Type 2 Diabetes Mouse Model: Insights into the Contribution of Metabolic Defects to Neurocognitive Decline
Loncharich, Alexa   (Indiana University-Purdue University-Indianapolis)
Mentor: Hongxia Ren, (Indiana University - Indianapolis)
Metabolic diseases have become increasingly prevalent worldwide. Type 2 diabetes (T2D) is the predominant form of diabetes. T2D is associated with serious comorbidities and complications. Interestingly, recent epidemiological evidence suggests links between metabolic defects, ageassociated cognitive impairment, and neurodegenerative diseases, such as Alzheimer’s Disease (AD). The increasing coincidence of AD and T2D, and unmet treatment needs, necessitates research investigating potential shared mechanisms. In order to study glucose defects and neurocognitive deficits, we have generated a non-obese insulin resistant mouse model, named GLUT4-mediated Insulin Receptor KnockOut (GIRKO). Insulin-responsive glucose transporter, GLUT4, is used as a vestigial marker for tissue insulin sensitivity. Our studies revealed that GLUT4 is expressed in muscle, fat, and a subset of neurons in the brain. Our previous publications show that GIRKO mice are highly insulin resistant and insulin sensitive GLUT4 neurons are critical mediators for glucose metabolism. We hypothesize that central insulin resistance in GIRKO mice instigates neurocognitive defects. To test this hypothesis, we measured the neurocognitive function of 3- to 4-month old GIRKO mice using Morris water maze (MWM) test. We discovered that GIRKO mice exhibited increased escape latency. Additionally, they spent less time in the target quadrant in the probe trial, in which the platform is removed. GIRKO performed equally compared to control mice in raised platform tests, which demonstrates that motor competencies do not confound our findings. MWM test depends upon hippocampal function, therefore, we conclude that GIRKO mice have learning and memory deficits. This illustrates a possible link between metabolism and neurocognition. Our results support the notion that insulin resistance precedes cognitive decline and necessitates early intervention therapy to treat insulin resistance and protect cognitive function.