15 March 2010

Diabetes treatment: replace insulin with leptin?

Leptin instead of insulinElena Novoselova, STRF
Recently, a report appeared in the press about a sensational discovery by American scientists – the hormone leptin, involved in the process of regulating appetite, can become an alternative to insulin therapy for diabetes.

The prospects for the clinical application of the results of this study drew attention to the publication SciBX (Science-Business eXchange): Leptin instead of insulin.

In their work, specialists from The University of Texas Southwestern Medical Center (The University of Texas Southwestern Medical Center at Dallas, USA) demonstrated that the hormone leptin can replace insulin, taking over the functions of controlling blood sugar levels in patients with type I diabetes. This work attracted the attention of the biotech company Amylin Pharmaceuticals Inc., the result of cooperation with which is the beginning of the second stage of clinical trials of a new therapeutic approach for the treatment of diabetes.

Type I diabetes (insulin-dependent) develops when the beta cells of the pancreas that produce insulin, as a result of an autoimmune attack, lose the ability to secrete it. The inability to control blood sugar levels leads to many complications, including disorders of the kidneys and cardiovascular system.

Since the 1920s, after the role of insulin in regulating blood sugar levels was determined, insulin therapy has become the standard treatment regimen for diabetes. In a typical treatment regimen, insulin is delivered non-physiologically and requires precise glycemic control by the patient. Many laboratories are developing alternative treatments for this disease.

In a study led by Roger Unger, scientists were able to prove on model mice that the hormone leptin, secreted by adipocytes, can, like insulin, effectively regulate blood glucose levels, while having fewer side effects. The effect of leptin on blood sugar levels has been discovered quite recently; before that, its main functions were called appetite regulation and weight control. Leptin is often called the satiety hormone. It is believed that it acts on the hypothalamus, blocking the synthesis and release of neuropeptide Y, which causes hunger. The concentration of leptin plays the role of a physiological signal about the sufficiency of the body's energy resources to perform reproductive function and affects the production of steroid hormones in the ovaries.

Based on previous studies, scientists from the University of Texas studied the role of leptin in controlling glucose metabolism in transgenic mice of the NOD line (nonobese diabetic mouse is a standard animal model for studying insulin–dependent diabetes).

When compared with mice treated with insulin, animals injected with leptin showed a similar decrease in blood sugar and similar metabolic parameters of glucose in the blood and ketones in the urine. It was also found that the combination of low doses of leptin and insulin provided stable long-term control of blood glucose levels, which exceeded the effect of insulin alone. According to the authors, leptin can be used as a supplement to traditional insulin therapy.

Experts believe that the antidiabetic effect of leptin is a consequence of the hormone's action on the alpha cells of the pancreas, which secrete glucagon. Glucagon neutralizes the effect of insulin by stimulating the conversion of glycogen into sugar. Usually, insulin suppresses the production of glucagon, but with a decrease in the level of insulin, the concentration of glucagon steadily increases, which leads to the further development of hyperglycemia. Very high systemic doses of insulin are required to reduce glucagon synthesis, but the required effective dose of leptin is much lower.

In addition, leptin had a more favorable effect in the regulation of lipid metabolism – mice treated with leptin had lower levels of fatty acids and cholesterol synthesis enzymes. According to the authors, this can be used to prevent dyslepidemia, a side effect of long–term insulin therapy.

Jay Schuyler, professor of medicine, pediatrics and psychology at the University of Miami, said in a comment for SciBX that Unger's work "opens the door" to a completely new approach for the treatment of type I diabetes. And although Skyler is a member of the Amylin Pharmaceuticals team, he insists on the objectivity of his opinion.

At the same time, Rohit Kulkarni from Joslin Diabetes Center notes that the mechanism of regulation of glucose levels by leptin is not fully understood. Two years ago, studies under his leadership demonstrated that mice "knocked out" by leptin receptor genes (LEPR; CD295; OBR) had an increased concentration of insulin, and a change in the activity of the hormone leptin led to the development of type II diabetes. Therefore, the results of the study by Roger Unger's team need to be tested on other models of type I diabetes. Kulkarni also noted the possible side effect of leptin therapy on appetite and libido through the central nervous system and suggested using small molecules stimulating LEPR receptors that do not overcome the blood-brain barrier for therapy.

Despite the ambiguity in the mechanism of action of leptin in the treatment of type I diabetes, David Muggs, head of R&D at Amylin Pharmaceuticals, believes that the reliability of Unger's preclinical studies indicates the possibility of clinical trials of leptin.

Amylin Pharmaceuticals is developing leptin receptor agonists for obesity therapy. Amylin Pharmaceuticals and Takeda Pharmaceutical Co. Ltd. have completed the second phase of trials of metreleptin (an analogue of leptin) and pramlintide (an analogue of the appetite-suppressing hormone amylin) jointly used for the treatment of obesity. Thus, leptin analogues have passed clinical safety tests and the company sees no reason to stop development.

The results of the work were published in the Proceedings of the National Academy of Sciences: Leptin therapy in insulin-deficient type I diabetes.

Portal "Eternal youth" http://vechnayamolodost.ru15.03.2010

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