Where is glut2 transporter

We will discuss how studies in mice help interpret the role of GLUT2 in human physiology. Abstract 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.

Publication types Research Support, Non-U. Gov't Review. In addition, further narrowing of this regions using additional chimeric proteins is unlikely. As continuous amino acids are not required, future efforts will require assessment of glucose affinity after mutation of combinations of amino acids widely separated in the primary amino acid sequence of GLUT2. The present results contrast with those of Arbuckle et al. One possible explanation is that the current study used 3OMG, which measures only glucose transport, whereas Arbuckle et al.

In addition, the current study used a series of chimeric proteins that span transmembrane segments 7—10, whereas Arbuckle et al. The K m of this chimeric protein in the work of Arbuckle et al. As none of the chimeric proteins examined by Arbuckle et al. The reason why chimera 3 containing transmembrane segments 7—12, part of the carboxy-terminal tail, and nine amino acids of the intracellular loop of GLUT2 had a K m significantly higher than that of wild-type GLUT2 is not clear.

One possible explanation is that this altered the glucose-binding site and therefore affected the glucose affinity 32 , Thus, the current findings, integrated with our prior work and the findings of Arbuckle et al. Our findings clarify conflicting results from other laboratories regarding fructose transport.

However, none of the chimeric proteins used in that study exhibited increased glucose transport, so a conclusion about their ability to transport fructose is not possible. These researchers concluded that the amino-terminal region of GLUT2 was important for fructose transport. The current study and the work of Arbuckle et al. Arbuckle et al. The current study cannot assess whether transmembrane segments 9—12 modulate the affinity for fructose.

Thus, the ability of GLUT2 to transport fructose requires amino acids in transmembrane segments 7 and 8, but transmembrane segments 9—12 may modulate the affinity for fructose. Chimeric proteins that contained the amino-terminus, the first transmembrane segment, and the extracellular loop of GLUT2 were not expressed either in the oocyte system or in mammalian cells using adenovirus-mediated gene transfer. Even when the entire amino half of the chimeric protein was GLUT2, there was no glucose transport.

Both our laboratory and that of Noel and Newgard were able to in vitro translate chimeric proteins with the amino-terminal regions of GLUT2 into a protein of the expected size These findings suggest that a failure of the amino-terminal regions of GLUT2 to interact with other GLUT isoforms interferes with protein stability within the cell.

Cope et al. Based on the results of the current study and the work of other laboratories, a model of functional domains of glucose transporter proteins is emerging. The intracellular carboxy-tail of the transporter also appears to independently module affinity for the substrate and is involved in the targeting of GLUT4 to its distinctive intracellular location 36 , These functional domains interact to produce the final substrate specificity and substrate affinity that are distinctive for each GLUT isoform.

As yet, no functional role has been identified for the extracellular loop between transmembrane segments 1 and 2 or the intracellular loop between transmembrane segments 6 and 7, but specific interactions of the amino-terminus of GLUT2 are required for protein stability.

Whether regions of any GLUT isoforms interact with other membrane or cytoplasmic proteins is not known, but such interactions could provide yet another mechanism for modifying transporter function.

It is also unresolved whether GLUT isoforms are interchangeable. Have the distinctive transporter kinetics and the tissue-specific expression patterns evolved in response to certain requirements of cellular physiology? Studies in vivo to ablate a GLUT isoform in a certain tissue, then introduce a different GLUT isoform and assess the physiological consequences will be required to answer such questions.

After this manuscript was submitted, Buchs et al. Endocrinology —, reported that the aminoterminus and transmembrane domains 5—11 of GLUT5 were required for fructose transport by GLUT5.

Diabetes Metab Rev 2 : — Google Scholar. J Biol Chem : — Cell 55 : — Diabetes 39 : — Am J Physiol : E1 — E Diabetes Care 13 : — Mueckler M Facilitative glucose transporters. Eur J Biochem : — Science : — Biochim Biophys Acta : — Biochem Soc Trans 20 : — Biochemistry 30 : — Biochem Soc Trans 18 : — Relationship to glucokinase activity. Relationship to glucose metabolism. J Clin Invest 90 : 77 — Diabetes 44 : 75 — Am J Physiol : G — G Niculescu L , Veiga-da-cunha M , Van Schaftingen E Investigation on the mechanism by which fructose, hexitols and other compounds regulate the translocation of glucokinase in rat hepatocytes.

Biochem J : — Van Schaftingen E , Vandercammen A Stimulation of glucose phosphorylation by fructose in isolated rat hepatocytes. Endocrinology : — J Neurochem 68 : — Biochemistry 35 : — J Cell Physiol : — Biochemistry 36 : — J Cell Biol : — Oxford University Press is a department of the University of Oxford.

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Note Added in Proof. Lan Wu , Lan Wu. However, this was not associated with changes in plasma cholesterol in either the fed or fasted stated.

As cholesterol is also the precursor of bile acids, we measured their concentrations in faeces and plasma. When islets from control mice were incubated for 24 h in the presence of bile acids, GSIS measured in subsequent incubations was strongly increased, and this effect was not seen in islets from mice with genetic inactivation of Fxr , which encodes a nuclear receptor for bile acids.

Thus, bile acids may form a functional link between hepatic glucose metabolism and beta cell function. GLUT2 is expressed in the central nervous system of humans [ 57 , 58 ], rodents and zebrafish [ 59 ].

In rats, a careful immunohistochemical mapping of GLUT2 expression at the light and electron microscopy levels revealed its presence in most brain structures, and expression was found in neurons, astrocytes, endothelial cells and tanycytes, which are specialised astrocytes lining the lower part of the third ventricle [ 60 — 62 ]. In mice, using a genetic reporter system in which a fluorescent protein is expressed under the control of the Glut2 promoter Glut2-Cre transgenic mice crossed with Rosa26tdTomato mice , the distribution of GLUT2 expressing cells in the brain was found to be very similar to that of the rat [ 63 ].

Initial investigations of the role of rat brain GLUT2 in glucose homeostasis and feeding control used intracarotid [ 64 ] or intracerebroventricular i. In the first study this led to reduced body weight with no change in feeding and a reduced insulin response to intracarotid glucose administration.

In the second one, Glut2 silencing reduced feeding and body weight gain. These data indicated that central GLUT2-dependent glucose sensing regulates feeding through control of the melanocortin pathway.

This was shown by the much lower hypothermic response induced by i. This was secondary to reduced activation of brown fat uncoupling protein 1 and deiodinase-2 expression by the sympathetic nervous system and was associated with fasting-induced torpor in the Glut2- null mice. Abnormal sympathetic tone was caused, at least in part, by the reduced sensitivity to leptin of arcuate nucleus neurons, further supporting a role for central GLUT2-dependent glucose sensing in the control of the melanocortin pathway.

However, they are in contact with nerve terminals from Glut2 -expressing neurons, which probably have their soma outside the arcuate nucleus, suggesting an indirect control by glucose of the melanocortin pathway. 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. Thus, Glut2 is required for normal control by glucose of both branches of the autonomic nervous system. Absence of parasympathetic nerve regulation by glucose had two consequences.

However, the difference in proliferation rates was not seen when the mice were weaned on a high-fat, carbohydrate-free diet.

Thus, during the weaning period, when there is a high rate of beta cell proliferation [ 69 ] and when the diet changes from a lipid-rich milk to a carbohydrate-rich chow [ 70 ], GLUT2-dependent nervous glucose sensing and parasympathetic activity play a critical role in stimulating beta cell proliferation to achieve normal adult beta cell mass. The second consequence of the lack of glucose regulation of the autonomic nervous system was a loss of first-phase insulin secretion.

In vivo, this early secretion response depends on nervous glucose sensing, in particular activation of the hepatoportal glucose sensor. This response was lost in NG2KO mice, whereas first-phase insulin secretion from isolated and perifused islets from young mice was normal. Thus, the defect in achieving normal adult beta cell mass together with the loss of first-phase insulin secretion led to the progressive development of glucose intolerance. This became evident at around 24 weeks of age and was caused by a defect in GSIS observed in vivo as well as in isolated islets.

These physiological defects were accelerated by high-fat-diet feeding and were also associated with the development of hyperglucagonaemia. In order to better define the role of Glut2 -expressing neurons in glucose regulation, we studied a small group of such cells present in the nucleus tractus solitarius NTS. This brainstem structure is at the crossroad of afferent signals coming from different segments of the absorptive track, it can directly sense changes in nutrient and hormone concentrations, and the neurons forming this structure send projections not only to neighbouring nuclei such as the area postrema AP and the dorsal motor nucleus of the vagus also referred to as the DMNX or DMV but also to various forebrain regions [ 71 — 73 ].

Mice expressing a fluorescent protein in Glut2 -expressing neurons Glut2Cre;Rosa26tdTomato were used to prepare acute brainstem slices for patch-clamp analysis.

The Glut2-Cre mice were then crossed with Rosa26ChR2 [ 76 ] mice to express channelrhodopsin-2, a light-sensitive cation channel [ 77 ], in Glut2 -expressing neurons. Patch-clamp analysis demonstrated that pulses of blue light could induce firing of the NTS Glut2 -expressing neurons.

Stimulation by light in living mice with simultaneous recording of vagal activity showed that activation of the NTS Glut2 -expressing neurons increased vagal nerve firing and this led to a strong stimulation of glucagon secretion [ 75 ]. Thus, Glut2 -expressing neurons from the NTS are part of a neuronal circuit that links hypoglycaemia detection to the counter-regulatory response. These observations are also in agreement with the fact that when hypoglycaemia develops, vagal activity is increased first and sympathetic activity increases only at deeper hypoglycaemic levels [ 78 ].

They are also relevant in the context of the insulin treatment of type 1 and type 2 diabetes. Indeed, insulin-treated patients are at risk of developing hypoglycaemia, a risk that increases following antecedent hypoglycaemic episodes [ 79 ].

This condition, referred to as hypoglycaemia-associated autonomic failure, is due to impaired hypoglycaemia detection.

The identification of an NTS glucose-sensing system involved in glucagon secretion provides a new pathway to investigate the molecular mechanisms of counter-regulation control and defects in these. The role of GLUT2 in human physiology and pathogenic processes can be inferred from genetic studies. First, inactivating mutations in the GLUT2 gene cause Fanconi—Bickel syndrome, a condition associated with hepatomegaly, growth retardation and renal Fanconi syndrome [ 80 , 81 ].

The liver and kidney phenotypes of the Fanconi—Bickel patients are very similar to those of Glut2 knockout mice [ 82 ]. There is a similar increase in liver weight and increased glycogen accumulation, but a preserved hyperglycaemic response to glucagon injection, indicating that glycogen degradation can be followed by hepatic glucose release in the absence of GLUT2, both in humans and mice. Patients with Fanconi—Bickel syndrome have aminoaciduria, hyperphosphaturia and hypercalciuria, which are also observed in the Glut2 -null mice [ 83 ].

In the mouse, exaggerated secretion of phosphate is linked to the suppressed expression in the proximal tubule of the type 2 sodium—phosphate co-transporter NPT2C. Thus, defects in glucose reabsorption in the proximal tubule leads to secondary changes in other transporters expression, which may explain the observed renal syndrome. Impaired GSIS in adult Fanconi—Bickel patients have only been reported in a few cases [ 84 — 86 ], but inactivating mutations in GLUT2 have been found to cause transient neonatal diabetes mellitus [ 87 ].

As this condition disappears after approximately 18 months, this indicates that there is a transient requirement for GLUT2 for the control of insulin secretion in the first months of life. However, transient neonatal diabetes was not reported in all Fanconi—Bickel patients. This may be because such cases went undiagnosed. Alternatively, defects caused by GLUT2 mutations may be compensated for by the expression of other genes.

Another, attractive possible explanation for the impact of the mutation is that GLUT2 expression in the nervous system has similar functions in humans as in mice. If this were the case, impaired GLUT2 expression in glucose-sensing cells of the nervous system would prevent the normal expansion of beta cell mass in the postnatal period and prevent first-phase insulin secretion, leading to hyperglycaemia.

Glycaemia is, however, normalised at a later stage of development, when other signals, independent from autonomic nervous activity, are activated to increase beta cell mass, leading to a sufficient insulin secretion capacity.

Interestingly, a role for GLUT2 expression in the control of food preference has been suggested by studies of two cohorts of individuals with the common ThrIle variant of GLUT2 [ 88 ]; these individuals show a significant preference for high-sugar-containing food.

Thorens, unpublished observations. However, when expressed in Xenopus oocytes the GLUT2 ThrIle variant is normally transported to the cell surface and its glucose transport activity is normal [ 89 ]. Thus, in humans, the genetic mutation that codes for the ThrIle variant may also be involved in mechanisms regulating GLUT2 expression at a pre-translational level; alternatively, it may suppress a putative signalling mechanism that is distinct from GLUT2 sugar transport activity and is dependent on Thr Genome-wide association studies have found that variants in GLUT2 including the ThrIle variant encoded by the rs single nucleotide polymorphism are associated with impaired fasting glucose [ 90 , 91 ], type 2 diabetes and an increased risk of transition from impaired fasting glycaemia to diabetes [ 90 , 92 — 94 ].

When GLUT2 SNPs are investigated in association with other phenotypes, such as intensity of exercise, the presence of the major allele predicts that low physical activity increases the risk of developing type 2 diabetes by about threefold as compared with high physical activity; the presence of the minor allele has no predictive value [ 93 ]. A search for genetic regions associated with plasma lipid profiles and adjusted for diet and physical activity found that the GLUT2 locus has a major influence on serum cholesterol levels [ 95 ].

Another study found that out of 46 genetic variants examined, only the minor risk allele of GLUT2 was significantly associated with a risk of cardiovascular diseases [ 96 ]. These genetic studies therefore indicate that GLUT2 is involved in regulatory mechanisms that control impaired fasting glucose, the risk to transition to type 2 diabetes, preference for sugar-containing foods, as well as cholesterol levels and risk of cardiovascular disease. Because GLUT2 is only one of the glucose transporters present in beta cells, it is unlikely that slight changes in expression could have an impact on insulin secretion.

Studies in mice showed that Glut2 expression in the nervous system controls glucose-regulated autonomic nervous activity, which could impact liver, adipocytes and heart function. It is tempting to speculate that GLUT2 has a dominant role in glucose sensing in the nervous system in humans and that its deregulation precedes the development of type 2 diabetes.

Studies of the facilitated diffusion glucose transporters have revealed a multitude of novel regulatory systems controlling glucose homeostasis [ 17 , 97 ]. The investigations of GLUT2 function reported here shed light on some unique regulatory mechanisms, in particular related to blood glucose monitoring and the control of pancreatic hormone secretion, activity of the autonomic nervous system, and feeding and thermoregulation. The results of mouse physiological studies and human genetic-physiological studies to date suggest that, in humans, the association of GLUT2 mutations with transient neonatal diabetes, fasting hyperglycaemia, and risk of type 2 diabetes may be best explained by defects in neuronal glucose sensing, which induce loss of first-phase insulin secretion, deregulated feeding behaviour, hyperglucagonaemia, and progressive development of glucose intolerance and impaired GSIS.

This suggests that loss of nervous glucose sensing may actually precede the establishment of the alpha and beta cell defects that are characteristic of overt type 2 diabetes. Thus, it would be highly interesting to test the loss of nervous glucose sensing in humans. The investigations could include assessment of the cephalic phase of insulin secretion, which relies on nervous glucose sensing. If this response shows a conserved pattern in healthy individuals, a decreased response may indicate a prediabetic state.

Designing specific clinical investigations to test this hypothesis could be an important goal of future research. A still unresolved question is why is a high K m glucose transporter required in glucose-sensing cells in the brain when the parenchymal glucose concentration is approximately one-third of that in the blood [ 11 ], i. Related to the first question, it is still unknown whether the high K m for glucose represents an advantage for glucose sensing in the brain or whether GLUT2 has signalling properties that are independent of its transport capacity.

Concerning the role of GLUT2 in both GI and GE neurons, we previously proposed a model to explain the observation that plasma glucagon levels in Glut2 -null mice are elevated in the basal state and no longer increased by hypoglycaemia or suppressed by hyperglycaemia [ 37 ].

This model proposes that during hypoglycaemia, GI neurons generate a positive signal to stimulate autonomic nervous activity and glucagon secretion; in the absence of GLUT2 this positive signal can no longer be suppressed when euglycaemia is restored.

On the other hand, when glycaemia increases GE, neurons generate an inhibitory signal that suppresses autonomic activation of alpha cells; in the absence of GLUT2, this signal cannot be generated. Thus, Glut2 knockout leads to permanently elevated stimulation of glucagon secretion [ 98 ]. Our studies on NTS Glut2 -expressing neurons have shown that these are indeed activated by hypoglycaemia to control parasympathetic activity and glucagon secretion [ 75 ].

On the other hand, Glut2 -expressing neurons of the basolateral medulla are activated by glucose injections as revealed by c-fos immunostaining [ 63 ]. Whether they are GE neurons that negatively control glucagon secretion will, however, require direct analysis using electrophysiological and optogenetic techniques. These studies will be important to further validate our hypothesis that GE and GI Glut2 -expressing neurons functionally interact to fine-tune autonomic nervous activity and glucagon secretion.

The identification of these neurons will also pave the way to a new understanding of the mechanisms leading to hypoglycaemia-associated autonomic failure. 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. Nature — Neuron — PubMed Article Google Scholar. Neuroanatomical and physiological characterization. Diabetologia 20 Suppl — J Nutr — Diabetes — J Biol Chem — Cell Metab — Physiology Bethesda — Routh VH Glucose-sensing neurons: are they physiologically relevant?

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