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Sarah E Elzinga1, Diana M Rigan2, Crystal Pacut2

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Summary
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Dual SGLT1/2 inhibitor sotagliflozin improved metabolic health in mice with or without metabolic stress. However, cognitive benefits were only observed in healthy controls, suggesting cognitive impairment in metabolic stress may be glucose-independent.

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Area of Science:

  • Neuroscience
  • Metabolic Science
  • Pharmacology

Background:

  • Rising rates of metabolic stress (obesity, prediabetes, diabetes) increase dementia risk, particularly Alzheimer's Disease and Related Dementias (AD/ADRD).
  • Targeting midlife metabolic stress offers a potential strategy for preventing later-life cognitive decline.
  • Sodium-glucose cotransporter (SGLT) inhibitors show promise for metabolic conditions and may benefit brain health, but their specific effects on cognition, especially dual SGLT1/2 inhibition, require further investigation.

Purpose of the Study:

  • To investigate the impact of a dual SGLT1 and SGLT2 inhibitor, sotagliflozin (SOTA), on cognitive function and metabolic health in a mouse model of metabolic stress.
  • To determine if SOTA treatment can mitigate cognitive deficits associated with diet-induced metabolic dysfunction.
  • To explore the relationship between metabolic improvements and cognitive outcomes following SOTA administration.

Main Methods:

  • Metabolic stress was induced in male C57BL/6 mice using a high-fat diet (HFD) and L-Nitro_L-arginine methylester.
  • Mice received daily oral gavage of sotagliflozin (SOTA; 30 mg/kg) or vehicle for 10 weeks.
  • Cognitive function was assessed using puzzle box and Morris Water Maze tests; metabolic parameters (body weight, glucose tolerance, HbA1c) and plasma cytokines were analyzed.

Main Results:

  • SOTA treatment significantly reduced body weight, improved glucose tolerance, and lowered HbA1c levels in both HFD and control mice.
  • Elevated plasma CCL-2 cytokine levels in HFD mice were reduced by SOTA treatment.
  • While HFD impaired cognitive outcomes, SOTA improved executive function in control mice but did not affect cognitive performance in HFD mice.

Conclusions:

  • Sotagliflozin effectively improved metabolic parameters irrespective of diet-induced stress.
  • Cognitive improvements were observed only in non-stressed control mice, suggesting that metabolic stress-induced cognitive impairment may not be solely dependent on glucose levels.
  • These findings highlight a potential dissociation between metabolic and cognitive benefits of SGLT inhibition in the context of metabolic stress.