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-β-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 the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals.
Highlights
The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide [1], creating a strong demand for the development of more effective anti-diabetic drugs
We previously reported that a silkworm infection model can be utilized to evaluate antibacterial and antiviral agents, and that there are a number of similarities in the pharmacokinetics of antibiotics between silkworms and mammals [2,3,4,5,6]
The hypoglycemic effect of human insulin was blocked by the administration of wortmannin (Figure 4F). These results suggest that human insulin induces glucose uptake via the activation of phosphoinositide 3 kinase in the silkworm fat body, as in insulin-stimulated mammalian adipose tissue
Summary
The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide [1], creating a strong demand for the development of more effective anti-diabetic drugs. Evaluation of the effects of anti-diabetic drugs requires the use of an animal model. The use of mammalian animals to screen for anti-diabetic drugs, is very expensive from an animal husbandry perspective, and presents ethical problems in terms of animal welfare. We previously reported that a silkworm infection model can be utilized to evaluate antibacterial and antiviral agents, and that there are a number of similarities in the pharmacokinetics of antibiotics between silkworms and mammals [2,3,4,5,6]. Screening of therapeutic agents can be performed with a large number of individual silkworms without the same ethical concerns involved in the use of mammals. We propose an invertebrate animal model of the disease utilizing the silkworm to evaluate the therapeutic effects of drugs
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