第二型糖尿病胰小島細胞功能之分子機制研究(3/3)
Other Title
Molecular Studies on Mechanism of Beta Cell Dysfunction Relating to Type 2 Diabetes
Date Issued
2005
Date
2005
Author(s)
莊立民
DOI
932314B002137
Abstract
We have focused studies on the pathogenesis of type 2 diabetes that involves both defects in the
insulin action and insulin secretion. It is striking that insulin stimulated first phase insulin secretion
is impaired in the early stage of development of type 2 diabetes. Previously, we demonstrated that
an insulin sensitizer of thiazolidinedione class can potentiate glucose-stimulated insulin secretion.
In rat pancreas perfusion system, both first- and second-phase of insulin secretion are affected by
rosiglitazone via a PI-3 kinase dependent pathway. In the present proposal, we plan to find out
molecular mechanisms by which rosiglitazone potentiate glucose-stimulated insulin secretion. We
have obtained and established the culture of a glucose-responsive rat pancreatic beta cell line,
MIN6 in our laboratory. We can study the ion channels that affect insulin secretion by the
patch-clamp techniques. Basically, ATP-sensitive K + -channel is involved in glucose-stimulated
insulin secretion. However, other ion channels might also possibly involve the effect of
rosiglitazone on potentiation of insulin secretion. How ion channel regulated by PI-3 kinase could
be studied in the cultured cells. In this way, we will answer in cellular mechanisms that might
explain how rosiglitazone potentiate insulin secretion.
Type 2 diabetes is a slowly progressive disorder in which long-standing hyperglycemia
can cause multiple cellular defects, a process termed glucose toxicity. Previous studies have
suggested that an increase flux of the glucose metabolites through the hexosamine biosynthetic
pathway maybe the mechanism by which hyperglycemia leads to insulin resistance. Usually,
only 2-3% of the total glucose taken up by the cell is metabolized by this pathway that ultimately
produces UDP-N-acetylglucosamine, which serves as a substrate in the formation of glycoprotein,
glycolipids, and proteoglycans. Both insulin target cells like muscle and adipocytes, and insulin
secreting pancreatic beta cells are all affected. We and other have noticed that glucosamine,
increased after long-standing hyperglycemia, might contribute to glucose toxicity of the islet
cells. In collaboration with Dr. Yang at Chung-Hsin University, we have found that pretreatment
with glucosamine could down-regulate glucose-stimulated insulin secretion. Moreover, treatment
with rosiglitazone markedly reversed the inhibition. This encouraging data suggest to us that
rosiglitazone might reverse the glucose toxicity of pancreatic beta cells. Detailed cellular
mechanisms, including how glucosamine and rosiglitazone affect intracellular ATP, calcium ion
concentration, mitochondrial membrane potential, and the interacting proteins for some
candidate genes will be studied.
Subjects
insulin secretion
beta cells
calpain10
protein-protein interaction
SDGs
Publisher
臺北市：國立臺灣大學醫學院內科
Type
report
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