Metabolic Homeostasis is mediated through multi-organ endocrine signaling. Because many systems are involved, therapeutics used to treat these disorders have wide-ranging effects. We propose that ‘drugs’ targeted to specific cell types within the homeostatic system will provide outcomes with limited side-effects. We have shown cell-type specificity can be achieved ifa ligand with multiple binding domains can be developed that binds to a combination of cell surface receptors which distinguish the cell type of interest from other cells1,2. We have synthesized several such bivalent ligands that may target cells within the homeostatic axis; melanocyte stimulating hormone linked to CCK (MSH/CCK) and Glucagon Like Peptide 1 (GLP-1) linked to Glibenclamide (Glb, a Sulfonyl urea receptor antagonist), or Yohimbine3 ( α2 adrenergic receptor antagonist). An apparent Kd of ~5 nM for MSH/CCK, ~10nM for GLP-1/Glb and ~5nM for GLP-1/Yhb were observed when binding was assessed using a high throughput screening assay with live cells expressing the respective complementary receptor pairs. Binding constants for individual ligand domains within the bivalent ligands were 100 nM or greater, based on binding to cells expressing only one of the pair, indicating that these ligands will only bind with high affinity only to cells expressing both complementary receptors. All three bivalent agents maintain signaling capacity, though in each case both the magnitude and sensitivity of 2nd messenger and physiological effects differ from the constituent monomers. Using the βTC3 cell line, GLP-1/Glb was found to elicit a half maximal Ca2+ response at ~10nM reflecting its Km but the magnitude of the Ca2+ response was 10X less than monomeric Glb. Unlike the Ca2+ response, cAMP production was depressed by only ~20% compared to monomeric GLP-1. Although signaling is depressed, glucose stimulated insulin secretion (GSIS) was potentiated to similar levels as elicited by the combined monomers (133 +/- 25% vs 110 +/- 15%). Like GLP-1/Glb, the maximal potentiation of GSIS by GLP-1/Yhb was equal to that elicited by the combined monomers, however the EC50 was reduced from 10 nM to 1.3nM for the dimer. The effects of GLP-1/Yhb on glucose disposal during i.a. glucose challenge (1 gm/kg) in conscious male Sprague-Dawley rats was tested. Compared to equal concentrations of monomers, GLP-1/Yhb decreased the peak glucose concentration following an injected glucose load by greater than 30% (320 mg/dl vs 420 mg/dl), and the recovery to baseline from 15 to 5 min. Both findings suggest that GLP-1/Yhb exhibits a strong β-cell specific enhancement of GSIS potentiation. Thus, these bivalent ligands exhibit enhanced affinity, cell type specificity3,4 and maintain functional efficacy, and thereby hold promise as cell specific therapeutic agents.