Aging is a significant risk factor for lifestyle diseases-such as type 2 diabetes mellitus (T2DM), a complex heterogeneous metabolic condition characterized by hyperglycemia and insulin resistance and associated with an increased risk factor for cognitive impairment and sporadic dementia, such as Alzheimer’s disease (AD) [1,4]. As the global population ages, the increasing number of patients with T2DM and AD will likely pose societal challenges. Unfortunately, potential relationships between T2DM and cognitive dysfunction remain unclear.

Deficient insulin/IGF-1 signaling in rodents and humans causes impaired glucose metabolism-including glucose intolerance and hyperinsulinemia, potentially progressing to T2DM [5]. The IRS proteins are major components of insulin/IGF-1signaling, which transmit upstream signals via the insulin receptor (IR) and/or IGF1Receptor (IGF1R) to multiple downstream kinases like AKT/Protein Kinase B (PKB) and extracellular-signal-regulated kinase (ERK) [6]. IRS2 is an important IRS family member ubiquitously expressed throughout the brain and body that positively regulates brain growth, fertility, and nutrient homeostasis [7-9]. IRS2-deficient (IRS2^−/−) male mice develop severe T2DM, regardless of genetic background (both mixed C57BL/6x129sv and C57BL/6J) and experimental environment [6,9,10]. In our experimental environment, male IRS2^−/− mice live longer (~24 weeks) than mice maintained in other experimental environments at different institutes [10]. Because environmental differences lead to epigenetic changes and affect the intestine’s bacterial composition, life span may also be affected [11,12].

T2DM-induced brain energy metabolism abnormalities can lead to cognitive deficits [13-15]. In the hippocampus, IRS2 deficiency causes the aberrant activation of AMPK, a metabolic energy sensor induced under low-energy states [10]. IRS2 deficiency is also associated with decreased adenosine triphosphate (ATP) levels following abnormal elevation during fasting [10]. Furthermore, insulin stimulation decreases lactate levels, a product of glucose metabolism generated via glycolysis, and increases glucose transporter1 (GLUT1) and GLUT3, crucial in glucose uptake in astrocytes or neurons, in the hippocampi of WT mice [16]. However, lactate and GLUT3 levels were the same in the model that used male IRS2^−/− mice with hyperglycemia [10]. These alterations observed in the hippocampi of male IRS2^−/− mice with hyperglycemia were not observed in the hippocampi of middle-aged mice fed a high-fat diet (HFD)/with diet-induced obesity (DIO) (middle-aged DIO mice) and showing amyloid-β (Aβ)-unrelated cognitive decline [14,17]. Although middle-aged DIO mice displayed increased phosphorylation of hippocampal IRS1 at three serine (Ser) sites (Ser 307, Ser 612, and Ser632/635) found in postmortem brain samples from patients with AD, IRS2 deficiency with hyperglycemia had no effects on the phosphorylation at Ser 307 and 612 sites and reduced the phosphorylation of Ser632/635 on hippocampal IRS1 [10,14,18]. Conversely, young APPKI^{NL -G-F/NL -G-F} mice-a novel Knock-In (KI)-AD mouse model-with normal cognitive function exhibited increased phosphorylation of IRS1 at those Ser sites [14]. Thus, there is a possibility that the mechanism of cognitive dysfunction observed in IRS2^−/− mice is different from that in middle-aged DIO mice and that Ser phosphorylation of IRS1 in AD can be changed independent of altered cognitive function.

Interestingly, young APPKI^{NL -G-F/NL -G-F} mice fed an HFD demonstrated normal cognition despite exhibiting more-severe glucose intolerance than WT mice fed an HFD [19]. These results suggest that young APPKI^{NL -G-F/NL -G-F} mice with accumulated Aβ from childhood may have increased vulnerability to HFD-induced chronic neuroinflammation, potentially leading to more-severe metabolic dysfunction than WT mice fed an HFD. Furthermore, given that IRS2 deficiency reduces Aβ deposition in the Tg2576 mouse AD model without hyperglycemia, hippocampal IRS2 may rise in young APPKI^{NL -G-F/NL -G-F} mice with glucose intolerance [20-22].

While IRS2 deficiency causes dopamine-associated motor dysfunction in C57BL/6J (6J) male mice during puberty and early adolescence, it leads to hippocampus-related behavioral deficits, such as anxiety behaviors and memory impairment in 6J young male mice [10,23]. Consistent with the previous studies, depression- or anxiety-like behaviors occur concomitantly with T2DM [10,23,24]. In contrast, IRS2 deficiency reduces Aβ pathology, rescues mortality, and improves behavioral deficits in a Tg2576 mice AD model without hyperglycemia [21,22]. These data suggest the distinct effects of systemic IRS2 inactivation with (detrimental) and without (beneficial) hyperglycemia on brain function, which is consistent with the beneficial effects observed following a 50% reduction in IRS2 (IRS2^+/-) or brain-specific IRS2 deactivation with euglycemia on life span and/or brain function in WT mice and mouse models of neurodegenerative diseases, such as AD and Huntington's disease (HD) [21,22,25,26]. Moreover, neuron-specific overexpression of IRS2 exacerbates HD model phenotypes and causes glucose intolerance [26,27].

Collectively, these data suggest that, in the brain, IRS2 inactivation with euglycemia benefits lifespan and improves cognitive functions. In contrast, IRS2 overexpression in neuronal cells may accelerate neurodegeneration and impaired glucose metabolism. In glial cells (especially astrocytes), IR, and IGF1R appear to play specific roles in regulating glucose metabolism and cognitive function, respectively [28,29]. Because IRS2 is also expressed in astrocytes (unpublished data), further studies are needed to determine its regulatory role while developing new therapeutic strategies for T2DM and AD.

This work is supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (20H04137) (A.T.), Research support from DAIICHI SANKYO COMPANY, LIMITED (A.T.), and the Research Funding for Longevity Science from the National Center for Geriatrics and Gerontology, Japan (A.T.).

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