Blood glucose homeostasis is controlled by a well-concerted secretion and action of pancreatic hormones from the various cell types in the endocrine pancreas, the islets of Langerhans. The secretion of insulin, glucagon and somatostatin from the pancreatic b-cells, a-cells and d-cells, respectively, is regulated very precisely by nutrients as well as by autocrine, endocrine, paracrine and nervous signals. The islet of Langerhans has an important role in integrating these various signals. If hormone release is disturbed diabetes develops. The molecular mechanisms involved in the regulation of insulin secretion from the b-cell are relatively well understood and involve an exocytotic apparatus that in principle resembles the well studied presynaptic machinery mediating exocytosis from synaptic vesicles in neurons. Much less is known about the detailed mechanisms regulating exocytosis of glucagon from the a-cell and somatostatin from the d-cell. Whereas there is a wealth of information about the physiology of rodent islets in vitro, the biology of the human islet both in vitro and in vivo remains poorly understood. Our studies have suggested that the human pancreatic islet has a unique structure-function relationship. I will discuss a systems biology approach where signal-transduction can be investigated in innervated and vascularized human pancreatic islets in vivo at single cell resolution. This will allow us to define eventually the molecular machinery involved in regulating hormonal output from the human endocrine pancreas and thereby maintenance of adequate glucose homeostasis.