Abstract
The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet β-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in β-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic β-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.
Highlights
Diabetes mellitus (DM) is currently a major social and economic burden worldwide
We review the evidence that supports a main role for the central nervous system (CNS) in glucose homeostasis, with a special focus on astrocytes, and how interventions that simultaneously target both the CNS and pancreatic islets may synergistically improve the regulation of blood glucose levels and metabolism in type 2 diabetes mellitus (T2DM) patients
We found that HMG20A expression in islets is essential for metabolism/insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NEUROD, MAFA, and insulin, and that its depletion induces expression of genes such as PAX4 and REST implicated in β-cell de-differentiation as observed in T2DM islets [41]
Summary
Diabetes mellitus (DM) is currently a major social and economic burden worldwide. The global epidemic proportion of DM is one of the most important health problems of the 21st century, being the cause of four million deaths in 2017 [1]. Over nutrition-derived metabolic dysfunctions, denoted as metabesity, contributes to the apparition of a chronic low-grade inflammation [2,3], which is recognized as the pathogenic link with T2DM This inflammation initially targets peripheral tissues specialized in metabolism such as liver, adipose tissue, and pancreatic islets, and it plays a key role in insulin resistance and β-cell dysfunction [4,5,6]. Guidelines for T2DM management include, as first-line therapy, serious lifestyle interventions such as physical exercise, while long-term add-on therapies include medication in order to increase insulin secretion and sensitivity [11] These treatments are adequate to improve hyperglycemia, they alleviate symptoms rather than target the root-cause of the disease and lead to the development of secondary complications [12]. We review the evidence that supports a main role for the CNS in glucose homeostasis, with a special focus on astrocytes, and how interventions that simultaneously target both the CNS and pancreatic islets may synergistically improve the regulation of blood glucose levels and metabolism in T2DM patients
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