<i>Tmem117</i> in AVP neurons regulates the counterregulatory response to hypoglycemia

Gaspari, Sevasti; Labouèbe, Gwenaël; Picard, Alexandre; Berney, Xavier; Sanchez-Archidona, Ana Rodriguez; Thorens, Bernard

doi:10.15252/embr.202357344

Cited by 4 publications

(3 citation statements)

References 53 publications

(74 reference statements)

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“…We also observed a strong decrease in the expression of Avp , which encodes the precursor of AVP, a hormone produced by magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus [ 6 , 40 ]. It is secreted in response to hypoglycaemia and stimulates glucagon secretion.…”

Section: Discussionmentioning

confidence: 99%

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia

Castillo-Armengol,

Marzetta,

Rodriguez Sanchez-Archidona

et al. 2023

Diabetologia

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Aims/hypothesis Repeated exposures to insulin-induced hypoglycaemia in people with diabetes progressively impairs the counterregulatory response (CRR) that restores normoglycaemia. This defect is characterised by reduced secretion of glucagon and other counterregulatory hormones. Evidence indicates that glucose-responsive neurons located in the hypothalamus orchestrate the CRR. Here, we aimed to identify the changes in hypothalamic gene and protein expression that underlie impaired CRR in a mouse model of defective CRR. Methods High-fat-diet fed and low-dose streptozocin-treated C57BL/6N mice were exposed to one (acute hypoglycaemia [AH]) or multiple (recurrent hypoglycaemia [RH]) insulin-induced hypoglycaemic episodes and plasma glucagon levels were measured. Single-nuclei RNA-seq (snRNA-seq) data were obtained from the hypothalamus and cortex of mice exposed to AH and RH. Proteomic data were obtained from hypothalamic synaptosomal fractions. Results The final insulin injection resulted in similar plasma glucose levels in the RH group and AH groups, but glucagon secretion was significantly lower in the RH group (AH: 94.5±9.2 ng/l [n=33]; RH: 59.0±4.8 ng/l [n=37]; p<0.001). Analysis of snRNA-seq data revealed similar proportions of hypothalamic cell subpopulations in the AH- and RH-exposed mice. Changes in transcriptional profiles were found in all cell types analysed. In neurons from RH-exposed mice, we observed a significant decrease in expression of Avp, Pmch and Pcsk1n, and the most overexpressed gene was Kcnq1ot1, as compared with AH-exposed mice. Gene ontology analysis of differentially expressed genes (DEGs) indicated a coordinated decrease in many oxidative phosphorylation genes and reduced expression of vacuolar H+- and Na+/K+-ATPases; these observations were in large part confirmed in the proteomic analysis of synaptosomal fractions. Compared with AH-exposed mice, oligodendrocytes from RH-exposed mice had major changes in gene expression that suggested reduced myelin formation. In astrocytes from RH-exposed mice, DEGs indicated reduced capacity for neurotransmitters scavenging in tripartite synapses as compared with astrocytes from AH-exposed mice. In addition, in neurons and astrocytes, multiple changes in gene expression suggested increased amyloid beta (Aβ) production and stability. The snRNA-seq analysis of the cortex showed that the adaptation to RH involved different biological processes from those seen in the hypothalamus. Conclusions/interpretation The present study provides a model of defective counterregulation in a mouse model of type 2 diabetes. It shows that repeated hypoglycaemic episodes induce multiple defects affecting all hypothalamic cell types and their interactions, indicative of impaired neuronal network signalling and dysegulated hypoglycaemia sensing, and displaying features of neurodegenerative diseases. It also shows that repeated hypoglycaemia leads to specific molecular adaptation in the hypothalamus when compared with the cortex. Data availability The transcriptomic dataset is available via the GEO (http://www.ncbi.nlm.nih.gov/geo/), using the accession no. GSE226277. The proteomic dataset is available via the ProteomeXchange data repository (http://www.proteomexchange.org), using the accession no. PXD040183. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia

Castillo-Armengol,

Marzetta,

Rodriguez Sanchez-Archidona

et al. 2023

Diabetologia

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“…44 Under normal conditions, the body is able to ensure that blood glucose levels remain balanced through hormonal regulation and neuromodulation. 45 Yet, blood glucose rises during pathology, such as when the body does not produce or has difficulty utilizing insulin or when there is abnormal regulation of glucose metabolism by the nervous system. 46 When the organism is in a prolonged state of hyperglycemia, it induces pathologies in various organs.…”

Section: Dfu Wound Microenvironmentmentioning

confidence: 99%

“…Hyperglycemia, one of the typical features of the DFU microenvironment, is associated with insulin disorders (deficiency or resistance) . Under normal conditions, the body is able to ensure that blood glucose levels remain balanced through hormonal regulation and neuromodulation . Yet, blood glucose rises during pathology, such as when the body does not produce or has difficulty utilizing insulin or when there is abnormal regulation of glucose metabolism by the nervous system .…”

Section: Dfu Wound Microenvironmentmentioning

confidence: 99%

Nanozymes for the Therapeutic Treatment of Diabetic Foot Ulcers

Xiao,

Zhao,

DuBois

et al. 2024

ACS Biomater. Sci. Eng.

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Diabetic foot ulcers (DFU) are chronic, refractory wounds caused by diabetic neuropathy, vascular disease, and bacterial infection, and have become one of the most serious and persistent complications of diabetes mellitus because of their high incidence and difficulty in healing. Its malignancy results from a complex microenvironment that includes a series of unfriendly physiological states secondary to hyperglycemia, such as recurrent infections, excessive oxidative stress, persistent inflammation, and ischemia and hypoxia. However, current common clinical treatments, such as antibiotic therapy, insulin therapy, surgical debridement, and conventional wound dressings all have drawbacks, and suboptimal outcomes exacerbate the financial and physical burdens of diabetic patients. Therefore, development of new, effective and affordable treatments for DFU represents a top priority to improve the quality of life of diabetic patients. In recent years, nanozymes-based diabetic wound therapy systems have been attracting extensive interest by integrating the unique advantages of nanomaterials and natural enzymes. Compared with natural enzymes, nanozymes possess more stable catalytic activity, lower production cost and greater maneuverability. Remarkably, many nanozymes possess multienzyme activities that can cascade multiple enzymecatalyzed reactions simultaneously throughout the recovery process of DFU. Additionally, their favorable photothermal-acoustic properties can be exploited for further enhancement of the therapeutic effects. In this review we first describe the characteristic pathological microenvironment of DFU, then discuss the therapeutic mechanisms and applications of nanozymes in DFU healing, and finally, highlight the challenges and perspectives of nanozyme development for DFU treatment.

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Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion

Thorens

2024

Physiological Reviews

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Glucose homeostasis is mainly under the control of the pancreatic islet hormones insulin and glucagon, which, respectively, stimulate glucose uptake and utilization by liver, fat, and muscle or glucose production by the liver. The balance between the secretion of these hormones is under the control of blood glucose concentrations. Indeed, pancreatic islet b-cells and a-cells can sense variations in glycemia and respond by an appropriate secretory response to restore euglycemia. However, the secretory activity of these cells is also under multiple additional metabolic, hormonal, and neuronal signals that combine to ensure the perfect control of glycemia over a lifetime. The central nervous system (CNS), which has an almost absolute requirement for glucose as a source of metabolic energy and, thus, a vital interest in ensuring that glycemic levels never fall below ~5mM, is equipped with populations of neurons responsive to changes in glucose concentrations. These neurons control pancreatic islet cells secretion activity in multiple ways: through both branches of the autonomic nervous system, through the hypothalamic-pituitary-adrenal axis, and by secreting vasopressin (AVP) in the blood at the level of the posterior pituitary. Here, we will present the autonomic innervation of the pancreatic islets; the mechanisms of neurons activation by a rise or a fall in glucose concentration; how current viral tracing, chemogenetic, and optogenetic techniques allow to integrate specific glucose sensing neurons in defined neuronal circuits that control endocrine pancreas function. Finally, how genetic screens in mice can untangle the diversity of the hypothalamic mechanisms controlling the response to hypoglycemia.

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Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia

Cited by 4 publications

References 53 publications

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia

Disrupted hypothalamic transcriptomics and proteomics in a mouse model of type 2 diabetes exposed to recurrent hypoglycaemia

Nanozymes for the Therapeutic Treatment of Diabetic Foot Ulcers

Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion

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