The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes

Abstract

The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.

Keywords: Agents, Brain insulin resistance; Brain glucotoxicity; Cognitive impairment; Injectable; Insulin, Noninsulin oral; Type 2 diabetes.

Fig. 1

Risk factors associated with the development of brain insulin resistance and cognitive decline in type 2 diabetes

Fig. 2

The sequelae of acute hyperglycemia under physiological conditions begin with acute elevations in glucose within the brain and lead to increased transport of insulin across the blood–brain barrier (BBB). This results in elevated levels of insulin available for brain cells. Insulin activates the intracellular signaling pathway that ultimately favors cognitive and learning functions. However, chronic hyperglycemia leads to persistent elevated levels of glucose and insulin in the brain. The resulting neuronal impairment manifests as cognitive and learning deficits that may culminate in dementia over time