ANTIDIABETIC AGENT

BIOLOGICAL EFFECT OF GLP-1

INSULINOTROPIC ACTION
The insulinotropic effect of GLP-1 are strictly glucose dependent; it has no effect on insulin secretion at glucose concentration below 4.5mM.In addition , GLP-1 strongly potentiates the insulinotropic actions of glucose itself. It enhances all the steps of insulin biosynthesis and transcription of insulin gene, which provides a continuous, augmented supply of insulin for secretion. The expression of genes that are essential for beta cell function, such as glucokinase and Glut 2 are up regulated following GLP1 treatment.GLP-1 also has tropic effects on beta cells. It both stimulate beta cell proliferation and enhances the differentiation of new beta cells from progenitor cells in the epithelium of the pancreatic duct. GLP-1 mediated endocrine proliferation in glucose intolerant aging rats with resultant improvement in glucose tolerance. This indicates that GLP-1 might be capable of stimulating the growth of new beta cells in individuals such as type 2 diabetic patiants who have an insufficient number of functioning cells.

INHIBITION OF GLUCAGON SECRETION
GLP-1 inhibits glucagon secretion in glucose dependent manner. Glucagon opposes the effects of insulin on maintaining blood glucose leves which contributes significantly to the development of hyper glycemia in diabetic subject.

GASTROINTESTINAL EFFECTS
GLP-1 inhibits gastrointestinal secretion and motility, most notably gastric empting. The speed of gastric empting response is indicative of either a neural or endocrine signaling mechanism from the upper gastrointestinal area. GLP-1 is one of the main hormones of the ‘ileal break’, the primary, inhibitory feedback mechanism that controls the transit of meal through the upper gastrointestinal track to optimize nutrient digestion and absorption. During physiological malabsorption, GLP-1 secretion is stimulated and gastric and pancreatic secretion inhibited. Infusion of GLP-1 during the ingestion of meal dose dependently diminishes the insulin responses, rather than enhance them. This is likely to be related to reduced gastric empting and subsequent decrease in absorption of insulinotropic nutrients.

CNS EFFECT OF GLP-1
GLP-1 receptor are present in brain and hypothalamic nucleus. Receptor at hypothalamic nucleus indicating a role of GLP-1 in the central regulation of food intake. The stimulus for activation of neuronal GLP-1 receptor in CNS is unclear. GLP-1 in blood stream enter brain but its function is unknown. recent study shows that GLP-1 can induce the differentiation of neuronal cell in culture.

EFFECT OF GLP-1 ON APPTITE AND FOOD INTAKE
Recent studies shows that GLP-1 dose-dependently inhibit feeding behavior, because peripheral administration of GLP-1 significantly enhances satiety and reduces appetite in both healthy and diabetic subjects. Whether GLP-1 receptor-mediated signaling pathways are essential for the physiological control of appetite and body weight remain unclear but certainly, inhibition of gastric empting might account for the satiety after GLP-1 administration. Likewise, nutrients in the ileum are thought to have satiating effect and decrease food intake. It has been suggested that peripheral GLP-1 might exert indirect effects on satiety center in the CNS through neuronal relay mechanisms.

NEUROPROTECTIVE EFFECTS OF GLP-1
Activation of GLP-1 receptor modulates cell survival in diverse cell types. GLP-1 treatment reduces the number of apoptotic cells in pancreas with an associated increase in islet size and beta cell mass. GLP-1 protects against H2O2 induced apoptotic cell death in an insulin secreting cell line. It also protect against glutamate-induced cell death in the manner similar to other neurotrophic factors. This provided the first indication of a neuroprotective role for GLP-1 receptor agonists and demonstrates the antiapoptotic action mediated by GLP-1 might not be restricted to the insulin-secreting cells.


GLP-1 AND DIABETES
GLP-1 when given continuous intravenous infusion is effective in patients with type2 diabetes by increasing insulin secretion normalizing fasting as well as postprandial (after meal) blood glucose. GLP-1 is used in advanced type2 diabetes long after sulfonylurea secondary failure. The effects of single subcutaneous injection of GLP-1 were disappointing. Although high plasma levels of immunoreactive GLP-1 were achieved, insulin secretion rapidly return to pretreatment values and blood glucose concentration were not normalized but the effect of repeated subcutaneous administration on fasting blood glucose was as good as intravenous administration. Continuous subcutaneous administration for 6 weeks also reduce fasting and postprandial glucose concentrations.
The progressive loss of beta cell function and mass is an early feature of type2 diabetes, eventually leading to insulin dependence in many patients. Intervening early in course of diabetes or perhaps in the prediabetic state to stimulate beta cell differentiation and/or reduce apoptosis could theoretically halt the progression of the disease. Both GLP-1 and exenatide have shown promise in this respect.