Glucagon like peptide 1 (GLP-1) is the ileal endocrine cells secrete a brain-gut peptide, mainly as a type 2 diabetes drug action targets. Because GLP-1 inhibits gastric emptying, reduced motility, and therefore helps to control food intake, weight loss. In 19 cases of obese patients a prospective placebo-controlled, randomized, double-blind, crossover study, GLP-1 administered subcutaneously in patients with increased postprandial satiety, food intake and make every meal an average reduction of 15 %. However, GLP-1 is a polypeptide, not oral administration is one major shortcoming.
These drugs currently in development is most rapid progress in the United States Amylin Pharmaceuticals synthetic GLP-1 receptor agonist Exenatide (containing 39 amino acid peptide). Amylin Pharmaceuticals, Inc. in November 2003 announced the Exe-natide treatment of type 2 diabetes in three pivotal Phase Ⅲ clinical trial results, have reached the end of the treatment of diabetes. High-dose group (10 micrograms three times a day) can mean weight loss of 2 kg in patients, compared with the control group was significant. April 2005 FDA has approved Exenatide for type 2 diabetes.
Effect: GLP-1 biology how? How to play hypoglycemic effect?
Studies have confirmed incretin glucose concentration-dependent manner to promote insulin secretion from pancreatic β cells and reduced islet α cells secrete glucagon (glucagon), thereby reducing blood sugar. Normal after a meal, incretin secretion begins, thereby promoting insulin secretion to reduce postprandial blood glucose fluctuations. But for patients with type 2 diabetes, the "incretin effect" damage, mainly for post-meal GLP-1 concentration has been reduced rate lower than normal, but its promotion of insulin secretion and lowering blood sugar does not damage is evident, therefore GLP-1 and its analogues can be used as the treatment of type 2 diabetes is an important target.
Following aspects play a hypoglycemic effect GLP-1 has a protective role in β cell GLP-1 may act on islet β cells, promote insulin gene transcription, insulin can stimulate the synthesis and secretion of pancreatic β cell proliferation and differentiation, inhibition of insulin β cell apoptosis, increased islet β cells [2-5]. In addition, GLP-1 may also act on the pancreatic α cells, strongly inhibited the release of glucagon, and the role of islet δ cells, and promote the secretion of somatostatin, somatostatin can be suppressed in a paracrine hormone glucagon glucagon secretion.
Studies have shown, GLP-1 can be significantly improved through a variety of mechanisms animal models of type 2 diabetes in patients with glucose or circumstances which promote islet β cell regeneration and repair, increasing the role of islet β cells is particularly significant, which for type 2 diabetes The treatment provides a very good prospect.
GLP-1 has a concentration-dependent hypoglycemic effect of glucose as a source of intestinal hormone, GLP-1 is particularly carbohydrate nutrient stimulation before being released into the blood, and its role in insulin secretion was glucose concentration dependent, Nauck etc. [6] on 10 cases of poor glycemic control in type 2 diabetic patients were studied, and in the fasting state, patients were treated with GLP-1 or placebo, the results showed that patients in the infusion of GLP-1, its insulin and C-peptide levels were significantly increased glucagon levels were significantly reduced fasting blood glucose levels to normal after 4 hours. In normal blood sugar levels, though still continuous infusion GLP-1, in patients with insulin levels are no longer elevated blood sugar levels remain stable and not decline further. This shows that GLP-1 has a glucose concentration-dependent hypoglycemic effect, that only in the case of elevated blood glucose levels, GLP-1 was played hypoglycemic effect, and blood glucose levels are normal, then it will not be further reduced. GLP-1 glucose concentration-dependent hypoglycemic This feature is its basis for clinical application security and protection, eliminating one of the existing diabetes medications and solutions may cause severe hypoglycemia in patients with worry.
GLP-1 has the effect of weight loss Can Del (Zander), etc. [7] studies have shown that GLP-1 in the acceptance, after 6 weeks of treatment, 20 patients participated in the study in patients with type 2 diabetes, mean weight loss of 1.9 kg. Researchers believe, GLP-1 is produced by a variety of ways to reduce body weight effects, including inhibition of gastrointestinal motility and gastric secretion, suppress appetite and food intake, delayed emptying of the stomach contents. In addition, GLP-1 may also act on the central nervous system (especially the hypothalamus), allowing the body to produce a sense of fullness and loss of appetite.
In addition, GLP-1 also has many other biological characteristics and functions, for example, GLP-1 may play a lowering, antihypertensive effect, so that a protective effect on the cardiovascular system; It can also enhance the learning effect on the central and memory function, protects nerve.
However, to be applied to clinical GLP-1 is also facing the problem, and that is the body's own GLP-1 produced by the body can easily be dipeptidyl peptidase Ⅳ (DPP-Ⅳ) degradation, the plasma half-life of less than two minutes, you must continuous subcutaneous continuous infusion or to produce effects, which greatly limits the clinical application of GLP-1.
To solve this problem, scholars have proposed two solutions, one developed GLP-1 analogues, allowed both to maintain the efficacy of GLP-1, but also resist degradation; two is to develop inhibitors of DPP-Ⅳ, so that the body itself GLP-1 secretion is not degraded. Currently, both studies have made some progress. I believe that with people on GLP-1 signaling system of research, the role will find more new targets, in order to develop more new drugs to treat diabetes, to benefit diabetes.
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