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Dapagliflozin improved neural circuit connectivity in type 2 diabetes (T2D) patients, while liraglutide enhanced local brain activation. Both drugs show unique neuroprotective effects, suggesting combined metabolic and neural pathway targeting for T2D cognitive decline.

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Area of Science:

  • Neuroscience
  • Endocrinology
  • Pharmacology

Background:

  • Comparative neuroprotective effects of hypoglycemic drugs are not well-established in randomized controlled trials.
  • Type 2 diabetes (T2D) is associated with cognitive decline, potentially linked to altered brain function.
  • Investigating the impact of dapagliflozin, liraglutide, and acarbose on neural circuits in T2D is crucial.

Purpose of the Study:

  • To compare the neuroprotective effects of dapagliflozin, liraglutide, and acarbose in patients with type 2 diabetes (T2D).
  • To assess the impact of these treatments on the directed functional connectivity of the primary olfactory cortex (POC) circuit and local brain activation during olfactory stimulation.
  • To explore the relationship between treatment-induced changes in neural activity and cognitive/metabolic improvements.

Main Methods:

  • A 16-week randomized, parallel-group, open-label trial involving 36 T2D patients inadequately controlled on metformin, randomized to dapagliflozin, liraglutide, or acarbose.
  • 36 healthy normal controls were recruited for comparison.
  • Olfactory task functional MRI and olfactory/cognitive tests were performed pre- and post-intervention. Generalized psychophysiological interaction analysis was used to determine directed functional connectivity.

Main Results:

  • Dapagliflozin treatment restored odor-induced functional integration of the POC-sensorimotor cortex-middle temporal cortex circuit and tended to improve attention.
  • Liraglutide enhanced odor-induced activation in the left hippocampus, while dapagliflozin and acarbose did not show these specific effects.
  • Decreased odor-induced directed functional connectivity correlated with improvements in lipid levels, olfactory threshold, executive function, and memory.

Conclusions:

  • Dapagliflozin and liraglutide exhibit distinct neuroprotective effects in T2D patients.
  • Liraglutide appears to influence local olfactory-related region activation, whereas dapagliflozin impacts neural circuit functional integration.
  • These findings underscore the significance of targeting both metabolic and neural pathways for managing T2D-related cognitive decline.