栄養素によるインスリン分泌抑制機構と糖尿病における異常

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  • 清野 裕
    京都大学医学研究科病態代謝栄養学

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タイトル別名
  • Mechanism of Insulin Secretion Induced by Nutrient Abnormalities in Diabetes Mellitus.
  • エイヨウソ ニ ヨル インスリン ブンピ ヨクセイ キコウ ト トウニョウビョウ ニ オケル イジョウ

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Nutrients ingested orally are important physiological insulin secretagogues: a much greater inslin response is observed after oral glucose loading than after intravenous injection of the same amount of glucose. Gastroz inhibitory polypeptide (GIP) is the primary hormonal messenger relaying information from the gut to pancreatic β cells. To investigate the role of GIP as an incretin, we have generated mice with a targeted mutation of the GIP receptor gene. GIPR-/-mice have higher blood glucose levels with an impaired insulin response after an oral glucose load, suggesting that the early insulin secretion mediated by GIP determines glucose tolerance after oral glucose loading in vivo. In the Goto-Kakizaki rat, a new genetic model of type 2 diabetes, the insulin response to glucose is selectively impaired. We exanined the properties of ATP-sensitive K+ channels, whose inhibition is a key step in insulin secretion induced by fuel substrates, using the patch-clamp technique. The sensitivity of the KATP channels to glucose is considerably reduced in GK rats. It appears that the impaired insulinotropic action of glucose in the β cells of GK rats is insufficient closure of the KATP channels, probably because of deficient ATP production due to impaired glucose metabolism. In order to elucidate which step in ATP production by the metabolic pathway is responsible in diabetic β cells, we tested glyceraldehyde and KIC (ketoisocaproate, which can be metabolized in mitochondria via acetyl-CoA). KATP-channel activities in both control and diabetic β cells were equally suppressed by glyceraldehyde and 2-ketoisocaproate. We also investigated the insulin-secretory capacity of β cells by stimulation with dihydroxyacetone (DHA), which is known to be directly converted to DHA-phosphate and preferentially enter the glycerol phosphate shuttle. The DHA sensitivity of the KATP channels was found to be reduced in the β cells of GK rats. These results suggest that the intracellular sites responsible for the impaired glucose metabolism in pancreatic β cells of GK rats are located both in the glycolytic pathway proximal to glyceraldehyde and in the glycerol phosphate shuttle.

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