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.
Potent therapeutic actions of dietary manipulations and food factors on nephritis and cancer were evaluated using in vivo and in vitro disease models. In rats with glomerulonephritis, dietary manipulations of amino acids-fortified low-protein diets reduced proteinuria, hypoalbuminemia and hyperlipidemia without severe protein malnutrition. A cysteine derivative from cabbage, S-methyl-L-cysteine sulfoxide, suppressed hypercholesterolemia in response to hepatoma (AH109A) growth by upregulating cholesterol catabolism. Fish oil suppressed hyperlipidemia secondary to glomerulone-phritis and presence of hepatoma. Screening of food factors with the potential to suppress the proliferation and invasion of cancer cells was conducted using in vitro assay systems in which AH109A cells were employed as model cancer cells. Food factors such as catechins from teas, curcumin in turmeric, and astaxanthin in crustaceans were effective in suppressing hepatoma proliferation and/or invasion. The antioxidative properties of these food factors were suggested to be involved in their anti-invasive activities. Both advantageous and disadvantageous aspects of in vivo and in vitro disease models were discussed in evaluating the therapeutic actions of food factors.