Not only metformin, but also D-allulose, alleviates metabolic disturbance and cognitive decline in prediabetic rats

Nutr Neurosci. 2022 Jun;25(6):1115-1127. doi: 10.1080/1028415X.2020.1840050. Epub 2020 Nov 5.


Background: Prediabetes can be characterized as obesity with metabolic disturbance, leading to cognitive decline and brain pathologies. D-allulose administration in obese animals decreased metabolic disturbance. However, the comparative effects of D-allulose and metformin on cognition and brain functions in the diet-induced prediabetic condition are unclear. We assume that both D-allulose and metformin equally restore cognition and brain functions in prediabetic rats to an equal extent.

Materials and methods: Fifty-six rats were randomly divided into two groups: a control and diet-induced prediabetic group which had received a normal diet (ND) and a high-fat diet (HFD) for 24 weeks, respectively. After dietary protocol had been followed for 12 weeks, ND rats were given solely drinking water daily for 12 weeks. HFD-prediabetic rats randomly received drinking water with either D-allulose (1.9 g/kg/day of D-allulose) or metformin (300 mg/kg/day of metformin) for 12 weeks. Following this, cognition and brain parameters were determined.

Results: Brain oxidative stress, mitochondrial dysfunction, microglial hyper-activation, apoptosis, brain insulin insensitivity, hippocampal synaptic dysfunction, and cognitive decline were observed in prediabetic rats. D-allulose and metformin equally attenuated brain oxidative stress, brain mitochondrial ROS production, hippocampal apoptosis, brain insulin insensitivity, hippocampal synaptic dysfunction, resulting in improved learning process in prediabetic rats. Metformin conferred greater advantage on the amelioration of brain mitochondrial dysfunction and brain microglial hyper-activation than D-allulose, resulting in improvement in both learning and memory processes in prediabetic rats.

Conclusions: Not only metformin, but also D-allulose, has beneficial effects on the enhancement of brain function and cognition in prediabetic condition.

Keywords: D-allulose; brain apoptosis; brain function; brain mitochondrial dysfunction; cognition; diet-induced obesity; metformin; microglial hyper-activation.

MeSH terms

  • Animals
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / etiology
  • Cognitive Dysfunction* / metabolism
  • Diet, High-Fat / adverse effects
  • Drinking Water*
  • Fructose
  • Insulin Resistance* / physiology
  • Insulins*
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Obesity / metabolism
  • Prediabetic State* / drug therapy
  • Rats
  • Rats, Wistar


  • Drinking Water
  • Insulins
  • psicose
  • Fructose
  • Metformin