1994 Fiscal Year Final Research Report Summary
Physiological and molecular biological studies on functional alterations in ion channels of pancreatic beta cells in diabetes mellitus.
| Project/Area Number |
05670857
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ISHIDA Hitoshi Assistant Professor, Department of Metabolism and Clinical Nutrition, Kyoto University School of Medicine, 医学部, 助手 (80212893)
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| Co-Investigator(Kenkyū-buntansha) |
SEINO Yutaka Associate Professor, Department of Metabolism and Clinical Nutrition, Kyoto Univ, 医学部, 助教授 (40030986)
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| Project Period (FY) |
1993 – 1994
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| Keywords | Diabetes mellitus / Pancreatic beta-cells / Insulin secretion / Intracellular calcium concentration / Patch-clamp technique / ATP-sensitive K^+ channels / Voltage-dependnet Ca^<2+> channels |
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| Research Abstract |
The selective impairment of glucose-induced insulin secretion has been known as one of the major characteristics of pathogenetic aspects in non-insulin-dependent diabetes mellitus (NIDDM) . We have recently reported that the intracellular calcium responses to glucose are selectively impaired in pancreatic beta cells of NIDDM rat models. In order to clarify the molecular mechanism underlying this impairment, we investigated the activities of ATP sensitive K^+ channels (K_<ATP> channels) and voltage-dependent Ca^<2+> channels (VDCCs) directly using the patch-clamp technique, both of which are known to play an important role in the elevation of intracellular calcium levels after the glucose stimulation. The inhibition of K_<ATP> channels activities by glucose was reduced in beta cells of GK rats, a genetic model of NIDDM,whereas the ATP sensitivity of channels was intact. This clearly indicates that the intracellular glucose metabolism is impaired in NIDDM beta cells. On the other hand, the channels inhibition by glyceraldehyde or ketoisocaproate, which are matabolizad through the intermediates in glucose metabolism, was similar between GK and control rats. However, the inhibition of channel activities by dihydroxyacetone (DHA) -phosphate, an isomer of glyceraldehyde-3-phosphate, was reduced in NIDDM beta cells. Since DHA-phosphate can enter the glycerol phosphate shuttle which is thought to be a direct link in the metaolic pathway between glycolysis and mitochondrial oxidation, the responsible sites for impaired glucose metabolism is speculated to be located in this shuttle. In addition, the direct augmentation of VDCC activities through glucose metabolism was also found to be reduced by perforated-patch recording in beta cells of GK rats. These facts are though to be closely related to the selective impairment of glucose induced insulin secretion from NIDDM beta cells.
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