Abstract
Diabetes is a chronic metabolic disease that seriously compromises human well-being. Various studies highlight the importance of maintaining a sufficient glucose supply to the brain and subsequently safeguarding cerebral glucose metabolism. The goal of the present work is to clarify and disclose the metabolic alterations induced by recurrent hypoglycemia in the context of long-term hyperglycemia to further comprehend the effects beyond brain harm. To this end, chemically induced diabetic rats underwent a protocol of repeatedly insulin-induced hypoglycemic episodes. The activity of key enzymes of glycolysis, the pentose phosphate pathway and the Krebs cycle was measured by spectrophotometry in extracts or isolated mitochondria from brain cortical tissue. Western blot analysis was used to determine the protein content of glucose and monocarboxylate transporters, players in the insulin signaling pathway and mitochondrial biogenesis and dynamics. We observed that recurrent hypoglycemia up-regulates the activity of mitochondrial hexokinase and Krebs cycle enzymes (namely, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and succinate dehydrogenase) and the protein levels of mitochondrial transcription factor A (TFAM). Both insults increased the nuclear factor erythroid 2–related factor 2 (NRF2) protein content and induced divergent effects in mitochondrial dynamics. Insulin-signaling downstream pathways were found to be down-regulated, and glycogen synthase kinase 3 beta (GSK3β) was found to be activated through both decreased phosphorylation at Ser9 and increased phosphorylation at Y216. Interestingly, no changes in the levels of cAMP response element-binding protein (CREB), which plays a key role in neuronal plasticity and memory, were caused by hypoglycemia and/or hyperglycemia. These findings provide experimental evidence that recurrent hypoglycemia, in the context of chronic hyperglycemia, has the capacity to evoke coordinated adaptive responses in the brain cortex that will ultimately contribute to sustaining brain cell health.
Highlights
Diabetes mellitus, a metabolic disease hallmarked by uncontrolled high blood glucose levels, has become an epidemic disease with an exponential increase all over the world [1]
While this therapeutic plan is required for the survival of type 1 diabetes (T1D) individuals, the limitations of exogenous insulin therapy include the frequent occurrence of glycemic excursions and recurrent episodes of hypoglycemia, situations that, in due course, will contribute to the development and/or exacerbation of debilitating secondary complications, some of which are life-threatening [4]
The diabetes phenotype was confirmed in chemically induced diabetic rats by significant elevations in blood glucose levels and glycated hemoglobin and a concomitant decrease in body weight when compared to age-matched control rats (Table 1)
Summary
A metabolic disease hallmarked by uncontrolled high blood glucose levels, has become an epidemic disease with an exponential increase all over the world [1]. Among the main types of the disease, type 1 diabetes (T1D) is described to affect 5–10% of diagnosed cases, which is characterized by a widespread autoimmune destruction of insulin-secreting pancreatic β-cells For this reason, this type of diabetes entails, since its diagnosis, a substitution therapy regimen consisting of multiple daily exogenous insulin injections, frequent blood glucose tests and careful dietary monitoring (e.g., carbohydrate counting) [3]. There is epidemiological evidence for links between diabetes and dementia [9,10] For neuronal cells, this fuel requirement is mainly fulfilled by mitochondria, the multifunctional life-sustaining organelle that ensures the required energy supply through the production of adenosine triphosphate (ATP) via oxidative phosphorylation [11]. Different aspects of abnormal mitochondrial function (e.g., altered mitochondrial content and morphology, increased production of reactive oxygen species and altered redox system machinery, and altered energy metabolism) seem to exacerbate brain damage under peripheral variations in glucose levels [12,13,14,15,16,17]
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