Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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First, we observed abundant GLP-1R expression in early stage
breast cancer (Stage I) tissue extracted from patients without
diabetes, but not advanced breast cancer (Stage IIb). In human
breast cancer cell lines, MCF-7, MDA-MB-231 and KPL-1 cell,
GLP-1R was expressed abundantly. 0.1∼10 nM Ex-4 treatment
significantly decreased cell number of breast cancer cells in
growth curve, in dose-dependent manner. Although Ex-4
did not induce apoptosis in breast cancer cells, BrdU assay
revealed that Ex-4 attenuates cell proliferation of breast
cancer cells in dose dependent manner. If we transplanted
MCF-7 cells into non-diabetic nude mice subcutaneously
and treated them with 300 pM/kg/day Ex-4 for 6 weeks, we
observed decreased tumor size of MCF-7 in Ex-4-treated mice,
in both male and female mice with no change in body weight
and blood glucose level. Immunohistochemistry with Ki67, a
marker of cell proliferation, revealed that breast cancer cell
proliferation was significantly decreased in tumor extracted
from mice treated with Ex-4. Further, 60% high fat diet
significantly increased breast cancer size and weight in
nude mice. Further, Ex-4 treatments decreased tumor size
and weight in high fat fed mice similar to that of control diet
level.
These data suggest that GLP-1 action could attenuate breast
cancer via inhibition of breast cancer cell proliferation.
OL09-3
Activation of heat shock response improves glucose
metabolism and inflammation in obese subjects with type 2
diabetes
Tatsuya KONDO1, Rieko GOTO1, Kaoru ONO1, Sayaka KITANO1,
Motoyuki IGATA1, Junji KAWASHIMA1, Hiroyuki MOTOSHIMA1,
Takeshi MATSUMURA1 , Hirofumi KAI2, Eiichi ARAKI1.
1 Kumamoto University, Metabolic Medicine, 2Kumamoto University,
Molecular Medicine, Japan
Decreased heat shock response (HSR) is reported to be asso-
ciated with insulin resistance in type 2 diabetes. Activation of
HSR improves accumulated visceral adiposity and metabolic
abnormalities in type 2 diabetes. This study was designed
to identify the optimal intervention strategy of the activation
of HSR provided by mild electrical stimulation with heat
shock (MES + HS) in obese type 2 diabetes patients. We have
previously reported that MES + HS improved HbA1c by − 0.43%
in male subjects with obese type 2 diabetes.
This study was a prospective, frequency-escalating, rando-
mized, open-label, triple-arm trial. A total of 60 obese type 2
diabetes patients were randomized into three groups of two,
four, or seven times treatments per week for 12 weeks.
No adverse events were identified. In comparison to the
baseline, MES + HS treatment over time significantly improved
visceral adiposity (− 11.69 cm2. p < 0.001), glycemic control
(HbA1c: − 0.36%: from 7.64% to 7.28%. p < 0.001), insulin
resistance (HOMA-IR: − 1.09. p < 0.001), systemic inflammation
(TNF- α: −0.40 pg/mL. p < 0.001. CRP: −663.6 ng/mL. p = 0.008),
renal function (eGFR: +2.96 mL/min/1.73 m 2. p < 0.001), hepatic
steatosis (AST/ALT: +0.06. p = 0.007) and lipid profiles (trigly-
ceride: −30.02 mg/dL. p = 0.015). The clinical target of HbA1c
less than 7.0% was achieved by 38.3% (n = 23) of participants
after MES + HS treatment. The reduction in HbA1c was
significantly greater in 4 per week ( −0.36%. p = 0.036) or 7 per
week ( −0.65%. p = 0.001) than that in 2 per week (−0.10%) of
treatment. The decrease in the visceral fat area showed similar
trend of changes ( −5.37, −14.24, −16.45 cm2 by two, four, seven
per week, respectively), indicating that the beneficial effects
depend on its frequency. More pronounced effects were
observed in males (HbA1c: −0.44%. from 7.70% to 7.25%.
p < 0.001) than those in females (HbA1c: −0.17%. from 7.50%
to 7.33%. p = 0.140).
This research provides additional lines of evidence to support
the positive impacts of MES + HS in improving metabolic
outcomes in obese type 2 diabetes patients. Those who do
not reach the glycemic control goal of HbA1c less than 7.0%
could be offered additional personalized medical care includ-
ing MES + HS treatment.
OL09-7
Dipeptidyl peptidase-4 inhibitor prevents diabetic
nephropathy through STRA6 signaling
Kun-Der LIN1, Chao-Hung CHEN2, Hsing-Yi LIN3,
Mei-Yueh LEE2, Yu-Li LEE2, Wei-Wen HUNG2, He-Jiun JIANG2,
Pi-Jung HSIAO2, Shyi-Jang SHIN4*. 1Division of Endocrinology and
Metabolism, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, 2Graduate Institute of Medicine, College of
Medicine, Kaohsiung Medical University, 3Cheng Ching Hospital,
4Department of Internal Medicine, School of Medicine, College of
Medicine, Kaohsiung Medical University Hospital, Kaohsiung
Medical University, Taiwan
We recently found that O-GlcNAcosylation of RBP4 receptor
(STRA6) with a decrease of RBP4 binding activity suppressed
CRBP-1 and RARα expression and thereafter activate apoptosis
and fibrosis in high-glucose cultured renal cells and in the
kidneys of diabetic mice. Dipeptidyl peptidase-4 inhibitors
(DPP-4i) was reported to capably ameliorate kidney fibrosis in
diabetic mice. We hypothesized that DDP-4i can produce its
pleiotropic action to prevent kidney damage beyond glycemic
control.
STRA6, CRBP1, RARα, caspase 3, collagen 1 and fibronectin was
measured by Western blot analysis for protein and PCR for
mRNA expression in the kidney in normal fat diet(NFD)-fed,
high fat diet(HFD)-fed mice and sitaglitipin-treated HFD-fed
mice. We aimed to investigate whether the reciprocal appear-
ance of STRA6 cascade down-regulation and fibrosis increase
in the kidney of HFD-fed mice, and whether DPP4i reverses
these alterations beyond glycemic control.
The expression of STRA6, CRBP1 and RARα protein and mRNA
expression remarkably decreased, while caspase 3, collagen 1,
and fibronectin significantly increased in kidney of HFD-fed
mice as compared with NFD-fed mice. All these changes in the
aorta of HFD-fed mice were reversed in sitaglitipin-treated
HFD-fed mice. The blood glucose values in HFD-fed mice and
sitaglitipin-treated HFD-fed mice are not different, but are
higher than NFD-fed mice.
We conclude that DDP-4 inhibitor can produce its beneficial
action to prevent HFD-induced fibrosis and apoptosis in kidney
of HFD-treated mice by reversing the suppression of RBP 4
receptor/CRBP-1/RARα signaling beyond its glycemic control.
OL09-8
Trans-S-1-propenyl-l-cysteine sulfoxide from Allium cepa
(onions) has appreciable antidiabetic potential in
streptozotocin-induced diabetic mice
Okechi ODUORI1,2, Kenji SUGAWARA1, Sakura YOSHIDA2,
Harumi TAKAHASHI1, Norihide YOKOI1, Morio NAKAYAMA2,
Susumu SEINO1*. 1Department of Molecular and Metabolic
medicine, Graduate School of Medicine, Kobe University, 2Graduate
School of Biomedical Sciences, Nagasaki University, Japan
Previous researches have shown that Allium cepa (onions)
possess appreciable antidiabetic effects in both animals and
human beings. Among the active compounds in A. cepa,
Alk (en) yl cysteine sulfoxides (ACSO) are believed to play a
major role in the onion’s pharmacological properties. Since
trans-S-1-propenyl-l-cysteine sulfoxide (PeCSO), is the major
ACSO in onions, our study was aimed at evaluating antidia-
betic potential of PeCSO in streptozotocin (STZ) induced
diabetic mice. To isolate PeCSO, onion bulbs were macerated
and subjected to a series of chromatographic techniques to
obtain PeCSO with a yield of 1.65 mg/g fresh weight and purity
of 98%. Type 1 diabetic mice was induced by a single high dose
STZ i.p injection while type 2 diabetes was induced by a
combination of high fat diet (HFD) and single low dose STZ.
Oral Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S40–S64 S61