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

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Selective serotonin reuptake inhibitors (SSRIs) are the most
common prescribed drugs for anxiety and mood disorders.
Long term use of SSRIs is associated with an increased risk of
diabetes, but the mechanism(s) underlying this association
is not fully elucidated. Evidences showed that E-cadherin-
mediated cell adhesion plays an important role on glucose-
stimulated insulin secretion (GSIS) in pancreatic β-cells.
Calcium signaling is essential for the release of insulin
granules. We showed that Fluoxetine significantly reduced
GSIS of mouse insulin secreting MIN6 cells. MIN6 cells formed
smaller colonies of loosely packed cells with reduced cell-cell
contact after fluoxetine treatment. Immunohistochemistry
revealed that E-cadherin largely accumulates in cytosol,
mainly in Golgi apparatus. Fluoxetine reduces the mem-
brane-localized E-cadherin due to increase of its endocytosis.
Fluoxetine inhibits spreading of cells attached to E-cad/Fc
as well as disrupts E-cadherin-mediated actin filament.
Furthermore, single β-cell calcium measurement indicated
that fluoxetine significantly suppresses ER calcium release
and the activation of store-operated calcium entry (SOCE) via
reduction of ER calcium storage and inhibition of STIM1
trafficking after ER calcium depletion respectively. Our
results suggested that exposure to fluoxetine results in
impaired β-cell function, occurring in concert with reduction
of E-cadherin-dependent cell adhesion and alterations of
calcium homeostasis.
PH-08
A comparison of intraportal islet transplantation outcome
between intraportal and intravenous injection of bone marrow
derived spheroids
Bae Jun OH1, Jin Myung CHOI1, Seung-Hoon OH1, You-Bin LEE 1,
Sang-Man JIN 1, Moon Kyu LEE1, Jae Hyeon KIM1*. 1Division of
Endocrinology and Metabolism, Department of Medicine, Samsung
Medical Center, Sungkyunkwan University School of Medicine, Korea
Object: Recently stem cells have emerged as a helper for
supporting islet engraftment following islet transplantation.
Previously, we showed the enhanced therapeutic efficacy of
islet after co-transplantation of bone marrow-derived spher-
oids (BM-spheroid) formed using 3-dimension culture from
BM-derived mononuclear cells (BM-MNCs) in a marginal mass
renal subcapsular islet transplantation model. In the present
study, we compared the intraportal islet co-transplantation
outcome with BM-spheroid between two injection routes via
portal vein and peripheral vein (portal-spheroid vs. venous-
dissociated spheroid).
Methods: Transplanted BM-spheroids were traced using green
fluorescent protein transgenic (GFP-Tg) mice and MRI with
nanoparticle labeling. The morphology of intraportally trans-
planted islet, revascularization of islets and iron-labeled BM-
spheroids were examined by immunohistochemistry. The
efficacy of co-transplanted BM-spheroids via intraportal or
intravenous route was investigated using a syngeneic mar-
ginal mass intraportal islet transplantation model. Blood
glucose concentration was monitored for 1 month.
Results: Portal-spheroid co-transplantation with islets
improved the post-transplant outcomes in terms of glucose
tolerance, serum insulin levels, and diabetes reversal rate
when compared with islet alone or venous-dissociated
spheroid co-transplantation. The area of grafted endocrine
tissue and vascularization of individual islets within the graft-
bearing liver was significantly higher in the portal-spheroid
group compared to the islets alone or the venous-dissociated
spheroid group. Also, BM-spheroid cells were found more
frequently within the graft-bearing liver in the intraportal
administration group compared to the intravenous adminis-
tration group.
Conclusion: Our results suggest that co-transplantation of BM-
spheroids via portal vein presents a promising strategy for
improving the efficacy of intraportal islet transplantation.
PH-09
Impaired incretin-induced insulin secretion in enlarged
pancreatic islets in a novel animal model of obese type 2
diabetes
Ghupurjan GHENI1, Norihide YOKOI1, Takuro YAMAGUCHI1,2,
Kohei HONDA1, Mahira HASHIM 1, Kanako TAMURA1,
Susumu SEINO1*. 1Division of Molecular and Metabolic Medicine,
Kobe University Graduate School of Medicine, Kobe, 2Kansai Electric
Power Hospital, Clinical Laboratory Center, Fukushima-ku, Osaka,
Japan
Objective: We recently reported the prediabetic changes in
glucose tolerance and insulin resistance in a novel animal
model of obese type 2 diabetes (T2D), the Zucker fatty diabetes
mellitus (ZFDM) rat (Gheni et al., J Diabetes Res, 2015). Our data
suggests that impaired incretin secretion and/or impaired
incretin-induced insulin secretion are involved in the patho-
physiology of the disease. In fact, the latter was confirmed by
insulin secretion experiment using isolated pancreatic islets,
but the mechanism is still unclear. In this study, we aimed to
elucidate the mechanism of the impaired incretin-induced
insulin secretion in prediabetic ZFDM rats.
Methods: The ZFDM rats harboring the fatty mutation (fa) in
the leptin receptor gene were used in this study (fa/fa, obese
diabetic; fa/+, non-obese control). We measured plasma
glucagon-like peptide 1 (GLP-1) and glucose-dependent insu-
linotropic polypeptide (GIP) concentrations during OGTT in 8-
and 12-week-old prediabetic rats. We also measured the
diameter of isolated islets, and defined enlarged islets as
those with diameter more than 300 μm and normal islets as
diameter less than 300 μm. We then evaluated the mRNA
expression levels of GLP-1 receptor and GIP receptor as well as
incretin-induced insulin secretion from these islets.
Results: Plasma GLP-1 and GIP concentrations during OGTT in
fa/fa rats were higher than those in fa/+ rats, indicating no
impairment in the incretin secretion in fa/fa rats. The relative
number of enlarged islets of fa/fa rats was significantly
increased at 12 weeks of age as compared to that at 8 weeks
of age. The mRNA expressions of GLP-1 and GIP receptors in fa/
fa rats at 12 weeks of age were significantly decreased in both
enlarged and normal islets as compared to those at 8 weeks of
age. Incretin-induced insulin secretion from enlarged islets of
fa/fa rats was significantly decreased than that from normal
islets.
Conclusion: Our data suggests that the enlargement in
pancreatic islets with age may be associated with impaired
incretin-induced insulin secretion in prediabetic state of ZFDM
rats.
PH-10
The role of leucine in stimulation of adipocyte lipolysis
Poh Ling KOH1, Jia Pei HO1, Cheryl PANG1, Hong Chang TAN2,
Jean-Paul KOVALIK1*. 1Duke-NUS Medical School, Cardiovascular
and Metabolic Disorders Program, 2Department of Endocrinology,
Singapore General Hospital, Singapore
Branched chain amino acids (BCAA), including leucine, have
been shown to be linked to the development of insulin
resistance under high fat conditions in both human subjects
and mouse models ). While some evidence
suggests that activation of mammalian target of rapamycin
(mTOR) is important for the effects of BCAA on whole body
metabolism, the exact mechanism is unknown. Adipose tissue
is a major site of BCAA metabolism and is thus a potential
driver of BCAA-related insulin resistance. We conducted
studies to determine the effects of the BCAA leucine on
adipocyte metabolism and function.
Leucine is taken up and processed by cultured adipocytes
with expected changes in the levels of amino acids, organic
acids and acyl-carnitines related to BCAAmetabolism. A novel
finding was that leucine enhances the ability of isoproterenol
to stimulate lipolysis in adipocytes. The downstream
Poster Presentations / Diabetes Research and Clinical Practice 120S1 (2016) S65–S211 S181