Obesity, insulin resistance, and a host of environmental and genetic factors can drive hyperglycemia, causing β-cells to compensate by increasing insulin production and secretion. In type 2 diabetes (T2D), β-cells under these conditions eventually fail. Rare β-cell diseases like congenital hyperinsulinism (HI) also cause inappropriate insulin secretion, and some HI patients develop diabetes. However, the mechanisms of insulin hypersecretion and how it causes β-cell dysfunction are not fully understood. We previously discovered small molecules (e.g. SW016789) that cause insulin hypersecretion and lead to a loss in β-cell function without cell death. Here, we uncover the protein target of SW016789 and provide the first time-course transcriptomic analysis of hypersecretory responses versus thapsigargin-mediated ER stress in β-cells. In mouse MIN6 and human EndoC-βH1 β-cells, we identified and validated VDAC1 as a SW016789 target using photoaffinity proteomics, cellular thermal shift assays, siRNA, and small molecule inhibitors. SW016789 raises membrane potential to enhance Ca 2+ influx, potentially through VDAC1. Chronically elevated intracellular Ca 2+ appears to underpin the negative impacts of hypersecretion, as nifedipine protected against each small molecule hypersecretion inducer we tested. Using time- course RNAseq, we discovered that hypersecretion induced a distinct transcriptional pattern compared to ER stress. Clustering analyses led us to focus on ER-associated degradation (ERAD) as a potential mediator of the adaptive response. SW016789 reduced the abundance of ERAD substrate OS-9 and pharmacological inhibition of ERAD worsened β-cell survival in response to hypersecretory stress. Changes in other ERAD components in MIN6 and EndoC-βH1 at the protein level were minor with either SW016789 or thapsigargin. However, immunostaining for core ERAD components SEL1L, HRD1, and DERL3 in non-diabetic and T2D human pancreas revealed altered distributions of SEL1L/HRD1 and SEL1L/DERL3 rations in β-cells of T2D islets, in alignment with altered ERAD in stressed β-cells. We conclude that hypersecretory stimuli, including SW016789- mediated VDAC1 activation, cause enhanced Ca 2+ influx and insulin release. Subsequent differential gene expression represents a β-cell hypersecretory response signature that is reflected at the protein level for some, but not all genes. A better understanding of how β-cells induce hypersecretion and the mechanisms of negative feedback on secretory rate may lead to the discovery of novel therapeutic targets for T2D and HI.