Over 130 million Americans are either diabetic or pre-diabetic. A significant fraction of them is obese or overweight. There are seven classes of diabetic therapies against type II diabetes available including insulin therapy. But all these drugs are associated with some side effects including the danger of hypoglycemia. Therefore, more options to treat T2D are needed. We found that Catestatin (CST) and its analog, retro-inverso (RI)-CST have anti-diabetic properties. CST is a Chromogranin A-derived peptide that improves insulin sensitivity and reduces blood glucose levels in diet-induced obese (DIO) mouse model of diabetes by acting on multiple pathways including anti-inflammatory and glucose metabolism. Its anti-inflammatory activity prevents the infiltration of pro-inflammatory macrophages in the liver. It inhibits gluconeogenesis and glycogenolysis but induces glycogenesis. Also notable is that CST and RI-CST can be administered orally, and plasma CST appears within 15 min with a half-life of around 7 hrs. These remarkable properties position CST and RI-CST as highly potential diabetes therapies which we plan to investigate in this proposal. We further plan to investigate the therapeutic potential of CST and its mimic RI-CST as combination therapies. All currently used diabetes therapy is associated with side effects which include gastrointestinal, cardiovascular, pancreatitis, polyurea, angioedema, and LDL cholesterol. We hypothesize that toxic side effects of currently used diabetes medicine will be minimized if their doses can be lowered which can be accomplished by the addition of CST. Indeed, our preliminary results confirm our hypothesis where we found two-fold lower amounts of TZD are more effective when used in combination with CST than the regular dose of TZD alone. We propose two aims: in Aim 1, we plan to investigate the absorption and tissue distribution of RI-CST and determine the toxicity of both CST and RI-CST in mice. In aim 2, we plan to investigate the effectiveness of both mono and combination therapy of CST and RI-CST.