Dr. David Rivera
Institution: Universidad Central del Caribe
Diabetes and Astrocytes: impact on normal astrocyte function and its consequences
Diabetes mellitus is a metabolic disorder that also affects the central nervous system (CNS) by raising brain glucose levels. High blood glucose (diabetes) alters function, metabolism, and behavior of brain cells such as astrocytes. Furthermore, diabetic patients have a higher risk of suffering from a stroke when compared to non-diabetics and the brain damage that occurs may be more severe or extensive if blood glucose levels are high when a stroke occurs, but the mechanism is still unknown. Astrocytes, the most abundant cells in the CNS, provide support to neurons by maintaining extracellular homeostasis. Astrocytes have a highly hyperpolarized membrane due to the presence of Kir4.1 inwardly rectifying potassium channels that helps sustain K+ spatial buffering and glutamate uptake. Astrocytes exposed to high glucose levels show impairment in such functions which can lead to neuronal dead. There is a critical need to elucidate the precise mechanism of action in which uncontrolled levels of glucoses may affect the expression of Kir4.1 channels. The rationale for the proposed study is based on the findings that diabetic mice treated with metformin had significant increases in Kir4.1 and AMP-activated protein kinase (AMPK) protein expression in retinal Müller glial cells, providing evidence for the correlation of AMPK regulation of Kir4.1 in glia. Previous work has demonstrated the regulation of Kir4.1 via DNA methylation specifically through the role of DNMT- 1, a DNA methyltransferase, whose role is to maintain DNA methylation, hence reducing gene expression including the Kir4.1 gene. There is a gap in our knowledge, which we will address in this proposal, concerning the regulation of Kir4.1 via DNMT-1 when astrocytes are exposed to hyperglycemic conditions. Our central hypothesis is that elevated levels of glucose induce a reduction of AMPK, thereby, affecting the expression of KIR4.1 via the activation of DNMT-1. We will address this in the following specific aims: 1) To assess differences in metabolite levels and the regulation of metabolic pathways in astrocytes from diabetic mice compared to control and 2) To test the hypothesis that activation of AMPK via metformin will inhibit DNMT-1, hence increasing Kir4.1 expression. Our long-term goal is to understand how hyperglycemic conditions can negatively impact astrocytes normal functions specifically through the regulation of AMPK, DNMT-1 and Kir4.1. The impact of our findings will provide understanding of a specific mechanism of regulation and possible targets for the recovery of astrocytes functions in diabetics and why diabetics have more severe outcomes after stroke.