MON-544 - Integrase Inhibitors Impair Insulin Secretion by Disrupting Β-Cell Mitochondrial Function and Ca²⁺ Signaling

Initiation of integrase strand-transfer inhibitors (INSTIs) has been associated with metabolic disturbances in people living with HIV, including an increased risk of developing diabetes. However, the β-cell defects underlying these clinical observations are not well defined. We therefore investigated how two commonly used INSTIs, Dolutegravir (DTG) and Elvitegravir (ELV) alter the signaling pathways that regulate insulin secretion in pancreatic β-cells.

Methods: INS-1 β-cells were cultured in (basal, physiologic) 4 mM or (high-glucose, hyperglycemic) 11 mM conditions and exposed for 72 hours to DMSO (control), DTG, or ELV at physiologically relevant concentrations. Basal and glucose-stimulated insulin secretion were measured after preincubation in 1 mM glucose using a commercial insulin assay. Mitochondrial function was assessed with a Seahorse mitochondrial stress test, and intracellular Ca²⁺ responses were measured in fura-2–loaded cells. Group differences were evaluated using Student’s t-test or ANOVA.

Results: Exposure to DTG significantly reduced insulin secretion (16.4±7.5 vs 44.5±13.2ng/106cells; p=0.018, n=3) in cells cultured at 11G, even when normalizing for insulin content. In contrast, Elvitegravir did not affect cells cultured at either low or high glucose conditions. Oxygen consumption rates showed no difference between control, Dolutegravir or Elvitegravir in cells cultured at 4 mM glucose. However, at 11 mM glucose, DTG but not ELV, reduced basal and maximal oxygen consumption compared with control (62±13 vs 89±13; 87±13 vs 140±46pmolO2/min/40000 cells; p< 0.05, n=3). Consistent with reduced oxygen consumption, INS-1 cells cultured at 11 mM glucose with DTG saw reduced glucose-stimulated increases in intracellular Ca²⁺ by 80% (p < 0.001, n=4).

Conclusion: Our study indicates that DTG impaired mitochondrial ATP production and glucose-stimulated Ca²⁺ influx, leading to reduced insulin secretion under high-glucose conditions. These glucose dependent effects suggest that DTG-induced β-Cell dysfunction becomes apparent when metabolic demand is increased, such as in chronic hyperglycemia or insulin resistance, which could mechanistically explain the increased diabetes risk observed clinically in individuals starting DTG therapy. Further work should define the β-cell pathways affected by DTG and determine whether similar effects occur with other antiretroviral. Better understanding of the metabolic consequences of antiretroviral therapies can help reduce metabolic complications and the rising prevalence of diabetes and metabolic disease, now major determinants of long-term health in people living with HIV.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*