12449 Mechanisms Underlying Progressive Loss Of Sulfonylurea Sensitivity In T2D In Vivo

Disclosure: S. Patel: None. Z. Yan: None. M.S. Remedi: None. Type 2 Diabetes (T2D) is characterized by a gradual loss of functional pancreatic β-cell mass, along with insulin resistance in peripheral tissues. Sulfonylureas (i.e. glibenclamide/glyburide) have long been used to treat T2D because of their ability to inhibit pancreatic β-cell KATP channels and therefore enhance insulin secretion. Although initially beneficial, sulfonylureas inevitably fail as sole therapy for unknown reasons. To determine the mechanisms underlying this secondary failure, slow-release sulfonylurea glibenclamide pellets (2.5 mg/pellet, 60-day release) were implanted in 6-week-old KK mouse model of polygenic T2D. As expected, KK mice implanted with placebo pellets (KK-Placebo) spontaneously develop hyperglycemia (230 mg/dL), glucose intolerance, impaired insulin secretion and insulin resistance. Interestingly, KK mice chronically treated with glibenclamide (KK-Glib) did not show improvement in blood glucose levels over time, nor in glucose tolerance at day 28 and 42 post treatment. Fed plasma insulin levels were decreased in KK-Glib mice compared to KK-Placebo mice. Moreover, KK-Glib mice did not show increase in plasma insulin in response to glucose challenge during glucose tolerance test at either 28- or 42-days post-treatment. Intriguingly, KK-Glib mice demonstrated improvement in insulin sensitivity at day 30 of treatment, but surprisingly not at day 45 of treatment. Fasting-refeeding study further showed decreased insulin secretion after 2 hours of feeding in KK-Glib mice compared to the KK-Placebo mice. KK-Glib mice demonstrated islet hypertrophy, and reduced β-cell number, which drive the increase in α:β cell ratio. Strikingly, islets from the KK-Glib mice showed a marked increased expression of α-cell identity markers: Gcg, Irx2, MafB and Arx with respect to KK-Placebo mice. While β-cell identity markers did not change in islets from KK-Glib mice with respect to KK-Placebo, there was a significant increase in Ngn3 mRNA levels in islets from KK-Glib mice, suggestive of β-cell dedifferentiation. Importantly, while glucose stimulated glucagon secretion was unchanged between KK-Glib and KK-Placebo islets, glucagon content was significantly increased in islets from KK-Glib mice. These findings show that secondary failure to sulfonylureas could be partly due to the increased turnover of α-cells upon treatment. Presentation: 6/2/2024