Diabetes and Insulin Resistance

Diabetes mellitus is a condition in which an individual's glucose metabolism is abnormal due to an absolute or relative insulin deficiency. Type 2 diabetes mellitus (T2DM) arises as a product of insulin resistance (IR) and an insufficient compensatory production of insulin by pancreatic β-cells. 

While causes of IR have not been fully established, there are several well-established risk factors, including obesity, poor diet, physical inactivity, advancing age and genetic predisposition. T2DM is generally preceded by pre-diabetic stages of glucose dysmetabolism, also known as impaired glucose tolerance. However, rather than thinking in stages, glucose dysmetabolism is best considered as a continuum from normal glucose tolerance to T2DM, in which a progressive loss of β-cell function determines the levels of plasma glucose on a background of increasing IR. 

Given the population trends of an increased incidence of T2DM and IR, this is an issue of concern that calls for preventive strategies. A very relevant question now is whether alleviating IR is a potential target for treatment. Clinical studies link T2DM and IR to cognitive dysfunction and dementia, although it is unclear whether specific impairments in brain or systemic insulin receptor signaling are responsible for these neurological consequences. 

The hippocampus is a critical integration center for learning and memory and activation of hippocampal insulin receptors are proposed to facilitate cognitive function. Conversely, IR also has deleterious consequences on hippocampal synaptic plasticity. Clinical studies have demonstrated that T2DM affects hippocampal volume and impairs hippocampal-based memory performance. Importantly, intranasal insulin administration improves cognitive function in T2DM patients and in patients with age-related dementia without impacting peripheral glucose homeostatis. These exciting data support the idea that the cognitive-enhancing properties of insulin may be mediated through insulin receptors expressed in the hippocampus.