Gastroprotective effects of intranasal or intraperitoneal insulin and oral metformin in rats with type 1 diabetes: investigation of the mechanisms

With the increase in the prevalence of diabetes, the number of severe complications of this disease is also growing. Diabetic gastropathy is among them. Previously, we demonstrated a significant aggravation of indomethacin-induced gastric ulceration in rats with type 1 diabetes (T1D). We hypothesized earlier that antidiabetic medications could be effective for preventing this aggravation and used insulin and metformin to verify the hypothesis. The results obtained indicate that both insulin, intraperitoneal (i.p.) and intranasal (i.n.), and oral metformin are highly effective in preventing the proulcerogenic action of T1D (Filaretova et al., 2024). This study aimed to elucidate whether the gastroprotective effects of these drugs in rats with T1D are mediated through reductions in blood glucose levels. To induce T1D, streptozotocin (STZ, 60 mg/kg, i.p.) was administered once 2 weeks before indomethacin (IM, 35 mg/kg, s.c.) in rats. The development of diabetes was assessed by blood glucose levels, changes in the rats' body weight, and water consumption. Insulin (2 IU/kg, i.p. or 0.5 IU/rat, i.n.) or metformin (100 mg/kg, orally) were administered daily, starting from the 8th day after the administration of STZ, for 7 days. Blood glucose testing was performed on days 8 and 14 following STZ administration, coinciding with the first and seventh (final) administrations of insulin or metformin. Blood glucose levels were measured before drug administration and at five subsequent time points (1, 2, 3, 4, and 5 h post-administration). After the final drug administration and blood glucose testing, the rats were fasted for 20 hours prior to IM administration. Four hours after IM administration, the rats were decapitated, the stomachs were removed to estimate the erosion area; and trunk blood was collected to test glucose levels. The study was conducted with all appropriate controls, including the vehicles for STZ and for the drugs, administered according to their respective methods. During the first week after STZ administration characteristic signs of diabetes developed: increased blood glucose, increased water consumption, and slower body weight gain. The development of STZ-induced diabetes led to a pronounced worsening of the ulcerogenic effect of IM. Insulin (i.n. and i.p.) and metformin given for 7 days prevented the erosion-promoting effect of STZ. Although all drugs effectively countered the erosion-promoting effects of STZ, their impact on the time course of blood glucose reduction varied. A pronounced glucose-lowering effect was observed after the first intraperitoneal insulin administration on day 8, with blood glucose levels decreasing by approximately 50% within the first hour post-administration and remaining low throughout the 5-hour testing period. A similar effect was observed on day 14. In contrast, intranasal insulin, which also prevented the erosion-promoting effects of STZ, did not reduce blood glucose levels in diabetic rats, either after the first or the final administration. Metformin administration resulted in a reduction in blood glucose levels on day 8 and day 14, but this reduction occurred later and was less pronounced compared to the decrease observed following intraperitoneal insulin administration. In conclusion, the findings confirm that both intraperitoneal and intranasal insulin, as well as metformin, are highly effective in preventing the proulcerogenic effects of T1D. However, these results highlight different mechanisms underlying their protective effects. Grant for WCSC "Pavlov Center “Integrative Physiology - to medicine, high-tech healthcare and technologies of stress resistance” from MES RF 075-15-2022-303 от 21.04.2022. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.