Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system (CNS) that is characterized by degenerative neurochemical and structural changes leading to impaired cognitive function. While the exact pathophysiology of diabetic encephalopathy is not well-understood, it is likely that neuroinflammation is one of the key pathogenic mechanisms that cause this complication. Lipocalin-2 (LCN2) is an acute phase protein known to promote neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes, thereby inducing proinflammatory mediators in a range of neurological disorders. In this study, we investigated the role of LCN2 in multiple aspects of diabetic encephalopathy in mouse models of diabetes. Here, we show that induction of diabetes increased the expression of both Lcn2 mRNA and protein in the hippocampus. Genetic deficiency of Lcn2 significantly reduced gliosis, recruitment of macrophages, and production of inflammatory cytokines in the diabetic mice. Further, diabetes-induced hippocampal toxicity and cognitive decline were both lower in Lcn2 knockout mice than in the wild-type animals. Taken together, our findings highlight the critical role of LCN2 in the pathogenesis of diabetic encephalopathy.

Hypothalamic inflammation plays an important role in disrupting feeding behavior and energy homeostasis as well as in the pathogenesis of obesity and diabetes. Here, we show that pyruvate dehydrogenase kinase (PDK)-2 plays a role in hypothalamic inflammation and its sequelae in mouse models of diabetes. Cell type-specific genetic ablation and pharmacological inhibition of PDK2 in hypothalamic astrocytes suggest that hypothalamic astrocytes are involved in the diabetic phenotype. We also show that the PDK2-lactic acid axis plays a regulatory role in the observed metabolic imbalance and hypothalamic inflammation in mouse primary astrocyte and organotypic cultures, through the AMPK signaling pathway and neuropeptidergic circuitry governing feeding behavior. Our findings reveal that PDK2 ablation or inhibition in mouse astrocytes attenuates diabetes-induced hypothalamic inflammation and subsequent alterations in feeding behavior.

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Objective: The objectives of the study are to screen out various phytochemicals and to evaluate the antioxidant and antidiabetic potential of the stem bark of Holarrhena pubescens Wall (Holarrhena antidysenterica). Materials and Methods:The antioxidant activity was determined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity where ascorbic acid was taken as positive control. The antioxidant property was later exploited and the methanolic extract of plant was tested for antihyperglycemic activity in glucose overloaded hyperglycemic mice. The extract was tested for its hypoglycemic activity at two-dose levels, 250 and 500 mg/kg respectively where Glipizide 5 mg/kg was taken as standard reference drug. All results are presented as mean ± SD (Standard Deviation). Significant differences between experimental groups were determined by Student's t-test. Results:The methanolic and water extract showed strong antioxidant activity with inhibition of more than 90% DPPH free radicals at the concentration of 100µg/mL. The hypoglycemic activity of methanolic extract on glucose tolerance test were significant (p <0.05) for the effects of 500 mg/kg after 120 min of treatment and (p <0.01) for 250 mg/kg of extract after half hour of treatment compared to control.

Diabetic encephalopathy is a severe diabetes-related complication in the central nervous system that is characterized by degenerative neurochemical and structural changes leading to impaired cognitive function. While the exact pathophysiology of diabetic encephalopathy is not well understood, it is likely that neuroinflammation is one of the key pathogenic mechanisms that cause this complication. Lipocalin-2 (LCN2) is an acute phase protein known to promote neuroinflammation via the recruitment and activation of immune cells and glia, particularly microglia and astrocytes, thereby inducing proinflammatory mediators in a range of neurological disorders. In this study, we investigated the role of LCN2 in multiple aspects of diabetic encephalopathy in mouse models of diabetes. Here, we show that induction of diabetes increased the expression of both Lcn2 mRNA and protein in the hippocampus. Genetic deficiency of Lcn2 significantly reduced gliosis, recruitment of macrophages, and production of inflammatory cytokines in the diabetic mice. Further, diabetes-induced hippocampal toxicity and cognitive decline were both lower in Lcn2 knockout mice than in the wild-type animals. Taken together, our findings highlight the critical role of LCN2 in the pathogenesis of diabetic encephalopathy.

The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin‐2 (LCN2) is a pro‐inflammatory acute‐phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes‐induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus‐mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate‐keeping regulator pyruvate dehydrogenase kinase‐2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2‐PPARβ/δ‐PDK2‐lactic acid axis in progression of DPN. Our results establish a link between pro‐inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia‐based mechanism and drug target for therapy of DPN. Main Points Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.