Insulin resistance can be compensated by increased insulin secretion and increased β-cell number. However, long-term insulin resistance can lead to β-cell failure, β-cell death and the development of type 2 diabetes. With its genetic, chemical, and anatomical tractability, zebrafish is poised to help elucidate the mechanisms that are involved in β-cell failure and death. To this end, we generated a transgenic model with skeletal muscle-specific insulin resistance, zMIR. When challenged with repeated exposure to overnutrition, the β-cell number in zMIR larvae initially increased as in control animals, but rapidly declined after the third exposure, indicating that β-cells of zMIR fish are more susceptible to metabolic stress. The β-cell loss can be prevented by anti-diabetic drugs and chemical chaperones. This β-cell loss was not through apoptosis or de-differentiation, but through necroptosis. Consistent with this, inhibitors of necroptosis protected the β-cells. Furthermore, genetic ablation of ripk3, a key regulator of necroptosis, also protected the β-cells. The β-cell loss coincided with islet macrophage infiltration in the zMIR animals. Macrophage depletion by clodronate liposomes or by genetic ablation of irf8 protected β-cells. Interestingly, necroptosis inhibitors also suppressed macrophage infiltration. These data support a model in which metabolic stress triggers proinflammatory necroptosis of a small subset of β-cells in zMIR fish and the consequent macrophage infiltration causes death of additional β-cells.