Abstract
Ever since Claude Bernards discovery in the mid 19th-century that a lesion in the floor of the third ventricle in dogs led to altered systemic glucose levels, a role of the CNS in whole-body glucose regulation has been acknowledged. However, this finding was later overshadowed by the isolation of pancreatic hormones in the 20th century. Since then, the understanding of glucose homeostasis and pathology has primarily evolved around peripheral mechanism. Due to scientific advances over these last few decades, however, increasing attention has been given to the possibility of the brain as a key player in glucose regulation and the pathogenesis of metabolic disorders such as type 2 diabetes. Studies of animals have enabled detailed neuroanatomical mapping of CNS structures involved in glucose regulation and key neuronal circuits and intracellular pathways have been identified. Furthermore, the development of neuroimaging techniques has provided methods to measure changes of activity in specific CNS regions upon diverse metabolic challenges in humans. In this narrative review, we discuss the available evidence on the topic. We conclude that there is much evidence in favor of active CNS involvement in glucose homeostasis but the relative importance of central vs. peripheral mechanisms remains to be elucidated. An increased understanding of this field may lead to new CNS-focusing pharmacologic strategies in the treatment of type 2 diabetes.
Highlights
The global prevalence of diabetes in adults – approximately 90% consisting of type 2 diabetes – was estimated to 6.4% in 2010 and is predicted to increase to 7.7% in 2030 (Nolan et al, 2011)
Pharmacological targets in the treatment of type 2 diabetes have been largely limited to the peripheral domain. This “islet-centric” model has these last decades been challenged by mounting evidence in favor of a “brain-centric” model, according to which the brain is actively involved in systemic glucose regulation. Further advances in this area may change the way we look at metabolic disorders and may result in new CNS-targeted strategies for the pharmacological management of type 2 diabetes
Some studies suggest that the link between the metabolic syndrome and autonomic dysregulation as measured by HRV is fully explained by insulin resistance (Balcioglu et al, 2016; Saito et al, 2017) and while low HRV was reported to predict the development of the metabolic syndrome in one study (Wulsin et al, 2016), another study demonstrated that this correlation was only significant for development of hyperglycemia and high blood pressure, whereas the risk of developing obesity and dyslipidemia were not significantly correlated to low HRV (Wulsin et al, 2015)
Summary
The global prevalence of diabetes in adults – approximately 90% consisting of type 2 diabetes – was estimated to 6.4% in 2010 and is predicted to increase to 7.7% in 2030 (Nolan et al, 2011). The macro- and microvascular complications that are associated with diabetes lead to increased morbidity and mortality and the economic burden posed by management of diabetes and its complications is substantial (Ng et al, 2014; Norhammar et al, 2016). An initial phase of insulin resistance with maintained normoglycemia is followed by a transitional phase of impaired fasting glucose and/or impaired glucose tolerance until manifest diabetes is established. Since the discovery of the pancreatic hormones insulin and glucagon, the prevailing understanding of type 2 diabetes development has circled around processes in the periphery, in the pancreas
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