Metformin improves neurobehavioral impairments of streptozotocin-treated and western diet-fed mice: Beyond glucose-lowering effects

Fundam Clin Pharmacol. 2023 Feb;37(1):94-106. doi: 10.1111/fcp.12825. Epub 2022 Aug 31.


Brain insulin resistance has been pointed to as a possible link between diabetes and neuropsychiatric disorders; therefore, therapeutic approaches using anti-diabetic drugs to improve insulin levels or signaling could prevent type 1 (T1D) and type 2 diabetes mellitus (T2D)-induced brain dysfunction. The present study aimed to determine whether metformin exerts beneficial effects on metabolic and neurobehavioral outcomes in the streptozotocin (STZ)-induced T1D model and western diet (WD)-induced obesity model in male Swiss mice. T1D was induced by intraperitoneal injection of STZ (50 mg/kg, for five consecutive days). The animals were then treated daily with saline or metformin (200 mg/kg/day, oral gavage), and a battery of tests recapitulating different neurobehavioral anomalies related to anxiogenic/depressive-like phenotype was conducted after 18 days. WD-induced obesity was modeled in mice by high-fat and high-fructose diet (HFFD) feeding for 15 days. In the sequence, control and diet-induced obesity mice were treated daily with saline or metformin (200 mg/kg/day), and a battery of behavioral tests was performed after 17 days. STZ injection and WD feeding induced metabolic and neurobehavioral impairments in mice. Remarkably, metformin improved the metabolic and neurobehavioral parameters in WD-induced obesity mice. Moreover, metformin ameliorated STZ-induced neurobehavioral deficits while it failed to improve the associated metabolic impairments. The beneficial effects of metformin in STZ-induced neurobehavioral impairments were not mediated by improving peripheral insulin signaling. Our results suggest that conventional diabetes treatment could be repurposed to simultaneously improve neurobehavioral symptoms and diabetes.

Keywords: behavioral; diabetes; metformin; mice; obesity.

MeSH terms

  • Animals
  • Blood Glucose
  • Diabetes Mellitus, Experimental* / chemically induced
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetes Mellitus, Type 1*
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / metabolism
  • Diet, High-Fat / adverse effects
  • Diet, Western / adverse effects
  • Glucose / metabolism
  • Hypoglycemic Agents / therapeutic use
  • Insulin
  • Male
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Mice
  • Obesity / drug therapy
  • Streptozocin


  • Metformin
  • Hypoglycemic Agents
  • Streptozocin
  • Insulin
  • Glucose
  • Blood Glucose