Metformin and cognition from the perspectives of sex, age, and disease

Abstract

Metformin is the safest and the most widely prescribed first-line therapy for managing hyperglycemia due to different underlying causes, primarily type 2 diabetes mellitus. In addition to its euglycemic properties, metformin has stimulated a wave of clinical trials to investigate benefits on aging-related diseases and longevity. Such an impact on the lifespan extension would undoubtedly expand the therapeutic utility of metformin regardless of glycemic status. However, there is a scarcity of studies evaluating whether metformin has differential cognitive effects across age, sex, glycemic status, metformin dose, and duration of metformin treatment and associated pathological conditions. By scrutinizing the available literature on animal and human studies for metformin and brain function, we expect to shed light on the potential impact of metformin on cognition across age, sex, and pathological conditions. This review aims to provide readers with a broader insight of (a) how metformin differentially affects cognition and (b) why there is a need for more translational and clinical studies examining multifactorial interactions. The outcomes of such comprehensive studies will streamline precision medicine practices, avoiding "fit for all" approach, and optimizing metformin use for longevity benefit irrespective of hyperglycemia.

Role of Thioredoxin-Interacting Protein in Diseases and Its Therapeutic Outlook

“…Conversely, it is also suggested that both diseases significantly correlate at early onsets of AD-symptoms [ 115 ]. At present, it is an emerging concern since anti-diabetic Food and Drug Administration approved insulin-sensitive drugs are showing positive effects on dementia risk factors via blocking TXNIP expression downstream associated with inflammatory signaling [ 116 , 117 , 118 ].…”

Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus

“…Metformin (MET), a drug broadly used for treating type 2 diabetes mellitus (T2DM), has caught considerable attention as a promising anti‐aging drug because of its ability to prolong the lifespan in several species (Chaudhari et al, 2020; Rotermund et al, 2018). MET treatment in early or late middle age also appears attractive because both animal and human studies have implied that dysregulation of insulin function contributes to aging and age‐related neurodegenerative diseases (Craft & Watson, 2004; Verdile et al, 2015).…”

Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats

“…Sex differences were detected in expression of the organic cation transporter (OCT2), one of the transporters responsible for moving metformin across the cellular membrane. 50 Higher mRNA expression was detected in cortex and hippocampus of female compared to male mice although no sex differences were observed at the protein level. 50 Estrogen lowers the activity of OCT2 in males while testosterone increases OCT2 activity in both males and females in the rat kidney.…”