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

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Incretin/Islet Biology and Insulin
Secretion
S30-1
β -cell glutamate signaling in insulin secretion: the
physiological and pathophysiological roles
Susumu SEINO1. 1Division of Molecular and Metabolic Medicine,
Kobe University Graduate School of Medicine, Kobe, Japan
Insulin secretion from pancreatic β-cells plays the central role
in the maintenance of glucose homeostasis; impaired insulin
secretion contributes to the pathogenesis and pathophysi-
ology of diabetes. Glucose-induced insulin secretion (GIIS) is
the primary mechanism of insulin secretion, in which glucose
metabolism in β-cells is prerequisite. In addition to GIIS,
neuro-hormonal amplification of insulin secretion is also
critical in normal regulation of insulin secretion. Incretins
such as glucose-dependent insulinotropic polypeptide (GIP)
and glucagon-like peptide-1 (GLP-1), which are released from
enteroendocrine cells in response to meal ingestion, potenti-
ate insulin secretion primarily through cAMP signaling in
pancreatic β-cells. The glucose-dependent action of incretin in
insulin secretion provides the basis for the recently developed
incretin-based anti-diabetic drugs. However, the mechanism
of the link between glucose metabolism and incretin/cAMP
action in insulin secretion was not clear. Using a metabolo-
mics-based approach, we recently found that cytosolic glu-
tamate produced through the malate-aspartate shuttle links
glucose metabolism to cAMP action in insulin release , acting
as a key cell signal in incretin-induced insulin secretion (IIIS).
We also investigated the pathophysiological role of glutamate
signaling in insulin secretion using various rat models of
diabetes and obesity. The insulin secretory responses to
glucose and the incretins GLP-1 and GIP were assessed by
batch incubation of isolated pancreatic islets. Contents of
glutamate isotopomers were measured by 13C-enrichment
analysis with uniformly-labeled [U- 13C]-glucose as a substrate
using capillary electrophoresis mass spectrometry (CE-MS).
Pancreatic islets of control Wistar rats exhibited both GIIS and
IIIS. However, in islets of Goto-Kakizaki (GK) rats, a model of
diabetes with impaired insulin secretion, GIIS was markedly
decreased while IIIS was somewhat retained. In contrast, in
Zucker fatty (ZF) rats, a model of obesity, GIIS was evident,
but there was no IIIS. The islets of Zucker fatty diabetes
mellitus rats (ZFDM, a model of diabetes with obesity) at 11
weeks of age were found to comprise a mixture of relatively
larger and smaller islets. Interestingly, while the smaller islets
(<100 μm in diameter) exhibited IIIS, the larger islets (>300 μm)
did not. Glutamate production in GK islets was slightly but
significantly increased by glucose stimulation. In contrast,
glutamate production in neither ZF islets nor the larger ZFDM
islets was increased by glucose stimulation, although it was
increased in the smaller islets of ZFDM rats. These data
indicate that IIIS is well correlated with glutamate production
by glucose in β-cells. Our findings serve to clarify the
mechanism of impaired IIIS in type 2 diabetes and to suggest
novel therapeutic strategies.
S30-2
Intracellular membrane trafficking and insulin secretion
Wanjin HONG 1. 1Institute of Molecular and Cell Biology, A*STAR,
Singapore
My lab has been interested in defining the underlying
mechanisms governing membrane trafficking in mammalian
cells. Over the years, we have identified over half of mamma-
lian SNARE proteins, defined several SNARE complexes and
identified downstream effectors for small GTPases Arl1, Rab34
and Rab7. In addition, we have discovered that PX domain is a
novel motif capable of interacting with phosphoinositides.
Other regulators of membrane trafficking such as BIG3 and
p125A and Tom1L1 were discovered. In addition to the
overview of the research, I will discuss our work on VAMP8
and BIG3 in insulin secretion.
S30-3
Sorcs1: From diabetes quantitative trait locus to cellular
function
Melkam A. KEBEDE1. 1School of Life and Environmental Sciences,
Charles Perkin Centre University of Sydney, Sydney, Australia
Type 2 diabetes occurs when pancreatic β-cells are unable to
produce enough insulin to meet the increased demand for
insulin brought about by insulin resistance. Most of the
genetic loci that have been discovered through genome-wide
association studies in humans point to defects that affect β-
cell mass or β-cell function. Using mouse genetics, we
positionally cloned a diabetes susceptibility locus and identi-
fied the causal gene, Sorcs1. Subsequent studies show that
Sorcs1 is involved in type 2 diabetes and diabetes complica-
tions in humans. Sorcs1 is a member of the Vacuolar protein
sorting-10 (Vps10) gene family. Vps10 was originally discov-
ered in yeast where it is a receptor for carboxypeptidase Y and
is essential for its transport to the yeast vacuole (equivalent to
the mammalian lysosome). We derived a mouse with a
deletion of the Sorcs1 gene. When made obese, the mouse
develops severe diabetes. This is due to a defect in the
production of insulin granules and a dramatic increase in the
post-translational degradation of insulin. Our preliminary
studies point to a second vps10 protein, which plays an
important role in post-translational degradation of proteins,
by targeting to the lysosome. We are currently investigating
the role of this second vps10 family member on insulin
degradation in pancreatic β-cells. In this seminar I will describe
the methods we used to identify Sorcs1 as a T2D gene and
describe what we have learn from the phenotype of the Sorcs1
KO mouse and our preliminary data on receptor mediated
degradation of insulin in pancreatic β-cells.
S30-4
New insights into mechanisms regulating insulin secretion
Peter SHEPHERD1. 1University of Auckland, New Zealand
The capacity of β-cells to secrete insulin is reduced during the
development of type-2 diabetes but the mechanisms regulat-
ing insulin secretion in response to glucose and incretins
remains only partially understood. This presentation will
describe our evidence indicating that β -catenin and proteins
that associate with it represent an important component of
the nutrient responsive insulin secretory mechanism. We
find that β-catenin is necessary for insulin secretion in
response to both these glucose and GLP-1. What is more we
find β-catenin levels change in β-cells in response to changes
in glucose levels indicating this is part of the way β -cells
regulate insulin secretion in response to changes in glucose. A
potential role for this in vivo is supported by the finding that
number of SNPs associated with increased risk of type-2
diabetes have been identified in genes that regulate β-catenin
function (e.g. TCF7L2, CTNNA2, BTRC, IGFBP2 and MAGI1). Our
mechanistic information suggests that β-catenin is acting as
rheostat to regulate the amount of insulin that can be secreted
at any one time. This presentation will describe the evidence
supporting this.
S30-5
Role of Activin B/FSTL3 axis in the control of glucose
homeostasis
Kohjiro UEKI1. 1Department of Molecular Sciences on Diabetes, the
University of Tokyo, Tokyo, Japan
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39 S25