Thesis title: The therapeutic efficacy of metformin as a treatment for insulin-related central nervous system disorders.
Type 2 Diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycaemia, a physiologically abnormal elevation in blood glucose concentrations, dependent on deficits in insulin secretion, insulin action, or both. Although alterations in insulin signalling have been primarily associated with somatic disorders, recent studies indicate that insulin also plays a role in the central nervous system (CNS). Ample evidence demonstrate that the spectrum of insulin-related syndromes also include brain disorders such as Alzheimer’s disease (AD), obsessive compulsive disorders (OCD), mild cognitive impairment (MCI), attention deficit hyperactivity disorder (ADHD) and addiction. Thus, understanding the role of insulin as a common risk factor for the comorbidity of mental and somatic disorders may disclose novel preventative and therapeutic approaches. My Ph.D. project aims to: (i) detail the potential association between insulin-related metabolic and central disturbances; and (ii) address the therapeutic potential of metformin (the drug of choice in T2DM) as a treatment for the aforementioned comorbidities. Specifically, after conducting a thorough literature review of preclinical studies investigating the association between metabolic dysfunction and mental disorders (chapter 1), I first verified (chapter 2) the association between mental and somatic disorders in TALLYHO/JngJ mice (TH), an experimental model of T2DM; and then (chapter 3), I evaluated the therapeutic efficacy of metformin as a treatment for insulin-related central nervous system disorders. TH mice, selectively bred for baseline hyperglycaemia, have been reported to constitute a valid experimental model of T2DM due to impaired insulin signalling. In chapter 2, I conducted an extended test battery to evaluate general metabolism (glucose tolerance, insulin sensitivity, energy expenditure, lipid metabolism, and polydipsia) and cognitive capabilities (attention, cognitive flexibility, and memory), in adolescent, young adult, and adult male and female TALLYHO/JngJ mice (TH). The observed marked deficits in cognitive flexibility, in TH mice, arose much earlier than (males) or independent of (females) full-blown T2DM-like abnormalities. Thus, the results obtained suggest that deficits in insulin signalling may represent a common risk factor for both T2DM and CNS-related deficits, and that this association may depend on (partly) independent mechanisms. Based on these results, in chapter 3, I tested whether a drug designed to treat metabolic disorders (metformin) could be repurposed to counteract the cognitive deficits observed in adult male TH mice. Metformin is the most widely used oral hypoglycaemic drug in the treatment of T2DM due to its relatively low cost, consolidated safety profile, but above all its many clinical advantages. I conducted an extended test battery for the assessment of behaviour and metabolism. I observed that the chronic administration of 300 mg/kg/day of metformin contrasts the deficits in cognitive flexibility, and spatial and working memory observed in TH mice. The results obtained in my Ph.D. thesis demonstrate that deficit in insulin signalling pathways seems to cause cognitive deficits. The evidence that a drug used to treat diabetes also treat cognitive deficits on the one hand confirm this hypothesis and on the other hand suggest the use of metformin as therapy for insulin-related CNS disorders. Furthermore, future studies to understand the central mechanisms of action of metformin could provide additional therapeutical perspectives.