Summary: In this small MRI sub-study of the MemAID randomised controlled trial, 24 weeks of intranasal insulin increased several resting-state functional connectivity (rsFC) measures involving the hippocampus and medio-prefrontal cortex versus placebo in adults with type 2 diabetes (all p<0.05). Only 11 participants (8 insulin, 3 placebo) completed paired imaging, so these are exploratory mechanistic signals, not evidence of clinical benefit.
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with type 2 diabetes enrolled in the MemAID trial; MRI sub-study with 18 participants imaged at baseline and 11 with paired baseline and end-of-treatment functional MRI. Single-trial sub-study, United States. |
| Intervention | Intranasal insulin for 24 weeks, with resting-state and BOLD functional MRI. Insulin arm with paired imaging n=8. |
| Comparison | Intranasal placebo for 24 weeks. Placebo arm with paired imaging n=3. |
| Outcome | Versus placebo, the insulin arm showed increased rsFC for mPFC-postcentral, left hippocampus-frontal, left hippocampus-postcentral, right hippocampus-frontal, and left hippocampus-mPFC connections (all p<0.05). The reduction in HOMA-IR seen in the parent trial was associated with increased mPFC-basal ganglia rsFC (p<0.05). No effect sizes, 95% confidence intervals, ARR, or NNT were reported; no clinical efficacy endpoint was tested in this sub-study. |
Expert Commentary
This is a hypothesis-generating imaging sub-study, and it should be read as such rather than as evidence that intranasal insulin helps the diabetic brain. Nested within the MemAID randomised trial, it reports that 24 weeks of intranasal insulin was accompanied by increased resting-state connectivity across several hippocampal and medio-prefrontal circuits compared with placebo, and that the reduction in insulin resistance observed in the parent trial tracked with one of those connectivity changes. The biological story is coherent and consistent with prior work, yet the verdict has to stay cautious. The dominant limitation is sample size: only 11 participants had paired scans, with just three in the placebo arm, so the comparison rests on a handful of people and is highly vulnerable to chance and to single-participant influence. No connectivity-to-cognition or connectivity-to-walking-speed clinical benefit was demonstrated here, and no effect sizes or confidence intervals were provided. Can I use this with my patients? Not yet. Nothing here changes management for a person with type 2 diabetes and cognitive concerns, and intranasal insulin remains investigational. The authors themselves call for validation in a larger trial, which is the right next step. I would like to see adequately powered imaging tied to pre-specified cognitive endpoints before any clinical inference is drawn.
References
Zhang Z, Novak V, Novak P, Mantzoros C, Ngo L, Lioutas V, Dai W. Intranasal insulin enhances resting-state functional connectivity in Type 2 Diabetes. PLoS One. 2025;20(5):e0324029. doi:10.1371/journal.pone.0324029