题名：Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function.
作者：WANG C; LI X; MU K; LI L; WANG S; ZHU Y; ZHANG M; RYU J; XIE Z; SHI D; ZHANG WJ; DONG LQ; JIA W;
来源：Diabetologia. 2013 Sep;56(9):1999-2009. doi: 10.1007/s00125-013-2971-4. Epub 2013 [ IF= 6.49 ] ]
摘要：AIMS/HYPOTHESIS: Adaptor protein, phosphotyrosine interaction, pleckstrin
homology domain and leucine zipper containing 1 (APPL1) is an adapter protein
that positively mediates adiponectin signalling. Deficiency of APPL1 in the
target tissues of insulin induces insulin resistance. We therefore aimed, in the
present study, to determine its role in regulating pancreatic beta cell function.
METHODS: A hyperglycaemic clamp test was performed to determine insulin secretion
in APPL1 knockout (KO) mice. Glucose- and adiponectin-induced insulin release was
measured in islets from APPL1 KO mice or INS-1(832/13) cells with either APPL1
knockdown or overproduction. RT-PCR and western blotting were conducted to
analyse gene expression and protein abundance. Oxygen consumption rate (OCR), ATP
production and mitochondrial membrane potential were assayed to evaluate
mitochondrial function. RESULTS: APPL1 is highly expressed in pancreatic islets,
but its levels are decreased in mice fed a high-fat diet and db/db mice compared
with controls. Deletion of the Appl1 gene leads to impairment of both the first
and second phases of insulin secretion during hyperglycaemic clamp tests. In
addition, glucose-stimulated insulin secretion (GSIS) is significantly decreased
in islets from APPL1 KO mice. Conversely, overproduction of APPL1 leads to an
increase in GSIS in beta cells. In addition, expression levels of several genes
involved in insulin production, mitochondrial biogenesis and mitochondrial OCR,
ATP production and mitochondrial membrane potential are reduced significantly in
APPL1-knockdown beta cells. Moreover, suppression or overexproduction of APPL1
inhibits or stimulates adiponectin-potentiated GSIS in beta cells, respectively.
CONCLUSIONS/INTERPRETATION: Our study demonstrates the roles of APPL1 in
regulating GSIS and mitochondrial function in pancreatic beta cells, which
implicates APPL1 as a therapeutic target in the treatment of type 2 diabetes.