Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

Tarussio, David; Metref, Salima; Seyer, Pascal; Mounien, Lourdes; Vallois, David; Magnan, Christophe; Foretz, Marc; Thorens, Bernard

doi:10.1172/jci69154

Cited by 66 publications

(76 citation statements)

References 59 publications

(82 reference statements)

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“…This discrepancy could be due to differences in the species used in these experiments. Also, in our experiments, the reduction in GLUT2 expression was limited to ependymal cells and tanycytes, while in the transgenic line, expression was also affected in neurons sensitive to hypoglycemia located in the brainstem (Tarussio et al, 2014) or neurons in the thalamus involved in carbohydrate preference (Labouebe et al, 2016). We also showed that suppression of GLUT2 expression in tanycytes leads to the loss in response to increased icv glucose, supporting a role for indirect control of glucose over the expression of neuropeptides that control hunger and satiety.…”

Section: Discussionmentioning

confidence: 47%

“…In contrast, icv injections of antisense constructs, designed to specifically to silence GLUT2 expression, reduced feeding and body weight gain in rats (Leloup, Orosco, Serradas, Nicolaidis, & Penicaud, 1998). In mice with specific inactivation of GLUT2 in the central and peripheral nervous systems, no differences in body weight were observed, but progressive glucose intolerance developed (Tarussio et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Barahona

Llanos

Recabal

et al. 2017

Glia

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Glucose is a key modulator of feeding behavior. By acting in peripheral tissues and in the central nervous system, it directly controls the secretion of hormones and neuropeptides and modulates the activity of the autonomic nervous system. GLUT2 is required for several glucoregulatory responses in the brain, including feeding behavior, and is localized in the hypothalamus and brainstem, which are the main centers that control this behavior. In the hypothalamus, GLUT2 has been detected in glial cells, known as tanycytes, which line the basal walls of the third ventricle (3V). This study aimed to clarify the role of GLUT2 expression in tanycytes in feeding behavior using 3V injections of an adenovirus encoding a shRNA against GLUT2 and the reporter EGFP (Ad‐shGLUT2). Efficient in vivo GLUT2 knockdown in rat hypothalamic tissue was demonstrated by qPCR and Western blot analyses. Specificity of cell transduction in the hypothalamus and brainstem was evaluated by EGFP‐fluorescence and immunohistochemistry, which showed EGFP expression specifically in ependymal cells, including tanycytes. The altered mRNA levels of both orexigenic and anorexigenic neuropeptides suggested a loss of response to increased glucose in the 3V. Feeding behavior analysis in the fasting‐feeding transition revealed that GLUT2‐knockdown rats had increased food intake and body weight, suggesting an inhibitory effect on satiety. Taken together, suppression of GLUT2 expression in tanycytes disrupted the hypothalamic glucosensing mechanism, which altered the feeding behavior.

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Barahona

Llanos

Recabal

et al. 2017

Glia

View full text Add to dashboard Cite

show abstract

“…Analysis of mice with genetic inactivation of Glut2 in the nervous system (NG2KO mice), generated by crossing Glut2 flox mice with a strain of nestin-Cre mice that do not show any metabolic or growth abnormalities [67], provided a new view of the role of nervous glucose sensing in autonomic regulation of the endocrine pancreas [68]. Direct recording of nerve activity showed that the firing rate of the parasympathetic nerve was lower in NG2KO mice than in control mice and was not increased by i.p.…”

Section: Nervous Glucose Sensing and The Regulation Of Islet Cell Masmentioning

confidence: 99%

“…Finally, because knocking out Glut2 in the nervous system leads to suppressed regulation of parasympathetic activity by glucose and impaired control of beta cell mass and function [68], it will be important to identify the glucose-sensing neurons that control this autonomic activity. Identification of these glucose sensing cells may lead to alternative ways of improving insulin secretion capacity in diabetic patients.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

GLUT2, glucose sensing and glucose homeostasis

2014

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The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

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“…), and insulin tolerance tests (5-h fasted mice, 0.3 units/kg insulin i.p.) were performed as described previously (30). IGF2 ELISA was purchased from R&D Systems (Minneapolis, MN).…”

Section: Biochemical Measurements Glucose and Insulin Tolerance Testsmentioning

confidence: 99%

Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function

et al. 2015

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Insulin-like growth factor 2 (IGF2), produced and secreted by adult b-cells, functions as an autocrine activator of the b-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in b-cell and whole-body physiology is not known. Here, we studied mice with b-cell-specific inactivation of Igf2 (bIGF2KO mice) and assessed b-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female bIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female bIGF2KO mice displayed lower GSIS compared with control mice, but reduced b-cell mass was observed only in female bIGF2KO mice. During pregnancy, there was no increase in b-cell proliferation and mass in bIGF2KO mice. Finally, b-cell mass expansion in response to acute induction of insulin resistance was lower in bIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult b-cell mass and function to preserve in vivo GSIS in aging and to adapt b-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.Glucose homeostasis depends on the balance between insulin secretion by pancreatic b-cells and insulin action on peripheral tissues (1). In response to the development of insulin resistance in muscle, liver, and fat, pancreatic b-cells increase their insulin secretion capacity in order to maintain normoglycemia. This compensatory response depends not only on an enhanced secretion capacity of individual b-cells but also, at least in rodents, on an increase in their number (2). In adult life, this plasticity is essential to maintain normoglycemia in insulin resistance conditions associated with obesity, pregnancy, and aging (3-5). Failure of this b-cell compensatory response leads to the onset of type 2 diabetes.The mechanisms by which insulin resistance in peripheral tissues induces compensatory insulin secretion capacity are incompletely understood. Their identification is, however, of highest interest for the development of novel therapies for diabetes. Evidence suggests that both circulating and nervous signals are involved. Glucose was one of the first signals identified to induce b-cell proliferation (6-8) through a signaling pathway that requires glucose metabolism, insulin secretion, and activation of the insulin receptor (IR)/Akt pathway (9,10). Incompletely characterized soluble factors, distinct from glucose, are produced by insulinresistant hepatocytes to increase b-cell mass (11,12), whereas bile acids can increase b-cell secretion capacity, independent of a change in b-cell number (13). Nerve connections between the liver and the islets can also potently stimulate b-cell proliferation (14).Increased b-cell proliferation and secretion capacity is a hallmark of pregnancy both in rodents and humans (3,15). This adaptive response i...

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Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

Cited by 66 publications

References 59 publications

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

GLUT2, glucose sensing and glucose homeostasis

Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function

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