Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. The two main forms of the disease are distinguished by different pathogenesis, natural histories, and population distributions and indicated as either type 1 (T1DM) or type 2 diabetes mellitus (T2DM). It is well established that T1DM is an autoimmune disease whereby β-cells of pancreatic islets are destroyed leading to loss of endogenous insulin production. Albeit less dramatic, β-cell mass (BCM) also drops in T2DM. Therefore, it is realistic to expect that noninvasive measures of BCM might provide useful information in the diabetes-care field. Preclinical studies have demonstrated that BCM measurements by positron emission tomography scanning, using the vesicular monoamine transporter type 2 (VMAT2) as a tissue-specific surrogate marker of insulin production and [11C] Dihydrotetrabenazine (DTBZ) as the radioligand specific for this molecule, is feasible in animal models. Unfortunately, the mechanisms underlying β-cell-specific expression of VMAT2 are still largely unexplored, and a much better understanding of the regulation of VMAT2 gene expression and of its function in β-cells will be required before the full utility of this technique in the prediction and treatment of individuals with diabetes can be understood. In this review, we summarize much of what is understood about the regulation of VMAT2 and identify questions whose answers may help in understanding what measurements of VMAT2 density mean in the context of diabetes.