Recently in Korea, the intake of lipid components from food has increased due to economic growth and westernized food lives, and metabolic diseases, such as obesity, diabetes, hyperlipidemia, hypertension, arteriosclerosis, and fatty liver, are increasing due to lack of exercise or the like. Obesity may hurt the appearance of slim body types that young people like, and persisting obesity may cause a variety of diseases.
Current medicines for treating obesity may be largely divided into medicines that act on the central nervous system to affect appetite and medicines that act on the gastrointestinal tract to inhibit absorption. The medicines acting on the central nervous system include, depending on the mechanism of each medicine, those inhibiting serotonin (5-HT) in the central nervous system, such as fenfluramine and dexfenfluramine, those acting on noradrenaline in the nervous system, such as ephedrine and caffeine, and those acting on both serotonin and noradrenaline in the central nervous systems to inhibit obesity, such as sibutramine. The foregoing medicines are available in the market.
In addition, a typical example of the medicines that act on the gastrointestinal tract to inhibit obesity is orlistat, which reduces lipid absorption by inhibiting lipase in the gastrointestinal tract and is approved as a medicine for obesity. However, among the existing medicines, fenfluramine and the like were recently withdrawn from the market due to the side effects thereof, such as pulmonary hypertension or heart valve disease, and other medicines are inapplicable to patients with renal diseases or heart failure due to the occurrence of reduced blood pressure, lactic acidosis, and the like.
Diabetes is a type of metabolic disease wherein impaired insulin secretion or absence of normal functions occurs (DeFronzo, 1988), and is characterized by hyperglycemia, for example, increased blood glucose levels. Hyperglycemia causes several symptoms and signs and results in the discharge of glucose into urine. In recent years, the incidence of diabetes is an explosively growing trend due to increased obesity rates, especially, increased abdominal obesity.
The number of diabetic patients was estimated to be 170 million worldwide in 2000 and is expected to reach 370 million in 2030, but according to a recent analysis report, the number of diabetic patients already reached about 350 million worldwide in 2008 (Danaei et al., 2011), which is far worse than expected. It is reported that about 80% or more of type 2 diabetic patients are obese while less than 10% of obese patients have diabetes (Harris et al. 1987). Such correlation between diabetes and obesity is due to the fact that adipokines and free fatty acids are irregularly secreted to induce fatty acids to accumulate in insulin-sensitive tissues, such as beta cells, kidneys, liver, and heart, resulting in lipotoxicity. If left without suitable treatment, chronic hyperglycemia is accompanied by various pathological symptoms in the body, and representative symptoms include retinopathy, renal dysfunction, neuropathy, and vascular disorder. Indispensable for preventing such complications is effective blood glucose management.
Nowadays, the control of blood glucose is accomplished by correction of lifestyle (diet therapy or exercise therapy), and medicinal therapy. However, diet therapy or exercise therapy is difficult to strictly manage and practice, with limitations of the effects thereof. Hence, most patients with diabetes rely on the control of blood glucose by medicines, such as insulin, insulin secretagogues, insulin sensitizers, and hypoglycemic agents, as well as correction of lifestyle.
The insulin that is produced using a recombinant method is used as a drug indispensable to type 1 diabetic patients, and type 2 diabetic patients failing to control blood glucose. Such insulin is advantageous in blood glucose control, but has disadvantages of aversion to syringe needles, difficulty in administration, hypoglycemic risk, and weight gain.
Meglitinides, which are a kind of insulin secretagogue, are fast-acting agents and are taken before meals, and examples thereof include NovoNorm (repaglinide), Fastic (nateglinide), and Glufast (mitiglinide). Insulin sensitizers are characterized by almost no hyperglycemic incurrence when taken alone, and may be exemplified by biguanide drugs, such as metformin, and thiazolidinedione drugs, such as Avanida (rosiglitazone) and Actos (pioglitazone).
Recently, GLP-1 agonists have been developed using the action of glucagon-like peptide-1, which is an insulin secretion-stimulating hormone, and include exenatide and Victoza (liraglutide). In addition, dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the action of DPP, an enzyme responsible for the rapid inactivation of GLP-1, are newly developed drugs and are representatively exemplified by Januvia (ingredient name: sitagliptin).
However, these medicines are reported to have side effects of hepatoxicity, gastrointestinal disorders, cardiovascular disorders, and carcinogenicity, and such medicines cause high annual treatment costs, resulting in a barrier to the treatment of diabetes. Indeed, health care costs of pre-diabetes and diabetes approached about 200 trillion won in the USA as of 2007 (Dall et al., 2010), and health care costs of obesity are also near 150 trillion won only in the USA as of 2008 (Finkelstein et al., 2009). Therefore, there is an urgent need for the development of a drug that can effectively lower blood glucose levels and can be applied to both diabetes and obesity-induced diabetes, with few side effects.
Above all, the present inventors have recently paid attention to energy metabolism-regulating mechanisms in order to find an improved method for the treatment of obesity, and have made research of signals responsible for lipid accumulation and proteins affecting lipid accumulation upon the intake of high-fat diets in humans, with the premise that the compound to be developed should of higher safety (lower toxicity). Though the research on signals for suppressing the expression of proteins responsible for lipid accumulation and for breaking down accumulated lipid and on proteins involved in the signaling, the present inventors developed peptides that stimulate lipolysis. In addition, the peptides of the present invention show outstanding therapeutic efficacy on diabetes and obesity-induced diabetes. The lipid accumulation induced by high-fat diets, the suppression of insulin signaling attributed to lipid accumulation in the liver or muscle, and the resulting insulin tolerance are causes of diabetes.
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