Diabetes is increasing at an alarming rate worldwide even in the developing countries. The high blood glucose in diabetic patients damages blood vessels, nerves, eyes and kidney, which finally causes severe cardiovascular diseases, neuropathy, blindness and renal failure. Therefore, control of blood glucose is the key battle ground to fight for diabetes.
For type-1 diabetic patients who lack insulin, the administration of insulin before food intake prevents hyperglycemia. For the most diabetic patients classified as type-2 diabetes in which either the body does not produce enough insulin or the cells ignore the insulin, elevated levels of blood glucose are considered responsible for excess complications causing morbidity and mortality. Many drugs have been developed to control blood sugar in type-2 diabetes as classified as following, 1) sulphonylures, which increase insulin release from pancreatic islets; 2) metformin, which acts to reduce hepatic glucose production; 3) glitazones, which are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and sensitize insulin receptor downstream signaling; 4) α-glucosidase inhibitors, which interfere with gut glucose absorption; 5) incretins, which are agonists for GLP-1 receptor and promote insulin secretion; 6) DPP-IV inhibitors, which suppress degradation of endogenous GLP-1 and enhance insulin secretion; and finally insulin itself, which suppresses glucose production and augments glucose utilization (Moller, 2001). However, the magic bullet to treat type-2 diabetes has yet to be discovered, since these medicines have limited efficacy.
Studies using mouse mutations have helped to define the regulatory circuits that govern energy expenditure, and to further understand the causes of obesity and diabetes. The well known example is the study of leptin. Mice lacking leptin (lep−/−) or leptin receptor (lepr−/−) are obese, diabetic, infertile, hyperphagic and hypoactive (Chua et al., 1996).
Brain hypothalamus expressed several secreted molecules that function in regulating feeding behavior. NUCB2/nucleobindin 2 (also called NEFA for DNA binding/EF-hand/acidic protein) is a hypothalamus-secreted protein containing 396 amino acids that is highly conserved in human, mice and rat. Polypeptide encoded by the NEFA gene has a calcium-binding domain (EF domain) and a DNA-binding domain. NEFA has a high homology with nucleobindin and is considered to be a member of the DNA-binding factor called the EF-hand superfamily having reactivity with calcium.
NUCB2 when injected directly into the brain of rats promotes anorexia and decreases body weight. NUCB2 has been postulated to be cleaved posttranslationally by prohormone convertases into an N-terminus-fragment Nesfatin-1 (NEFA/nucleobindin2-encoded satiety- and fat-influencing protein) and two C-terminal peptides, Nesfatin-2 and Nesfatin-3. Nesfatin-1 possesses all of the anorexigenic property of NUCB2. Intracerebroventricular (i.c.v.) or i.p. injection of nesfatin-1 inhibits food intake and thereby reduces body weight. The conversion of NUCB2 into Nesfatin-1 is indispensable for its activity in vivo. Nesfatin-1 is found in discrete nuclei of the hypothalamus where it probably activates a leptin-independent melanocortin pathway. Nesfatin-1 crosses the Blood Brain Barrier (BBB) in both the blood-to-brain and brain-to-blood directions by a nonsaturable system.
NUCB2 is also expressed in the adipocyte cell line 3T3L1 suggesting other functions of Nesfatin-1 outside brain or peripheral source of Nesfatin-1 affecting brain function. Nesfatin-1 in rat stimulates calcium influx and interacts with a G protein-coupled receptor still to be characterized.
Although the plasminogen system is primarily responsible for fibrin degradation, its roles in brain and neurological function have been implicated. Plasminogen and its activators (TPA and uPA) are expressed in developing/adult brains, including hippocampal large pyramidal neurons and dendrites. Plasmin was reported to be involved in the process of hormones derived from the POMC precursor in the intermediate pituitary. Plasminogen was found to affect adipocyte formation (Selvarajan et al., 2001).