Early Prediction of Mild Cognitive Impairment in Glucose Normotolerant Subjects With 1-hour Post-load Plasma Glucose >155 mg/dL

Insulin resistance (IR), beyond its well-defined role in the appearance and progression of diabetes mellitus (DM), is the recognized pathogenetic factor underlying vascular aging, in the continuum from endothelial dysfunction to atherosclerotic vascular lesions. Two different types of IR have been described: 1) a "central" IR, particularly expressed in the liver, affecting all the metabolic pathways operating at this site, and 2) a "peripheral" IR, particularly expressed in the muscle. Recently, the existence of a "cerebral" IR, responsible of the appearance and progression of many forms of dementia and mild cognitive impairment (MCI), has been hypothesized. On the other hand, for decades DM was considered only as a hyperglycemic status, disregarding its important negative impact on vascular function and its role as a cardiovascular (CV) risk factor per se. For these reasons, in the past, DM management only consisted in reducing plasma glucose levels. In the last years our group demonstrated that also glucose normotolerant subjects who exhibit plasma glucose levels >155 mg/dL 1h-post load, have a CV risk similar to that of diabetic patients.

Hypothesis and Significance The hypothesis of this study is based on the concept that glucose normotolerant subjects with 1h-post load glycemia >155 mg/dL exhibit an insulin-resistant status characterized by enhanced insulin production but reduced tissues sensitivity to the hormone action. This reduced insulin sensitivity is present many years before the appearance of the clinical conditions such as DM, arterial hypertension, dyslipidemia, etc. Insulin, insulin receptor, and its substrates are expressed in the whole central nervous system; in this site, insulin regulates food intake and body weight, and it is also involved in neurotransmitters release and synaptic plasticity. It is thus plausible that insulin may have an important role in many cognitive processes. Evidences indicate that the cognitive impairment commonly seen in many diabetic patients could be mediated by an altered signaling insulin-like growth factor-1 (IGF1)-insulin. In fact, a stream of human and experimental studies has provided convincing evidence that many forms of dementia, such as Alzheimer's disease, are metabolic diseases characterized by the brain loss of its capacity to efficiently utilize glucose for energy production and respond to critical trophic factor signals due to insulin as well as insulin-like growth factor (IGF) resistance. Thus, being MCI the expression of IR in the brain, the principal hypothesis of our study is that these subjects may also develop neuropsychological alterations, earlier with respect of the general population. This hypothesis may have an important clinical significance and a great social impact, since a great amount of health costs are due chronic diseases, included all forms of dementia. Furthermore, the results of this study will add important information about the understanding of the complex network of pathways operating in the appearance and progression of many of the chronic diseases, such as diabetes mellitus and dementia.

Aim of the study To investigate the presence of early neuropsychological and/or cerebral morphological alterations in two groups of subjects (Group 1: glucose normotolerant subjects with 1h-post load glycemia >155 mg/dL; Group 2: healthy subjects with 1h post-load glycemia < 155 mg/dL).

Experimental Design

Visit 1: evaluation of inclusion/exclusion criteria, MMSE, clinical visit, all laboratory determinations, OGTT