Targeting Insulin Resistance to Treat Cognitive Dysfunction

Abstract

Dementia is a devastating disease associated with aging. Alzheimer's disease is the most common form of dementia, followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus, characterized by chronic hyperglycemia and insulin resistance, as a risk factor for Alzheimer's disease and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported by recent clinical and preclinical studies. The findings from these studies suggest that antidiabetic drugs have the potential to be used to treat dementia. In this review, we discuss the physiological functions of insulin in the brain, studies on the evaluation of cognitive function under conditions of insulin resistance, and reports on the beneficial actions of antidiabetic drugs in the brain. This review covers clinical studies as well as investigations in animal models and will further highlight the emerging link between insulin resistance and neurodegenerative disorders.

Keywords: Alzheimer’s disease; Dementia; Diabetes; Insulin resistance; Metabolic syndrome; Obesity.

Fig. 1

Insulin action on multiple tissues. Insulin is primarily produced by the β cells of the pancreatic islets and secreted in response to glucose. In addition, food consumption promotes intestinal secretion of GLP-1, which acts on the β cells to enhance insulin release. Insulin release may also be modulated by the vagus nerve. Insulin acts on multiple tissues to regulate glucose metabolism. It stimulates glucose uptake and utilization in the muscle, while suppressing hepatic glucose release. Insulin promotes lipogenesis and suppresses lipolysis in the adipose tissue. While the effect of insulin action in the brain on appetite control is known, it may not play a significant role in glucose uptake. Insulin action on neuroprotection and cognitive function are being recognized recently

Fig. 2

Mechanisms of action of antidiabetic drugs. The lifespan of type 2 diabetic patients is increasing steadily because of the availability of a wide range of antidiabetic drugs. These drugs decrease blood glucose levels by multiple mechanisms. Metformin, a widely used hypoglycemic drug, acts by increasing glucose utilization in the peripheral tissues and by reducing hepatic glucose output. Sulfonylureas stimulate insulin secretion from pancreatic β cells. The use of this class of drug is associated with hypoglycemic episodes. Thiazolidinediones (TZDs) improve the sensitivity of adipose tissue, skeletal muscles, and the liver towards insulin. Incretin therapies, such as DPP-4-resistant GLP-1 analogs and DPP-4 inhibitors that enhance endogenous GLP-1 levels, promote pancreatic release of insulin. In addition, they are reported to have insulin-independent actions in other tissues, including the brain. Recently introduced SGLT2 inhibitors increase glucose excretion in the urine by preventing glucose reabsorption in the renal tubules. Overall, these antidiabetic drugs have been shown to have beneficial actions in the brain either directly or indirectly through glycemic control