetes as cut-off point of AhRT

was 1.96 (OR = 30.44, p < 0.001, n = 1,537, 95% C.I.). Similarly,

ATP (<83.6%; OR = 8.83) and ROS (>122.4%; OR = 24.43) were

found to be independent risk factors of diabetes (p < 0.001, 95%

C.I.). Circulating environmental pollutants in diabetic patients

disrupted mitochondria via AhR-mediated mechanism and

AhR antagonists reversed the mitochondrial damages. We

suggest that serum AhRT, ATP, and ROS parameters would

be critical biomarkers to predict diabetes development and

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

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