The insulin resistant brain: impact on whole-body metabolism and body fat distribution

Abstract

Insulin exerts its actions not only on peripheral organs but is also transported into the brain where it performs distinct functions in various brain regions. This review highlights recent advancements in our understanding of insulin's actions within the brain, with a specific emphasis on investigations in humans. It summarises current knowledge on the transport of insulin into the brain. Subsequently, it showcases robust evidence demonstrating the existence and physiological consequences of brain insulin action, while also introducing the presence of brain insulin resistance in humans. This pathophysiological condition goes along with an impaired acute modulation of peripheral metabolism in response to brain insulin action, particularly in the postprandial state. Furthermore, brain insulin resistance has been associated with long-term adiposity and an unfavourable adipose tissue distribution, thus implicating it in the pathogenesis of subgroups of obesity and (pre)diabetes that are characterised by distinct patterns of body fat distribution. Encouragingly, emerging evidence suggests that brain insulin resistance could represent a treatable entity, thereby opening up novel therapeutic avenues to improve systemic metabolism and enhance brain functions, including cognition. The review closes with an outlook towards prospective research directions aimed at further elucidating the clinical implications of brain insulin resistance. It emphasises the critical need to establish feasible diagnostic measures and effective therapeutic interventions.

Keywords: Brain; Diabetes; Insulin; Insulin resistance; Obesity; Prediabetes; Review.

Fig. 1

Putative model of brain insulin’s role in peripheral metabolism and the impact of brain insulin resistance. (a) Presumed situation in people with an insulin-sensitive brain. Upon food intake, insulin is released from the pancreas into the bloodstream. It reaches the brain, passes the BBB in a receptor-mediated process and activates specialised neurons (e.g. in the hypothalamus). This introduces signals to the pancreas that propagate second-phase insulin secretion. More insulin is released into the portal vein and acts as a strong suppressor of hepatic glucose production. Endogenous glucose production is further suppressed by direct signals from the brain to the liver. This mechanism likely contributes to the adequate suppression of hepatic glucose output after food intake and all-together coordinates energy fluxes throughout the organism. (b) Presumed situation in people affected by brain insulin resistance. In this scenario, insulin cannot properly pass the BBB and cannot properly activate specialised neurons in the brain. Signals towards the periphery are compromised. Hence, there is no acute stimulation of pancreatic insulin secretion through brain-derived signals. Of note, chronic lack of these regulatory signals could contribute to insulin hypersecretion due to an overabundance of stimulatory non-neuronal signals. Furthermore, in brain insulin resistance, signals towards the liver and other metabolic organs are lacking. Altogether, this could contribute to an impaired suppression of hepatic glucose output in the postprandial state and to an impaired brain-derived modulation of whole-body energy fluxes. Over time, this could facilitate an unfavourable body fat distribution with visceral obesity, a key phenotype of high-risk subgroups of diabetes and prediabetes. This figure is available as part of a downloadable slideset

Fig. 2

Overview of brain insulin action derived effects on peripheral metabolism. In response to food intake, insulin is released into the bloodstream. After passing the BBB, insulin reaches the brain where it acts in specialised areas, including the hypothalamus, frontal areas, insula and the dorsal striatum. This induces signals towards the periphery to suppress hepatic glucose production, to enhance peripheral glucose uptake into tissues (e.g. skeletal muscle and adipose tissue) and to propagate second-phase insulin secretion from the pancreas. These functions appear to be disturbed in brain insulin resistance. This figure is available as part of a downloadable slideset