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an invertebrate hyperglycemic model for the identification of anti-diabetic drugs无脊椎动物高血糖的模型识别的抗糖尿病药物
An Invertebrate Hyperglycemic Model for the
Identification of Anti-Diabetic Drugs
Yasuhiko Matsumoto, Eriko Sumiya, Takuya Sugita, Kazuhisa Sekimizu*
Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Abstract
The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal
insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic
drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic
animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic
effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph
increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin
and 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator,
decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat
body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt
phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover,
AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction
inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the
hyperglycemic silkworms and restored growth, suggesting that
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